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Autumn 2009

Autumn 2009

International Pharmaceutical Industry ‘Supporting the industry through communication’

Designing Biobetter Monoclonal Antibody Therapeutics By Glycoengineering IPI - International Pharmaceutical Industry

Leveraging Today’s Technology for Clinical Trials Imaging

New Models for Cost Coverage of Drugs call for Improved Patient Compliance

Managing Pharmaceutical Globalization: A Work in Progress




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Contents EDITOR: Dr. Patricia Lobo Email: DIRECTORS: Martin Wright Mark A. Barker



PUBLISHER: Clive Baigent EDITORIAL ASSISTANT: Linda Stewart Email: BOOK MANAGER: Anthony Stewart Email: BUSINESS DEVELOPMENT: Marie Powell, Chris Harradine Email: DESIGN DIRECTOR: Anika Mistry





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. 2009 PHARMA PUBLICATIONS


Managing and Assuring Safety and Quality Throughout the Pharmaceutical, Biopharm, Medical Device and Healthcare Provider organisations, safety and quality remain at the top of the agenda driven by adverse events and the responses to them, especially when they are well covered in the media. The industry has come a long way over the past 20 years. Improvements have been driven by, for example the development and application of standards for pharmaceuticals and medical devices such as ISO 15378 and ISO 14971, and the creation of standards by regulators such as the NHSLA standards and Standards for Better in England. Mark Boult of DNV explains how the overall performance against the standards by the healthcare organisations has improved over the years. Göteborg – World Leader in Biomaterials Göteborg, on the west coast of Sweden, is the site of numerous breakthroughs in research and development within medicine, and the city is today a leading cluster in biomaterials and cell therapy. (IPI Market Review 2009) DRUG DISCOVERY, DEVELOPMENT & DELIVERY

COVER PHOTOS: In-House Productions

PUBLISHED BY: Pharma Publications Diamond Key Building, Unit 4, Burwell Industrial Estate, Burwell Rd, London E10 7QG Tel: 0044(0)208 5917584 Fax: 001(480)247 5316 Email: 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 autumn 2009 and quarterly thereafter. ISSN No. International Pharmaceutical Industry ISSN 1755-4578




Molecular Modelling for Optimization of Stabilized Therapeutic D-Peptides Peptides have become an important class of active therapeutic agents. In the last decade, a lot of synthetic peptide-based drugs entered the market as therapeutic agents. Dr. Udo Haberl & Prof. Dr. Hans-Georg Frank of Aplagen discusses Isosteric transformation which is a new and fast molecular modelling procedure enabling structure-based design of D-amino acid based peptides. It generates D-peptide based drug candidates in very short time. Biobridge-event 2009 Geneva: The Regenerative Medicine Conference Monday, 26th of October 2009 at the United Nations Office Geneva (UNOG), Palais des Nations, Switzerland, the Biobridge Foundation and its Scientific Committee will once again create a stimulating environment for debate and discussion on the topic of regenerative medicine, in which officials, scientific researchers, professionals and specialized scholars are invited to participate. It will take place under the Conseil d’Etat de la Republique et Canton de Genève high patronage. Big Pharma R&D—thinking big, acting small In order to mitigate the considerable risks in developing drugs, the pharmaceutical industry is going through an extended phase of consolidation to try to realise economies of scale. In this paper James Man & Andy Black of Kinapse outlines critical success factors for making disintegration work. This includes having talent management with a clear focus on leadership development, structuring operating units around clear areas of competence and performance, having clear divisions of accountabilities and transparent cost accounting between operating units.

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Contents 38



Designing Biobetter Monoclonal Antibody Therapeutics By Glycoengineering Monoclonal antibodies (MAbs) currently comprise the fastest growing class of protein therapeutics - primarily for the treatment of cancers and autoimmune, infectious and inflammatory diseases. One area of great interest to developers, copiers and improvers of therapeutic antibodies is glycosylation since it can significantly influence the safety and efficacy profiles of the drug in this article, By Dr. Claire Morgan and Dr. Daryl Fernandes of Ludger shows how both the original drug manufacturers and the designers of follow-on biologics could produce biobetter antibodies through glycoengineering. In vitro alternatives to reduce animal use and to decrease drug development costs In preclinical drug development in vitro studies have obtained a more prominent position. Because of ethical considerations an increasing number of in vivo tests have been replaced by in vitro experiments. These tests are recommended by many organizations. The National Institutes of Health (NIH) and other federal agencies are committed to the welfare of research animals. These animals are protected by law, regulations and policies to ensure use in the smallest number possible and with the greatest commitment to their comfort. By: Ida A.J. Verbaan-Giebelen of NOTOX B.V. High-Throughput Antioxidant Determination – The ORAC Assay performed on Multidetection Microplate Readers Antioxidants, present in fruits, vegetables and whole grains, act as free radical scavengers and thus are thought to protect living cells from being damaged by reactive oxygen species (ROS). In this article Franka Ganske, Marjan Orban, and Michael Fejtl, of BMG LABTECH, presents s the ORAC assay as a tool to measure antioxidant capacity in fruit juices in a highthroughput microplate format.







Leveraging Today’s Technology for Clinical Trial Imaging Over the last decade, medical imaging has been playing a greater role in the diagnosis of disease and, logically, there has been an analogous increase in the use of imaging in all phases of clinical trials to evaluate new drug candidates. Leveraging telecommunication tools for file transfer and integrating imaging with electronic data capture (EDC) has the potential to transform the manner in which imaging is used in clinical trials. Abraham Gutman of AG Mednet & Robert Quinn of Phase Forward analyses new tools that are now available that make this integration a reality and could provide better transparency for sponsors, improve data quality, reduce costs, give more de-identification options, and even reduce a firm’s carbon footprint.

Central Component of Drug Development Contemporary lifecycle drug development encompasses in silico computer simulation modeling of drug molecule binding to both target and off-target receptors, nonclinical investigation, preapproval clinical studies, and postmarketing surveillance.1 Since cardiac and cardiovascular adverse drug reactions are serious and potentially lethal, their lifecycle assessment is critical.2 While assessment in all of these four phases is important, this paper focuses registration studies. J. Rick Turner, Senior Director, Cardiac Safety of Quintiles ECG Services has provided a sample of cardiac and cardiovascular safety assessments during contemporary drug development. An Interview with Kenneth G. Faulkner and James Paskavitz of Perceptive Informatics on a robust medical imaging methodology for Central Nervous System (CNS) clinical trials involving Alzheimer’s disease India – Worlds best choice for clinical trials India has the potential to attract 5-10% of the global contract research outsourced market (all services including chemistry, toxicology and clinical research) over the next 5 years. The Indian government has recognized that India can become a hub for conducting global clinical trials. The Planning Commission’s Report of the High Level Group on Services Sector highlights the opportunities and identifies the gaps that need to be addressed by the government for this sector. Dr. Rajam Jaishanker of Quest Life Sciences discusses the factors contributing to a gradual but steady growth. Ethics Committees in India- An insight Ethics Committee (EC(s)) constitutes the third arm of the research triangle and it can make significant contribution towards the ethical conduct of clinical trials. Post 2005, i.e. after schedule Y has been amended, obtaining ethics committee approval is one of the mandatory step towards conduct of the trial. While amended Schedule Y1, ICHGCP Guidelines2, Indian GCP3 specifies standards to be maintained by ECs, the majority of institutions in India still lack compliance with the applicable standards in a true sense. Deepti Goel of Cliniminds takes a look at major areas that require immediate attention and correction. LABS & LOGISTICS


Successfully involving central laboratories: How to avoid fundamental errors No doubt, central laboratory services are complex, particularly due to the logistical tasks involved. One aspect renders central lab services different to almost any other service outsourced by Pharma or Biotech companies during a clinical trial: biological samples have a limited stability and if the lab provider does not take this into account in many cases the samples may

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Contents get spoiled before they arrive at the laboratory. A poor understanding of processes during the planning phase has the irrevocable consequence that sites may prepare their samples inappropriately. Dr. Hermann Schulz of Interlab GmBH identifies some selection criteria to identify the right central laboratory. 78


Managing Pharmaceutical Globalization: A Work in Progress Like a high-speed train, globalization in the pharmaceutical industry is accelerating steadily, driven by factors too numerous to name – growing healthcare reform and awareness, slowing growth in traditional markets, the imperative to reduce drug development time and costs, and the opportunity to leverage aging populations and emerging markets. Sean Smith, & Ian Hunter of ThermoFisher Scientific argues that while the advantages of going global are obvious, globalization creates new challenges that the industry will need to address moving forward.



Innovation in Endotoxin Detection – Moving Out of the Stone Age With the threat of the H1N1 virus and the upcoming flu season upon us, vaccine manufacturers are working diligently to provide an H1N1 vaccine to help protect us from a large outbreak of illness. In addition to safety and effectiveness, part of the quality testing for products such as vaccines and pharmaceuticals includes ensuring that the product passes specifications for sterility and endotoxin. Maribeth Donovan Janke, Ph.D., the Sr. Product Manager for Endotoxin Detection in the Rapid Testing Systems unit of Lonza Walkersville, Inc, gives a brief history of Endotoxin Detection.

Efficiency gains in cell-line development: Why and how? During the last decade, significantly more biopharmaceuticals have entered pharmaceutical development, increasing the number of protein-based drugs on the market. Besides monoclonal antibodies - the largest product class in development - many companies are investing in developing second-generation biologics and vaccines. A key prerequisite for producing many of these products is the development of a high-producing mammalian cell line that stably expresses large volumes of the active substance. Thomas Eldered & Christel Fenge of Recipharm explains why, the selection of mammalian cell lines to manufacture these products remains a key step in their early development affecting the whole lifecycle and economy of the potential future drug.



New Models for Cost Coverage of Drugs call for Improved Patient Compliance One of the world’s top ranking business consulting agencies describes new models of medication reimbursement as the health care payers will no longer be able to cover the cost of medicines which quite often don’t work. These new models will include guaranties for the effectiveness of a drug or it will not be paid for. The classical way by which the health care system pays the price once negotiated with the pharma company will become the exception in a few years time. Tassilo Korab of HCPC Europe examines the need for improved patient compliance as new models for Cost Coverage of Drugs indicate. Compliance Packaging – extending supply chain security beyond the pharmacy to the patient The entire pharma community is focused on devising and implementing measures to secure the supply chain, including e-pedigree authentication through Track and Trace strategies based on mass serialisation at unit of sale level. The objective is to ensure that, however convoluted the supply chain, the pack reaches the pharmacy exactly as it left the manufacturer. The supply continues to the safe administration of the medication to the patient. This feature by Steve Kemp of Brecon focuses on Compliance Packaging and extending supply chain security beyond the pharmacy to the patient. Intelligent packaging: 21st century secret of patient compliance? As Protomed’s founder Norman Niven prepares to bring together pharma’s key opinion leaders at a pioneering industry seminar this month, Mark Barker of IPI finds out why ‘smart packaging’ could be the future of improved patient care.

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Dr Patricia Lobo, Every Dark Cloud has a Silver Lining With the forecast for vaccines in preventive healthcare set to increase dramatically worldwide, this trend is predicted to drive the demand for novel vaccine delivery technologies, improvements in formulation, outsourced development and sterile production The number of vaccines potentially available for use in low to middle income countries (LMICs) will increase during the period 2008–2025. Without clear incentives, most of the existing and even the new vaccines may continue to be delivered by needle and syringe. This will spur the continued development of novel vaccine technologies, many of which are needlefree and/or employ alternative immunisation routes. With reduced needle and syringe use there will be a reduction in the dose of vaccine required while delivering the vaccine by a route which will stimulate an appropriate immune response. This means that the novel vaccine delivery technologies need to be incorporated much earlier in the development path of novel vaccines. Vaccines are the best hope for tackling many diseases in poor countries, but in many cases they are either too expensive or are unsuited to tropical conditions. Merck & Co has teamed up with Britain’s Wellcome Trust in a not-for-profit joint venture to develop affordable vaccines for poor countries. Vaccines could prevent 2.3 million child deaths a year, according to GAVI. Abbott is to acquire Solvay’s pharma business, which includes amongst the assets to be added to Abbott’s portfolio Solvay’s vaccines business. This will provide Abbott with an entry into the global vaccines market. Meanwhile, J&J has bought an 18% stake in Crucell, while entering into a strategic collaboration for the discovery, development and commercialisation of monoclonal antibodies and vaccines for the treatment and prevention of influenza and other infectious and non-infectious diseases. Among the majors, the battle for market share of HPV vaccines between Merck’s Gardasil and GSK’s Cervarix is heating up. Merck has been accused of ‘overselling’ Gardasil while seeking FDA approval for use in boys, by paying grants to medical organisations that advocate HPV vaccination. After cornering the US market, sales of Gardasil have started to drop. The results of an FDA panel’s vote on GSK’s Cervarix for the US market is awaited after recently hearing about the product. Last week Merck announced a scheme to donate $500 million worth of Gardasil to help protect women in developing countries from cervical cancer. Viral vaccine preparations must be proven (validated) to be both stable and to contain known proportions of active elements. A laserbased, single-nanoparticle tracking analysis 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

system (NanoSight) is now available which allows nanoscale particles, such as viruses and virus aggregates, to be directly and individually visualised in liquids in real time, from which high-resolution particle size distribution profiles can be obtained. The technique is fast, robust, accurate and low cost, representing either an attractive alternative, or complement, to existing methods of nanoparticle analysis, such as Dynamic Light Scattering (DLS) Photon Correlation Spectroscopy (PCS) or Electron Microscopy. Demand for biopharmaceutical contract manufacturing will grow 16 per cent a year over the next five years, according to analysis by US market research group HighTech Business Decisions, who predicted that the worldwide market for biopharmaceutical contract manufacturing services will be worth some $2.6bn (Đ1.8bn) this year alone. According to reports, there are about 12,000 large molecule biotechnology medicines in research and development, over 4600 of which are in clinical development. However, if new biotherapeutics are to be made more accessible and affordable, there is a need for continual improvements in performance and optimisation of manufacturing processes. As the global demand for production of biotherapeutics grows, the question of whether current manufacturing capacity and production performance are sufficient to deal with the challenge becomes an important strategic issue. Thomas Eldered and Christel Fenge of Recipharm look at mammalian cell lines to develop and manufacture second-generation biologics and vaccines (page 90), and Claire Morgan and Daryl Fernandes of Ludger discuss “biobetter” monoclonal antibody therapeutics by glycoengineering (page 38). Part of the quality testing of products such as vaccines and pharmaceuticals means ensuring that the product passes specification for sterility and endotoxin (see article by Maribeth Donovan Janke of Lonza, page 86). On the acquisition front, Swiss firm Lonza has tabled a $3.55 per share bid for Canadian CMO Patheon, bettering the $2 per share offered by investment group JLL (there has been an extended due diligence period for the possible takeover to October 15). An acquisition of Patheon would take Lonza into the complementary activities of finished dosage development, and manufacturing for both small molecule and biological active ingredients. With the industry sourcing more raw materials and services from around the world and distributing its products in new markets, companies are adapting their business processes to suit a more complex global operating environment. The FDA opened offices

in Bejing in late 2008 as part of its global safety strategy to build safety into products at every step of the way, rather than just monitoring it upon importation at US borders. Globalisation brings about complexities. Sean Smith and Ian Hunter of ThermoFisher Scientific address the challenges faced by going global, whilst Hermann Schultz of Interlab assesses the different criteria to select the right Central Laboratory to consolidate global test results (see page 74). Shippers, distributors, wholesalers, freight forwarders, consolidators and airlines are working more closely with drug manufacturers to rein in the process under the careful eye of the regulators. I look forward to meeting visitors to the ICSE/CPHI event from 13-15 October in Madrid where they can pick up a copy of IPI hot off the press for hours of interesting reading. Thank you for your support of IPI. Keep the articles rolling in.

Patricia Lobo, MSc, PhD Managing Director & Senior Consultant for Life Science Business Solutions (LSBS). I have worked in the pharma sector for over 30 years after graduating in Chemistry, Microbiology and Biochemistry and gaining an external PhD in Biochemical Pharmacology and a business training course. My industrial career in the UK led from the QC department of a generics CMO to the R&D department of GD Searle (now Pfizer), followed by working as a CRA with Stiefel Laboratories, as Senior Clinical Research Scientist with Farmitalia Carlo Erba (now Pfizer), Oncology Business Unit Manager with Schering Plough, and for nearly 17 years as a Management Consultant for Technomark and RSA Consulting Ltd. There I have supported international Life Science clients with assignments in manufacturing , clinical research, development and marketing, providing specialised advice in drug development, outsourcing, due diligence, including advice to corporate finance and equity organisations on M&As, JVs, alliances and investment. I have published over 20 scientific articles, organised a major conference and exhibition in London and have set up a database of Contract Manufacturers. Email:



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Managing and Assuring Safety and Quality Throughout the Pharmaceutical, Biopharm, Medical Device and Healthcare Provider organisations, safety and quality remain at the top of the agenda, driven by adverse events and the responses to them, especially when they are well covered in the media. The potential costs were recently highlighted in the front page news, which stated that the annual clinical negligence bill for the NHS is now over £800 million. Before this, failings at Mid Staffordshire NHS Foundation Trust and the C-diff outbreak at Maidstone and Tunbridge Wells NHS Trust were news stories which ran over several days. In response to incidents and learning, regulatory authorities put out alerts regularly in regard to drugs and devices. The industry has come a long way over the past 20 years. Improvements have been driven by, for example, the development and application of standards for pharmaceuticals and medical devices, such as ISO 15378 and ISO 14971, and the creation of standards by regulators such as the NHSLA standards and Standards for Better Health in England. These have been used to drive improvement. The creation of hospital accreditation is an added driver to

“A biotechnology organisation recognised the importance of safety and of creating a strong safety culture to the success of their business through the prevention of all accidents.” improve quality and safety. Such schemes are provided by independent bodies, such as Det Norsk Veritas (DNV), and are being applied across geographical boundaries. Helping Pharmaceutical, Biopharm, Medical Device and Healthcare Providers at both local and national levels is the not-for-profit foundation Det Norsk Veritas (DNV). DNV is a global risk management 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

company with a mission statement to “Safeguard Life, Property and the Environment”. Its successful track record from its establishment in 1864 has been in safety-critical industries including maritime, transport, nuclear, oil and gas, aviation, and rail, in addition to the healthcare industries. DNV supports these organisations to deliver and assure safety and quality in their own processes and the products and services they deliver. In this article, we share work undertaken in the past and currently by DNV with Pharmaceutical, Biopharm, Medical Device and Healthcare Providers / Agencies to support them in managing and assuring safety and quality. These projects are helping these organisations to perform successfully and to reduce the potential for adverse events which harm patients, their staff, the environment and their reputations, or result in losses (financial, product, etc.). Biorisk Management Biological containment laboratories are critical for vaccine development and diagnostic work, as well as basic research into human, animal and plant pathogens. The importance of managing biorisks can be seen by the response to biorisk incidents by organisations, governments and the media. Biorisk in laboratories encompasses both biosafety and biosecurity, where biosafety involves harm to people and other organisms, whereas biosecurity covers the deliberate unauthorised removal of materials. In DNV we see biosafety and biosecurity as being closely interlinked, and believe that common systems are required to manage both effectively. Case Study – Biomedical Research Facility A biotechnology organisation recognised the importance of safety and of creating a strong safety culture to the success of their business through the prevention of all accidents. The accident prevention goal was set as a top-level goal by the organisation’s senior management. This organisation turned to DNV for a range of biorisk management services to support their drive to enhance their systems and

culture by taking a proactive approach to managing these risks. DNV’s support covered both biosafety and biosecurity (collectively referred to as biorisk). The work included conducting safety management system assessments, reviewing containment laboratory facilities, and providing specialist biorisk training. The study drew on DNV’s experience of managing risk in a wide variety of industries, together with their people’s knowledge of laboratories and biorisks. Core risk

“The standard is performancebased and sets out requirements for, and places responsibility on, organisations to demonstrate that appropriate and validated risk reduction procedures have been established and implemented.” management principles were successfully applied. A major emphasis of the work was on people and their safety attitudes “safety culture”. The study helped the organisation to gain a better understanding of the risks associated with the diverse range of activities they undertake involving biological organisms, and to successfully enhance their management of these risks. International Project DNV recently managed an international project to develop the Laboratory Biorisk Management Standard (CWA 15793:2008), which has the scope to set requirements necessary to control risks associated with the handling or storage and disposal of biological agents and toxins in laboratories and facilities.

The standard is performance-based and sets out requirements for, and places responsibility on, organisations to demonstrate that appropriate and validated risk reduction procedures have been established and implemented. The standard is based on a traditional management systems approach. The organisation’s

“In addition to certifying the management systems of pharmaceutical companies against relevant ISO standards DNV has worked with such companies to aid them in managing risks to patients and their staff. ” ability to deal with the hazards associated with biological agents and toxins is hence improved through the identification, understanding and managing of a system of interrelated and relevant processes. Efforts to address this global issue gathered momentum in June this year when a regional seminar for South East Asia on Promoting and Implementing Biosafety and Biosecurity Management was held in Jakarta. The seminar was co-hosted by Indonesia, Norway and the Biological Weapons Convention Implementation Support Unit, with DNV and Eijkman Institute as technical organisers. More than 70 representatives from 17 countries took part in the seminar, which also benefited from substantive contributions by the World Health Organisation, the Asia Pacific Biosafety Association, and academia. Pharmaceuticals In addition to certifying the management systems of pharmaceutical companies against relevant ISO standards DNV has worked with such companies to aid them in managing risks to patients and their staff. The range of recent projects includes development of assessment protocols for assessing the robustness of plant to minimise and manage potential major accident hazards, to a drug product TSE (transmissible spongiform encephelopathies) risk assessment suitable for submission to regulatory authorities. The example discussed below comes from 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

work looking at the packaging of drugs. Consider the Patient Safety Risk in the Medication Process Ensuring that a patient receives the right drug at the right time(s), in the right dose and through the right route, depends on the actions of many parties. When medication adverse events (patient safety incidents) occur, the root causes and contributory factors will go back to the parties involved. The pharmaceutical companies have the ability to influence the potential root causes and contributory factors for both themselves and the other parties. A major focus of the risk management is assuring the drug is safe (i.e. the risk of an adverse response to an acceptable dose correctly delivered is acceptably low). With a client, we have helped them look at how drugs are delivered in the real world. Some examples of the causes and contributory factors that came up in the work included: • Naming The wrong drug is selected because it has a similar name to another drug or because of confusion caused by brand and generic names and changes in naming conventions. • Packaging The wrong drug is selected because it has a similar coloured and patterned package to another drug. Branding can result in all drugs provided by a company looking the same at first glance (for example this risk was realised when over 90 children in the UK received the wrong vaccine where the packaging, names and storage of the desired vaccine was similar to that of another). The wrong frequency is selected by the patient because the packaging indicates a different frequency message. For example, a drug to be taken once a week was provided in a 4 by 7 tablets blister pack. The pack indicated either once a day for four weeks or four times a day for a week to many people. The user does not administer safety because the instructions provided by the pharmaceutical company are obscured by the pharmacist’s label. • Labelling The wrong dose is provided because of the use of unclear or unfamiliar units on the package. • Similarity in tablets The wrong dose is taken because tablets of different strengths come in similar looking tablets (size, shape and colour). The wrong drug is taken by a patient on several medications because the tablet

looks similar (size, shape and colour) to that of another drug. Solutions to help minimise these risks have been identified, for example the use of tall man lettering to highlight different drugs more easily.

PenicilLIN - PenacilAMINE Medical Devices DNV works both as a notifying body, and in an advisory role to different medical device organisations. An example of the support we are providing to clients can be seen from the work we are doing with one medical device organisation. This has involved advisory services and training to support them in developing their risk management plans for their full range of medical device products with a specific focus on extending their activities from a “hardware only” failure point of view to consideration of all causes, particularly taking on board human error. The programme of activities has included reviews of past incidents and the application of a range of risk assessment techniques. For current products this has helped achieve compliance and smooth progress in audits by the FDA and others. They are now working on a new product and the risk work has driven the design to consider the users of the device (both the operator and the patients) from the beginning. It has linked the technical work with the usability activities and is leading to a product that meets the needs of the users, and minimises risks from hardware, software, user and external failures. Healthcare Provision DNV work with those providing healthcare services including acute, primary care, ambulance and mental health services, as well as with healthcare agencies. Examples of way we support the delivery of safer, quality care are described below. Hospital Accreditation and ISO 9000 – the Story for a Hospital CMS (in the US) approved DNV as a deeming authority for US hospitals in September last year (2008). Since then, Mr Dror (MD of DNV Healthcare Inc.) reports “very substantial interest from major hospitals and health systems, as well as from regional and community hospitals in the USA”, and a range of hospitals across the US have already gained DNV’s new ISO 9001-linked accreditation. The Group Health Central Hospital in Seattle, Washington, part of Group Health Cooperative, is one of these organisations. From a meeting at a conference the hospital

started the process of becoming accredited by DNV. The hospital’s director of quality and regulatory compliance met DNV to discuss their situation and share her interest with their leadership team. The hospital was already accredited, but without ISO 9000. They formally reviewed the pros and cons to come to their decision to be accredited by DNV. A few of the positive reasons given, in addition to the benefit of gaining ISO 9000 accreditation, for going with hospital accreditation from DNV, were: • Annual surveys. “We saw a benefit to an annual survey,” which DNV requires, says their director. The upside of this frequency would be having some sense of when to anticipate the survey, and also keeping on top of everything all the time. • The training by DNV of one person in the facility to be a surveyor. This designee is also trained in ISO 9001 and must survey three other facilities per year. “We liked the idea of a collaborative approach,” says their director. “We liked the idea of having one of our own internal quality folks become a DNV surveyor and becoming our in-house expert.” “When I’d see a different way of doing something well, I’d bring that knowledge back to my facility. You’re always learning, finding different ways to accomplish your goals.” says their

“BMH also sees the inclusion of ISO 9001 as a real valueadded feature, and has taken their quality management system to the next level, allowed them to adopt a language that is universally understood by their stakeholders. ” quality consultant (their trained surveyor). • The requirement to have a corrective action plan in place and meet the timeframes established for that plan. • Clear assessment scoring system. They did not understand their previous accreditatopn organisation’s assessment scoring system. The hospital achieved accreditation. “ISO 9001 is centred around quality,” says their quality consultant. “Industry has been

doing it for a long time. It’s looking at processes, making sure you’re meeting the standards you’re reaching for, and if not, adjusting them to make sure you do.” The values of hospital accreditation with DNV can also be seen from the views of others: • “DNV based its programme on the integration of the ISO 9001 quality management system with standards set by the Centers for Medicare and Medicaid. This innovative approach to an aging accrediting model emphasizes organisation wide improvements. In turn, it increases the quality of patient care.” Citizens Medical Center, Victoria, Texas, USA. • “The annual DNV surveys have the advantage of maintaining momentum, continuity — with the same surveyors coming back for repeated visits — and predictability.” Bud Pate, REHS Vice President, The Greeley Company, a division of HCPro, Inc. • “The emphasis is on the application of engineering processes designed to reduce variability and improve standardization. Ultimately, it is the reduction of error and, in our world, reducing harm to our patients.” Thomas K. Gardiner, MD, Executive Vice President for Clinical Development at Ball Memorial Hospital, Indiana. BMH also sees the inclusion of ISO 9001 as a real value-added feature, and has taken their quality management system to the next level, allowed them to adopt a language that is universally understood by their stakeholders. It has also strengthened the bonds between clinical and nonclinical departments, and in doing so, has reduced variability and error. It has also been good to hear from our accreditation clients that they feel DNV fosters an “atmosphere of partnering” and that the “the weight … is not totally on their [the hospital’s] shoulders”. Committed to Safety The National Health Service Litigation Authority and DNV are working together to improve the safety of NHS patients and staff. The National Health Service Litigation Authority (NHSLA), which is responsible for handling negligence claims made against NHS bodies in England, aims to improve the safety of NHS patients and staff. To meet this goal, a dedicated team of DNV’s UK-based healthcare experts provide the NHSLA with integrated risk management services through a five-year contract. “We look upon this as a partnership which we’re confident will improve both patient and staff safety and help the NHS to better manage its risks,” says Alison Bartholomew, Risk Management Director at the NHSLA.

The programme has three primary elements: 1. The development and maintenance of risk management standards for acute care, primary care, mental health, ambulance and maternity services. 2. The assessment of organisations providing NHS healthcare in England against these standards. 3. The education of organisations providing NHS healthcare in England in what constitutes good risk management and how to achieve these standards.

“The National Health Service Litigation Authority (NHSLA), which is responsible for handling negligence claims made against NHS bodies in England, aims to improve the safety of NHS patients and staff. ” Supporting these activities the DNV team also provides focused advice to the healthcare organisations on an as-needed basis. The overall performance against the standards by the healthcare organisations has improved over the years, giving the improving organisations and the NHSLA greater confidence in their management of their risks.

MARK BOULT ASSOCIATE DIRECTOR Mark was the risk advisor in the National Patient Safety Agency from 2002 to 2006, where his work included involvement in medication safety projects. He has undertaken risk management projects for pharmaceutical and medical devices companies as well as for healthcare delivery organisations. Contact: DNV, Palace House, 3 Cathedral Street, London SE1 9DE, UK Tel: +44 20 7357 6080 (W-Switchboard) +44 20 7716 6536 (W-Direct) +44 777 165 2882 (M) E-mail: Website: INTERNATIONAL PHARMACEUTICAL INDUSTRY 13

Göteborg – World Leader in Biomaterials Göteborg, on the west coast of Sweden, is the site of numerous breakthroughs in research and development within medicine, and the city is today the site of a leading cluster in biomaterials and cell therapy. The city of Göteborg has an excellent record of achievements within the biomedical field. One key to Göteborg´s strength is its combination of high-calibre academic research capabilities and a well-established industrial base. Among its pioneers are Professor Arvid Carlsson, awarded the Nobel Prize in 2000 for his research into dopamine, Professor Per-Ingvar Brånemark, who introduced osseointegration as a method for attaching prostheses directly into bone, and Professor

Jan Lindhe, who through his research of the biological mechanisms within the mouth has created both understanding and treatments for diseases leading to tooth decay. Strong research tradition Biomaterials research at the University of Gothenburg, and at Chalmers University of Technology, has resulted in well above 150 PhD dissertations over the years. Two of these are by the noted Professors Tomas Albrektsson and Peter Thomsen. Prof Albrektsson was instrumental in the development of the first bone-anchored dental implant system and the first boneanchored hearing aid implant system. Prof Thomsen focuses on the interface between

material surfaces and cells using modern methods in cell and molecular biology. Dental implants are today an accepted treatment for patients with missing teeth all over the world, and more than eight

“Dental implants are today an accepted treatment for patients with missing teeth all over the world, and more than eight million people have so far received dental implants.” million people have so far received dental implants. The procedures are taught to dental professionals at most universities worldwide, and the global dental implant market is valued at over €12 billion annually, and is still growing. This is enabled by the revolutionary research done by Professors Brånemark and Albrektsson and their coworkers over time. Biomaterial specialisation New materials, modification of materials and characterisation of materials are other

“One key to Göteborg´s strength is its combination of high-calibre academic research capabilities and a well-established industrial base.”


Göteborg specialties. Professor of polymer technology, Per Flodin of Chalmers and co-workers, developed the slowly biodegradable polyurethanurea, a material later manufactured by Artimplant for

World Leader in Biomaterials The Gรถteborg region has a strong research tradition with well above 150 PhD dissertations in biomaterials. Gรถteborg is home to world leading scientists such as Professors Albrektsson, Brรฅnemark, Flodin, Kasemo and Thomsen, to mention a few.

The Gรถteborg region has also a very strong life science industry within areas such as dental implants, bone anchored hearing aids, polymers for implantable prosthesis and wound care and incontinence applications.

orthopaedic and dental applications. Today Artimplant is a public company located in Göteborg offering degradable implants for regeneration of body functions. Another world-leading researcher is Professor Bengt Kasemo at Chalmers, whose work focuses on nano-scale surface phenomena and properties. Professor Kasemo and co-workers developed a unique method for surface analysis – the QCMD-technology, which is today marketed and sold to the biomaterial community by another Göteborg-based company, Q-Sense. Since 1999, when the first commercial system for measurements in liquid was launched, Q-Sense has become the leading supplier of acoustic resonator-based instruments for analysis of various surfaces. Professors Paul Gatenholm of Chalmers and Bo Risberg of the University of Gothenburg are also two very prominent scientists in the Göteborg biomaterial arena. Prof Gatenholm focuses on biopolymer technology, while Prof Risberg allocates his time to Tissue Engineered Blood Vessels (TEBV). A company that originates from this research is Arterion. Arterion commercialises artificial blood vessels consisting of microbially-derived cellulose for revascularisation of patients

with cardiovascular disease. Stem cell technology is also a thriving research area in the Göteborg region, and one-third of the world’s stem cell lines are from Sweden, the majority of which are from Göteborg. The Göteborg-based company Cellartis has developed over 30

“Stem cell technology is also a thriving research area in the Göteborg region, and onethird of the world’s stem cell lines are from Sweden, the majority of which are from Göteborg.” well-documented stem cell lines, and is today one of the world’s largest stem cell providers. Göteborg is also strong in clinical trials, thanks to its clinical research capabilities, outstanding international networks and university-affiliated CROs, such as

A+Science. Strong life science industry There are some 170 companies and over 8,000 employees in life science companies within the Göteborg Region. One of the largest employers is AstraZeneca, which has a large research site and global headquarters for cardiovascular and gastrointestinal research in the adjoining town of Mölndal. The biomaterial/cell therapy cluster includes leading companies in dental implants – Nobel Biocare and Astra Tech; human embryonic stem cells – Cellartis; polymers for implantable prosthesis – Anatomica, Artimplant, Astra Tech, Cochlear and Integrum; and wound care and incontinence applications – Mölnlycke Health Care Group, Astra Tech, SCA, and Biopolymer products, to mention a few.

GöteborgBIO is a joint project for long-term growth in the biomedical field. Principals are AstraZeneca, Business Region Göteborg AB, Chalmers University of Technology, University of Gothenburg/The Sahlgrenska Academy, Innovationsbron AB, Mölnlycke Health Care AB, Nobel Biocare AB, VINNOVA and Region Västra Gö

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Molecular Modelling for Optimisation of Stabilised Therapeutic D-Peptides Therapeutic peptides Peptides have become an important class of active therapeutic agents. In the last decade, a lot of synthetic peptide-based drugs entered the market as therapeutic agents. Peptides are on the borderline between

“Peptides can be optimised by a rational, structurebased approach by molecular modelling when sufficient structural information is available.” small drugs and classical biotechnological drugs. They resemble recombinant drugs regarding their general protein nature, but are usually produced by chemical methods in a solid phase synthesis process. The strongest attribute for their potential use as drugs is their protein nature. Most of the interactions inside cells and inside the whole body are based on protein-protein interactions, at least as far as phenotypic changes – including changes in disease state – are concerned. Many of these interactions are already characterised and there are numerous endogenous peptides known which prove the general concept of peptides as drugs. Thus, there is an entry to drug design and discovery which is much more direct and easy in comparison to small molecule drugs. Usually, small molecule drugs do not show such a close relationship to internal body processes and interactions as peptides do. Currently, a lot of peptide-based drugs are in clinical or registration phases. There are certainly many more peptides that have biological activity and could be used as


drugs. However, most of them never make it to the early stages of development. Actually, only 1.5 % of drug candidates will find their way from target identification to approval ( ). One of the main reasons is their inherent instability and degradability in biological systems. The body presents many barriers to the entry of peptides. For example, peptides do not readily cross biological membranes, are metabolised by proteolytic enzymes, and are rapidly excreted through the liver and kidneys. As a consequence, many natural peptides suffer from low bioavailability and short biological half-life. The primary objective of pharmacological peptide optimisation is to develop analogues that can overcome the problems and barriers related to peptides, while retaining or even enhancing selective activity, usually based on thorough understanding of the structureactivity relationship. Thus, there is certainly an enormous pharmacological value in a design-based peptide optimisation strategy. Optimisation of peptides by molecular modelling Peptides can be optimised by a rational, structure-based approach by molecular modelling when sufficient structural information is available. If threedimensional structural data of the complex with the target (e.g. a receptor) are available, even a target-based approach is possible. Molecular modelling can not only be an effective approach to identify a lead structure, but also to optimise the peptide properties, and furthermore to increase the hit rate of the candidates in a rationally designed synthetic library. The most obvious approach to optimise a peptide is the mutation with other natural amino acids. However, besides the limited supply of natural options, the chemist can also use non-natural amino acids (e.g. with shorter or longer sidechain) or D-amino acids. Non-binding parts of a sequence might be replaced by longer flexible amino acids, like amino valeric acid, to reduce the number of coupling steps. Other mutations

with non-natural amino acids can result in higher affinity to the desired target. Using this approach, not only the affinity but also the specificity of a peptide might be optimised. In the case of missing structural data of the target, it might be possible to use a homology modelling approach, where a homologue receptor is taken as the basis for the computational approach. Stabilized D-peptides and the retroinverso strategy Natural peptides are prone to proteolytic degradation because natural proteins

“The primary objective of pharmacological peptide optimisation is to develop analogues that can overcome the problems and barriers related to peptides, while retaining or even enhancing selective activity, usually based on thorough understanding of the structure-activity relationship. ” need to be metabolised. This property limits their therapeutic application. Most naturally occurring polypeptides are composed of L-amino acids. A lot of work has been done focussing on peptide analogues in the search for mimetics with enhanced biological half-lives. Examples

of modifications are the replacement of L- amino acid residues by D-amino acids. These modifications produce mimetics with a higher metabolic stability, since most natural proteases cannot cleave Damino acid residues ( ). However, a given L-amino acid sequence – if synthesised in D-analogues – has a clearly different orientation of the sidechains. Usually, this straightforward approach is thus abolishing biological activity. For this reason, a more reasonable

“Isosteric transformation is a new and fast procedure enabling structure-based rational design of D-amino acid-based peptides which act as isosters of corresponding native L-peptide precursors. ” strategy to create peptide mimetics is the retro-inverso (RI) transformation. In this approach, the reverse synthesis of a peptide using D-amino acids results in a

peptide analogue, wherein the direction of the peptide bonds is reversed and the N- and C-terminals are interchanged. This procedure produces a structural isomer that maintains the original stereochemical configuration of all sidechains, but reverses the sequence. This type of transformation leads to mimetics of natural peptides showing a high degree of sterical similarity with the parent peptide, but with higher stability. This approach has been exploited to design various peptidomimetic drugs ( , ). Thus, in contrast to the straightforward approach mentioned above, the RI approach keeps sidechain orientation close to the original, while the backbone is reversed. This is more feasible for pharmaceutical strategies, since the most relevant interactions of a peptide with a target are usually based on the sidechain, not on the backbone. Isosteric Transformation With a new molecular modelling technique, D-peptide mimetics can be designed and optimised in silico very efficiently ( ). One major way to integrate natural binding properties of peptides with superb stability in biological systems is to start with Lpeptides of known binding properties and biological effects and to improve their drugability by turning them into D-peptides based on an RI-sequence. In practice, however, this encounters the problem that a given L-peptide structure cannot easily be transformed into a D-peptide of the

Figure 1: left: backbone of the native dimeric L-peptide; right: reversed backbone of the D-peptide after isosteric transformation. The direction of the arrows indicates the direction of the backbone from the N-terminal ends to the C-terminal ends.


equivalent structure, because the respective structural transformations are very complex and in some cases unpredictable.

“Since the peptide sequence harbours two proline residues, structural distortions at the site of the prolines occur in the primary structure obtained by isosteric transformation. ” This challenge is addressed by a new technology called “isosteric transformation”. It is an in silico technology, which provides a very fast tool to transform the structure (not only the sequence) of a given L-peptidic motif into a corresponding D-peptidic motif with the same three-dimensional structure. If this is not possible due to general problems (e.g. the so-called “proline-problem”) it is immediately clear in the procedure, and respective strategies for solution can be implemented under in silico guidance. The whole technology can be used to check very fast whether a lead in L can be transformed structurally effectively into a more stable D-analogue. As an entry point, the technology needs structural data of the native L-peptide, either deduced from an NMR or from crystallographic data. Isosteric transformation is a new and fast procedure enabling structurebased rational design of D-amino acidbased peptides which act as isosters of corresponding native L-peptide precursors. The central idea of the rational design is to maintain the spatial orientation of the sidechains of the amino acids during the whole procedure. Thus, there is no need for exchange of phi and psi dihedral angles and complete de novo construction of the intended molecule. The procedure achieves this by just changing the backbone structure of the precursor peptide, while avoiding the exchange of complete amino acid moieties (no formal substitution of Lamino acids by D-amino acids). Since the peptide bonds of the backbone are strictly planar structures, this approach does not change the orientation or structural properties of the sidechains, including that of covalent sidechain modifications like disulfide bridges, helical constraints or other structural properties like e.g. helices or beta-sheets. The workflow of these operational steps can easily be automatised on standard modelling software. Isosteric transformation offers fast access to structural data of an intended

D-analogue of an L-peptidic precursor. This allows instant assessment of the three main problems which can render the newly-designed molecule stereochemically incompatible with its precursor: • the consequences of the occurrence of Lproline(s) in the sequence of the precursor, and • the charges at the terminal ends of the peptide. • Interactions of the peptide backbone with the target receptor. A number of structural and synthetic solutions for these problems are available. Isosteric transformation thus offers fast solutions for the stereochemical mirroring of L-peptide precursors – even of prolinecontaining peptides – into respective Dpeptide analogues. Example: Isosteric transformation of a peptide which binds to the erythropoietin (EPO) receptor The following example demonstrates the transformation of a peptide which binds to the erythropoietin receptor. The coordinates representing the native structure are publicly available in the Protein Data Bank. This file contains the structure of the complex between a dimeric agonist peptide and the dimeric erythropoietin receptor. This structurally well-documented peptide offers an ideal example for the implementation of isosteric transformation. The procedure comprises the following steps: 1. The coordinates of the homodimeric peptide in receptor-bound conformation are imported into the modelling software. 2. The atoms of the native carbonyl(CO) backbone groups are replaced by amide-(NH) groups. 3. The atoms of the native amide-(NH) backbone groups are replaced by carbonyl-(CO) groups. The direction of the arrows in Figure 1 indicates the direction of the backbone from the N-terminal ends to the C-terminal ends. After isosteric tranformation, the structure is ready for further geometry optimisation and molecular dynamics simulations. Since the peptide sequence harbours two proline residues, structural distortions at the site of the prolines occur in the primary structure obtained by isosteric transformation. However, it is also obvious that the secondary structure of the peptide in “induced fit” position is stabilised by numerous other molecular interactions and does potentially not require the specific conformations induced by proline-specific properties. Proline – though supportive for the induced fit conformation – is thus not essential for it and can be replaced in the most simple cases by the very flexible glycine. The procedure of isosteric transformation leaves the conformation of the sidechain 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 2: left: native dimeric L-peptide; right: resulting structure of the reversed D-peptide after isosteric transformation, mutation and optimisation. The direction of the arrows indicates the direction of the backbone from the N-terminal ends to the C-terminal ends. After geometry optimisation, the conformation of the sidechains is similar.

atoms (with the exception of the native proline residues) unchanged, because the modifications only take place in the backbone. A comparison of the structure of the native dimeric peptide with the resulting structure after isosteric transformation and replacement of prolines by glycines in Figure 2 demonstrates the structural similarity of the native peptide and the transformed molecule. One of the effects of the backbone reversal is not only the reversal of the amino acid sequence but also the inversion of the configuration of the alpha carbon atoms of the amino acids, which changes from L to D. Threonine contains two chiral centres and therefore, while maintaining sidechain chirality, the appropriate isoster is D-alloThr. In addition to the steps above, the Cterminal carboxyl groups are interchanged by amino groups, and the N-terminal amino groups are interchanged by carboxyl groups. The further optimisation can include possible modifications of the C- and N-terminal ends of the peptide by e.g. addition of additional non-binding amino acids such as glycine or alanine, as well as amidation and/or acetylation of the N- and C-terminal ends. Summary Isosteric transformation is a new and fast molecular modelling procedure enabling structure-based design of D-amino acid based peptides. It generates D-peptide based drug candidates in a very short time. These stable D-peptides act as isosters

of the corresponding native L-peptide precursors. DR. UDO HABERL IS DIRECTOR OF DRUG DESIGN AT APLAGEN GMBH. He obtained a Ph.D from the University of Bonn, specializing in theoretical organic chemistry and the development of anti-cancer drugs. He developed molecular modelling software and worked at the University of Notre Dame (USA) and at different biotech companies, where he gained more than 10 years of experience in the design of pharmaceutical drugs. At AplaGen, he is focusing on design and optimization of peptide sequences, linker structures and new technologies for peptide stabilization. Email: PROF. DR. HANSGEORG FRANK IS CEO AND COFOUNDER OF APLAGEN GMBH. He is a physician and obtained his Ph.D/MD from the Free University of Berlin. He worked scientifically at the Free University of Berlin and the University of Technology in Aachen, Germany, where he focused on embryology, developmental biology and oncological topics. Besides working as an academic scientist, he also managed clinical studies at Sandoz AG. He was appointed as a Professor at the University of Technology in Aachen. Email: hgfrank@

Analytical Biochemical Laboratory BV

Clinical Research Organization Analytical Biochemical Laboratory BV (ABL BV) is an independent contract laboratory and a central laboratory serving (multicentre) clinical trials for pharmaceutical and biotechnological companies. ABL is a laboratory that operates world-wide, supporting clinical trials and pre-clinical drug development studies (PK-PD-and safety samples). ABL is subdivided into two departments

Bio Analytical Services Focuses on the analysis of samples derived from pre-clinical and clinical studies. Available techniques include: ■ LC-MS/MS ■ GC-MS ■ GC-FID, NDP and ECD ■ HPLC with UV, fluorescence and electrochemical detection ■ Immunochemistry (RIA, EIA, FIA) ■ Clinical chemistry ■ Hematology Contact: Mr. E. Oosting MSc, technical director E-mail:

Clinical Trial Services Offers support services for the conduct of multi-site clinical trials ranging from sample logistics and source verification to data and project management. Contact: Mr. H.J. Trip, manager CTS E-mail: By combining these two activities, ABL is able to optimize the overall efficiency, quality and data integrity while saving costs and time. We operate under a set of strict protocols and procedures to ensure transparency whilst not affecting the capability to adapt to the requirements and needs of the individual client. Analytical Biochemical Laboratory BV W.A. Scholtenstraat 7 P.O. Box 232, 9400 AE Assen The Netherlands Telephone +31 (0) 592 34 42 11 Fax: +31 (0) 592 34 44 25

Biobridge-event “Generation Regeneration” 2009 Geneva: The Regenerative Medicine Conference On Monday 26th October 2009 at the United Nations Office Geneva (UNOG), Palais des Nations, Switzerland the Biobridge Foundation and its scientific committee will once again create a stimulating environment for debate and discussion on the topic of regenerative medicine, in which officials, scientific researchers, professionals and specialised scholars are invited to participate. It will take place under the high patronage of the Conseil d’Etat de la Republique et Canton de Genève. Focusing on adult stem cells Stem cell research and therapy continue to make significant advancements in medical treatments. The aim of the conference is to showcase these developments with the focus on regenerative medicine. Conclusions to the 2008 presentations and debates put adult stem cells firmly on the map of advanced and promising clinical applications. This forthcoming conference will investigate new areas of research from the laboratory to current clinic uses. The organisers are honoured to have Prof. Luc Montagnier, the Nobel Prize of Medicine in 2008, take the lead by delivering the first lecture, with his discoveries on natural medicine, “Fighting for Life: Prevention is Better than Cure”. Key participants and the venue Research and development in biotechnology requires the collaboration of its industry members, in a common effort to drive advancements in health through innovations as well as building a profit centre in this growing area. The Biobridgeevent offers a platform through which scientific researchers, industry professionals, manufacturers and investors can forge and strengthen ties on an international and regional level. Naturally, the Palais des Nations has been identified as the most suitable venue for the meeting to be held. Usually home to high-profile international and interstate political meetings, the conference centre will 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

open its doors to the cause of regenerative medicine. The location has been chosen on the basis that the Lake Geneva Region, and specifically the state of Geneva, continues to bring together the world’s most respected research organisations and laboratories, and it has been named the leading biotechnology cluster in continental Europe by Science magazine. As the host of the event, His Excellency Sergei Ordzhonikidze, the UNOG DirectorGeneral, will be welcoming delegates and participants in the Assembly Hall. The day

“Research and development in biotechnology requires the collaboration of its industry members, in a common effort to drive advancements in health through innovations as well as building a profit centre in this growing area.” will conclude with a talk by the Minister of Economy and Public Health of the Canton of Geneva, Prof. Pierre-François Unger. He will share his insights into the regulatory and inter-governmental aspects that surround the topic of regenerative medicine today. Some background on the event The event is organised by the Biobridge Foundation, based in Switzerland, which supports research and professional education worldwide by means of conferences and symposiums. Biobridgeevents act as platforms to share and discuss the latest findings in regenerative medicine

at the highest level. Central to its purpose is to encourage research and discussion in stem cell related treatments as well as forging working relationships between reputable scientists and physicians. As the primary sponsor of the conference, Regenlab actively encourages developments in regenerative medicine and has helped give shape to the event, tapping into its network of reputable actors within the scientific community. As a company that develops, manufactures and markets patented and CE certified medical devices for regenerative medicine and autologous tissue regeneration, it believes that being part of a strong global network of trade partners is essential to maintaining excellence within its field. Throughout the remainder of the article, we aim to provide you with a selection of the topics that will be discussed at the conference. Public policies, research and medical applications Policy formation within medical research and application can have extensive implications for practitioners and customers, some of which are detrimental, while others are used as a vehicle for achieving greater safety measures. There is an array of interesting case studies to demonstrate its relevance with regenerative medicine today. One of these will be held by Dr Luca Santoleri, under the title “Transfusionist’s Rule in Regenerative Medicine, the Italian Environment”. It recounts the ensuing decisions made by the Italian government after fibrin glue and platelet gel were first defined as blood components for topical use. The introduction of a law that put all procedures related to production, storage and distribution of topical blood components under the management of blood transfusion centres resulted in some limitations on the practice of the product’s users, which practitioners challenged by coming up with alternative models that would allow for more flexible procedures to fit their needs. The final agreements will

be outlined in the talk, with mention of the advantages that emerged from the initial critique. Developments in ophthalmology Research in ophthalmology has often been described as a somewhat tedious, yet incredibly rewarding activity. Its relevance at this year’s event is evident, with ophthalmology applications representing significant developments in stem cell research. Specific insights will be presented by Prof. Odile Damour (France), who works on corneal epithelial reconstruction, and Prof Gerd Geerling (Germany), who will be presenting the case of dry eye and natural tear substitutes. Looking to the future In this part we will receive an update on exciting medical growth areas. This includes the research area endometrial/ menstrual stromal stem cells, which has identified menstrual blood as a valuable source of multipotential stem cells for use in regenerative medicine. The advantages it has over other sources have made it the attractive research area it is today: non-controversial, easily collectable and inexpensive. Expectations within this field are far reaching, as scientists discover the potential for menstrual blood stromal cells in regenerative transplantation therapies for many different organs and tissues. Other studies anticipate strong results for these cells in several different areas including heart disease, diabetes and neurodegenerative disease. Dr Julie G. Allickson will deliver a comprehensive lecture in this new stem cells field. Other novel insights will be provided by Dr Marisa Jaconi, who investigates possible stem cell routes in neurosciences, and by Prof. Camillo Ricordi, who sheds light on new cellular therapies for the treatment of diabetes.

“Different materials can be used as scaffolds, most of them being biodegradable polymers, whose biodegradation must comply with and also control the kinetics of the repair process.” Scaffolds for tissue engineering The role of a scaffold is to promote cell 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

adhesion and proliferation (in some cases differentiation) with the final goal of inducing them to produce an extracellular matrix (ECM) and, hence, tissue repair and regeneration. Different materials can be used as scaffolds, most of them being biodegradable polymers, whose biodegradation must comply with and also control the kinetics of the repair process. Natural polymers can offer some advantages over synthetic ones: they can in fact be spontaneously bioactive, thus resulting, in specific cases, in a faster and more effective crosstalk with the biological environment. This talk will focus on the various natural polymers widely investigated or used for tissue engineering applications, with specific reference to silk fibroins, human albumin etc… fabrication processes and physical and biological properties will be illustrated, with reference to selected potential applications. Fibrin microbeads Stem cells research has soared in recent years with the attempt to apply it to regenerative medicine. Different types of such stem cells including adult, embryonic and induced cells have been introduced, while new sophisticated matrices assembled from synthetic or bio-polymers have been proposed as scaffolds for such cellular implants. Nevertheless, a major difficulty in translating this knowledge for tissue engineering is that without immediate vascularisation the in-vitro built 3D cellular structures do not survive following implantation in the damaged tissues. Targeting isolated cells alone to repair tissues has also yielded controversial results with poor survival and difficulty in integrating the cells in the target tissues. Prof. Raphael Gorodetsky from the Hadassah Hebrew-University Medical Centre will propose an alternative approach with the use of fibrin-microbeads (FMB) to overcome the difficulties associated with 3D bulk implants. These are slowly biodegradable micro-matrices that allow integration of the desired intact progenitors in damaged organs. Participants of the conference will be introduced to some favourable findings, such as their high binding capability for mesenchymal stem cell (MSC), which can be used to isolate them with a high yield from different sources. These are cells which can be implanted with minimally invasive procedures to repair tissues. Cancer stem cells through the lens of radiation This will represent a highly interesting part of the conference, with P.D. Jacques Bernier from the Genolier Swiss Medical Network in Geneva sharing his insights on novel developments in stem cell research related

to cancer. He has been heavily involved with clinical research, including studies of novel technologies in radiotherapy and “Hadrontherapy the so called proton therapy!”, and biochemical and biological modifiers of tumour response to ionising radiation. Participants will hear about the recent notion that there exists a relationship between cholesterol and cancer. In the light of recent studies, the talk will also focus on new technologies that allow sorting of tumour cells according to their surface marker expression, thereby selecting subpopulations that are enriched in cancer stem cells. While the development of surface-marker-based assays is a highly important step in cancer stem cell research, to date there are still challenges to be met and the data on this topic are still very limited. Introduction of stem cell therapy in a developing country To round up the event, the conference organisers will look to the challenges in the healthcare faced by developing countries and the role stem cell therapies may play in reducing some of these challenges. It is well known that 90% of the burden of disease occurs in developing countries and, unlike developed countries, these countries suffer the dual burden of chronic and infectious diseases. It has been established that

“It has been established that stem cell therapy has a high potential for treatment of humans diseases, especially in emergent nations.” stem cell therapy has a high potential for treatment of humans diseases, especially in emergent nations. In the last two decades, a great number of methods have been developed to repair damaged tissues, and are being used successfully in the treatment of a good number of diseases in developed countries, but the treatment costs are very high in poor countries. Many public and private institutions are implementing facilities for stem cell storage and therapy in developing countries; the high demand for these services makes it cost effective and feasible. However, there is a gap in their laws and regulations on embryonic stem cell research and therapeutic use, and it is important to mention that almost exclusively adult stem cells are used in therapy today.

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Company Profile


CellGenix Technologie Transfer GmbH is an innovative biopharmaceutical company headquartered in Freiburg, Germany. CellGenix, which was founded in 1994 as a spin-off of the University Medical Center Freiburg, currently has more than 50 employees. CellGenix develops, manufactures and markets cell and protein therapeutics for cancer and orthopedic patients, as well as high-quality reagents for therapeutic ex vivo cell processing. The company owns Metreon Bioproducts GmbH, which was founded in 1996 and which is specialized on cell processing. Innovative research and development CellGenix’s research focuses on stem cell therapy for the regeneration of tissues and organs, cancer immunotherapy and the development of GMP-grade ex vivo cell processing tools, like cytokines, serumfree media and closed kit systems. A patient-specific idiotype vaccine (IdioVax®) against Non-Hodgkin´s B-cell lymphoma is in a Phase II clinical trial which is being conducted in collaboration with Freiburg’s University Medical Center and the Center for Clinical Research.

various competent authorities assures compliance with highest quality standards in the fields of individual biopharmaceuticals and cell based medicinal products. Since the Fall 2001, with the expansion of its office and production complex near the Freiburg airport, CellGenix has at its disposal one of the most technologically advanced GMP facilities for the processing and manufacturing of individual cell and protein therapeutics Ex Vivo Therapeutics Medical devices, tools and reagents for clinical ex vivo cell processing. Ancillary materials for clinical cell therapy applications require highest quality standards. CellGenix has extensive experience in the field of GMP-compliant ex vivo cell processing tools as well as strong concurrent regulatory expertise (i.e. various FDA Drug Master Files). • CellGro® GMP Cytokines • CellGro® Research Cytokines • CellGro® Serum-free Media • CellGro® Closed Kit Systems • VueLife™ Culture Bags

• Metreon autologous and allogenic cord blood cell preparations • Metreon autologous chondrocyte transplantation (CartiGro® ACT) Molecular Therapeutics The production of human recombinant biologics by E.coli fermentation is the main focus of Molecular Therapeutics. This currently comprises a patient-specific biopharmaceutical vaccine, produced with recombinant technology and manufactured under GMP (in phase II clinical trials; Non-Hodgkin´s B-cell lymphoma vaccine IdioVax®) as well as various human recombinant GMP cytokines produced for the clinical cell therapy applications.

Cellular Therapeutics These are cell based medicinal products for cancer therapy and tissue repair, manufactured and processed under GMP conditions. Over a decade of experience (first European manufacturing license in 1995) accumulates in our comprehensive product and process know-how.This currently comprises:

Cutting edge products and services Together with its distribution partners CellGenix markets a variety of superior products and services for clinical cell therapy applications: cord blood cell processing and banking, autologous chondrocyte transplantation as well as GMP-grade cytokines, serum-free media and kit systems for ex vivo cell processing. Additionally, we offer specialized contract manufacturing services. Safety and superior quality CellGenix’s extensive experience has enabled the company to build up a strong portfolio of products in the field of GMPcompliant production of cell and protein therapeutics. Continuous interaction with


Big Pharma R&d-thinking Big, Acting Small In order to mitigate the considerable risks in developing drugs, the pharmaceutical industry is going through an extended phase of consolidation to try to realise economies of scale (the latest of which is the Pfizer-Wyeth deal announced on January 26 2009). However, our analysis suggests that Big Pharma might now be too big. We found that productivity (as indexed by cost per NDA approval) falls, the more one spends on R&D. The cost a company appears to incur per approval falls with decreasing scale to around 10% for companies ranked between 51-157 as compared with Top 20 ‘Big Pharma’ companies (indexed by their 2006 R&D spend). We believe that the main reason for the apparent fall in productivity with increasing scale is the concomitant increase in organisational complexity. It is our premise that breaking Big Pharma into entities of more manageable scale will assist them in increasing R&D productivity. Horizontal disintegration (where end-to-end processes in the value chain are kept together, but the scopes of these activities are limited) and vertical disintegration (where end-

to-end processes in the value chain are broken down and carried out by separate companies) should be actively considered as methods of dividing Big Pharma into more manageable units. Disintegration is illustrated with two case studies. This paper outlines critical success factors for making disintegration work. This includes having talent management with a clear focus on leadership development, structuring operating units around clear areas of competence and performance, having clear divisions of accountabilities and having transparent cost accounting between operating units. In order to thrive, we believe that Big Pharma needs to start thinking ‘big’ and acting ‘small’. Simply tweaking the old business model is no longer a viable strategy. Given the mooted wave of Big Pharma mergers & acquisitions this year, disintegration needs to be at the forefront of every senior pharmaceutical executive’s thinking. Introduction Developing new drugs is a risky business. Taking a drug through development and

onto the market may take 10-15 years and cost on average, according to a recent estimate, around $1.2 billion US.1 There is less than a 5% chance of a compound progressing from first in human administration through to becoming a licensed therapeutic.2 Over the past 10 years or so, the pharmaceutical industry has mitigated these risks by extensive consolidation, the most recent examples being Bayer Schering Pharma, Merck Serono and now the Pfizer-Wyeth deal which was announced in January 2009. Consolidation is a way for companies to exploit economies of scale and scope.3 Scale gives an investment tolerance to deal with risks and the opportunity to utilise new technologies. Scope allows access to diverse technologies and intellectual capacity. The two work hand-in-hand; scale enables a company to survive a degree of project failure, whilst scope allows the sharing of knowledge and skills, mitigating further risks in the future.3 Whilst the benefits of sharing knowledge and skills across a company are obvious, it has resulted in greater organisational complexity. Pharmaceutical companies

Cohort Type


Total R&D Spend in 2004 (US $ million)

Total R&D Spend in 2005 (US $ million)

Total R&D Spend in 2006 (US $ million)

Cohort 1

Top 10 companies by 2006 R&D Spend




Cohort 2

Top 11-20 companies by 2006 R&D Spend




Cohort 3

Top 21-30 companies by 2006 R&D Spend




Cohort 4

Top 31-40 companies by 2006 R&D Spend




Cohort 5

Top 41-50 companies by 2006 R&D Spend




Cohort 6

Top 51-157 companies by 2006 R&D Spend




Cohort 7

Outside Top 157 companies by 2006 R&D Spend




Table 1: Cohort Classification Information Sources: PharmaExec Top 50 Companies Report 2007, 2006, 2005 R&D spends calculated based on Department of Innovation’s G1250 pharmaceutical and biotechnology sector R&D spend analysis. In 2006, the 157 companies in the sector spent £47388 GBP million on R&D. In 2005 the figure was £40356 GBP million. Cohort 6’s spend was calculated based on the total spend on the top 50 companies. 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

have swelled to a size where matrix working appears unwieldy. We believe this has contributed to a corresponding decline in R&D productivity. Data analysis The pharmaceutical industry is finding fewer and fewer drugs, whilst at the same time investing more and more money. In the period between 2002 and 2006, the industry brought to market 43% fewer new chemical-based drugs than in the last five years of the 1990s, despite more than doubling R&D spending.4 We looked at the distribution of New Drug Applications (NDA) and the New Molecular Entity (NME) approvals issued by the Food and Drug Administration

(FDA) between 2004 and 2007 across the pharmaceutical sector, and paired this information with R&D spend to look at productivity. We first divided the sector into tranches, which are defined in Table 1. The Top 50 companies by 2006 R&D spend were divided into cohorts of 10, with the remainder of the sector being divided into the Top 51-157 companies and the rest. We next looked at the distribution of NDA and NME approvals from 20042007, across these different cohorts (see Figure 1). There appears to be a positive correlation in terms of greater investment results in greater output (as measured by total NDA approvals). In terms of NME approvals, there is again a positive correlation where greater investment results

in greater output. The NME to non-NME approval ratio is highest in Cohorts 2 and 3. As NME approvals are generally taken as a surrogate for innovation, could we infer that the greatest innovation is taking place in these cohorts? Finally, we examined the productivity of each cohort by looking at the average spend per NDA approval (see Figure 2). Unlike the number of approvals, where there was a positive correlation with R&D spend, here the reverse appears to be true. Productivity, as indexed by spend by NDA approval, is negatively correlated with R&D spend. Productivity increases as one spends less on R&D, the cost per approval declining with scale to circa 10% for Cohort 6. It appears from our analysis that Big

Figure 1: Total NDA approvals for 2004-2007 by cohort


2346 2098

Spend Per NDA Approval (US $ million)

2000 1530 1500



834 677

500 235 0 Overll Source: Kinapse Analysis

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Cohort 5

Cohort 6


Figure 2: Average cost per NDA approval between 2004 and 2007 by cohort. Figures generated by taking the average across the years of the mean cost per approval per year by cohort. INTERNATIONAL PHARMACEUTICAL INDUSTRY 31

Pharma’s output productivity is relatively low and that the cost per NDA approval declines with decreasing scale. We recognise that this is an imperfect analysis, not least because of the fact that we have not accounted for the time lag in R&D investment versus approvals. Also, this analysis does not take into account the possible confounding effects of in and out-

inertia’, with an R&D environment where ‘there is a loss of personal accountability, transparency and the passion of scientists in the organisation’.5 Other factors which may contribute to a sub-optimal working environment as organisations increase in complexity include increased difficulty in effective leadership and communications, increased

• Focus on key elements of the value chain where the company has distinct competitive advantage • Reduce risk while unlocking cash and other value by partnering deprioritised assets • Spin out business units into TA/ market/tech-focused independently traded companies • Reduce business complexity • Increase investor transparency • Have greater strategic and financial flexibility.

Figure 3: Breaking up Big Pharma

licensing where smaller companies outlicense their compounds to Big Pharma (who pick up the development costs) but remain the applicant on the FDA approval. Nevertheless, from this initial analysis, it appears that although there are benefits to size for a pharmaceutical company, the repeated rounds of consolidation may have left Big Pharma too big to support a highly productive R&D environment. Organisational causes of reduced R&D productivity with increased scale We do not think it surprising that large scale causes problems with R&D productivity. Back in the 1960s, the largest pharmaceutical companies employed in the region of 1000 scientists, grouped together on one or two sites with few management layers and relatively straightforward resource planning.5 The reality today can involve in excess of 10,000 staff, working across multiple sites in multiple geographies coordinated by multiple management layers trying to balance the needs of many more projects and portfolio permutations. According to JP Garnier, this increased organisational complexity ‘may result in a culture of risk aversion, promises with no obligation to deliver and bureaucratic 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

vertically. Horizontal disintegration is an organisational form where end-to-end processes in the value chain are kept together, but the scopes of these activities are limited. For example, it is possible to horizontally disintegrate a company’s R&D activities by therapeutic area or by geography. Vertical disintegration is an organisational approach where the end-to-end processes in the value chain are broken down and carried out by separate companies, each performing a limited subset of activities needed to create the finished product. Contract Research Organisations (CROs) are an example of companies who typically only provide services in the Development / Regulatory part of the R&D value chain. Horizontal and vertical disintegration allows a pharmaceutical organisation to:

potential for political conflict and topheavy management, and reduced ability of an individual to make a difference and positively impact the bottom line. It is also worth noting that other factors have been postulated for the decline in R&D productivity. These include tougher challenges than in the past (diseases which are easiest to treat/cure have been tackled already), greater regulatory requirements and the increase in cost of R&D activities. Whilst all of these are likely to be contributing factors, we believe that the main reason for the R&D productivity decline is down to increased organisational complexity as a result of increased size. How can Big Pharma break up? Big Pharma has utilised its ‘fully vertically integrated’ R&D operating model since its inception. Vertical integration refers to the degree to which a firm owns its upstream suppliers and downstream buyers. In the pharmaceutical industry, it is typified by one single firm engaged in all the different aspects along the R&D value chain; i.e. from Discovery and Development through to Manufacturing, Distribution and Sales. There are two ways in which Big Pharma could disintegrate – horizontally and

Of the two models, vertical disintegration is the more radical. Breaking the explicit linkage between discovery-developmentcommercial allows more decision-making freedom to be exercised. It allows the commercial organisation to make more unencumbered portfolio decisions, whilst allowing the R&D organisation to develop deep skills in certain discrete competencies. However, just as we have recognised the limits of Big Pharmas, so we also acknowledge the limits of this more ‘disintegrated’ approach. The constraints facing biotech companies also illustrate the need for scale in certain areas.3 The costs of late development and launch mean that many biotechnology companies require large pharma support through licensing deals to develop their compounds into medicinal products.3 Indeed, a company needs critical mass to be able to conduct global drug development and to acquire crucial new technologies.5 What we are advocating therefore, is an approach which combines scale with agility. Attempts by Big Pharma to disintegrate Horizontal disintegration case study: GSK Centres of Excellence for Drug Discovery

(CEDDs) and Medicines Development Centres (MDCs) At the time of the merger between Glaxo Wellcome and SmithKline Beecham in 2001, the industry’s interest was piqued by a novel organisation announced by Tachi Yamada and Jean-Pierre Garnier (then the R&D Chairman and CEO respectively) for drug discovery. The six Centres of Excellence for Drug Discovery (CEDDs) were configured along TA lines and charged to take drug candidates generated by GSK’s Discovery Research group and bring these as fast as possible to proof of concept (POC). Proof of concept was to be determined based on a contract agreed with the Full Development organisation. While positioned as autonomous groups, the CEDDs continued to be overseen closely by Dr Yamada, and were required to source routine services from GSK’s own infrastructure, and also team with full development staff through a bridging organisation – Clinical Pharmacology & Discovery Medicine – either side of proof of concept. The CEDD Heads were incentivised largely on achieving POCs delivered. After a relatively lean period the CEDD model has apparently delivered increased productivity as judged by the number of POCs achieved, although the commercial viability of these assets has yet to be fully determined. The CEDD model has been reinforced since, and one has been fully virtualised to focus on Discovery through external collaborations. More recently, as part of further reorganisation under the leadership of Moncef Slaoui and Andrew Witty (new GSK R&D Chairman and CEO) horizontal disintegration has been further pursued through the strengthening of Medicines Development Centres (MDCs), accountable for developing assets transitioned from the CEDDs at POC to successful commercialisation. Different organisational models are being pursued for different MDCs in order to tailor the organisation to the needs of the portfolio in that area. This approach should help GSK in its goal of ‘differentiated development’ but will doubtless cause many leadership and interface challenges as heterogeneous organisational units interact with their many and various internal and external stakeholders. Some of the advantages of GSK’s R&D structure include: 1. Clarity of incentives for CEDD and MDC leadership with a healthy and focused negotiation on the definition of POC around each asset 2. Increased freedom of decisionmaking within each group allowing for

greater flexibility and focus on the scientific specifics of the respective therapeutic area 3. Reduced scale of operation and span of control within each group allows for increased local leadership and management effectiveness. However, some disadvantages are:




1. Both CEDDs and MDCs appear to be challenged by being ‘quasi’-businesses. We believe that neither of these organisation units is likely to have full visibility and control over their actual costs which is an impediment to true entrepreneurialism. This means that decisions can be taken in practice without a full appreciation of the business implications, particularly in terms of cost management. 2. Operations groups within the GSK organisation need to interface differently with the more entrepreneurial CEDD and MDC groups which may suffer from a lack of operational expertise that crossTA groups tend to build up. It is also likely that the leadership and management capability required (in terms of numbers of people) will increase as an organisation disintegrates in this way. 3. Resource inefficiencies tend to occur in these types of organisations, in particular where cost accountability is uncertain. This is a risk in both the CEDD/MDC and its services organisations and could become a particular challenge where the tendency is often to consolidate all resources required to get the job done under ‘one roof’ which risks increased inflexibility and underutilisation of resources with fluctuating workload. Vertical disintegration case study: LillyChorus7 Lilly set up Chorus between 2002-2003 as an independent division charged with speeding up early-stage development by getting compounds to POC stage faster and cheaper than Lilly’s main development engine. Utilising proprietary management software, Chorus aimed to increase the number of late-stage, riskreduced development candidates, or to ‘de-risk’ development projects. Chorus pursues only what it needs to demonstrate POC, forgoing other activities which are required before starting pivotal clinical trials, but which also increase time and cost to POC. Chorus assumes that most of its compounds will fail, whereas most of the industry assumes ‘successbased behaviour’. Chorus operates as a lean, virtual

organisation (24 people oversee all aspects of development for a maximum 10 compounds), utilises software which allows all the key players instant access to all the key information, and outsources 75-80% of the work, relying on external networks of experts and service providers. As well as ties with Lilly, Chorus also has a partnership with Versant Ventures, testing compounds sourced by the venture group. This arrangement gives Lilly access to compounds it might not have seen, and gives Versant preferential access to Lilly’s de-prioritised candidates. Some of the apparent advantages of Chorus are: 1. Productivity gains: rapid POC and potential to save money by failing the failures faster and more cheaply. Chorus reaches POC in 29 months (compared with Lilly average of 40 months) at a cost of $3.2 million (Tufts data quotes Phase I only, without reaching POC, costs about $15 million). 2. Value creation: additional time required post POC is offset by the savings accrued getting to POC because there is a big valuation increase for compounds which demonstrate positive POC. It allows Lilly to unlock value that would be otherwise trapped in its R&D pipeline. Drugs which don’t make Lilly’s criteria for full Development or even positive POC might be well suited to another company. 3. Benefits of being independent from, yet linked with, the larger parent company. As Chorus works autonomously from Lilly, it is not restricted by the organisational infrastructure of the larger organisation. Chorus is also compound ‘agnostic’; noone at Chorus has a driving loyalty to a molecule which might sway them to select one project over another. However some of the potential disadvantages are: 1. There is no evidence that the Chorus model works well for successful compounds. A Chorus POC-approved compound cannot immediately be put into registration trials; many of the activities which were skipped over in pursuit of POC need to be completed. It is possible that development may actually take longer in the long run. 2. Chorus has limited capacity and the Chorus approach is not right for all development programmes. For example, it won’t work for novel compounds which don’t have predictive biomarkers; probably slow down drug programmes pursing well-validated mechanisms, or where time to submission is crucial and confidence is high. Also, because Chorus works autonomously, in isolation from other INTERNATIONAL PHARMACEUTICAL INDUSTRY 33

groups, it seems less suitable for working on molecules with challenges that require more substantial work, e.g. complex CMC or manufacturing problems. 3. The level of outsourcing which Chorus requires is likely to be troubling to most Big Pharma. It seems unlikely that companies would be willing to adopt such a strategy unless there is significant proof that it improves R&D productivity. How to make disintegration work It is our premise that breaking organisations into entities of more manageable scale will assist Big Pharma in increasing its R&D productivity. We believe that both horizontal and vertical disintegration should be actively pursued, breaking up Big Pharma into more manageable organisational units. A good operating model from which to learn in setting up such organisational units is the military’s concept of mission command.8 The two main aspects of mission command are to establish alignment by setting out the ‘what’ and the ‘why’, and granting a high degree of decision-making authority to appointed leaders in the organisation who deal with the issue of ‘how’. Instead of following detailed orders, the responsibility of subordinates is to understand their commander’s intention and to take whatever actions are deemed necessary to complete it.3 When the situation changes, the original intent dictates subsequent decision-making. Much like the concept of ‘empowerment’, this involves giving decision-making power to those who need it, and not allowing it to be withheld by those who do not. By aligning everyone on the ‘what’ and ‘why’ and pushing down decision-making, it creates organisational units that can adapt rapidly in the face of uncertainty while retaining cohesion.3 With governance provided by a Management Board in the parent company, we propose ten high-level steps that need to be taken to implement a disintegrated operating model: i) Determine areas of distinctive R&D competence and performance, where possible using objective and externally validated process performance measures. Classify processes at which the R&D organisation excels, performs acceptably and under-performs the industry. ii) Structure operating units in support of these processes. These units should trade clearly defined inputs and outputs which can be bought from suppliers and sold to customers. Exit processes which significantly underperform through closure or divestment. iii) Define clear and separate 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

accountabilities which can be written in a simple list for each operating unit head. These accountabilities will include financial performance of the unit, successful delivery to customer requirements, people and team development and retention of key talent. Review leadership talent across iv) the R&D organisation. Identifying the right talent is a must; leaders should have a track record of implementing new ideas with a willingness to take measured risks. Leaders who bring engagement and passion to get the job done ‘whatever it takes’ should be at the top of the list. v) Appoint existing best leaders to the most critical business areas, wherever possible aligning technical and therapeutic skillsets with the organisational unit. Where clear gaps exist, seek external talent from smaller R&D and services organisations where a clear track record for business leadership has been demonstrated. vi) For all unit leaders and potential successors, invest in leadership development, career development and succession planning. In all units, leaders must spend time with their team members, and units should therefore have no more than three organisational layers below the leader. vii) Increase emphasis on business skills, including communication and negotiation skills, as well as customer and supplier management. Seek regular career moves for best performers between organisational units to increase ‘joined up’ thinking between customers and suppliers in the network. viii) Invest in an enabling infrastructure which allows transparent cost accounting at the level of each organisational unit, with unit leaders accountable for individual profit and loss, cash flow and balance sheet performance. Service centres in areas such as finance, IT, HR, quality, outsourcing management should also be considered in the network, ideally as financially selfstanding operating units which may or may not be owned by the parent organisation. Ensure operational decisionix) making resides within the unit. The management board should intervene only when fact-based operational performance issues become apparent through predefined performance metrics. Consider exiting under-performing operating units. Accept that successful units x) will tend to grow as unsuccessful ones will contract or disappear. This raises the question of the ideal size of organisational units. It is interesting that many organisations, including the military, hunter-gather societies and some businesses, favour Dunbar’s magic number of 150 (the postulated maximum number

of individuals with whom we can have a genuine social relationship).9. Over time, the network needs to be managed with incorporation of new units and breaking up of larger units to ensure the benefits of disintegration are maintained in the long term. Conclusion In order to thrive, Big Pharma needs to start thinking ’big’ and acting ‘small’. The ‘industrialised’ business model which has served Big Pharma well in the past appears to be faltering. In today’s R&D environment, Big Pharma needs to consider the benefits of a more radically disintegrated model – groups need to use different processes, become more nimble and develop a culture which allows individuals to ‘try new things’. Individuals need to be empowered and unit leaders need to lead. Although disintegration is a radical and potentially risky approach, simply tweaking the old business model no longer seems a viable strategy. Given the mooted wave of Big Pharma mergers & acquisitions this year (e.g. Roche’s hostile bid for Genentech, reports that Sanofi Aventis is lining up funds for an acquisition and news that Merck is considering a major buyout) – disintegration needs to be at the forefront of every senior pharmaceutical executive’s thinking. References Tufts Center for the Study of Drug Development (2006). Accessed June 2008 I Kola & J Landis. Nature Review Drug Discovery, 711-715 (2004) S Bungay, D Roblin & D Slavin. Pharmaceutical Executive Europe (2006) Accessed June 2008 JP Garnier. Harvard Business Review (2008) Accessed June 2008 R Longman. In Vivo May (2007) S Bungay, British Army Review, 137, 22-29 (2005) M Gladwell. The Tipping Point. Abacus (2000) JAMES MAN is a Manager in the consulting practice at Kinapse. He joined in 2006 and has worked mainly in Clinical Development. James holds a PhD in Neuropharmacology from Bristol University. Email: ANDY BLACK is a Co-founder of Kinapse and the Global Head of Client Services. In the last 15 years Andy has consulted to the majority of global R&D organisations. Email:

Company Profile

Quality Control: The missing piece in your trial jigsaw!

With advances in automated technology and new clinical trials, quality assurance may seem like another complication in an already difficult puzzle. It is under precisely these conditions that quality assurance will provide increased reliability for the user in an environment with multiple variables. Quality assurance of analytical systems is important to ensure the accuracy and precision of test results. The choice of supplier can have a massive influence on the ease of use and suitability of quality control sera for trials being undertaken. The specific requirements for each trial must be carefully assessed and a determination made of the most appropriate internal quality assessment, peer-reviewed or external QA schemes. Internal quality control involves a set of procedures that daily monitor analytical processes and their emergent results. The best quality control manufacturers will also supply reference method values and traceability to international reference methods, so you can be sure the target values quoted are correct. This gives additional accuracy and ensures confidence in the test results. To be an accredited laboratory, you need to run an international EQA scheme. EQA provides a means of assessing the analytical performance of a laboratory compared to others using the same instruments and methods. Such comparisons would not normally be available in IQC schemes. In summary, internal QC, peer group and EQA programmes ensure quality results from whatever analysis you perform. This applies to clinical use or clinical trials, but in all cases, having confidence in results makes sense. Finding the right scheme will be determined by the size, duration and complexity of each trial, but for every test, you can be sure there will be a suitable control that will fit. The clinical trial jigsaw will then be complete.

About Randox Randox is an international diagnostics company, headquartered in the UK. Randox develop, manufacture and market clinical diagnostic products worldwide. Core products are: Quality Controls and EQA; Biochip Array Technology; clinical chemistry analysers and reagents; environmental diagnostics; recombinant proteins and antibodies. For further details of Randox’s Quality Controls and EQA, or any other aspects of the portfolio of multi-analyte biochip arrays, contact


Now in it’s 9th successful year, with new features for 2009, including: ŸExhibition runs over 2 days ŸBoth conference days held at one venue (QEII Conference Centre) ŸRe-focused programme on the challenges of drug discovery, bio-financing and Innovation show-

casing by therapy and technology area ŸAwards Dinner- Celebrating the best the UK has to offer, the awards will recognise the great success achieved by the UK’s leading companies, universities and inward investors over the previous 12 months

Take advantage of this great opportunity to showcase your organisation and network with hundreds of like-minded people by logging on to Please call Tony Jones 020 7665 1403 or email to discuss sponsorship

Organisations registered to date xAllmi-Care xAmgen xArk Therapeutics Group plc xArrow Therapeutics Ltd xAseptika Ltd xAstex Therapeutics Ltd xAstraZeneca xAvecia Biologics xBiotransformations Limited xBiovex xBirkbeck College / freelance xCambridge Healthcare & Biotech xCambridge Major Laboratories xCelentyx Ltd xCell Medica Ltd xCellzome xCINETIQUE Translations xClinical Development and xSupport Services Ltd xCLS Communication Ltd xCMP Therapeutics Ltd xCompChem Solutions xConformetrix xCurapel xD2M xDomainex Ltd xElands & Partners

xEpistem Ltd xERA Consulting Group xEvotec (UK) Limited xForresters xFrench Embassy xGentronix Ltd xGenzyme xGlide Pharma xGlycoForm Ltd xHalo BioConsulting xHarpum Consulting Ltd xHealth Protection Agency xImagen Biotech xImmunocore Ltd xInstitute of Cancer Therapeutics xInterea International xInvest in Nottingham xIpso Ventures xIsogenica xKarus Therapeutics xLab21 Ltd xLondon Genetics Ltd xMcKenna Long Aldridge xMerck & Co. xMinster Pharmaceuticals plc xNorth West Development Agency xNorwich Research Park Novozymes


xPGXIS xPharmidex Ltd xPolytherics Ltd xProcarta Biosystems Ltd. xProximagen xPsyRING xQuay Pharmaceuticals Ltd xRiverbank IT Management Ltd xSareum Ltd xSelcia Limited xSelective Antibodies Ltd xSmartLife Technology Ltd xSpirogen Ltd xSRCL xStabillitech xSygnature Chemical Services Ltd xSyntaxin xTeva Pharmaceuticals Ltd xTherakind Ltd xTranScrip Partners LLP xUKTI xUniversity of Liverpool xViBio xW orld Courier UK

The London Biotechnology Network: For those doing life science business in, with and through London The dynamics of London’s biotechnology cluster are quite different to those reported in many other bioregions. Enter London’s environs and you wouldn’t expect to see large green leafy science parks, landscaped gardens and car parks; features that are frequently used to create a quality of life element in many locations. For certain, London has its fair share of parks, water features and car parks like any other city, however ours are less obviously framed by R&D facilities. That can be a misleading view however. London is home to the full spectrum of science and business, industry and academia, policymakers and regulators. It is this convergence of biotech stakeholders that makes London one of the best locations in the World in which to grow your company. Bird’s Eye View of London Biotechnology Network (LBN): x Formed in 2000 to provide the first coordinated approach to biotechnology in London. x Not a trade association funded by member subscription, LBN has remained a free to join network for biotechs, Pharma, academic and Govt bodies. x The main aim of the network is to provide effective meetings and communication channels to raise awareness of opportunities, share best practice and challenge current thinking through: - Monthly Biowednesday events - Bioguide London online directory - London Life Science Newsletter - Direct member communications - Bespoke seminars - Annual Genesis Conference - Global links through the Golden Triangle Partnership initiative

The monthly Biowednesdays provide an excellent means to network pre and post presentations from leading experts and forge links with overseas partners. (pictures by Chloe Chapman,

Key bio-facts about London’s Biotech Community: x 130+ biopharma companies with a growing medical– and clean tech sectors nurturing complementary skills x 60% of clinical trials in Europe are carried out in the UK, the majority of them in London. x London is home to 3 of the 5 comprehensive and 4 of the 6 specialist biomedical centres of the National Institute for Health Research; 17 of the MRC’s units centres and institutes; and CRUK’s London Research Institute x 39,000 life science students providing a large, highly trained talent pool x In excess of $1billion public research funding annually x The most bio-experienced cluster of professional service providers in Europe

The London Biotechnology Network (LBN) is a business network of over 800 organizations/2000 members from the biopharmaceutical industry, academia, venture capital community, legal and accounting services, and consultants with an interest in the sector. LBN strives to provide members with relevant information and networking opportunities to cultivate the right environment for innovation and Latest events, news, R&D pipeline information and all other collaboration in the life sciences information at community. Please contact Dr. Tony Jones at or 020 7665 1403 with membership enquiries or go to for more information.

In a recent study by Cambridge Healthcare & Biotech looking at the ‘UK R&D Pipeline’, shows London companies, with 200 drugs currently in development, to be the leading UK region with 22% of the UK total. Incredibly, this compares to 19% in Cambridge and just 8% in Oxford and excludes drugs in discovery units at HEIs.

Designing Biobetter Monoclonal Antibody Therapeutics By Glycoengineering

Introduction Monoclonal antibodies (MAbs) currently comprise the fastest growing class of protein therapeutics - primarily for the treatment of cancers and autoimmune, infectious and inflammatory diseases. Commercially, MAbs represent the most rapidly expanding segment of the pharmaceutical industry - by 2008 the US therapeutic antibody market was estimated to be around 40 billion USD with further significant increases predicted for the next decade. Furthermore, major advances in cell line development, bioreactor construction and operation, purification strategies and analytics (Sommerfield et al, 2005) have resulted in continual reductions in the manufacturing costs of MAbs which are now being produced in cell culture for 200 USD to 1,000 USD per gram. However, there is still a continual drive to produce more effective, safer and less expensive therapeutic antibodies. This drive has stimulated the development of ‘biosimilars’ (copies of original drugs) and ‘biobetters’ (improved versions of original drugs). Many regard this as an exciting prospect and of benefit to patients who could have access to a wider range of less expensive drugs - but it has prompted serious debates and initiatives relating to regulation, intellectual property (IP) and protection of commercial interests. One area of great interest to developers, copiers and improvers of therapeutic antibodies is glycosylation, since it can significantly influence the safety and efficacy profiles of the drug (Arnold et al, 2007; Fernandes, 2009a; Beck et al, 2008; Jefferis, 2009). In this article, we show how both the original drug manufacturers and the designers of follow-on biologics could produce biobetter antibodies through glycoengineering. In particular, we examine strategies for optimising both Fab and Fc glycosylation to produce MAbs with improved clinical performance and better commercial profiles compared to existing drugs. 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The Coming of Biosimilars and Biobetters Biosimilars The arrival of biosimilars and biobetters will have a tremendous impact on the therapeutic glycoproteins market. Some of the earliest biopharmaceuticals have already lost patent protection, and it is estimated that by 2013 about half of all products coming off patent will be biologics. The first biosimilars – Omnitrope and Valtropin (somatropin) – were approved in 2006, and the following year saw marketing authorisations for five epoetin products. In February 2008, the European Medicines Agency cleared four biosimilar filgrastims. Biosimilar antibodies will, no doubt, follow the same route. However, whilst the first biosimilars were relatively simple molecules, immunoglobulins are far more complicated in terms of size, structural complexity and their glycosylation patterns. A key problem for developing biosimilar antibodies will be demonstrating comparability of their glycosylation to the original drug. This was highlighted for a non-antibody biopharmaceutical when Genzyme scaled up production of its drug Myozyme - an enzyme replacement therapy which was approved in 2006 for the treatment of Pompe disease, an inherited muscle disorder. The scale-up in 2000 litre reactors was carried out at a different plant (Allston, Massachusetts) from the one that produced the drug for the original approval (Framingham, MA). The glycosylation pattern was found to be significantly altered in the scaled-up drug, and the FDA considered the Myozyme coming out of the Boston plant to be a new product. Genzyme would need to file a new application (and thus provide more clinical data) for Myozyme if it wanted to sell it on the US market. To resolve this, the company decided to launch the same biologic under two different names in the US - Myozyme for the original product and Lumizyme for the scaled-up product. Conversely, Atryn (manufactured by GTC

Biotherapeutics) which is a recombinant antithrombin produced in transgenic goats, was approved by the FDA earlier this year despite having a glycosylation profile different from plasma-derived antithrombin. In this case the different glycosylation pattern resulted in an increased heparin affinity but tests showed that the potency of the recombinant product is not different from that of the plasma-derived product. The complexity of the molecules, and therefore the more clinical data that companies have to generate in order to obtain approval, may hold back the progress of biosimilars. Indeed, biosimilars have still not made a significant impact on the pharmaceutical market. This is in part due to the lack of a legal and regulatory framework for the production of biosimilars around the world; a regulatory pathway for approving biosimilars is established in the European Union but is still under consideration in the United States. Despite this, it is clear that the potential is there for the future and biosimilar MAbs are already under development. In 2008, GTC Biotherapeutics initiated the first of several research programmes to develop biosimilar versions of marketed MAbs that will begin to come off patent in the US from 2014 onwards. The products targeted had combined sales in 2008 of greater than $17 billion. GTC is seeking development partners to help commercialise its portfolio of biosimilar monoclonal antibodies. Well-designed comparability studies and attention to glycosylation patterns will be key to their success. Biobetters We believe that ‘biobetters’ with improved glycosylation over the original drug are a more exciting proposition than biosimilars. Such drugs would offer medical advantages over biosimilars other than just lower price and increased choice. In the following sections we will focus on how to design glycovariant biobetter MAbs that share the same protein as the original drug

Ludger Specialists in biopharmaceutical glycoprofiling

Glycosylation can significantly affect the performance, consistency and cost of your biopharmaceutical. We provide glycoprofiling products and analytical services to help you optimise, measure and control your product’s glycosylation so you can deal effectively with:

Safety - e.g. levels of immunogenic non-human glycosylation Efficacy - e.g. glycans affecting mAb Fc receptor functions, Fab glycosylation Demonstrating Comparability - e.g. biosimilars vs innovator’s product Product Consistency - e.g. batch consistency during scale-up Half Life and Stability - e.g. sialylation of EPO and FSH Regulatory Compliance - e.g. IND submissions Patent Issues - e.g. patent infringement G0





We can design and execute appropriate glycoprofiling programmes for carbohydrate structure analysis of your therapeutic (during product development and for regulatory submissions), perform glycoprofiling QC for product lot release, and transfer the optimised methods to your labs. Glycoprofiling modules include: sialic acid profiling (to compare levels of NeuAc vs NeuGc), quantitative monosaccharide analysis, and Level 1 and Level 2 profiling of N- and O-glycans by a range of orthogonal HPLC and MS methods combined with detailed exoglycosidase sequencing. Ludger Ltd, Culham Science Centre, Oxfordshire OX14 3EB, UK Tel: +44 870 085 7011 Email:

but which have modified glycosylation to enhance safety and efficacy profiles of the therapeutic. What is a Glycovariant Biobetter MAb? The first step in designing a biobetter MAb is to define what exactly a biobetter is in relation to follow-ons and biosimilars. However, at present, in the biopharmaceutical industry, there seems to be a range of different interpretations of these terms. This confusion arises, in part, from the real difficulty in comparing variants of biopharmaceuticals that are heterogeneous mixtures of exceedingly complex structures with inherent batch-tobatch variability and for which we have only partial understanding of the mode of action and possible aberrant behaviour. For example, during an expert panel session at a recent conference on biopharmaceutical comparability (Informa conference, Cologne, June 2009) there was a discussion on whether two therapeutics sharing the same protein structure but with different glycosylation should always be considered as the ‘same’ drug. Two opposing opinions, with farreaching consequences, were expressed. The first was that the only consideration for ‘sameness’ should be amino acid sequence - so the variants should always be viewed as the same drug, no matter what the differences in glycosylation. This would strengthen the protection of a drug innovator from competition during the period of exclusivity, but subsequently would allow ‘biosimilars’ with vastly differing glycan profiles. The second opinion was that there could be conditions in which changes in glycosylation patterns would result in the biological behaviour altering so significantly that the variants should be considered as related but not the ‘same’. This could allow glycoengineered biobetters to be produced during the period of exclusivity, but then narrow the field for biosimilars which would have to

bear glycosylation that was substantially similar to that of the original drug. Clearly, this fundamental disagreement on the definition of sameness needs to be resolved to clarify both the legal and regulatory positions for all drug developers and manufacturers. At Ludger, we propose to answer this by systematically dividing the problem of ‘determining sameness’ into smaller, independent comparison tasks and dealing with each of these in turn. So, to determine the degree of similarity of a glycosylation variant of an innovator’s drug we compare it to the original with respect to a range of parameters. These include safety and efficacy profiles, biological behaviours (e.g. serum half-life and biological activities) and structural attributes (e.g. amino acid sequence and glycosylation patterns). The combination of comparison scores for the ‘copy drug’ indicates its similarity class. A simplified version of this procedure is given here, the first step being to define various parameters and comparison scores like so (each comparison is to the original drug): S0, S-, S+ = safety profile: scores for same, poorer or better respectively E0, E-, E+ = efficacy profile: scores for same, poorer or better respectively Prot0 = same protein: same primary and secondary structures ProtDiffs = different protein: differences in primary or secondary structures Gly0 = same glycosylation: same glycosylation sites, glycan species and relative proportions Gly1 = related glycosylation: same glycosylation sites and glycan species, different relative proportions GlyDiffs = different glycosylation: different glycosyation sites and/or glycan species

The state of the copy drug compared to the original can be indicated by making a list of these parameters and classifying it according to the following scheme (note that this is a partial list of comparison classes and does not including ‘bioworse’ variants with S- or E- profiles or biobetters with different protein structures): Type 1 Copy Drugs - Biosimilars Type 1A: [S0 E0 Prot0 Gly0] Type 1B: [S0 E0 Prot0 Gly1] (where glycosylation has little impact on safety or efficacy) Type 1C: [S0 E0 Prot0 GlyDiffs] (where glycosylation does not impact on safety or efficacy) Type 2 Copy Drugs – Biobetters with Related Glycosylation Type 2SE: [S+ E+ Prot0 Gly1] (the most desirable Type 2 profile) Type 2S: [S+ E0 Prot0 Gly1] Type 2E: [S0 E+ Prot0 Gly1] Type 2SEm: [S+ E- Prot0 Gly1] (improved safety at expense of efficacy) Type 3 Copy Drugs – Biobetters with Different Glycosylation Type 3SE: [S+ E+ Prot0 GlyDiffs] (the most desirable Type 3 profile) Type 3S: [S+ E0 Prot0 GlyDiffs] Type 3E: [S0 E+ Prot0 GlyDiffs] Type 3SEm: [S+ E- Prot0 GlyDiffs] (improved safety at expense of efficacy) Figure 1 illustrates how these variants relate to one another in safety-efficacy space. Such classification allows different types of copy drug to be treated appropriately with respect to regulation, intellectual property and commercial positioning. Provided the rules for the different treatments were clear, consistent, and agreed within the industry this would overcome many of the problems of using crude definitions of ‘sameness’.

Figure 1: Classification of glycovariants of copy drugs with different safety and efficacy profiles relative to the original drug


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This classification system is part of a theoretical framework called GTO-QbD currently being developed at Ludger to simplify the design, determination of comparability and analysis of complex biopharmaceuticals (Fernandes, 2009a). GTO-QbD is built on the principles of QbD (Quality by Design) introduced in ICH guidelines Q8 and Q8 annex with extensions, to cope with the complexity of biopharmaceutical PTMs (posttranslational modifications) – glycosylation being one of the most noticeable PTMs of most MAbs. The system borrows ideas from mathematical graph theory and ontology (hence ‘GTO’) to map relationships (ontology is the study of relationships) between safety, efficacy, biology, structural attributes, material attributes and process parameters for glycoprotein therapeutics, and is being used to design biobetter antibodies (Fernandes, 2009b). When is a Glycoengineered BioBetter Commercially Better than a Biosimilar? Our knowledge of structural-activity relationships for MAb glycosylation is now sufficiently advanced that improving existing drugs by glycoengineering is relatively straightforward. Given this, the choice between producing a biosimilar or a glycoengineered biobetter MAb is essentially a marketing one. The following illustrates how we can make such a choice based on commercial considerations: First, we define the following commercial comparison parameters: C0 C- C+ = manufacturing cost per therapeutic dose: similar to, or lower or higher than original drug P0 P- P+ = selling price per therapeutic dose: similar to, or lower or higher than the original drug For a biosimilar, you would pick a successful original drug coming out of its exclusive period, aim to make as close a copy as possible (e.g. a Type 1A biosimilar), and reduce both manufacturing costs and selling price - so the ideal drug copy profile would be [S0 E0 Prot0 Gly0 C- P- ]. In this case, your main advantages over the originator is that you have a lighter R&D effort than they had (you build on their efforts) and you can gain benefit from advances in manufacturing know-how to reduce your production costs (these are also reasons why some innovators object to the principle of biosimilars). However, your problems include the following: a. You may experience technical difficulties in reproducing the glycosylation pattern of the original drug – you would be 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

constrained to use a similar or identical cell expression system and would more likely achieve a Gly1 profile than a Gly0. b. If your drug does have a Gly1 glycosylation pattern then the regulatory authorities may classify it as a different but related drug - so you could lose the ability for physicians to prescribe your product as a generic substitute, weakening your commercial position. c. You are likely to have difficulties in proving complete equivalence of safety and efficacy profiles (it is easier to prove differences than equivalence in the clinic). d. Your drug is likely to be one of several biosimilars, all of which compete with the original drug on price but without the innovator’s brand recognition. The case for developing biobetters is generally more compelling. The main problems for follow-on companies would be the high costs of developing a new drug, building brand recognition and gaining market share from the originator. However: a. You have greater freedom in choosing your expression system (including non-mammalian cell lines or wholeorganisms). This increases the likelihood of significantly lowering manufacturing costs. b. If your drug has clear clinical benefits (e.g. it overcomes adverse reactions found with some patients treated with the original drug) then you can position it in the market as a ‘new and improved’ version, and may have less pressure to reduce the price per dose, so increasing your profitability. c. You could build a stronger IP position if your product has clearly distinct glycosylation from the original drug or other copy drugs. Of course, if you are the originator you could also make a biobetter as the nextgeneration of your own drug and enjoy even greater advantages over follow-on competitors. Strategy and Tools for Building Glycoengineered Biobetter MAbs The design strategy we suggest is as follows: a. Use a QbD-type paradigm for your drug development - its flexibility and power can simplify many tasks that would be difficult with older paradigms. In particular, ensure that you continually refine your models of the Design Space (DS) and Control Space (CS) both for your copy drug and the original drug - this is essential for demonstrating comparability or otherwise of drug variants. The GTO-QbD schema is an example of a QbD-based tool that you could use when glycoengineering MAbs

(Fernandes, 2009). b. Investigate the mode of action, clinical behaviour and glycan structurefunction relationships for the original drug. c. Identify GCQAs (glycosylation critical quality attributes) for the original drug. These are glycosylation features that significantly influence the safety or efficacy profiles of the therapeutic. GTO-QbD has methods for reliably determining and prioritising GCQAs. d. Use the GCQA list to work out what non-human or other glycosylation features should be eliminated to produce a drug with an S+ profile. e. Similarly, work out which glycosylation features need to be modified or designed in order to improve the in vivo efficacy in your target patients and achieve an E+ profile. Be aware that some glycan features may cause an increase in biological activities in vitro or in vivo animal models but the same effects may not be reflected in the clinic. f. Draw up a new GCQA list for your hypothetical, ideally glycosylated drug. g. Select glycoprofiling methods that allow reliable measurement of the GCQAs of your candidate drug and that are suitable for your analytical labs. Ensure that your glycoanalysis scheme complies with current regulatory guidelines – e.g. the 2008 Revised Guideline on Monoclonal Antibodies by the EMEA’s Biologics Working Party (BWP). h. Test a range of glycoprotein expression systems that could deliver your target glycosylation profile and select the best ones. Generally, if your target glycosylation is Gly1 then choose an expression system related to the one used for the original drug. This may reduce the possibility of producing a [C-] drug so it may affect profitability. However, if you are after a GlyDiffs pattern then you could use a totally different expression system with possible cost benefits. A bank of cell lines or other expression systems with diverse glycosylation machinery would be invaluable for this exercise. Designing Specific Glycosylation for Biobetter MAbs The following are the first glycosylation features to consider modifying when designing biobetter MAbs. These include changes to the N-glycans in the Cγ2 domain of the Fc region (see Figure 2) as well as modifications to Fab glycans if they exist in the therapeutic. In general, major changes can be achieved by switching cell lines, and smaller changes by modifying cell culture conditions. Note that the modification of one glycosylation feature will generally affect others, so when

glycoengineering the glycosylation should be viewed as a whole, rather than the sum of independent components. Figure 2: The Fc region of an IgG

Figure 2: The Fc region of an IgG showing the two N-glycans in the Cγ2 domain The antibody hinge region and pair of Fab arms are situated above this unit. The Fc glycans stabilise the configuration of the domain in which they sit and can confer functional diversity to the antibody. In particular, different monosaccharide residues on these glycans can alter the conformations of various parts of the peptide backbone that are involved in distinct Fc effector functions of the therapeutic.

showing the two N-glycans in the Cγ2 domain The antibody hinge region and pair of Fab arms are situated above this unit. The Fc glycans stabilise the configuration of the domain in which they sit and can confer functional diversity to the antibody. In particular, different monosaccharide residues on these glycans can alter the conformations of various parts of the peptide backbone that are involved in distinct Fc effector functions of the therapeutic. Design Out Gal-α(1,3)-Gal Gal-α(1,3)-Gal is an undesirable nonhuman disaccharide found on the glycans of some MAbs, particularly those expressed in mouse-derived cell lines. Immune reactions to Gal-α(1,3)-Gal are responsible for tissue rejection in xenotransplantation and the disaccharide has been shown to be directly recognised by NK cells (Lin et al, 2000; Inverardi et al 1997). All humans have IgG antibodies specific to the oligosaccharide Gal-α(1,3)-Gal, which is closely related to substances in the ABO blood group (Galili, 2005). Anti-Gal-α(1,3)-Gal IgE antibodies are found in high levels in some individuals who can show severe hypersensitivity reactions if treated with MAbs containing Gal-α(1,3)-Gal units on their glycans. Such anaphylactic reactions have been found in some patients treated with a form of the anti-cancer drug Cetuximab that was produced in a mouse cell and which contained high levels of Gal-α(1,3)-Gal in

the glycans on Asn-88 of the Fab portion of the antibody heavy chain (Chung et al, 2008). Gal-α(1,3)-Gal can be designed out by switching to a non-mouse cell line, but it is advisable to still check for low level presence of the disaccharide after the switch. Eliminating this disaccharide should give a biobetter with an [S+ ] or [S+ E+] profile. Design Out NeuGc The two main types of sialic acid residues found in MAbs produced in mammalian expression systems are N-acetyl-neuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc). NeuAc is the desired, normal human-type sialylation, while NeuGc is found in non-human glycoproteins and is considered an undesired, aberrant form of sialylation for therapeutic glycoproteins. Human cells are known to lack the enzyme CMP-NeuAc hydroxylase required for the synthesis of NeuGc, so any present will have become incorporated into a therapeutic via cell culture medium or from non-human cell lines producing the MAbs (Furukawa et al, 1988; Bardor et al, 2005). This can result in neutralisation by anti-NeuGC Abs (Nguyen et al, 2005). Controlling the ratio of NeuAc to NeuGc is important for biomanufacturers as (a) NeuGc may reduce drug efficacy through neutralisation by antiNeuGc antibodies found in the serum of some patients and (b) NeuGc is thought to be linked to chronic inflammation in some individuals (Pader-Karavani et al, 2009). NeuGc can be designed out by switching to cell lines that produce just NeuAc and eliminating animal serum from cell culture medium. If sialylation is not important for your MAb, consider using an expression system that lacks sialyltransferases (e.g. plant or yeast). Elimination or reduction of NeuGc should move your drug towards an [E+] or possibly [S+ E+] profile. Design Out Fab Glycosylation Some MAbs have potential N-glycosylation sites in their Fab region which may have full or partial glycan occupancy. These Fab glycans can reduce efficacy by interfering with antigen binding and increase product heterogeneity. In such cases, aim to reduce the Fab glycosylation via cell line switching. Note that for a [Prot0] biobetter you cannot remove glycosylation sites by modifying protein primary structure. Design Out Core Fc Fucosylation ADCC activity of therapeutic IgG1 type Mabs can be greatly increased by reducing the levels of fucosylation (Shields et al, 2002; Shinkawa et al, 2003; Niwa et al, 2005). The mechanism is improved binding to FcγRIIIa of the low fucose MAb glycoforms (Okazaki et al, 2004; Yamane-

Ohnuki et al, 2004). Engineered antibodies with low fucose are now being produced; their improved binding to FcγRIIIa allows them to evade the inhibitory effect on ADCC of plasma IgG (which is fucosylated and binds to FcγRIIIa with lower strength) (Iida et al, 2006; Natsume et al, 2008). Design out core Fc fucosylation of MAbs relying on ADCC by switching to a cell line producing low-fucose complex N-glycans (which now include commercially available galactosyltransferase knockout mammalian cells). This should give you an E+ biobetter. As an alternative, consider a high-titre non-mammalian expression system (e.g. producing oligomannose glycans) that could give you a drug with a C- profile. However, be aware of other effects (e.g. changes to pharmacokinetics). Modify β-Galactosylation Levels If your MAb relies on CDC (complementdependent cytotoxicity) for its mode of action then consider increasing the levels of terminal Gal-β(1,4) residues on the Fc glycans. The positive correlation between CDC activity and galactose has been found in the anti-CD20 antibody Rituximab where C1q binding to the Fc region increases with the percentage of galactosylation (Raju, 2008) and similar effects have been found in other CDC-dependent therapeutic antibodies (Jefferis, 2009; Kanda et al, 2007). Levels of terminal β-galactosylation can be modified by switching mammalian cell lines and changing cell culture conditions including dissolved oxygen (Kunkel et al, 1998). Conclusions The use of glycoengineering to significantly improve the safety and efficacy profiles of existing therapeutic antibodies is now very straightforward. This is due to (a) advances in our knowledge of structure-function relationships between glycosylation and the in vivo bioactivity of antibodies, (b) the availability of new expression systems with useful glycosylation machinery and (c) improvements in glycoprofiling methods. In this article we have explained the advantages to making glycoengineered biobetter antibodies for both follow-on companies and the manufacturers of the original drugs. We have highlighted possible barriers to commercial exploitation of these glycosylation variant biobetters and proposed simple ways to overcome some of these barriers. Finally, we have outlined a strategy for intelligent design of such therapeutics based on the QbD (Quality by Design) paradigm with extensions to cope with the complexity of biopharmaceutical glycosylation. The next few years will see many changes in the commercial and regulatory landscapes for INTERNATIONAL PHARMACEUTICAL INDUSTRY 43

therapeutic antibodies, and we believe that the development of glycovariant biobetters will play a positive part in shaping these for the advantage of both follow-on and originator companies. And most importantly, we look forward to affordable biobetter MAbs becoming available to the patients who need them. . References Arnold JN, Wormald MR, Sim RB, Rudd PM & Dwek RA. (2007) The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu Rev Immunol 25: 2150 Bardor M, Nguyen DH, Diaz S, Varki A. (2005) Mechanism of uptake and incorporation of the non–human sialic acid N-glycolylneuraminic acid into human cells. J Biol Chem 280:4228–37. Beck A, Wagner-Rousset E, Bussat MC, DR. CLAIRE MORGAN, BUSINESS DEVELOPMENT MANAGER AT LUDGER LTD. Claire is responsible for liaising with biopharmaceutical clients prior to setup of glycoprofiling and method development projects, as well as general business development. Claire has a background in Immunology. She gained her PhD at The Royal London Hospital and followed that with post doctoral research positions at the Anthony Nolan Bone Marrow Trust (the Royal Free Hospital, London) then St. Bartholomew’s Hospital, London. Before joining Ludger years Claire was in charge of Marketing and PR for the scientific events company EuroSciCon. DR. DARYL FERNANDES, FOUNDER AND CEO OF LUDGER LTD, OXFORD, UK Daryl has over 25 years’ experience in developing and using glycoanalysis technology. He gained his doctorate at the Glycobiology Institute, University of Oxford in the 1980s, was a consultant on biopharmaceutical glycoprofiling to Monsanto and G.D. Searle, and helped spin out Oxford GlycoSciences (OGS) from the University. He joined OGS as Process Development Manager and then as the Head of Analytical Services. Daryl left OGS to set up Ludger in 1999. Ludger has laboratories at the Culham Science Centre near Oxford, UK and develops technology to measure and control biopharmaceutical glycosylation throughout the drug life-cycle. Daryl’s research interests include the development of graph theoretic systems for analysis of complex glycosylation in biologics and high throughput glycoprofiling methods to support new drug development.


Lokteff M, Klinguer-Hamour C, Haeuw JF, Goetsch L, Wurch T, Van Dorsselaer A, Corvaïa N. (2008) Trends in glycosylation, glycoanalysis and glycoengineering of therapeutic antibodies and Fc-fusion proteins. Curr Pharm Biotechnol. 2008:482-501 Chung CH, Mirakhur B, Chan E, Le Q-T, Berlin J, Morse M, Murphy BA, Satinover SM, Hosen J, Mauro D, Slebos RJ, Zhou Q, Gold D, Hatley, T, Hicklin DJ, and Platts-Mills TAE. (2008) Cetuximab-Induced Anaphylaxis and IgE Specific for Galactose-α-1,3-Galactose. New Eng J Med 358:1109-1117 Fernandes DL. (2009a) ‘A QbD approach to biopharmaceutical glycosylation’ in ‘Quality for Biologics’, edited by Lyscom, N., published by Biopharm Knowledge Publishing Fernandes DL. (2009b) A QbD (Quality by Design) approach to monoclonal antibody glycosylation. Presentation at PDA’s 2nd Monoclonal Antibodies Workshop - QbD: Science To Submission Approaches, Munich, June 2009 Furukawa K, Yamaguchi H, Oettgen HF, Old LJ, Lloyd KO. (1988) Analysis of the expression of N-glycolylneuraminic acid-containing gangliosides in cells and tissues using two human monoclonal antibodies. J Biol Chem 263:18507–12. Galili U. (2005) The alpha-Gal epitope and the anti-Gal antibody in xenotransplantation and in cancer immunotherapy. Immunol Cell Biol 83:674-686 Iida S, Misaka H, Inoue M, Shibata M, Nakano R, Yamane-Ohnuki N, Wakitani M, Yano K, Shitara K and Satoh M. (2006) Nonfucosylated Therapeutic IgG1 Antibody Can Evade the Inhibitory Effect of Serum Immunoglobulin G on Antibody-Dependent Cellular Cytotoxicity through its High Binding to FcγRIIIa. Clin Cancer Res 12:2879-2887 Inverardi L, Clissi B, Stolzer AL, Bender JR, Sandrin MS, Pardi R. (1997) Human natural killer lymphocytes directly recognize evolutionarily conserved oligosaccharide ligands expressed by xenogeneic tissues. Transplantation 63:13181330 Jefferis R. (2009) Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action. Trends Pharmacol Sci 30:356-362 Kanda Y, Yamada T, Mori K, Okazaki A, Inoue M, Kitajima-Miyama K, Kuni-Kamochi R, Nakano R, Yano K, Kakita S, Shitara K, Satoh M. (2007) Comparison of biological activity among nonfucosylated therapeutic IgG1 antibodies with three different N-linked Fc oligosaccharides: the high-mannose, hybrid, and complex types. Glycobiology 17:104-118 Kunkel JP, Jan DC, Jamieson JC, Butler M. (1998) Dissolved oxygen concentration in serum-free continuous culture affects N-linked glycosylation of a monoclonal antibody. J Biotechnol. 62:55-71 Lin SS, Hanaway MJ, Gonzalez-Stawinski

GV, Lau CL, Parker W, Davis RD, Byrne GW, Diamond LE, Logan JS, Platt JL. (2000) The role of anti-Gaλα1–3Gal antibodies in acute vascular rejection and accommodation of xenografts. Transplantation 70:1667-1674 Natsume A, In M, Takamura H, Nakagawa T, Shimizu Y, Kitajima K, Wakitani M, Ohta S, Satoh M, Shitara K and Niwa R. (2008) Engineered Antibodies of IgG1/IgG3 Mixed Isotype with Enhanced Cytotoxic Activities. Cancer Research 68:3863-3872 Nguyen DH, Tangvoranuntakul P, and Varki A. (2005) Effects of Natural Human Antibodies against a Nonhuman Sialic Acid That Metabolically Incorporates into Activated and Malignant Immune Cells. J Immunol 175:228236. Niwa R, Sakurada M, Kobayashi Y, Uehara A, Matsushima K, Ueda R, Nakamura K and Shitara K. (2005) Enhanced Natural Killer Cell Binding and Activation by Low-Fucose IgG1 Antibody Results in Potent Antibody-Dependent Cellular Cytotoxicity Induction at Lower Antigen Density. Clin Cancer Res 11:2327-2336 Okazaki A, Shoji-Hosaka E, Nakamura K, Wakitani M, Uchida K, Kakita S, Tsumoto K, Kumagai I, Shitara K. (2004) Fucose depletion from human IgG1 oligosaccharide enhances binding enthalpy and association rate between IgG1 and FcγRIIIa. J Mol Biol 336:1239–1249 Padler-Karavani V, Yu H, Cao H, Chokhawala H, Karp F, Varki N, Chen X, Varki A. (2008) Diversity in specificity, abundance, and composition of anti-Neu5Gc antibodies in normal humans: potential implications for disease. Glycobiology 18:818-830 Raju TS. (2008) Terminal sugars of Fc glycans influence antibody effector functions of IgGs. Curr Opin Immunol 20:471-478 Shields RL, Lai J, Keck R. (2002) Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fc RIII and antibodydependent cellular toxicity. J Biol Chem 277:26733–26740 Shinkawa T, Nakamura K, Yamane N, ShojiHosaka E, Kanda Y, Sakurada M, Uchida K, Anazawa H, Satoh M, Yamasaki M, Hanai N, and Shitara K. (2003) The Absence of Fucose but Not the Presence of Galactose or Bisecting N-Acetylglucosamine of Human IgG1 Complextype Oligosaccharides Shows the Critical Role of Enhancing Antibody-dependent Cellular Cytotoxicity. J Biol Chem 278:3466-3473 Sommerfeld S and Strube J. (2005) Challenges in Biotechnology Production. Chem Eng Proc 44:1123-1137. Yamane-Ohnuki N, Kinoshita S, InoueUrakubo M, Kusunoki M, Iida S, Nakano R, Wakitani M, Niwa R, Sakurada M, Uchida K, Shitara K, Satoh M. (2004) Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity. Biotechnol Bioeng 87:614–622

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In Vitro Alternatives To Reduce Animal Use And To Decrease Drug Development Costs In preclinical drug development in vitro studies have obtained a more prominent position. Because of ethical considerations an increasing number of in vivo tests have been replaced by in vitro experiments. These tests are recommended by many organisations. The National Institutes of Health (NIH) and other federal agencies are committed to the welfare of research

“The National Institutes of Health (NIH) and other federal agencies are committed to the welfare of research animals. ” animals. These animals are protected by law, regulations and policies to ensure they are used in the smallest possible numbers and with the greatest commitment to their comfort. NOTOX advocates the use of alternatives to animal studies wherever possible. The company strategy incorporates principles based on the three Rs: Replacement of animals with nonanimal systems where possible; Reduction of the number of animals; and Refinement of the experimental procedures so that animals experience less pain and distress, and suffering is minimised. In addition, the use of predictive in vitro assays for drug screening in the discovery phase ultimately leads to more efficient candidate selection and, therefore, less attrition in the clinical phase, saving millions of euros. In vitro species comparison between human and animals yields valuable information for the design of in vivo and clinical studies. With the development of new, sensitive and robust in vitro models, the increasing access to human material and the identification of 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

suitable biomarkers, the number of in vitro alternatives will keep growing. Below is given an overview of current in vitro models that are implemented at NOTOX and that are appropriate alternatives mainly used in drug discovery and development. Hepatic metabolism and liver toxicity Metabolism is an efficient process to remove drugs from the body. With the recent finalisation of the FDA guideline for safety testing of metabolites it has been internationallyrecognisedthatuniquehuman metabolites should be detected as early as possible in the compound development process. In vitro liver models include the use of cDNA recombinant isoenzymes for the different CYP450 metabolic enzymes, human liver microsomes to study phase I metabolism and cryopreserved or fresh human hepatocytes to determine both phase I and phase II metabolism. As stated in the draft FDA guideline for drug interaction studies, in vitro metabolism studies including enzyme identification, CYP inhibition and CYP induction should be explored in the drug development phase. Often, results in these studies can eliminate the performance of later in vivo and/or clinical investigations. In addition, the performance of such in vitro studies is fast, efficient and relatively inexpensive. Metabolic stability and metabolite profiling studies provide useful information about interspecies differences (including human). Identification and structure elucidation of new metabolites has become easier and hence less time consuming with the introduction of accurate mass spectrometers such as the LTQ Orbitrap acquired by NOTOX Q1, 2008. Preclinical programmes can be optimised with the in vitro metabolic information using species with similar metabolite profiles. Furthermore, differences in toxicology between species might be explained by differences in the metabolic pathway. In vitro identification of drug metabolising

enzymes helps in the prediction of potential in vivo drug–drug interactions, the impact of polymorphic enzyme activity on drug disposition and the formation of toxic or active metabolites. If human in vivo data indicate that CYP enzymes contribute >25% of a drug’s total clearance, studies to identify drug metabolising CYP enzymes in vitro should be conducted. CYP characterisation studies are performed at NOTOX by using a tiered approach with (1) cDNA expressed isoenzymes, (2) correlation analysis with individual human liver microsomes and (3) chemical inhibition. In vitro evaluation of CYP inhibition is usually studied using human liver microsomes. The inhibition of a specific CYP enzyme can modify the plasma concentration of a co-administered drug, which is a substrate of this enzyme, and consequently its pharmacological or toxic effect. In vitro studies can help to prioritise

“The inhibition of a specific CYP enzyme can modify the plasma concentration of a co-administered drug, which is a substrate of this enzyme, and consequently its pharmacological or toxic effect. ” in vivo drug–drug interaction evaluations. In vitro CYP induction studies using freshly plated human hepatocytes provide valuable data for clinical trial design when co-medication with drugs that are prone to metabolism is expected. When the investigational drug does not induce




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metabolism, no further in vivo studies are needed, thereby reducing the number of laboratory animals. A second field in which in vitro hepatic models are currently explored is human hepatotoxicity. During the past years druginduced liver toxicity has been one of the

“The National Institutes of Health (NIH) and other federal agencies are committed to the welfare of research animals. ” main reasons for drug withdrawal from the market. Consequently, an EMEA draft guideline recommending nonclinical testing of drug-induced hepatotoxicity has recently been published. However, physiological differences between human and animal species limit a correct prediction from in vivo results to the human outcome. Currently, metabolically-active in vitro liver models such as hepatocytes are used to investigate cell toxicity and adaptive cell responses that might predict clinical hepatotoxicity, but the development of new innovative assays is expected in the near future.

Dermal absorption and skin toxicity Topical drug administration is increasingly used as a suitable alternative to conventional intravenous or oral administration. Potential advantages include the possibility of local application, less side effects, avoidance of hepatic first-pass effects and easiness of use. In vitro dermal drug absorption and/or penetration studies using human skin are used to predict the bioavailability in clinical settings. At NOTOX a flow-through system has been implemented, which has proven to be very suitable for the determination of skin absorption in order to compare different compounds, various formulations or even different species. After the collection of different fractions over a time period of at least 20 hours, permeability constants are calculated and absorption in the skin can be determined. Analysis techniques include liquid scintillation counting and liquid chromatography coupled to mass spectrometry. Flow-through systems have the advantage that they can also be used for skin metabolism studies. As metabolite concentrations are generally low in skin, accurate mass techniques such as the LTQ Orbitrap are necessary to increase detection sensitivity and facilitate structure elucidation. Completion of the general ADME studies with both skin studies optimises the selection of lead compounds intended for dermal use. Furthermore,

the combination of in vitro and in vivo dermal absorption and metabolism data contributes to the best clinical trial design for topically applied drugs. Until 2002 the evaluation of skin toxicity required the use of laboratory animals, in which the test substance was applied to the skin of healthy albino rabbits. Recently, alternatives in vitro methods have been developed. Many of these alternatives are currently accepted by federal regulatory agencies. NOTOX implemented in vitro tissue culture models of the human epidermis that provide a way in which the corrosive and irritation potential of chemical and physical stress can be assessed. Chemical and physical agents are applied

“The inhibition of a specific CYP enzyme can modify the plasma concentration of a co-administered drug, which is a substrate of this enzyme, and consequently its pharmacological or toxic effect. ” to and interact with three-dimensional multilayered in vitro tissues that closely approximate those of skin, both in terms of structure and properties. The major cause of irritant contact dermatitis is damage to the skin, specifically to the keratinocytes, which finally results in cytotoxicity. This cytotoxicity can be measured. Skin irritation is defined as the production of reversible damage to the skin, whereas skin corrosion is defined as the production of irreversible damage to the skin, namely, visible necrosis through the epidermis and into the dermis. Positive results in the in vitro skin testing usually eliminate the need for animal testing, and when further testing is necessary the number of animals will be reduced. Oral absorption Absorption by the intestinal epithelium is important for the oral bioavailability of a drug. Interactions of drugs with transporters can account for differences between drugs regarding bioavailability, toxicity, efficacy and excretion. Transporters can also be involved in drug interactions as recognised by the FDA in the draft guideline for drug interaction studies.

P-glycoprotein (P-gp) is the most abundant transporter protein in intestinal cells. There are several epithelial cell systems to study in vitro intestinal transport that have high P-gp expression. The Caco-2 cell line is a frequently-used human-derived cell line. At NOTOX a bi-directional transport assay using Caco-2 polarised monolayer cells has been validated. By measuring drug efflux, a drug can be defined as a substrate or inhibitor of the P-gp efflux transporter. If the investigational drug is a poor or non P-gp substrate, in vivo studies are not warranted. No inhibition or an IC50 that is at least 10 times higher than the maximal anticipated plasma concentration in human excludes the need of in vivo studies. Eye irritation The eye can be exposed to several products, and evaluation of eye irritation potential is, therefore, essential. The conventional test for the irritant and corrosive potential is the rabbit eye test which has become the international standard assay for acute ocular toxicity. In the interest of sound science and animal welfare, a sequential testing strategy is recommended to minimise the need of in vivo testing. While it is not considered valid as a complete replacement for the in vivo rabbit eye test, the Bovine Corneal Opacity and Permeability (BCOP) assay is recommended for use as part of a tiered-testing strategy for regulatory classification and labeling within

“The eye can be exposed to several products, and evaluation of eye irritation potential is, therefore, essential. ” a specific applicability domain. Substances (including formulations) can be classified as ocular corrosives or severe irritants without further testing in rabbits. In the BCOP assay, test substances are applied onto the epithelial surface of isolated corneas, which are obtained from cattle that have been slaughtered for the food industry or for other non-laboratory purposes. Toxic effects on the cornea are measured by decreased light transmission (opacity) and increased passage of sodium fluorescein dye (permeability). The opacity and permeability assessments of the cornea following exposure to a test substance are combined to derive an In Vitro Irritancy Score (IVIS), which is used to classify the irritancy level of the test substance. A second proposed in vitro eye irritation test is the Hen’s Egg Test on the Chorioallantoic Membrane (HET-CAM) assay.

Fertilised hen’s eggs are incubated under optimised conditions. Until day 10.5 of the incubation period a chicken embryo is not considered to be an animal. On day 9, the day on which the HET-CAM will be performed, the embryonic differentiation of the chicken’s central nervous system is sufficiently incomplete and suffering due to pain perception is unlikely to occur. In the HET-CAM assay the CAM is exposed to the test substance and after exposure evaluated for three important components that are predictive for conjunctival injury of the eye: haemorrhage, vessel lysis and coagulation. Although the HET-CAM test method is not yet validated, the EU national regulatory authorities accept positive outcomes of this test method for classification and labelling of severe eye irritants without further testing in rabbits. Cardiac safety A valuable study in cardiac safety testing (and recommended in the ICH S7B guideline) is the hERG study, in which the effect of a compound on the hERG or IKr potassium channel is determined in vitro. Most drugs that prolong QT interval and cause torsades de pointes inhibit the hERG channel in studies, making this in vitro study a very attractive approach for screening purposes. This has led to the development of various automated systems, although manual patchclamp techniques, as used at NOTOX, cannot yet be equalled. However, one controversial issue is that many drugs that cause hERG inhibition do not cause torsades de pointes (many false positives). Hence, the predictability of this

but also in vivo cardiac safety studies is still under debate. On the other hand, a better alternative is not yet available making this assay the current best in vitro option and, therefore, an important component of cardiac safety programmes. Conclusion Many in vitro alternatives for in vivo safety studies have been developed. It is expected that in the near future more alternative tests will become available and, importantly, recommended by regulatory authorities. The addition of alternative studies to the conventional preclinical package yields a more complete overview for optimising the selection of lead compounds. In addition, in vitro combined with in vivo data are of great value in the design of clinical trials with new pharmaceuticals. New developments in the field of in vitro toxicology are constantly monitored at NOTOX, contributing to the continuous development and integration of new tests into the programmes.

IDA A.J. VERBAAN-GIEBELEN obtained her Masters degree in Medical Biology from the Free University of Amsterdam in 1999. She has worked as a research technician at Organon NV and received her Ph.D. from the Centre for Experimental and Molecular Medicine at the Academic Medical Centre in Amsterdam. She joined NOTOX B.V. in 2008 as Study Director Genetic and In Vitro Toxicology. Email: INTERNATIONAL PHARMACEUTICAL INDUSTRY 51

High-Throughput Antioxidant Determination – the ORAC Assay performed on Multidetection Microplate Readers Introduction Antioxidants, present in fruits, vegetables and whole grains, act as free radical scavengers and thus are thought to protect living cells from being damaged by reactive oxygen species (ROS). In all biological cells, metabolism and oxidative stress generate several intermediates and by-products that are collectively known as ROS. They are necessary intermediates in the human body, but ROS are also thought to be involved in ageing and in the development of many degenerative diseases, including cancer, heart disease, Alzheimer’s and Parkinson’s. Further, ROS can be generated from exposure to other external sources such as cigarette smoke, radiation, pollutants, chemicals and environmental toxins. ROS are dangerous to cellular structures and functional molecules (i.e. DNA, proteins, and lipids) as they act as strong oxidising agents or free radicals. It is known that biological antioxidants are able to dispose of ROS; however, they are not completely effective in eliminating all of the free radicals, oxygen ions and peroxides which damage the body. Although it is a fact that carotenoids, flavonoids, and vitamins present common classes of antioxidants, it is often difficult to decipher the antioxidant capacity of an unknown compound. In this article we present the ORAC assay as a tool to measure antioxidant capacity in fruit juices in a high-throughput microplate format. One standardised method for determining the antioxidant capacity of a compound is the ORAC (Oxygen Radical Absorbance Capacity) assay (1). The ORAC assay is based upon the inhibition of the peroxylradical-induced oxidation initiated by thermal decomposition of azocompounds such as [2,2’-azobis(2methylpropionamidine) dihydrochloride (AAPH)]. Here, we describe the application of the ORAC assay on a POLARstar Omega and PHERAstar FS (Fig. 1) using Trolox® (a water soluble analogue of vitamin E) as a standard reference substance. Different commercially available fruit juices were tested for their capacity to inhibit the generation of ROS. 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Assay Principle Over time ROS, generated from the thermal decomposition of AAPH, will quench the signal from the fluorescent probe fluorescein. The subsequent addition of an antioxidant compound produces a more long-lived and stable fluorescence signal, and the signal stability then depends on the antioxidant’s capacity. Data points are collected and then compared to the standard reference compound, Trolox®. The antioxidant capacity of a fruit juice is expressed as micromoles of Trolox® equivalents (TE per gram or per millilitre of sample (μmole of TE/g or μmole of TE/ mL). Materials and Methods Black 96-well and 384-well plates were obtained from Greiner Bio-One (#655076 and #781076). Fluorescein sodium, 6hydroxy-2,5,7,8-tetra-methylchroman-2carboxylic acid (Trolox®), L (+)-ascorbic acid, Epicatechin gallate, [2,2’-azobis(2-methylpropionamidine) dihydrochloride (AAPH)], were obtained from Sigma-Aldrich. Eight different fruit juices were obtained from a local grocery store. All juices were indicated to contain 100 % fruit juice except for the peach and pear juice. They were labelled to contain 50 % of the respective fruit. Plate sealers were used from BMG LABTECH UK, Aylesbury, UK, cat. no. 77400-05, and the following instruments were used to conduct the ORAC assay: POLARstar Omega and PHERAstar FS multidetection plate readers, and THERMOstar microplate incubator. All instruments were from BMG LABTECH, Offenburg, Germany. Test Protocol Different dilutions of Trolox® (12.5 μM to 200 μM) and fruit juices were prepared in phosphate buffer (10 mM, pH 7.4). All solutions should be fresh and thus prepared just prior to performing the assay. In every working well of a 96-well plate the following was pipetted in triplicate. For a 384-well plate half of the volumes were used: 150 μL of a 10 nM Fluorescein solution (all wells)

+25 μL Trolox® dilution (standards) +25 μL sample dilution (samples) +25 μL phosphate buffer (blank) The microplates were sealed followed by incubation for 30 min at 37°C in a THERMOstar microplate incubator. Alternatively, incubation can also be performed in the microplate reader. Following incubation, fluorescence measurements (ex. 485 nm, em. 520 nm) were taken every 90 seconds to determine the background signal. After 3 cycles, 25 μL of 240 mM AAPH was injected using the onboard injectors. Alternatively, AAPH can also be added manually with a multichannel-pipette. This has to be done as quickly as possible since the kinetic reaction of the ROS-generator starts immediately after the addition of AAPH. The test was resumed and fluorescence intensity measurements were taken up to 120 minutes. Results and Discussion Fruit juices themselves can quench the fluorescence signal at high concentration. Figure 2 shows that non-diluted blueberry juice quenches the fluorescence signal below 10 % of the expected value, whereas diluted juice leads to nearly no quenching. The degree of quenching varies between the different fruit juices and thus must be taken into account for evaluating the ORAC results. Thus for the ORAC assay make sure to use a concentration of a compound which itself does not quench the fluorescent signal. Figure 3 shows the decrease of the fluorescence signal of fluorescein over time after addition of the ROS generator, AAPH. The area under the signal curve depends on the concentration of the antioxidant standard substance (Fig. 3). The area under the curve of the samples is used to calculate the Trolox® equivalents. In case of quenching ingredients that may still be active even in high dilutions, all signal curves should be normalised. This can be easily done with the Microplate Analysis and Reduction (MARS) software using the “Curve Scaling” feature. Applying Curve Scaling will allow for optimal calculation of the area under the curve. The Trolox®

standard curve then allows back-calculating the TE (Trolox Equivalents) of the samples. In Table 1 a summary of all tested fruit juices is given. Results show that sallow thorn and blueberry juices show the highest ORAC values. This is a very interesting result. However, it must be noted that juices may differ from manufacturer to manufacturer and thus the values should be interpreted with caution. Conclusion It was shown that the ORAC assay can be easily performed on the POLARstar Omega and the PHERAstar FS using the onboard reagent injectors. The results obtained in both plate formats, 96-well and 384-well, are similar. Further downscaling of the total

volume to increase throughput is possible in combination with the PHERAstar FS. The MARS data analysis software comes with every Omega and PHERAstar reader and allows automated evaluation. Predefined templates in combination with the curve scaling feature in MARS provide ORAC results quickly and easily. References: 1. Cao, G., Alessio, H. M., Cutler, R. G. (1993) Oxygen-radical absorbance capacity assay for antioxidants. Free Radical Biol. Med. 14, 303311. 2. Glazer, A. N. (1990) Phycoerythrin Fluorescence-Based Assay for Reactive Oxygen Species. Methods Enzymol. 186, 161-168.

Figure 1: Multidetection microplate readers POLARstar Omega and PHERAstar FS, both from BMG LABTECH.

Figure 2: Normalised fluorescence values of 10 nM fluorescein (prepared in phosphate buffered saline) in presence of blueberry and pomegranate juice (for different dilutions). Note that the actual concentration of the non-diluted juices in a well was 15%.

Figure 3: Signal curves for different Trolox® concentrations (red graphs) and a blank without Trolox® (blue graph) recorded on the PHERAstar FS in 384-well format. The curves were normalised to 100 %. The 100 % value is the maximum value that is obtained directly after injection of AAPH.

DR. FRANKA GANSKE developed enzymatic assays in ionic liquids at the Institute for Chemistry and Biochemistry and completed her Ph.D. degree in Biotechnology at the University of Greifswald (Germany) in 2005. Dr. Ganske is currently employed as an Applications Specialist at the microplate reader manufacturer BMG LABTECH GmbH in Germany. Email: Franka.Ganske@bmglabtech. com DR. MARJAN ORBAN developed biosensors at the Institute for Chemical and Biochemical Sensor Research (ICB) and completed his Ph.D. degree in Analytical Chemistry at the University of Muenster (Germany) in 1999. He worked as a Research Associate and as a lecturer at the Hong Kong University of Science & Technology and has earned an executive MBA degree at the Schiller International University in Strasbourg (France) in 2007. Dr. Orban is currently employed as International Sales & Marketing Manager at BMG LABTECH in Offenburg (Germany) DR. FEJTL received his PhD in Neuroscience from the Univ. of Vienna in 1989. He then worked as Application Specialist and subsequently CSO in multi-electrode array and automated patchclamp recording. In 2007 he joined BMG LABTECH as Intern. Sales & Marketing Specialist. Dr. Fejtl brings in more than 13 years experience working in the pharmaceutical and biotech sector. Email:

Table 1: ORAC values in μmol TE/mL of non-diluted fruit juices. The assay was measured on the POLARstar Omega and PHERAstar FS in 96-well and 384-well format. The data shows an average of three independent measurements. INTERNATIONAL PHARMACEUTICAL INDUSTRY 53

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Leveraging Today’s Technology for Clinical Trial Imaging Over the last decade, medical imaging has been playing a greater role in the diagnosis of disease and, logically, there has been an analogous increase in the use of imaging in all phases of clinical trials to evaluate new drug candidates. In most cases, the images taken during each patient visit during the study need to be sent to a Centralised Core Lab, which specialises in image review and analysis. The conventional method of transporting compact discs (CDs) with diagnostic image scans (including radiographs, magnetic resonance imaging (MRI), computerised axial tomography (CAT) and ultrasounds), even over short distances, is an expensive, opaque and environmentally unfriendly process. Leveraging telecommunication tools for file transfer and integrating imaging with electronic data capture (EDC) has the potential to transform the manner in which imaging is used in clinical trials. New tools are now available that make this integration a reality and could provide better transparency for sponsors, improve data quality, reduce costs, give more deidentification options, and even reduce a firm’s carbon footprint.

“Leveraging telecommunication tools for file transfer and integrating imaging with electronic data capture (EDC) has the potential to transform the manner in which imaging is used in clinical trials. ” The primary method used today to transmit diagnostic image scans is to physically ship the scans to central labs for review. This process has been identified for years as costly and inefficient by clinical trial sponsors. Previous attempts at electronic transport used ineffective 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

technologies such as File Transfer Protocol (FTP) or Hypertext Transfer Protocol Secure (HTTPS), which are simply file transfer processes that do not provide the workflow, redundancy, persistence and reliability necessary to allow for the fast submission of de-identified image exams as is needed in clinical research. In fact, no method in use today that runs exclusively over the open, unmanaged internet can achieve the reliability and efficiency needed in a global clinical trial. The point-to-point limitation of FTP and the Digital Imaging and Communications in Medicine (DICOM) standard, and their inability to achieve redundant and persistent connections over wide area networks, requires users to closely monitor and facilitate these lengthy transactions. While most people think of these technologies as “free”, this perception comes at a high cost. If the service is unmanaged, the management, in practical terms, is simply shifted to the individual users. Given the nature of investigator sites and the burden that’s already imposed on their staff, sites have been reluctant to adopt these “free” and unreliable solutions, which do not provide robust support at the technical and customer care levels. These electronic file transfer protocols can be particularly untrustworthy in global studies that have sites in locales with poor public internet infrastructure. If the internet connection drops, the entire file transfer process has to be initiated from start and cannot be resumed mid-transfer. Relying on the traditional standard courier service also has severe limitations. Burning clinical trial images onto a compact disc (CD) after patient visits and then physically mailing the CD to a central reviewer — typically a core laboratory — for analysis is an expensive, timeconsuming process that stresses clinical trial productivity. This labour-intensive process is also impeded when images need to be quickly transported to an international locale — all but eliminating the possibility of conducting global adaptive and eligibility trials that require fast turnaround and better control of subject data. It is easy to conclude that clinical trial sponsors need a way to transport patient images more quickly and efficiently for less

cost and with real-time capability to track and manage the images. Driving the Need for a New Solution Over the last decade, there has been a greater reliance on medical imaging in diagnosing disease, which in turn has spurred an increase in the use of imaging to evaluate new drug candidates.

“Over the last decade, there has been a greater reliance on medical imaging in diagnosing disease, which in turn has spurred an increase in the use of imaging to evaluate new drug candidates. ” Imaging can be effectively used to make drug development “go/no-go decisions” regarding the potential efficacy of a drug, so as to end or continue projects before they become too costly. Additionally, there has been an increased use of imaging as surrogate markers — that is, a biomarker that is a substitute for the actual clinical end result (often used when the actual end result would be undesirable, such as the death of a patient). Oncology, neurology and cardiovascular trials, in particular, benefit from the use of imaging. Positron emission tomography (PET) scans, for example, are used to detect whether a cancer has spread, which can help determine the effectiveness of a therapy or drug. And various imaging techniques can provide insight into the vascular system and the hardening of arteries, and identify blockages that are key to uncovering therapies for cardiovascular issues. The success of imaging in diagnosing diseases and therapy has only accelerated its use in clinical research and uncovered novel applications for the technology — imaging is already being used for such

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vital clinical activities as patient selection, optimisation of dose and schedule, and safety assessments. Trial Efficiency and Harmonising Image and Clinical Data With the increased use of imaging in clinical research, the challenges associated with traditional image transfer methods have also been exacerbated, namely, the costs associated with managing and reconciling images, and trial efficiency. It is expensive for sponsors to pay a courier service to transport images burned on a CD, and this can also negatively impact trial efficiency, mainly because of time delays and the fact that the sponsor has little insight into the location of the image, or its quality, until after the results are sent back in a report. Manually matching or reconciling image results back to the remainder of the clinical data is a laborious process that can significantly delay final analysis and data review. The reconciliation effort is a necessary step in the process, as images sent out for review must be de-identified from any subject reference to meet regulatory standards. Study personnel have to remove specific identifiers (up to 18 in all) from the image file before it can be shipped, in order to anonymise the image. Once the de-identified image has been analysed, the sponsor has to manually link the image results back to the clinical trial data. Before the image can be “re-identified” it must be extracted from either the CD or a file system and then imported into the trial repository. Because the clinical data and the imaging data are being transferred separately and require human intervention to synchronise the data, the process is opaque and often rife with error. The combination of all of these factors — increased use of imaging, inefficient and opaque processes with high costs — has been driving the need to replace the traditional methods for capturing and transferring images. The Future is Now As so often happens, it takes a novel approach to a problem to find the appropriate solution. In terms of diagnostic image transfer, it was the realisation that moving diagnostic image scans over long distances is really a telecommunications challenge and not a file transfer issue. A telecommunications-based solution with significant control over the infrastructure and bandwidth available for transfers, coupled with advanced workflow capabilities and technology to overcome local firewall constraints, can be an effective way to conduct these complex data transfers. Boston-based AG Mednet has developed just such a fully-managed


telecommunications solution. In contrast to standard courier services and FTP/HTTPS applications, the AG Mednet solution allows trial managers to receive images directly into their repositories, receive form data directly into their subject trackers without having to do data re-entry, and easily track the state of image submissions from every investigator site.

“Study personnel have to remove specific identifiers (up to 18 in all) from the image file before it can be shipped, in order to anonymise the image.” It is in use by Phase I, II and III clinical trials across therapeutic areas that include oncology, cardiovascular, neurology and respiratory. The rate of adoption by investigator sites is accelerating as more and more sponsors, sites, trial managers, imaging core labs and clinical research organisations realise that the value of this methodology is not just in the important cost reduction in transport. Just as critical to the trial is the new-found ability to reduce submission errors caused by non-validated pen-and-paper based forms, lack of proper de-identification, inability of sponsors and imaging core labs to extract images from CD, and, most importantly, the reduction in site queries. While this telecommunications approach solves many of the issues associated with physically (or electronically) transferring the actual images, it is the integration of a highly available image transfer network with a robust EDC system that provides sponsors the ability to fully synchronise the trial’s clinical and imaging data. This combination gives the sponsor insight into when images are shipped, tracked and received, improving the reconciliation process and leading to quicker database lock. AG Mednet has teamed up with Phase Forward, a leading provider of data management solutions for clinical trials and drug safety, to bring sponsors this integrated solution. AG Mednet’s image transfer platform queries Phase Forward’s InForm™ EDC system each time an investigator begins to process the scans, and provides him with well-defined options for completing deidentification and eCRF tasks. Once the data is submitted, the imaging network reports back to the EDC system, which in turn can update the status of image

submissions on its repository. This integration is presently being deployed as part of two clinical trials — oncology and cardiovascular technology assessments (TAs) — and should have a positive impact on the reconciliation tasks required to close a trial’s database. The process of mapping patient and image ID should be vastly streamlined; images cannot be sent without required information; and sponsors will be able to see when an image was shipped and received. The advent of AG Mednet’s managed network dedicated to the acquisition and transfer of imaging data, coupled with Phase Forward’s InForm EDC solution could transform the way in which imaging is utilised in clinical research.

ABRAHAM GUTMAN PRESIDENT AND CEO – AG MEDNET Abraham has had a long career in technology m a n a g e m e n t worldwide. Prior to founding AG Mednet in 2005, he founded Emperative, Inc., a telecommunications software startup of which he was the President and CEO. Mr. Gutman has a Bachelor of Arts degree in Computer Science from Cornell University and a Masters in Computer Science degree from Yale University. He is the inventor on US Patent 6449355 for the Method and system for providing assistance to users of a service, and has a number of Patents Pending related to both the technology and business processes associated with the exchange of diagnostic image studies across long distances between unrelated hospital and research entities. Mr. Gutman is a member of the Board of Trustees at Facing History And Ourselves, as well as the Community Advisory Board at WGBH. ROBERT QUINN – HEAD OF SOLUTIONS MARKETING, PHASE FORWARD For the last four years, Mr. Quinn has been in charge of managing all aspects of product launches for Phase Forward’s clinical data management and safety solutions, including product positioning and customer research. Prior to Phase Forward, Mr. Quinn worked for The MathWorks, Parametric Technology and Raytheon providing enterprise process improvement solutions to scientific and engineering professionals. He started his career as a design and project manager/engineer building missile systems for the United States military. Mr. Quinn holds a B.S. degree in mechanical engineering.

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Company Profile

Woodley Equipment

Woodley Equipment was founded in 1989 and 20 years later is one of the most respected medical equipment suppliers to the pharmaceutical industry across the globe. Specialising in equipment solutions, Woodley have successfully developed efficient and cost effective ways of providing equipment for clinical trials. October 2009 marks the 20th anniversary of Woodley Equipment Since January 2000, Woodley has operated out of offices and three large warehouses in the North West of England. In addition, they also have logistics bases in New Jersey and Pennsylvania, USA to streamline their operations in the Americas. Woodley Equipment opened its own inhouse Service Department in 2003 which is staffed by highly trained technical Service Engineers and Chartered Biomedical Scientists; The Service Department specialises in a wide range of infusion systems, centrifuges and ECG machines and is now used to service, calibrate and repair all their own medical and laboratory equipment. This affords Woodley the unique position of being able to provide full on-going support for the wide variety of equipment it supplies. The ISO 9001:2000 status was awarded to Woodley Equipment in 2004, recognising the quality of their administrative


and management systems. Through many years of experience being one of the leading medical equipment suppliers across the globe, Woodley have developed a quick and efficient service based on the specific requirements of their customers. This service can range from rental, purchase or fully tailored equipment management solutions. They provide an efficient, cost effective service to customers at all times. They have worked with many of the top Pharma companies, CRO’s, central laboratory’s and biotechnology companies on some of the largest studies across the globe. Providing a wide variety of equipment from centrifuges and ECG machines to blood pressure monitors and refrigeration equipment, and with rental periods from one month to several years, Woodley can provide any equipment and service tailored to your individual requirements. Woodley understand the urgency in the need to supply medical equipment at the last minute and for this reason, they hold stock of many products ready for next day delivery to mainland UK sites and 1 - 3 day international delivery. They offer a worldwide service and so contribute simplicity and continuity to your study by the use of one centralised supplier. With more and more studies now expanding across the globe, Woodley can effectively organise all your

equipment across all study sites. Ensuring all equipment arrives in the right place at the right time. Woodley Equipment are able to offer • Rental or purchase • No minimum hire period* • No deposits* • Exceptional service • 20 years experience in the industry • Experience of bringing simplicity to the most complicated clinical trials • Worldwide delivery • Plethora of clients from the largest clinical trial companies across the world *Except large orders Whilst they specialise in providing medical and laboratory equipment for hire, purchase and equipment management options are also available for all their ranges of equipment. Woodley can source and supply any equipment for your clinical trial, no matter how diverse. Woodley are now looking forward to the next 20 years in clinical trials and hoping to further relationships with existing customers and expand their customer base. If you are interested in finding out more about the equipment solutions Woodley Equipment have to offer, feel free to contact us at

Cardiac And Cardiovascular Safety Assessment: A Central Component of Drug Development Introduction Contemporary lifecycle drug development encompasses in silico computer simulation modelling of drug molecule binding to both target and off-target receptors, nonclinical investigation, pre-approval clinical studies, and post-marketing surveillance.1

“Since cardiac and cardiovascular adverse drug reactions are serious and potentially lethal, their lifecycle assessment is critical.2 While assessment in all of these four phases is important, this paper focuses on registration studies. ” Since cardiac and cardiovascular adverse drug reactions are serious and potentially lethal, their lifecycle assessment is critical.2 While assessment in all of these four phases is important, this paper focuses on registration studies. It starts by discussing the investigation of an investigational drug’s liability to prolong the QT interval of the surface electrocardiogram (ECG), a topic addressed in the 2005 ICH Guidance E143 and later “Question and Answer” documents.4-6 It then discusses assessment of a broader range of cardiac and cardiovascular parameters during pre-approval trials of new medications for Type 2 diabetes mellitus, as outlined in a December 2008 FDA guidance.7 Finally, the technique of echocardiography and 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

its ability to evaluate another broad range of cardiac and cardiovascular events of interest is considered. Rationale for the Assessment of QT/ QTc Liability The QT interval on the ECG is the distance (measured in the time domain in milliseconds) from the onset of the QRS complex to the offset of the T-wave. It encompasses both cardiac depolarisation and repolarisation. Delayed repolarisation is indicated by QT/QTc prolongation (QTc represents QT ‘corrected’ for heart rate). Delayed repolarisation is of clinical and regulatory concern since it is associated with Torsades de Pointes, a potentially fatal form of ventricular arrhythmia. • Torsades de pointes is associated with both inherited QT prolongation (long QT syndrome) and drug-induced QT prolongation. Several high-profile marketing withdrawals raised awareness of this occurrence. For example, terodiline, used for urinary incontinence, was removed from the market in the United Kingdom and the United States in 1991 following reports of cardiac arrhythmia, QT/QTc prolongation, Torsades de Pointes, and 14 deaths. Terfenadine, an antihistamine, was removed from the market in the United States in 1998 following reports of hepatic damage, QT/QTc prolongation, Torsades de Pointes, and 17 deaths.8 While these conditions can have a considerable impact on quality of life, the benefit-risk profile of symptom relief versus risk of death (admittedly very low but still finite) was regarded as unacceptable. As a result of these and other cases, regulators in various countries set up working groups, produced Concept Papers, and sparked the initiation of the ICH process, resulting in the issuance of ICH E14 in 2005. (ICH Guideline S7B, addressing the nonclinical investigation of proarrhythmia, was also released at this time.9) ICH E14 was adopted by the

European Medicines Agency and the FDA in 2005 and by Health Canada in 2006. This guidance details the Thorough QT/ QTc (TQT) study, a clinical trial devoted to the meticulous assessment of the QT/QTc prolongation liability of an investigational drug. The ICH E14 Thorough QT/QTc Trial The TQT study is reviewed briefly here: readers are referred to Turner10 and Beasley et al.11 for more detail. The TQT study employs healthy adults and is conducted in residential medical centres or clinical pharmacology units. The test drug’s pharmacokinetics determine whether a crossover or parallel group study design is more appropriate. A crossover study is considered the preferred choice unless the drug requires a long period to reach steady state, has a long half-life (making long washout periods between treatments necessary), or has late-

“Delayed repolarisation is of clinical and regulatory concern since it is associated with Torsades de Pointes, a potentially fatal form of ventricular arrhythmia. ” appearing metabolites. Four treatment arms are included: • The proposed therapeutic dose of the study drug; • A supratherapeutic dose of the study drug. This dose, which is several multiples of the proposed therapeutic dose, is intended to mimic the greater concentrations that

might occur in patients with compromised metabolism or excretion and/or taking other medications; • A placebo; • A positive control that is known to increase the QT/QTc interval. This arm assesses (and hopefully establishes) assay sensitivity by showing that the study can indeed detect a QT prolongation that is present. For each subject in each of the first three treatment arms listed, ECGs are captured in triplicate at various timepoints, with perhaps three timepoints falling before drug administration (to establish baseline values) and about nine falling post-administration. Several timepoints will occur at and around the drug’s known Tmax, and a 24-hour post-administration timepoint will typically be included. For the positive control arm, which typically uses the antibacterial agent moxifloxacin, baseline and several timepoints around its well-known Tmax are used. Mean differences for QTc prolongation (adjusted for baseline) between each of the three active treatment arms and placebo are calculated for each timepoint. Assay sensitivity is assessed by placing the lower bound of a one-sided 95% confidence interval (CI) on the mean difference point estimate for each measurement time. Compelling statistical evidence of assay sensitivity is provided if

the lower bound for any of the measurement times is greater than 5 msec. Once assay sensitivity is established, attention turns to the therapeutic and supratherapeutic doses of the test drug. For each dose, the upper bound of a one-sided 95% CI is placed on the mean difference point estimate for each measurement time. Compelling statistical evidence that the drug’s propensity to prolong the QTc interval does not exceed the ‘regulatory threshold of concern’ is provided if none of the upper bounds exceed 10 msec. Cardiovascular Safety Assessments for New Diabetes Drugs While evaluation of proarrhythmic liability remains very important, the December 2008 FDA Guidance for Industry entitled Diabetes Mellitus—Evaluation of Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes7 exemplifies current regulatory interest in a much wider range of cardiac and cardiovascular events during the development of new drugs for Type 2 diabetes. Events of concern include (but are not limited to) the clinical endpoints of myocardial infarction, stroke, acute coronary syndrome, cardiovascular mortality, and urgent revascularisation procedures. • During an investigational drug’s pre-approval development program, a Sponsor will conduct many trials. In each

trial, the number of adverse cardiac and cardiovascular events will be compared between the test drug and the comparator drug via the calculation of an estimated risk ratio, using the number of events for the test drug as the numerator and the number of events for the comparator drug as the denominator. A relative risk greater than 1.00 therefore indicates a greater number of events observed for the test drug. To obtain the best overall estimate of this relative risk using all available data from the drug’s development program, a metaanalysis is to be conducted. This analytical strategy results in an overall point estimate of the relative risk. Confidence intervals can be placed around this point estimate, and the guidance states that the threshold of regulatory concern in this setting is an upper bound of a two-sided 95% CI of 1.8. If the upper bound exceeds this value, the drug is considered to have an unacceptable risk. Doppler Echocardiography The employment of Doppler echocardiography provides another example of the broader range of cardiac and cardiovascular safety parameters that can be meaningfully evaluated. Consider the paradox that has arisen due to the fact that pharmacotherapy (sometimes in conjunction with surgery and/or radiation therapy) has proved very successful in the

treatment of many cancers, and patients live for considerable periods of time following their treatment. This is excellent news. However, since some treatments are cardiotoxic, cardiac/cardiovascular disease can be experienced by some patients years after the cessation of their treatment. Anthracyclines, for example, can produce myocardial damage by direct damage to subcellular systems within cardiac myocytes. Cardiovascular manifestations of cancer chemotherapy can include heart failure, cardiomyopathy, arterial hypotension and hypertension, myocarditis, and thromboembolism. Doppler echocardiography is a very useful noninvasive methodology that allows the identification of several forms of cardiac/ cardiovascular complications, including left ventricular dysfunction, valvular heart disease, pericarditis and pericardial effusion, and carotid artery lesions. • Strengths of echocardiography include that it is noninvasive, it is widely available, and it can be conducted by all sonographers. However, when multicentre trials are being conducted, use of a central echocardiography lab can be a very good strategy, a statement that is also true for core ECG labs. Concluding Comments This paper has provided a sample of cardiac

and cardiovascular safety assessments during contemporary drug development. While evaluation of QT prolongation/ proarrhythmic liability remains a cornerstone of cardiac and cardiovascular safety assessment, and also provides an instructive model for other evaluations, a broader range of events continues to garner attention. The establishment of regulatory thresholds of concern and the use of appropriate statistical methodology is a beneficial approach to excluding unacceptable cardiac and cardiovascular risk. However, it must ultimately be remembered that ‘unacceptable risk’ is beneficially evaluated in the context of the expected therapeutic benefit of the drug, the severity of the indication for which it is being developed, the availability (or not) of other drugs for this indication, and the safety and efficacy profiles of any other available drugs for the condition of concern. References 1. Turner JR, 2007, New Drug Development: Design, Methodology, and Analysis. Hoboken, NJ: John Wiley & Sons. 2. Turner JR, 2009, Drug safety, medication safety, patient safety: An overview of recent FDA initiatives and guidances, Regulatory Rapporteur: pp 4-8, April issue. 3. ICH Guideline E14, 2005, The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. media/MEDIA1476.pdf. 4. Health Canada, 2006, Health Canada Question and Answer Document Regarding the ICH S7B and E14

Guidances. hpfb-dgpsa/pdf/prodpharma/qt_qa_qr-eng.pdf. 5. European Medicines Agency, 2008, ICH Topic E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs: Questions and Answers (EMEA/CHMP/ ICH/310133/2008). human/ich/31013308en.pdf. 6. FDA Guidance for Industry, 2008, E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs: Questions and Answers. guidance/8466fnl.pdf. 7. FDA Guidance for Industry, 2008, Diabetes Mellitus— Evaluating Cardiovascular Risk in New Antidiabetic Drugs to Treat Type 2 Diabetes. Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm071627.pdf. 8. Talbot J, Walker P (Eds.), Stephens’ Detection of New Adverse Drug Reactions, 5th Edition. Appendix 1, 694. 9. ICH Guideline S7B, 2005, The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. http:// 10. Turner JR, 2009, Interpreting the Interval: The Design, Methodology, Analysis, and Interpretation of the ICH E14 Thorough QT/QTc Study. European Pharmaceutical Contractor, pp 84-86, September issue. 11. Beasley CM Jr, Dmitrienko A and Mitchell MI, 2008, Design and analysis considerations for thorough QT studies employing conventional (10s, 12-lead) ECG recordings, Expert Rev. Clin. Pharmacol 1:815-839. DR RICK TURNER is Senior Director, Cardiac Safety, Quintiles ECG Services. He specializes in the design, conduct, analysis, interpretation, and reporting of clinical trials, with a particular interest in the cardiac and cardiovascular safety of non-cardiac drugs. He has published over 50 peer-reviewed papers and 10 books. Email:

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An Interview with Kenneth G. Faulkner and James Paskavitz of Perceptive Informatics on a Robust Medical Imaging Methodology for Central Nervous System (Cns) Clinical Trials Involving Alzheimer’s Disease IPI: Perceptive Informatics, which is a leading eClinical solutions provider, developed a robust medical imaging methodology for Central Nervous System (CNS) clinical trials involving Alzheimer’s disease. What exactly is the method and why is it important for CNS clinical research? Kenneth G. Faulkner: Perceptive Informatics has developed a system for measuring ventricular size, providing a new approach to monitor brain atrophy

“With this new methodology, biopharmaceutical companies can more accurately monitor disease progression and bring important CNS treatments to patients sooner.” in Alzheimer’s disease and assess potential treatment effects. With this new methodology, biopharmaceutical companies can more accurately monitor disease progression and bring important CNS treatments to patients sooner. Scientific advances across a broad range of therapeutic areas, such as CNS, have increased the potential for medical imaging to serve as an endpoint in determining the safety and efficacy of new treatments in clinical trials. This methodology provides 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

greater accuracy in regard to brain atrophy, further advancing quantitative imaging endpoints for this significant disease area. IPI: What are the key advantages of this method, and how does it support the clinical trial and regulatory approval processes? James Paskavit: The key advantages of the methodology include providing higher quality and reproducible assessments of Alzheimer’s disease, which is especially critical for late phase development. The FDA requires rigour around establishing a ‘standard of truth’, so if biopharmaceutical companies rely solely on the use of fully automated image analysis methods to look at change in brain volume over time (or change in hippocampal volumes) they are taking a risk in terms of their regulatory submissions. The issue is that regulators may not view the automated image analysis as being able to appropriately establish a standard of truth, and traditionally it is required that experts must review each image as well. This methodology, which was created based on validated processes and software, provides a data set and workflow designed to be accepted by regulatory agencies. IPI: What are the differences in the application of the method in early and late phase development? James Paskavitz: The methodology is applicable to both early and late phase clinical study endpoints, which differ from mostly an exploratory function in early studies, to large, multi-centre, well-

controlled clinical trials with defined endpoints and outcomes. This method is useful for biopharmaceutical companies seeking to leverage medical imaging data from early into late phase studies. Perceptive designed this method to be able to reanalyse data regardless of any image collection approach used at any phase of development, and to provide validated data that is regulatory compliant. For early phases, the method assists in providing signals of efficacy that enable sponsors to make better and faster

“Perceptive designed this method to be able to reanalyse data regardless of any image collection approach used at any phase of development, and to provide validated data that is regulatory compliant.” go/no-go decisions about Alzheimer’s treatments in development. For late phase development, the method may provide a valid surrogate outcome to enable smaller but higher-powered studies.

IPI: How was the method developed and when was it introduced? James Paskavitz: To develop this method, the Perceptive Informatics team analysed Magnetic Resonance Imaging (MRI) scans from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, using Perceptive’s medical imaging system and regulatory compliant processes. Based on ADNI data, and in the opinion of other ADNI investigators, measuring ventricular change may be one of the most robust outcomes for imaging progression of Alzheimer’s disease. Perceptive has

“To develop this method, the Perceptive Informatics team analysed Magnetic Resonance Imaging (MRI) scans from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, using Perceptive’s medical imaging system and regulatory compliant processes. ” developed this novel method of ventricular measurement to accurately reflect brain atrophy. I presented the method, which is patent pending, on April 26, 2009 in Seattle, Washington during an invitationonly meeting of ADNI. The method is being offered by Perceptive Informatics to biopharmaceutical companies conducting medical imaging-based trials for Alzheimer’s treatments in development. IPI: What does the method measure specifically? James Paskavitz: Specifically, the method measures the third ventricle area in the axial plane at the level of the Anterior and Posterior Commissures, using a semi-automated region-growing tool in Perceptive’s proprietary medical imaging software. This brain region is geometrically simple, easily found on any high-resolution MRI scan, and resistant to imaging artifacts. This image analysis method, therefore, provides precise measurements on MRI

scans of any quality. Our ability to detect meaningful change in images that were obtained in a six-month timeframe makes it attractive for go/no-go decision-making in exploratory studies, as the clinical outcomes usually require at least one year. Additionally, the regulatory compliant workflow with transparent results makes it amenable to later phase trials, either immediately or further on in the process if automated approaches were initially promising. IPI: How does this method differ from other medical imaging approaches to assess Alzheimer’s disease progression? James Paskavitz: While there have been alternative approaches to using MRI to assess Alzheimer’s disease progression, this novel methodology of ventricular measurement is designed for practical clinical research application. Assessment of ventricular size can both inform early phase decisions and provide medical image data that is reproducible for later phase, multi-centre trials – a shortcoming of other approaches. Many computer-automated image analysis approaches have been developed to handle the complex geometric changes that occur as Alzheimer’s disease patients develop progressive atrophy. These approaches solve a problem in objectifying imaging outcomes and handling large amounts of data. But they also create a potential problem when images are transformed into intermediate states for comparison using complicated algorithms and scientific assumptions. Regulators do not like data being transformed from a native state or complex assumptions applied to the data, because it is difficult to determine the necessary ‘standard of truth’. IPI: What are the potential cost and time savings that may be realised by using this method? Kenneth G. Faulkner: Overall, the method was designed to support sponsors in reducing the time, cost, and risk associated with clinical development of Alzheimer’s treatments, by providing medical imaging data that both informs early phase decisions and is reproducible for later phase, multicentre trials. A key focus of this methodology is to establish a more accurate biomarker or surrogate endpoint to enable sponsors to make faster and better informed go/no-go decisions about investigational compounds, and to help speed important Alzheimer’s treatments to market at lower cost. Since the methodology is able to

generate higher quality, reproducible assessments quickly, this saves time for later phase multi-centre studies and decreases overall development time and cost. In

“These approaches solve a problem in objectifying imaging outcomes and handling large amounts of data.” contrast, alternative approaches are not as reproducible for later phase multi-centre trials. The methodology was designed with a view to scaling up imaging protocols to support late phase studies, bridging the gap for biopharmaceutical companies between early and late phase imaging where reproducibility is a common issue. In terms of time savings, this technique takes only minutes to perform, providing the ability for fast and cost-effective independent neuroradiology review. IPI: How will this method help meet increased demand for CNS therapies worldwide? Kenneth G. Faulkner: CNS disorders account for approximately 35% of the total disease burden in the world’s seven largest pharmaceutical markets, and the global market for treating these conditions is projected to exceed $69 billion by 2010. With significant unmet medical needs in the treatment of CNS diseases such as Alzheimer’s combined with an aging population, the demand for innovative CNS therapies is expected to grow rapidly. This methodology reflects the commitment by PAREXEL, which has participated in CNS studies involving more than 114,000 patients in five years, and its technology subsidiary Perceptive Informatics, which has helped to validate novel surrogate endpoints for a variety of CNS disorders, including Alzheimer’s disease, to advancing neuroimaging and bringing important CNS treatments to patients sooner by shortening development time. Ultimately, biopharmaceutical companies are turning to Perceptive for this methodology in order to assess new compounds, accelerate development, and decrease the cost of getting Alzheimer’srelated treatments to market. Kenneth G. Faulkner, Ph.D., Vice President of Medical Imaging, Perceptive Informatics James Paskavitz, M.D., CNS Imaging Medical Director, Perceptive Informatics INTERNATIONAL PHARMACEUTICAL INDUSTRY 67

India – World’s Best Choice for Clinical Trials Introduction India has the potential to attract 5-10% of the global contract research outsourced market (all services, including chemistry, toxicology and clinical research) over the next five years. The Indian government has recognised that we can become a hub for conducting global clinical trials, and the Planning Commission’s Report of the High Level Group on Services Sector highlights the opportunities and identifies the gaps for this sector that need to be addressed by the government. Today, most Big Pharma are conducting multi-centric trials out of India, with some of them having been operating for more than 15 years. A drug-naïve population and competent medical professionals gives India an edge. The MNC activities ramped up in the 2000s, with companies looking at therapeutic areas like oncology and cardiovascular diseases, amongst others. Today, India accounts for nearly 20% of clinical trial sites (Phase II-IV) in Asia. A gradual but steady growth is due to a number of factors. The Indian industry has been building capacities, ensuring informed consent and increasingly becoming conscious of the ethical requirements. This is coupled with a number of government initiatives pertaining to regulations, keeping in mind the essential principles of patient safety, speed and transparency. Clinical trial registrations, oversight audits and a multi-tier training programme for Indian regulators are some of the key elements. The government is adopting a collaborative approach, incorporating industry inputs at all stages, as well as inviting trainers from outside who have long experience of regulating this sector. The Indian government is also working closely with the USFDA and other regulators for training of their officers. The pressures of declining R&D output and increasing costs have resulted in the globalisation of clinical research, and emerging markets have begun playing a significant role in the drug development value chain. India too has seen a surge in clinical research activity, with an evolution over the last decade from being an industry focused on BA/BE services, to increasingly being viewed as the service provider of choice by the global pharmaceutical and biotechnology community in the arena of Phase I-IV trials and allied services. This article aims to present the reasons for the shifting clinical trial footprint toward emerging markets, the performance of India vis-à-vis emerging markets, and an 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

assessment of the capabilities and potential for growth of the Indian clinical research industry. Emerging markets are no longer an option, but instead a strategic imperative for global clinical research. The USD64b global clinical research industry is witnessing a transition as life sciences companies are turning toward emerging markets in Asia, Latin America and Eastern Europe, to pursue clinical research. Increasing costs, declining productivity and rising drug development timelines, combined with the strategic advantages offered by these emerging markets, is driving researchdriven pharmaceutical and biotechnology companies to conduct clinical research beyond established markets. Over the previous 15 months, the share of rest of the World countries (countries other than the USA, Canada and Western Europe) has increased by 4.3% in total global study sites, which in absolute numbers corresponds to 6500 sites. The rest of the World today accounts for nearly 25.9% of Phase I-IV sites, with the number of studies in some emerging markets growing nearly two to three times faster than the global average. Emerging markets now contribute to 36% of global patient enrolment as compared to 20% in 2001. India is one of the fastest growing clinical research destinations with a growth rate that is two and a half times the overall market growth rate. India participates in 7% of global Phase III and 3.2% of Phase II trials with industry-sponsored trials having grown at a spectacular 39% CAGR between 2004 and 2008. The number of industry-sponsored Phase II-III sites in India has moved from rank 18 to 12 across the 60 most active countries. India ranks second in Asia after Japan in its number of industry-sponsored Phase IIIII clinical trial study sites, and accounts for nearly 20% of all Asian study sites. As the world’s third-largest producer of drugs by volume, with the third-largest drug research and development workforce, India is a major player in the pharmaceutical industry. The most active 25 pharmaceutical companies worldwide, based on the number of study sites registered, are also active sponsors of clinical studies in the country. The number of investigators in India has also grown the fastest among Asian, Latin American and Eastern European countries, with a 42% CAGR between 2002 and 2008. India has one of the fastest subject recruitment rates globally (nearly three to

five times the global average), with screen failure and drop-out rates lower by nearly 4050%, as compared to global averages. As a result, India contributes 15-30% of global enrolment in multi-centric studies where it is a participant. Data submissions from India in the recent past have been part of at least 13 successful NDA approvals. India is ranked third across all countries after the USA and China in terms of its overall attractiveness as a clinical trial destination, according to a recent AT Kearney global survey. Further, India’s research landscape is undergoing a glorious metamorphosis, aided by many uniquely differentiating capabilities, a rapidly transforming healthcare market and an enabling environment that is rapidly adapting itself to global standards. India constitutes 16% of the global population with 20% of the global disease burden. With 32 million patients in urban areas and 72 million patients in rural areas at any given point of time, India has a diverse mix of subjects, who are relatively treatments-naïve, as well as subjects with a high standard of care to meet diverse study protocols. The country’s disease burden is also well aligned with the new drug development therapy focus of global pharma and biotech, with a shift toward non-communicable diseases. India has 65 million patients with CNS disorders, 31 million diabetics, 29 million cardiac patients, 41 million COPD and asthma patients, 0.8 million cancer patients, with most of these ailments expected to increase by over 50% in the number of cases by 2015. All the five major racial types- Australian, Mongoloid, European, Caucasian and Negroid – find representation among the people of India, with Caucasian being the most prevalent. The urban healthcare infrastructure, in terms of the number of beds/physicians/ nurses per 1000, is comparable with the global average; India has >8,40,000 urban beds. There are over 6,00,000 Englishspeaking physicians and nearly 1,00,000 specialists, with many of them having been trained in the best global institutes. There are 41 hospitals accredited under International Society for Quality in Healthcare providers (NABH) and Joint Commission International (JCI), while 84 hospitals are currently in the process of applying for NABH. The Clinical Establishment (Registration and Regulation) Act, which is being promulgated by the government to regulate private hospitals and laboratories across the country, will play a

4th Annual Conference on Drug Discovery and Clinical Development in India

Scientific and Regulatory Advances Across Borders November 15-18, 2009 New Delhi, India

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significant role in devising and implementing uniform standards of facilities/services and further enhance the quality of care provided by the Indian healthcare delivery system. There are 350 clinical trials that are ongoing in the country, with 64% of the studies being in the five key therapies of

Drugs Standard Control Organization, Directorate General of Health Services and the Ethical Guidelines for Biomedical Research on Human Participants issued by Indian Council of Medical Research, 2006, are consistent with the principles enshrined in the Declaration of Helsinki, which ensures

100 98 96 94 92 90 88 86 84 82 Rural


Graph I - Distribution of population in urban and rural areas

the credibility of clinical trial data emanating from India. The government is planning

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oncology, cardiovascular, neuro-psychiatry, diabetes and infectious disease. India has more than 2299 industry–sponsored Phase II-III clinical trial study sites that are carrying out clinical trial activity across the top 15 cities in the country. All medical records at the sites are maintained in English. There are 1500 investigators, with the investigator base growing at >40% per year, faster than in other emerging markets. The government is laying significant emphasis on training and capacity-building, with the Department of Biotechnology (DBT) setting up six Clinical Research Training Centers (CRTSs) to provide specialised training to clinical investigators (MBBS and MD). Nine of the top 15 global pharmaceutical and biotech companies have set up captive clinical research centres in the country. Seven of the top 10 global CROs have an established India presence. There are more than 20 CAP-certified central laboratories with a significant number of the international laboratories providing a suite of esoteric testing services. The policies and regulations governing clinical trial conduct in the country, e.g., Revised Schedule Y (of the Drugs and Cosmetics 2nd Amendment Rules, 2005), Good Clinical Practice Guidelines issued by the central

Graph III - India’s healthcare infrastructure

and executing a number of initiatives to strengthen the institutional machinery, e.g.

7 6 5 4 3 2 1 0 Type I DM

Type II DM

Pediatric Asthma

Parkinsons Disease

Graph II - Recruitment rate - patients per month/per site 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

mandatory registration of clinical trials (w.e.f. 15 June 2009), mandatory registration of stakeholders (viz. CROs, ethics Committees, investigator sites and investigators), enhanced monitoring and oversight (random audits, inspector training workshops by USFDA, imposition of penal provisions such as 10year imprisonment for misconduct and fraud in trials), and “e-governance” of the entire drug approval process. These are testament to the government’s commitment to create a regulatory environment in line with the highest global standards. The government is also embarking on a major multi-billion dollar initiative with 50% public funding through a public private partnership model to harness India’s innovation capability. The vision is to catapult India into one of the top five Pharma innovation hubs by 2020, with one out of every 5 - 10 drugs discovered worldwide coming from India by 2020. The Indian pharmaceutical market – the third-largest globally by volume – is expected to treble in value to USD20bn by 2015, to be counted in the top 10 markets of the world. The advent of the product patent regime in 2005 has instilled confidence in the intellectual

Total hip replacement

Duodenal Ulcers

Hepatitis C

property regime, with many patented drugs launched over the last two to three years. While pharmaceutical MNCs already present in India are further consolidating their presence through acquisitions, many MNCs have staged a re-entry post-2005. It is estimated that the share of pharmaceutical MNCs in the domestic pharmaceutical market will rise to 35% by 2015, from the current 25%. India’s value proposition extends beyond Phase I-IV trials with other allied services such as data management, medical writing, pharmacovigilance and biostatistics services gaining the attention of sponsors and CROs. Delivery of allied services requires an appropriate blend of system and domain skills and India’s proven IT/ITES track record, domain expertise and cost

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capability required to enhance its credibility further, and gain the confidence and trust of the global life sciences community to make this aspiration a reality.

Asian Clinical Trials




CROs Operating in India SIRO Clinpharm


Reliance Clinical Research Services

Ecron Acunova Lambda

Figure I- Names of some famous Indian CROs

30 30 60 75 90 90 90 90 95 95 90 105300

advantage has made it a destination of choice for these services. The Indian industry for these allied services is growing at 21%, which is almost thrice the global average. India has consistently been ranked as the most preferred destination for the provision of outsourcing services in the IT/ITES segment. India accounts

advantages, India still contributes only 1.5% of global patient enrolment and sites, and 2% of clinical trial volume. The global community is yet to harvest the full potential of its patient pool, medical infrastructure, clinical trial expertise, IT capabilities and regulatory reform to the fullest extent. A large part of

China Brazil Czech Poland India Australia/NZ South Africa


Russia Taiwan Korea Hongkong Singapore USA 0








Graph IV - Regulatory timeline approvals are comparable with the rest of the world……

for 65% of the global offshore IT services, with KPO exports growing at 51% p.a. (2004-08). There are more than 45 companies with six to seven years’ experience spanning CROs, IT/ITES companies, specialised providers and the captive centres of global sponsors that are offering the complete spectrum of allied services. At least eight of the top 10 Pharma companies are providing one or more of these services from India, either by setting up captive centres or through tie-ups with CROs and IT/ITES companies Paradoxically, despite its inherent

this is attributable to the perception and lack of awareness about the transformational changes currently taking place in the country’s clinical research environment. India is at the same time the most preferred choice for IT outsourcing, a unique advantage that is not enjoyed by any other emerging economy other than China. It is thus best placed to assume a leadership position among emerging economies as the location for clinical trial conduct worldwide by 2015. The Indian clinical research stakeholder community is committed to demonstrate the

Summary Among the emerging geographies, India enjoys an unmatched position by virtue of the uniquely differentiating capabilities. It has a large, genetically diverse and treatment-naïve population, and a patient profile aligned with the key research focuses of the global pharmaceutical industry, such as cardiology, oncology, central nervous system, antiinfective and asthma. India has a transforming provider-care environment characterised by a rapidly growing number of world-class medical and diagnostic facilities, investigators and abundant availability of scientific talent. There is a well-established presence of most of the global pharmaceutical companies and global clinical research organisations. India can offer end-to-end services in clinical research covering trials, data management, medical writing, biostatistics, pharmacovigilance and central laboratory services. India has a booming domestic pharmaceutical market growing at the rate of 12-14% annually. While many of these inherent advantages have been in existence for a long time, this glorious metamorphosis is now being driven by the booming economy, which is growing at a rate of 8-10% p.a., and a demonstrated commitment from the Indian government to create an enabling environment, in terms of regulations governing intellectual property protection, conduct of clinical activities, and quality assurance, that is in line with best global standards. Acknowledgements: The author wishes to thank Ernst & Young Publications for their statistical data.

DR. RAJAM JAISHANKAR did her graduation (MBBS) and post graduation (MS General Surgery) from Kilpauk Medical College, Chennai.Dr. Jaishankar has conducted a number ofupdates, workshops with evidence-based medicine as the theme, in the field of reproductive medicine in all most metros in India. She is the founder member of the Tamilnadu Pharmaceutical Welfare Trust and the former member of the Infertility subcommittee of the Association of obstetrics and Gynecology. She is associated with the “Indian Fertility Society” (IFS), the National Association of Reproductive and Child Health of India (NARCHI), the Federation of Obstetrician and Gynecological Societies of India (FOGSI) and the European Society of Human Reproduction and Embryology (ESHRE). Email: INTERNATIONAL PHARMACEUTICAL INDUSTRY 71

Ethics Committees In India An Insight Ethics Committees (ECs) constitute the third arm of the research triangle, and can make significant contributions towards the ethical conduct of clinical trials. An EC ensures a competent review of all ethical aspects of the clinical trial proposals received, and reviews them free from any interest and influence that could affect their decision. Specially post-2005, i.e. after schedule Y had been amended, obtaining ethics committee approval is one of the mandatory steps towards conduct of the trial.

“While amended Schedule Y1, ICHGCP Guidelines2, Indian GCP3 specifies standards to be maintained by ECs, the majority of institutions in India still lack compliance with the applicable standards in a true sense.” With so much importance given to ECs, we still have a question to ask the institutions. Are these committees trained enough to take up such a challenging role? Do we have trained personnel within the committee who can take a fair decision to approve or reject a trial? While amended Schedule Y1, ICHGCP Guidelines2, Indian GCP3 specifies standards to be maintained by ECs, the majority of institutions in India still lack compliance with the applicable standards in a true sense. Let us take a look at major areas that require immediate attention and correction. Additionally, an attempt has been made by an author to provide solutions which could be adopted by the committees to fix the problem areas. 1. Frequency of meetings: As per Schedule Y 2005 “Every IEC should have its own written SOPs according to


which the committee should function. The SOPs should be updated periodically based on the changing requirements.” As a matter of fact, none of the ethics committees have clear-cut guidelines on a reasonable timeframe for EC meetings. At most of the places, the meeting often takes place on an ad hoc basis as and when the need arises. In large institutions, the frequency of meetings varies from once a month to once in three months, whereas private institutions meet every now and then based on the need. In both the scenarios, it is difficult to do justice to the review process. Furthermore, there are some institutions which have a two-step review process where the research projects are first reviewed and approved by a Scientific Committee, followed by review and approval by an EC, or vice-versa. This at times creates a lot of confusion and duplication of effort without any benefit. Also, this delays the timelines, and unnecessarily the dirty business of the blame game starts among sponsors, CROs, investigators etc. Solution: In my opinion, the most practical solution is to have a procedure to conduct a meeting once a month. If for some reason the meeting does not take place, there must be a solid reason for it which should be approved by the chairperson. With respect to the two-tier process, members from both the committees can be combined to frame an EC which can review the project as a whole. 2. Amendments: We all understand that there might be changes in the study documents after the EC has approved the protocol, i.e. there could be minor amendments (for example: logistical change i.e. lab address change, CRO address change, rewording of sentences etc) or major amendments (for example: change in selection criteria, number of patients, safety or efficacy parameters) in the protocol, and none of the ethics committees that we have worked with so far have clear procedures with respect to the amendments. There are some institutions in which minor amendments are dealt with as notifications, whereas in others, minor (non-substantial) changes in the protocol

or study documents are discussed in the regular meeting which takes its own time to convene. Sometimes, due to nonavailability of quorum members, a meeting does not take place. As a result, one has to wait for a full-fledged meeting, which may occur once in three months, even for minor changes which have no impact on the safety and efficacy of the trial. Solution: All minor amendments should go as notifications to the ethics committees. A summary of amendments shall be prepared by the applicant mentioning the change made in the relevant sections and the reason for the change. This summary, along with the amended documents, should be submitted to the member secretary so that the documents can be notified. The trial should not be stalled waiting for the EC to give its decision. In case of substantial amendments, which may affect the safety and efficacy of the subjects participating in the trial, an applicant has to submit the documents in the same way as above and then wait for the meeting to hear the decision. The entire procedure shall be clearly laid down in the SOP of ECs and it is the sponsor’s duty to clarify all the above points during the pre-selection site visit (PSSV).

“A summary of amendments shall be prepared by the applicant mentioning the change made in the relevant sections and the reason for the change.” 3. Composition: Amended Schedule Y and ICH-GCP guidelines clearly mention the composition and quorum requirements. To date, at the majority of institutions, the chairperson is from within the institution. This is contrary to schedule Y which clearly states that the chairperson has to be from outside of the institution. Furthermore, there is still no clarity on the number of members

required for a quorum, and the meaning and importance of a lay person. The roles and responsibilities of each member are also not clearly defined. For example, the member secretary acts as an authorised signatory in some institutions, whereas in others the member secretary has no specific role to perform. Solution: In the author’s opinion, the EC members at most of the institutions are not offered any kind of training. Due to the lack of training, EC members are not aware of regulatory guidelines and operational procedures. It is mandatory that all EC members are trained as an ongoing process on ICH-GCP Guidelines, Schedule Y, Indian GCP, ICMR, Declaration of Helsinki and WHO guidelines.

“It is mandatory that all EC members are trained as an ongoing process on ICH-GCP Guidelines, Schedule Y, Indian GCP, ICMR, Declaration of Helsinki and WHO guidelines. ” 4. Standard Operating Procedures (SOPs): As per Schedule Y, ICH- GCP, ICMR and Indian GCP guidelines, it is mandatory for all ethics committees to have written procedures or SOPs. However, currently in the majority of the institutions, the SOPs do not exist, and even where the document is present, it doesn’t contain the basic elements, such as documents to be reviewed, number of copies required, membership criteria and quorum requirements, frequency of meetings, submission deadlines, expedited review process, document control system, record retention and archival procedures etc. It has been generally observed that ethics committees are reluctant to provide SOPs to the sponsors / CROs during the site evaluation visits, and this leaves all the parties in a situation of ambiguity as to whether or not to believe the investigator who has provided the information about his institution’s ethics committee. In all this, the investigator may cut a sorry figure and the decision of site selection may go against him/ her. Solution: ICMR4 provides the templates for writing SOPs for ethics committees. All ECs should appoint a quality assurance person (either internal or external) to

check out these activities. There is no need for ECs to prepare a bulky document of 100 pages; instead a simple 3-4 page document stating the basic elements should suffice, provided it is prepared, discussed, approved and authorised by an appointed team within the EC members. 5. Document of EC approval: After review, the ethics committee issues an approval letter. This document invariably contains errors and has to be quality checked by the sponsor / CRO after receipt. The following are the types of errors which are most often found in the approval letter: • Not stating correct version numbers of the documents reviewed • Incomplete list of EC members present/absent during the review process • Date of review and date of approval wrongly given • Format not as per schedule Y • Wrong protocol title given. As a result, it becomes burdensome for the applicant to keep communicating this to the investigator, then send it for correction, obtain a modified document, then resend it for further changes etc. All these activities unnecessarily take time without adding any value to the task. Solution: After the EC approval document is ready, it becomes the responsibility of the EC members (especially the member secretary and chairperson) to quality check the document before its release. A checklist of basic elements should be made at their end and the document should be checked against this. Ultimately, it is the quality that matters. A good quality work demonstrates the type and functioning of the ethics committee. 6. EC submission fee: Last but not least, there is no consistency and uniformity in the submission fees across ethics committees in India. In government institutes, the fee may be on the lower side, ranging between Rs. 5,000 (US$100) and 20,000 (US$400), whereas the majority of private / independent ethics committees charge a fee in a range of Rs. 20,000 (US$400) to as much as Rs.100,000(US$2,000). There is absolutely no justification of any kind that can be provided by anyone for charging such a high amount by the committee. Since the applicant is at the receiving end, they have little option but to pay this amount and push the trial. Solution: Charging fees is not a wrong

practice. But they should be nominal, and mentioned in their written procedures. All private and government institutions should be in sync with each other, and to the best possible extent should have uniformity and consistency in this process. The author has made an attempt to highlight the issues which are generally faced by the sponsor / CROs and the hardships one goes through in this process of EC submission. The solutions provided here may not suit all the ECs, but at least this will give institutions food for thought, and they can definitely step forward towards streamlining the entire process to the best possible extent. Currently DCGI fully depends on ECs for implementing ethical standards in clinical trials, but there is absolutely no direct linkage of any kind between the DCGI and ECs5. It is very important that the DCGI and ICMR join hands and take some concrete steps towards inspecting ECs in India on a regular basis. It is time now that individual ECs take ownership, and act to contribute towards the ethical conduct of clinical trials. The pharmaceutical industry has been, and will always be, ready to extend a helping hand in working towards improving the quality and working of ECs in India. References: 1. Amended Schedule Y 2005. 013595en.pdf ICH Topic E 6 (R1) Guideline for Good Clinical Practice. 3. Indian Council of Medical Research. Policy statement on ethical considerations involved in research on human subjects. New Delhi: ICMR; 1980 Feb. 4. 5. Amar Jesani. Ethics in ethics committees: time to share experiences, discuss challenges and do a better job Indian J Med Ethics.2009 AprJun;6(2) DEEPTI GOEL has over 9 years of experience in clinical research working with Pharma companies ,CRO and training academy. She has worked across various clinical research verticals including clinical operations, quality assurance and training. By education she is a pharmacist with a Master’s Degree in pharmacology. Deepti has monitored, managed various projects, mentored teams and trained clinical research professionals. She has been instrumental in setting up a QA and Training unit in one of the pharma companies in the past. In her current assignment she is the Head of Training and Operations at Cliniminds and is responsible for oversight of operations and training needs and development across India.



Successfully Involving Central Laboratories: How to Avoid Fundamental Errors No doubt, central laboratory services are complex, particularly due to the logistical tasks involved. One aspect renders central lab services different to almost any other service outsourced by Pharma or Biotech companies during a clinical trial: biological samples have a limited stability and if the lab provider does not take this into account in many cases the samples may get spoiled before they arrive at the laboratory. Consequently, each blood sample has an incomparable value and is unique in the sense that it reflects the status of a specific patient in a specific therapeutic timepoint. A poor understanding of processes during the planning phase has the irrevocable consequence that sites may prepare their samples inappropriately, that samples may undergo unexpected delays during shipment or may be transported in a wrong temperature environment, and that lab results may not be available at the site for the next patient’s visit. Sponsor companies generally make their service providers responsible for all such problems and are not aware that they could have done better during the laboratory selection process and also during the site initiation visits or investigator training sessions.

Global centralised laboratory services — if global means that two or more continents are involved in a clinical trial — have been offered by a reduced number of centralised laboratories now for ten to 15 years. The first central laboratories were founded in North America some 20 years ago: a logical step in view of the vast size of this region covering the USA and Canada, a region with no major borders and with nationwide couriers already available at that time. In the mid 1990s, cross-border transportation in Western Europe was simplified by the creation of the European Union and this triggered the setup of central laboratories in Europe. Since 1995 many centralised laboratories have been established to provide bi-continental (America–Europe) or more global central laboratory services; many have failed and only a few have survived and are today able to offer reliable and high-quality cross-border services. What is the major misunderstanding when using central laboratories? My impression is that many sponsors still do not invest sufficient time in developing appropriate selection criteria to allow them to identify the ideal central laboratory. This

Type of Service

may be due to the fact that the cost related to the laboratory portion of a clinical trial only ranges from 10% — if only routine safety panels are needed — to 20% of the overall study budget — if more complex analytical methods, PK testing, frozen shipment and other complex logistical tasks are requested by sponsors. Why invest too much time in laboratory selection if the analytical portion of the study might be considered to be marginal from the cost point of view? Proof of this could be that only a very few sponsors take the time to visit the laboratory candidates before awarding their contracts. This approach seems to be widespread and to me is based on the fundamental error in thinking that all laboratories are essentially comparable with each other. Yes, all laboratories are able to offer a more or less broad testing portfolio, but there are significant differences in quality, IT standards, staff training and pro-active thinking. Table 1 shows that sponsors should be looking for service providers able to provide all sub-services they need, and not only appropriate analytical support.

Standard reference lab

Central laboratory

Routine lab testing

Specialised methods, biomarkers


Dedicated project managers


Cross-border shipping logistics


Visit-specific kit building


Frozen sample library


Customised data formatting


QA available for all processes


Multi-lingual support


Table 1: Sub-services offered by “standard” laboratories and by central labs. 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

central lab services for clinical trials competitiveness = unexpected quality awareness = uncommon flexibility = unlimited why pay more elsewhere?

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How is this misunderstanding nurtured? One major reason for this misunderstanding, that is, to consider that a central laboratory is just a laboratory, is also found in many of the publications describing the use of centralised laboratory service providers. Hence scientists at a sponsor willing to know more about the use of a central laboratory may read publications generally only describing analytical processes as well as quality aspects relating to the laboratory testing itself.

“Proof of this could be that only a very few sponsors take the time to visit the laboratory candidates before awarding their contracts. ” Such laboratory-oriented publications thoroughly evaluate operational and quality aspects with respect to a) requirements for appropriate laboratory facilities, b) equipment and reagents, c) qualifications of the lab staff, d) quality control schemes and e) LIMS (laboratory information management systems). If we go back again to Table 1 we will easily find out that these laboratory related aspects only refer to the first one or two sub-service types. Consequently, many such publications miss the point when describing central laboratory services as they mainly concentrate on the analytical portion. But the analytical work — although very important — is only one more service type provided by central laboratories (1). Many questions have to be addressed when evaluating the analytical capabilities of a laboratory: Are all methods validated? Are SOPs (standard operating procedures) available for each and all methods as well as for maintenance and calibration of each and all analysers? Is continuous staff training available and are there training records? Is an audit trail implemented? Is the temperature of refrigerators and freezers monitored? Is access to the various areas controlled? And many more questions could and should be raised! How can this fundamental error be corrected? Although some sponsor companies may rely on the expertise of their scientists when selecting a central laboratory, other sponsors have set up specific teams with the aim of standardising the selection process. 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Such “outsourcing” teams may be located in R&D or purchasing departments and generally develop complex RFIs (request for information questionnaires) in order to collect information from the service providers in a structured grid-format. I do not intend to comment on the various RFI formats we have seen, only to say that in view of the reduced number of global central laboratories (not more than ten) and the significant differences between them, I would recommend those people responsible for the laboratory selection to personally visit all (!) these ten or so central laboratories. One day to view the lab facilities and limited travel expenses would deliver more reliable information than collecting information, the quality and truth of which may be very difficult to prove upfront. A second step would include sending qualified auditors to a selection of these central labs and hence separate the wheat from the chaff. It has been shown to be of additional help if such a qualifying team not only includes laboratory technicians but also data managers and QA experts. Are there different types of centralised laboratories? The author has described elsewhere the various types of central laboratories available and each sponsor should identify the more appropriate type for each study protocol (2). In view of the economic uncertainty, many sponsors are becoming more selective about the CROs (contract research organisations) and central laboratories they want to use to better capitalise on in-house competencies. Particularly in the central laboratory sector,

with a limited number of global players and each one with very specific strengths, the limitation to only two or three “preferred providers” may not turn out to be the right path. The dramatic changes in the financial environment envisioned since autumn 2008 forces not only sponsors but also service providers to restructure their organisations (3). Unhealthy players have already closed down or are near to disappearing. This should provide additional support for the above recommendation: only if you have personally visited all ten or so global central laboratories can you be sure to have an alternative service provider if one of your preferred ones suddenly reduces its capabilities or, in the worst case, closes down. How can the right central laboratory be identified? This is a very difficult task which in the end leads either to future satisfaction or unhappiness of the sponsor and other parties involved such as a CRO or the investigators. There are a number of questions that can help in identifying the appropriate candidates (Table 2). However, the answers should only be evaluated and balanced against each other if the respective laboratories have also been previously visited. The standard question raised by a sponsor is: do you perform the tests A, B and C? Most central laboratories might be able to say yes, even if they may need to refer such tests to a third party or to set up and validate a new method. Interestingly, sponsors tend to forget follow-up questions

TABLE 2: SELECTION C RITERIA                

are all tests required available routinely? or have samples to be referred to another lab? are all methods done on a daily basis? are in-house experts available? are all methods validated (SOPs available)? can training records be shown for the staff? are raw data archived and available for an audit? how are all samples identified? double-entry? is there proven experience in international logistics? are non-generic reagents used? are quality control and quality assurance in place? is design of lab reports flexible? in English? is data cleaning continuously performed? is customised data management available? are experienced project managers available? which languages are spoken?

such as the following: • Are all tests done in-house? What if you have selected a central laboratory with a wonderful QA management system which then refers your blood samples to a third party, for example a university department, with a lower quality awareness? • Are all tests measured daily? If this issue is not discussed, the contract may have been signed prematurely: if sites need their lab results soon after blood collection in order to re-evaluate their patients’ drug dosages it would be a major problem if the laboratory selected only runs the specific methods once every three or four weeks. The frequency of running a specific assay in the laboratory depends directly on the number of samples received. A small laboratory processing 50 or 100 samples a day may only receive five to ten samples for a specific immunology method. Consequently, it would hardly be able to run this specialised method due to the high cost of instrumentation (up to US$250,000) and reagents (US$1,000 for a kit to test approx. 40 samples) in addition to the need for qualified technicians. Sponsors should, therefore, find out at an early stage if the laboratory to be chosen is able to perform the study-specific test panel with the shortest delay. What is the added value of using centralised laboratories? As mentioned above, it would not seem sufficient to simply find out if a central lab is able to comply with the analytical requirements of a study protocol. A central laboratory has many other tasks to perform reliably. Table 1 shows the major differences between laboratories. Important questions should, therefore, include whether dedicated project managers would be allocated to the study, whether they would coordinate all activities and be the single contact for the sponsor, whether they would attend investigator meetings and there present the logistics involved with sample collection and transportation, whether they would write study-specific multi-lingual investigator manuals and shipping instructions, and whether they are aware of IATA regulations and customs requirements. Does the central laboratory have an IT platform appropriate enough to prepare customised electronic data transfers; in order to do so is data cleaning continuously performed and are sites or clinical monitors approached to clarify missing data or inconsistent data? Conclusions Most drugs being evaluated in clinical trials require analytical laboratory work to prove their safety and efficacy. This is different

Table 1 Selection criteria for choosing a central laboratory •

Are all tests done in-house and, if so, daily?

Are validated methods used and generic reagents avoided?

How are samples identified?

Is external accreditation available?

Are project managers allocated to the study?

Do they search for missing data and attend investigator meetings?

Does a quality assurance unit supervise all processes and training?

Are sampling kits and study specific instructions supplied to investigators?

Are lab reports, data transfer and progress reports customised?

from in the past where laboratory data were mainly used for safety reasons only. Whereas “standard” laboratories in major hospitals or universities may be able to run methods for more specialised parameters required in the study protocol, most local laboratories used by investigators are limited to offering routine lab testing. In contrast to using a central laboratory, local laboratories use different methodologies and reference ranges, different units and languages, and different analytical quality and staff training procedures. Such discrepancies related to the use of decentralised laboratories may jeopardise the outcome of multicountry studies as laboratory results from so many sources may not be able to be readily pooled in a single database. Language differences and also other ways of interpreting laboratory values, especially those outside the reference ranges, may further compound methodological differences. Globally operating central laboratories have established uniform SOPs, IT platforms and QA standards in all regional laboratory facilities and hence are able to provide all laboratory data in a single data format using global reference ranges and units. Data uniformity and comparability are the basis for reliable statistical analyses. Central laboratories provide a simple promise: perform high-quality analytical work centrally! This simple promise is not easily fulfilled. A number of potential challenges exists and must be taken into account during the setup of each individual study. To achieve their goal, centralised laboratories provide an added value if compared with “standard” laboratories. In order to obtain satisfactory results from the central laboratory selected sponsors are expected to invest more time and effort in the selection process and to base their decisions not only on questionnaires but on personal interviews and inspections. Preferred service providers selected some years ago may not be the most

appropriate candidates in today’s changing environment. Selection of service providers for clinical development continues to be a challenging job! References 1. Schulz, H , 2003. Outsourcing laboratory testing for clinical research: advantages for pharma and biotech companies. GOR Global Outsourcing Review Journal (with Japanese summary), 5(1), pp.27–30. 2. Schulz, H., 2007. Central labs: types, distribution and capabilities,. European Pharmaceutical Contractor Journal EPC. Summer, pp.114–120. . 3. Schulz, H., 2009. Financial crisis and its potential impact on clinical research — from the central laboratory perspective. Journal for Clinical Studies, January, pp.38–40. . Before founding INTERLAB in Munich in 1994, DR. HERMANN SCHULZ held senior R&D positions in the pharmaceutical industry (Merck & Co, AstraZeneca/ICI and UCB/Schwarz) for 12 years. As a visiting professor, Hermann is head lecturer for applied clinical pharmacology in the postgraduate course “Pharmaceutical Medicine” at the University Duisburg-Essen (formerly Witten-Herdecke), and also teaches at the University of Tuebingen. He was a member of the Board of the German Society of Pharmaceutical Medicine for six years and is a founding member of the International Association of Central Laboratories (IACL) based in London. Hermann has written more than 35 scientific publications and is invited as a speaker to international conferences. Contact Details: Dr. Hermann Schulz, MD Chief Executive Officer INTERLAB central lab services - worldwide GmbH Bayerstr. 53, D-80335 Munich, Germany. Fax: +49 89 741 39339 email:


Managing Pharmaceutical Globalisation: A Work in Progress Like a high-speed train, globalisation in the pharmaceutical industry is accelerating steadily, driven by factors too numerous to name – growing healthcare reform and awareness, slowing growth in traditional markets, the imperative to reduce drug development time and costs, and the opportunity to leverage aging populations and emerging markets. While the advantages of going global are obvious, globalisation creates new challenges that the industry will need to address moving forward. Consider for a moment the complexities associated with conducting clinical trials in China, manufacturing in Ireland and Singapore, and marketing medicines and vaccines in countries as distinct and far-flung as Argentina, Poland and Japan. Here we will briefly examine the pharmaceutical industry’s considerable progress in the ongoing journey called globalisation, as well as the issues that are cropping up along the way. One thing is certain: resolving them will require the same energy and diligence that a train engineer applies to negotiating an unfamiliar curve in the tracks. (1) Harmonisation Remains Critical Aside from the twin drivers of economics and demographics, perhaps the single most important factor enabling globalisation is the substantial progress to date in the harmonisation of regulatory strategies. Since its 1990 formation by regulatory authorities and research-based industry representatives of Europe, Japan and the United States, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - ICH for short - has improved the way drugs and vaccines are developed and registered by eliminating redundancy. Driving the need to rationalise and harmonise regulations were concerns that are even more relevant today than they were then: rising healthcare costs, escalating R&D expenses, and the pressure to make new treatments for cancer, HIV, heart disease and other serious diseases available to patients in need with a minimum of delay. Nearly two decades later, pharmaceutical companies can do what was not possible 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

then - demonstrate the quality, safety and efficacy of a new drug or vaccine using a single set of clinical studies, provide these data to regulatory agencies in a common format and, importantly, do so electronically. Since a hard copy of the typical new drug or biologics application is composed of thousands of pages, electronic filing is efficient, cost-effective and not least of all, green. Widespread adoption of harmonisation guidelines has gone a long way to easing regulatory requirements for research-based pharmaceutical companies working to develop and register new products. Today, industry and governments in both ICH and non-ICH countries use state-of-the-art ICH guidelines to address technical issues during the product development process. Meanwhile, harmonisation activities are continuing. In recognition of the industry’s laser-like focus on emerging markets, ICH has established regional harmonisation initiatives representing Asia Pacific, Southeast Asia, South American and South Africa. These steps, which broaden ICH’s global cooperation activities beyond its core geographic constituencies, acknowledge the critical role these regions play in the future of the pharmaceutical industry. (2) Economics Drive Continued Outsourcing Even before the recent economic downturn, the pharmaceutical industry was steadily increasing its reliance on outsourcing noncore services such as packaging, labelling, analytical testing and logistics as a means of driving down costs. Now more than ever, with companies under intense pressure to shed fixed assets like packaging facilities, they are turning to strategic outsourcing to fill global operating needs. While cost is the factor driving outsourcing, sponsors are increasingly recognising the need to weigh skills, experience and track record - as well as cost - in identifying and selecting outsourcing providers. A highly experienced provider who has teamed up with multiple sponsors on successful global projects can offer more than just cost savings, for example. The ability to engage best practices, enhance processes, access regulatory expertise and tap into deep knowledge of target markets

can reduce time and waste as well. Similarly, having a provider board earlier, when, for example, a global trial is in the planning stages rather than when the pressure to ship product to clinical sites is building, can make a major difference. Providers say their most strategic sponsors bring them aboard in the earliest stages of planning a trial, when the protocol concept and list of target countries are in development, enabling the supplier to begin mapping out deployment strategies months before trial materials are scheduled for packaging and shipping. Suppliers are urging sponsors to regard them as an integrated support system, rather than the provider of discrete functions. While economic pressures will remain the primary driver, savvy sponsors realise that strategic outsourcing can deliver the added bonus of higher-quality global services at lower cost. (3) (4) Supply Chain Issues Predicted to Rise It stands to reason that the increase in the number of clinical trials migrating to sites in Asia, Africa, the Middle East, Eastern Europe and South America would be accompanied by a host of new issues from a supply chain perspective. ClinicalTrials. gov, the registry of clinical trials taking place in the United States and around the world, recently included more than 72,000 trials taking place in 166 countries. Thanks to globalisation, the number, size and complexity of clinical trials are expected to rise dramatically by 2010, forcing organisations to confront new challenges in managing the clinical supply chain and completing trials efficiently – this according to a recent benchmarking survey of more than 100 pharmaceutical and biotechnology executives. Those surveyed reported that only 13 per cent of clinical trial materials shipments arrived on time and even then, one in 10 were incomplete. This suggests that there is a great deal of room for improvement, applying an additional layer of pressure on providers and sponsors. Sponsors, many of which appear to regard the supply chain as somewhat of an afterthought, may finally have to readjust their thinking. As the number and complexity of global trials grow, lack of

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proper supply chain management sharply raises the odds that trials could derail at significant cost to sponsors already facing economic pressures. (5) (6) Growth in Biologic Trials Raises Logistical Stakes Pharmaceutical companies seeking cost savings and rapid patient recruitment are turning to emerging markets that include China, India and Russia, among the topranked locations in the world for offshore clinical trials. The increase in the number of clinical trials migrating to cities like Shanghai, Mumbai and Moscow has been accompanied by a host of new supply chain challenges – from navigating a web of evolving government regulations for drug importation, to ensuring Good Clinical Practice (GCP) at trial sites, and navigating complicated logistical issues in countries plagued by limited infrastructure and experience. The increased complexity of trials taking place in these and other emerging markets is driven in large part by doubledigit growth in the number of studies for biologics, including vaccines and monoclonal antibodies, that require controlled temperature conditions during shipping and storage. Such growth reflects the efforts of sponsors to contain higher


development costs for biologics, which exceed those of the average small-molecule drug by a whopping $400 million. From a logistics perspective, the increase in trials of biologics means the stakes couldn’t be higher, since loss of temperature control requires replacement of costly product. First and foremost, complying with Good Distribution Practice (GDP) during the movement of product is mandatory for ensuring that material integrity and efficacy are uncompromised. Unfortunately, it’s not always enough. Supply chain managers responsible for transporting an increasing number of biologics for clinical trials are also seeking better ways to monitor and maintain the temperature of materials in transit. One solution under evaluation has been the use of radio frequency identification (RFID) transmitters to continuously monitor temperature-sensitive product. However, early votes are in and despite offering some value, RFID is no magic bullet. While it can alert supply chain managers earlier about the need to re-ship product upon failure, it has no mechanism for preventing failure and, like mobile phones, must be switched off while in transit by plane. The use of global positioning system (GPS) technology is now being explored. At least for the time being, however technological innovation notwithstanding

- proper packaging, shipping and storage of biologics continue to be the best ways of raising the odds of safe passage. So, too, is ensuring that product doesn’t sit for extended periods in customs, where the risks of temperature excursion threaten the viability of product. That’s why supply chain managers arm themselves with a thorough knowledge of the policies and regulations governing import and use of study drugs in trial markets. Such knowledge can help to prevent prolonged customs delays in countries like China, where jurisdictional disputes, such as a refusal by regional authorities to recognise drug import licenses issued by national authorities, are all too common. Since country policies and regulations are known to evolve and change without notice, especially in emerging markets, remaining current on the rule book is a top priority. Another key strategy is the use of a premium courier company with a local presence for assistance in managing the often time-consuming customs clearance. Ground handling on arrival is a highly vulnerable point in the clinical supply chain, especially with respect to temperaturesensitive materials. The use of performance metrics in selecting the right courier companies can go a long way to ensuring reliable, on-time delivery of product. The use of a centralised, regional distribution centre to receive trial materials improves distribution and logistics efficiencies, while limiting the times when trial drug must pass through customs. Coordination of customs transit locally is also a prerequisite to successful supply chain management. The distribution centre will receive, book and inventory trial drug using standard operating procedures (SOPs) and a single information technology (IT) system to ensure transparency and prevent inventory issues over the course of a trial. Inventory control with respect to biologics is particularly critical, because shelf life is not definitively known in the early testing stages, and product could fall out of specification in the course of a trial. The job of the supply chain manager doesn’t end once trial materials arrive at individual clinical sites. The supply chain manager must work closely with each site to ensure that storage locations for temperature-controlled drugs are appropriate, controlled and secure, and that the staff understands these special requirements. That’s when an understanding of the language comes in handy, along with good relationships and the ability to read between the lines. In many countries - China, India and Japan among them - a high level of cultural courtesy makes it difficult for

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people to say no. The ability to interpret what is actually being communicated is essential, saving time, money and face for all concerned. (7) (8) (9) Shared Mission Drives Effective Global Teams The globalisation of the pharmaceutical industry is taking place at every level, including that of the workforce. Multinational programmes have grown to include nontraditional markets, and establishing a strong global team takes time, just like any relationship. The hurdles are particularly high, however, when the team is spread across continents and time zones. The most important step in establishing a global team and culture is that of creating a shared sense of mission and goals. For supply chain managers, it is instilling in teams an understanding that patients are waiting around the world. This uniting concept translates across borders, regions, countries, languages and cultures. Having a common mission is the first step, but companies also need to provide time and opportunities for global team members to meet, know each other and interact face-to-face whenever feasible. In these cost-constrained times, technology can help fill the gaps, but personal meetings are preferred, especially in countries like Brazil and China, where knowing and liking someone can result in smoother business interactions. Finally, leveraging common information sources such as portals can allow team members to gather information expressed the same way, in the same format – keeping the global team, however widely dispersed, on the proverbial same page. (1) Costs at Risk in Some Markets As the number of clinical trials in emerging markets continues to climb, the cost to import trial drugs, supplies and equipment to some countries is creeping up as well. In a few emerging markets, customs officials are inflating the valuation of study drugs as a means of generating revenue. In a recent example, a shipment of study drugs valued at $80,000 six months ago was revalued at $750,000, driving up import costs and leaving the sponsor with the choice of paying the higher duty charges or dropping the trial site in midstudy. The sponsor paid. Cost pressures are also being felt in the area of supplies and equipment, which are typically purchased and shipped from a central location. In high-duty countries, where costs to import these items exceed those of purchasing them locally, the strategy is endangered. The practice of reusing costly equipment such as EEG and ECG machines may also 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

be ending, as customs officials in a growing number of countries routinely value all trial equipment as new for duty purposes. As a result, equipment may only be used for one study, and some large clinical sites are beginning to amass collections of leftovers. One site in India, for example, has five leftover EEG machines that were provided by five study sponsors. The motivation to purchase supplies and equipment locally is also the result of the requirement to re-qualify imported equipment in countries such as China and India, which have different electrical standards. The need to re-qualify a piece of equipment, including items like electronic glucose monitors, sometimes boils down to a single wire of an unapproved colour. Scientific and Ethical Issues Prompt Debate While the globalisation of clinical trials offers multiple benefits for pharmaceutical companies and for society, a February article in the New England Journal of Medicine suggested that scientific and ethical concerns are mounting. International standards and corporate and academic oversight must be improved to ensure that research goals are achieved and societal needs are met, say the authors, all of them researchers at Duke University School of Medicine. They maintain that quality of care, treatment choices, and hospital and clinic infrastructure vary widely between countries, and raise questions about qualifications of individual investigators and review boards, the commitment of local regulatory authorities and the ability of patients to fully understand the implications of testing. While they acknowledge that standards vary widely among countries, particularly in emerging markets, trial sponsors and outsourcing suppliers contend that manufacturing, packaging and conduct of clinical trials meet a single, consistent global standard, regardless of location. These scientific and ethical concerns will no doubt continue to be hotly debated, especially as clinical trials grow in number and complexity across the world. The future of the pharmaceutical industry is predicated on addressing these issues, say the Duke researchers. Meanwhile, the train that is pharmaceutical globalisation continues to accelerate. (10) (11) References (1) Robinson, Robin, “Going…Going…GLOBAL,” PharmaVoice, March 2009, pages 2-5. (2) Website of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH),, Sections entitled “History and Future” and “Frequently Asked Questions” (3) PharmaVoice Podcast, “Global Clinical Trials

Outsourcing: New Tips and Trends,” featuring Patrick Durbin of Fisher Clinical Services, March 2, 2009, industryevents/podcasts.html (4) Richards, Caroline, “Joined up thinking,” SCRIP 100: SCRIP’s Analysis of the Pharmaceutical Industry’s Performance and Prospects,” December 11, 2008, pages 106-107, http://www.scripnews. com/scripnews/multimedia/archive/00018/scrip_ 100_2008_18433a.pdf (5) U.S. National Institutes of Health website,, (6) BearingPoint press release, “BearingPoint Announces Results of Benchmarking Study on Managing the Clinical Trials Supply Chain,” January 21, 2008, Life+Sciences/BearingPoint+Announces+Results +of+Benchmarking+Study+on+%E2%80%9CM anaging+the+Clinical+Trials+Supply+Chain%E 2%80%9D?tab=press&nav=tab (7) Kearney, A.T., Pharmaceutical Executive, “Fishing for Opportunities,” June 1, 2006; http:// articleDetail.jsp?id=333301 (8) Smith, Sean and Fisher, Ian, “Best Practices for Managing a Global Clinical Supply Chain: A Spotlight on China and India,” Journal for Clinical Studies, January 2009, pages 60-62. (9) Roberts, Steven, “Supply & Demand,” Future Pharmaceuticals, Q1 2007, http:// w w w. f u t u r e p h a r m a u s . c o m / ? m c = s u p p l ydemand&page=sc-viewarticle (10) Glickman, Seth et al, “Ethical and Scientific Implications of the Globalization of Clinical Research,” New England Journal of Medicine, Volume 360:816-823, February 19, 2009, http:// (11) Silverman, Ed, “The Race for Global Clinical Trials,” Contract Pharma, April 2009, page 26, articles/2009/04/the-pharma-beat

IAN HUNTER has worked in the Lifesciences environment for over 25 years. This experience covers various disciplines including purchasing, sales, marketing and logistics from local, regional and global perspectives. Prior to joining Fisher Clinical Services Ian worked with DHL for 7 years developing their global Clinical Trials strategy and operations. DR SEAN SMITH has 18 years experience in the Pharmaceutical Industry. After completing his PhD in Medical Chemistry, Sean worked two years as a Post Doctoral Tutor at the University of Manchester. He began his Pharma career as a Formulation Chemist with a Japanese pharmaceutical company based in the UK moving on to become the UK based Product Development Manager in 5 years. Dr. smith joined Fisher Clinical Services in 2004 where he took up the post of General Manager UK. In August 2008 Sean was promoted to the new position of Vice President Clinical Supply Chain taking responsibility of the global logistics element of Fisher Clinical Services.

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Innovation in Endotoxin Detection Moving Out of the Stone Age Endotoxin Detection – a Brief History With the threat of the H1N1 virus and the upcoming flu season upon us, vaccine manufacturers are working diligently to provide an H1N1 vaccine to help protect us from a large outbreak of illness. In addition to safety and effectiveness, part of the quality testing for products such as vaccines and pharmaceuticals includes ensuring that the product passes specifications for sterility and endotoxin.

“In addition to safety and effectiveness, part of the quality testing for products such as vaccines and pharmaceuticals includes ensuring that the product passes specifications for sterility and endotoxin.” The history of endotoxin detection has always included the use of an animal. In the 1920s, a test for the presence of pyrogens in a solution was developed by Florence Seibert using rabbits. During World War II, there was a high demand for safe intravenous solutions, and Florence Seibert’s rabbit pyrogen test was used to check the products for contamination. The United States Pharmacopeia published the first pyrogen test in 1942. This test involved injecting the pharmaceutical into a rabbit and monitoring the animal for an increase in temperature or a fever. If the rabbit spiked a fever, it indicated that the sample contained an unacceptable level of a pyrogen, such as endotoxin, and the batch of product could not be sold. In the late 1960s, researchers studying the blood clotting system of the horseshoe crab found that it was extremely sensitive to endotoxin. Frederick Bang and Jack Levin 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

developed an endotoxin test that involved mixing the blood-clotting factors that are in the amebocyte with a drug sample in a test tube (1). If sufficient endotoxin was present, they found that the liquid in the tube would clot in such way that when the tube was inverted top to bottom, the clot stayed in the bottom of the tube. This was the first “LAL” test for endotoxin. LAL stands for Limulus Amebocyte Lysate and contains the factors inside the amebocytes (blood cells) of the horseshoe crab, Limulus polyphemus. In 1977, the FDA approved the use of the LAL test as a replacement for the Rabbit Pyrogen Test to detect endotoxin in human and animal injectable pharmaceuticals and biologicals, and implantable medical devices. The first commercialised LAL method, the gel clot LAL method, is not very different from the original test made by Bang and Levin. This test provides a simple yes or no answer as to whether or not the product being tested is contaminated with endotoxin. In the 1980s and 1990s, photometric methods were developed that would allow a manufacturer to determine the amount of endotoxin that may be in their product. In these tests, the mixture

of LAL and test sample turns the colour yellow or becomes turbid in the presence of endotoxin. The degree of colour change or how fast the change occurs makes it possible to calculate how much endotoxin is in the test sample. A New Technology for a New Century LAL-based methods continue to dominate the QC laboratories that conduct endotoxin detection tests. The horseshoe crab ancestors and their blood clotting system date back hundreds of millions of years. So, the evolution of the science behind the LAL-based methods was established a long time ago. It has taken humans some time to catch up. The horseshoe crab has also provided us with the endotoxin detection technology of the future. In LAL is the crab’s Factor C, the enzyme that is sensitive to the presence of endotoxin. Using a clone of the horseshoe crab’s DNA, a recombinant form of Factor C (rFC) was produced and an endotoxin detection assay has been developed from it. The rFC assay is the evolution of the LAL assay. It is equivalent to other photometric endotoxin detection methods that use LAL to detect endotoxin

Figure 1: Endotoxin standard curves using eight different lots of rFC. The log net fluorescence is proportional to the log endotoxin concentration and is linear in the 0.01 to 10 EU/ml range. Lot-tolot standard curves exhibit excellent reproducibility.

according to the parameters listed in United States Pharmacopeia (USP) chapter <1225> “Validation of Compendial Procedures” (2). In 2009, the US Food and Drug Administration approved 510(K) submissions that use the rFC method as the final release test. Predictable Assay Performance Due to the biological nature of LAL, utilising blood from the horseshoe crab introduces lot-to-lot variability. Differences between the blood of animals, seasonal changes and environmental factors all can contribute to the variability of the final product. Because rFC is a recombinant form of the horseshoe crab Factor C, it retains all of the endotoxin reactivity that

LAL is known for. However, the cloning and downstream manufacturing procedures result in a reagent that contains only Factor C and none of the other factors found in the traditional LAL cascade. The end result is greater control, leading to a product that has greater lot-to-lot consistency. Standard curves generated from different lots of rFC show remarkable consistency. This translates into more reproducible results and less variable recovery values for your PPCs (Positive Product Controls) (Figure 1). The rFC Assay is Endotoxin-Specific Endotoxin detection methods that rely on LAL suffer from the fact that the LAL enzyme cascade includes two pathways, one triggered by endotoxin and the other

Figure 2: Comparison of glucan activity between kinetic chromogenic LAL and rFC. The false positive signal from the LAL assay is reduced in the presence of a glucan blocker. The rFC assay is endotoxin-specific.

Figure 3: Endotoxin potency of four purified lipopolysaccharide preparations as tested by multiple methods.

triggered by glucans. A positive LAL reaction due to glucans is a false positive for an endotoxin detection assay. As recombinant Factor C is the only enzyme from the cascade in the rFC assay, the test method is specific for endotoxin. Figure 2 illustrates the comparison between the reactivity of the kinetic chromogenic LALbased method (Chromogenic) and the rFC method relative to the presence of glucan in the test product. The positive signal with the Chromogenic method is reduced when a glucan blocker is added into the reaction mixture. The rFC method does not react with glucans, thereby reducing false positive results. Comparable Detection of Endotoxin Studies were conducted to demonstrate the ability of the rFC assay to detect endotoxin from different bacterial species. Figure 3 includes the results of a comparison between the responses of the rFC, kinetic chromogenic LAL and kinetic turbidimetric LAL photometric methods to different sources of purified endotoxin. Three assays were performed for each endotoxin and method combination. From the results shown in Figure 3, the rFC method recognises endotoxin from different source materials similar to other photometric procedures, demonstrating comparability to the LAL-based methods. Endotoxin Recovery from Products Similar to Other Methods Comparisons of the recoveries of known amounts of endotoxin also were conducted. Our global, multi-centre study included testing of ten pharmaceutical or related products with the kinetic chromogenic LAL and rFC methods. The products tested in the multi-centre study included items such as Water for Injection, Lactated Ringer’s Injection USP, 0.9% Sodium Chloride Injection USP, Erythropoietin, Albumin (Human) USP 25% Solution, Vancomycin HCl USP, and Hemodialysate. Each product was spiked with 0.1 EU/ml of endotoxin and tested by the kinetic chromogenic LAL and rFC methods by three analysts at six different locations. Figure 4 illustrates the results of the recovery of the spike. The percent recovery of the 0.1 EU/ml spike in all products (except Human Albumin) was within the current USP specification of 50 – 200% for both methods (3). In an additional study, the recovery of an endotoxin spike of 0.1 EU/ml in Water for Injection was measured by the kinetic turbidimetric LAL photometric method for comparison. The turbidimetric assays were conducted by three analysts at one location. The results in Table 1 show the similarity in the detected level of the endotoxin spike between the methods. In summary, the recovery of endotoxin INTERNATIONAL PHARMACEUTICAL INDUSTRY 87


from water and the other tested products using the rFC method is comparable to that of the LAL-based methods. Standard Curves meet Linearity Requirements An acceptable USP method must elicit results that are proportional to the concentration of the analyte being tested (2). For an endotoxin test, the analyte is endotoxin and linearity is demonstrated by the correlation

coefficient. Table 2 summarises the linear regression statistics from eighteen rFC standard curves generated by the multicentre study. Each curve was comprised of four standards (0.01, 0.1, 1, and 10 EU/ ml) in replicates of three. The correlation coefficients for all eighteen standard curves were greater than the US FDA required 0.980 specification for a quantitative endotoxin detection test (4).

Evolution The speed and ease with which the current endotoxin detection tests can be run in comparison with the rabbit pyrogen test has given the vaccine and pharmaceutical industries the ability to quickly, efficiently and confidently test their products for endotoxin contamination. The rFC assay provides an improvement that diminishes the use of animals for endotoxin detection as well as moving the technology out of the Stone Age. As products using recombinant technology are developed to improve the lives of humans and animals, the same technology should be applied to the quality testing of those products. The rFC assay is the evolution of the LAL test. Combining 21st century technology with the horseshoe crabâ&#x20AC;&#x2122;s endotoxinsensitive protein, Lonza has developed an equivalent, reliable and sustainable endotoxin detection method for the future. Lonza is dedicated to bringing further innovative rapid testing systems to the healthcare industry to help manufacturers deliver their new products to the consumer and patient more quickly, while helping to make sure the products are safe. References: (1) Levin, J. and Bang, F.B. Clottable protein in Limulus: Its localization and kinetics of its coagulation by endotoxin, Thromb. Diath. Haemorrh, 19:186 (1968) (2) United States Pharmacopiea, Chapter <1225> Validation of Compendial Procedures (3) Unites States Pharmacopiea, Chapter <85> Bacterial Endotoxins Test (4) U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Interim Guidance for Human and Veterinary Drug Products and Biologicals (1991)

Figure 4: Recovery of a 0.1 EU/ml endotoxin spike in multiple products is comparable between methods.

Table 1: Recovery of a 0.1 EU/ml endotoxin spike in Water for Injection as tested by multiple methods.

MARIBETH DONOVAN JANKE, PH.D. is the Sr. Product Manager for Endotoxin Detection in the Rapid Testing Systems unit of Lonza Walkersville, Inc., Walkersville, MD, USA. For more information, please visit www.lonza. com/lal or email the author at

Table 2: Linear regression statistic summary, based on 18 standard curves, by six analysts at six sites.


Efficiency Gains In Cell-line Development: Why And How? Synopsis: During the last decade, significantly more biopharmaceuticals have entered pharmaceutical development, increasing the number of protein-based drugs on the market. Besides monoclonal antibodies - the largest product class in development many companies are investing in developing second-generation biologics and vaccines. A key prerequisite for producing many of these products is the development of a high-producing mammalian cell line that stably expresses large volumes of the active substance. In the last 20 years, the industry has developed and improved mammalianbased expression systems and there are now many platform systems that produce 2-4g/l or more of a drug. However, production cell line development is lengthy and resource intensive. Growing attrition rates and competition during the last decade has produced two industry trends - finding ways to shorten development timescales and reducing early development costs. To reduce costs, companies are increasingly considering automation. However, investment and day-today maintenance of laboratory robots is often expensive, meaning they must be routinely used to create a compelling business case. Biopharmaceutical companies thinking of streamlining and improving cell line selection with automation should, therefore, consider approaching a contract manufacturer with relevant experience and a good track record. Introduction: Biopharmaceuticals, such as monoclonal antibodies (mAbs), second generation biopharmaceuticals and vaccines, are becoming increasingly popular. Sales of these products are expected to grow rapidly for the foreseeable future, generating most of large pharmaceutical companiesâ&#x20AC;&#x2122; future growth. The most important cause of the popularity of biopharmaceuticals is they can treat diseases that small molecule drugs have struggled to tackle. Monoclonal antibodies (mAbs) may be the most rapidly growing category of pharmaceuticals. Janice Reichert (1) reported that in mid 2000 the average number of mAbs entering clinical trials had tripled from 12 in 1990 to 34.5. The market for mAbs alone is expected to be worth $50 million by 2013 (2). However, biopharmaceutical success rates have simultaneously decreased so they are now much closer to small molecule drugs (3). For example, CMR reported in 2005 a 13% 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

success rate for biologics moving from toxicity studies to market launched compared to 8% for small molecule drugs. These lowering success rates mean efficiency improvements are needed in biopharmaceutical development pipelines to prevent costs increasing, as has happened with small molecule drugs during the last decade. Successful strategies for past efficiency gains have been automation, standardization and outsourcing. Automation and standardization typically helps to reduce manpower costs whereas one of the main advantages of outsourcing is reducing the fixed costs associated with establishing and maintaining facilities inhouse. This article explains the advantages of automated cell line development and discusses how pharmaceutical companies can make best use of this technology to cut development costs and timelines and address increasingly stringent regulatory requirements. Status of mammalian expression technology: An early step in biopharmaceutical drug development is generating a production cell line or strain that can stably express large amounts of the desired recombinant protein or monoclonal antibody. Remarkably, in 2007, around 2/3 of biopharmaceutical drugs in development worldwide were produced by recombinant mammalian cells - numbers have further increased since (4). Development of high-titer cell lines is key as increasing cell culture productivity is the most important way to reduce manufacturing costs. Many powerful, mainly CHO-based expression platforms have been developed during the last decades, where cell lines, vector constructs and media were optimized in iterative cycles. This has helped increase titers for mAb´s from milligrams in the 80s and 90s to grams today. Today, typical early development targets for cell line development programs are 1-2g/l produced in a generic fed-batch process using an animal component-free medium. For a review of mammalian expression systems and improvements made to increase titers and shorten timelines see (5). Probably the most widely used systems today are CHO DHFRbased systems and the CHO GS system (6) that can be in-licensed from Lonza Biologics. Other systems, including human-cell based systems, are commercially available through in-licensing for in-house cell line development or through outsourced cell-line development. Despite the significant improvements in titers

and timelines, cell-line development remains a highly manual, labour-intensive and tedious process (7,8). Given the increasing attrition rates and pressure to shorten development timelines, it is unsurprising that the industry has asked for approaches that improve the efficiency of cell line development. Among the latest developments in cell line development are automated techniques for screening large numbers of transfected cell lines. Steps in cell line development Typically, the cell line development process consists of a well-orchestrated sequence of steps that are similar for many of the currently most established expression systems that are based on random integration of the gene of interest into the cellular genome (see figure 1). First, a cell pool is transfected with the plasmid DNA encoding for the biopharmaceutical product. The DNA is incorporated into the host cell chromosome together with a selection marker. Drug yield depends largely on the integration site, and there is enormous variation in transfectant productivity and ability to consistently produce high-quality drugs (7,9). When using the DHFR- selection system, a gene amplification step is often needed to improve cellular titers. The next phase in cell line selection is a screening process in multi-well plates to identify the highest-producing cell clones. Statistically, the chances of finding high producing clones increase with an increasing number of screened clones. Therefore, screening large number of clones is an advantage because product cost strongly depends on titer. The clones with the highest titer and acceptable growth rate are selected, expanded and screened again for productivity. After this initial screening, a reduced number of cell lines are expanded further, and productivity and product quality typically evaluated in simple batch and fed-batch cultures in shake flasks. A few production cell line candidates might be then evaluated for productivity and product quality in benchtop bioreactors. A limiting dilution step may also be performed to ensure the cell line is derived from a single clone. Benefits of automation in production cell line development: This screening and scale-up process is timeconsuming, labour intensive and error prone due to the tedious manual handling. Effort is further increased when screening many clones to identify high-titer cell lines and/or cell


Colony selection

Screen and expansion of transfectants

Suspension adaptation and cryo preservation

Elisa pre-screen assay and expansion to 24well plates

Secondary screen: Batch evaluation in shaker flasks

Fed-batch evaluation

Bioreactor evaluation

HPLC primary screen and expansion to 6-well plates

Fig 1: Schematic drawing of the typical steps involved in cell line development. At Recipharm Biologics, clone selection and expansion to 24-well and 6-well format is automated using the CelloTM robotics system from The Automation Partnership.

lines expressing the desired product quality with regard to glycosylation or other key posttranslational modifications. Consequently, the process is expensive because inspection of the wells, procedures for clone picking and cell culture expansion, and documentation, is mainly done manually. Techniques and products, such as fluorescence-activated cell sorting (FACS) (8), the Genetix ClonePix FL system (10) and, recently, automation of liquid handling and microscopic inspection have improved screening efficiency. Automation, however, is more like the manual procedure making it easier to use different expression systems without major modifications. Furthermore, no foreign substances have to be introduced for fluorescence sorting or clone picking, and documentation is also automated. The successful automation of cell-line selection using the Lonza Biologics CHO GS has been recently repeated (11). Now scientists working at Recipharm Biologics have also automated the invoitrogen OptiCHO DHFR expression system (12) on the basis of the same robotics equiptment. Studies using the CHO GS expression system showed the automated system could generate equal quality cell lines to those produced by manual selection, while allowing three times more cell lines to be screened by the same number of staff (11). They also showed screening more clones increases the number of high-titer cell lines identified. This, in turn, improves the likelihood of selecting a high-titer production cell line with desired product characteristics and stability. Comparative studies indicate, therefore, that higher titer cell lines could be developed using automation (unpublished data). The automation approach is based on the Cello robotic system manufactured by The Automation Partnership based in Royston, UK. The Cello system is shown in figure 2 and details of the liquid handling part are shown in figure 3. It consists of a plate-handling robot, up to three incubators, a cold storage unit, two liquid handling units with pipetting robots, and a high-resolution microscope (Digilab). Cello is used to automate early screening, including distribution of the cell pool after transfection, limiting dilution, microscopic monitoring, clone picking and expansion, sampling and documentation. The system is combined with a protein-A HPLC system capable of handling samples in multi-well plates. As well as screening enormous numbers

of cells per cell line, the capacity of the robotics system allows cell line development projects to be initiated weekly. This enables, for example, the frontloading of monoclonal antibody cell line development projects where many lead antibody constructs with different characteristics (e.g. epitope specificity) are tested in animal studies before selection of the final antibody candidate. Waiting until this selection has taken place often loses valuable time to clinic that not necessarily can be compensated as significant part of the development program is controlled by cell growth that is similar for the various systems. For biosimilars or second-generation biopharmaceutical programs, this huge capacity could help streamline the cell-line selection process. Here, often the challenge is to find a cell line that provides the product characteristics that is targeted as glycosylation pattern of different clones can vary largely as well as other post-translational modifications

that are key for biological activity. Jan Visser from Sandoz discussed the need to screen many cell lines for biosimilars development in his presentation at the 21th ESACT meeting in Dublin this year (13). Another area where large screens and automation might be useful is when Quality by Design is applied early in process development. For example, Carole Heath from Amgen reported in 2007 (14) how they have introduced QbD in cell line development by finding cell lines displaying a range of desirable characteristics. This allows them to delay process optimization until later in their drug development, while still relying on the robustness of the cell line. Another advantage of automation is that detailed information about each clone and related microscope images is automatically recorded. This improves traceability, is less prone to manual error and helps to simplify producing detailed documentation for regulatory purposes. More recently, robotics providers have also invested in developing systems to automate the subsequent shake flask evaluation steps which has become the next bottleneck in the cell-line development process. There are already commercially available systems that use multi-parallel miniaturized shaker systems (15). However, these systems still require a lot of manual handling. Automation: Worth the investment? Investing in robotic systems is expensive, with an initial capital cost that easily can exceed

Fig. 2: Schematic overview of the robotics system used at RecipharmBiologics showing the transfer robot in the central aisle, reader module and laminar airflow cabinets for sterile plate handling on the left hand side. On the right there is a control module and storage carousels. INTERNATIONAL PHARMACEUTICAL INDUSTRY 91

efficient screening and isolation of antibodyand biopharmaceutical-secreting cell lines. Nature Methods (Suppl S), pp.4–5 11. Lindgren, K. et al., 2009. Automation of cell line development. Cytotechnology, 59, pp.1–10 12. Salmen, A et al., 2009. Automation of cell-line development using the OptiCHO expression system, poster presented on the 21th ESACT meeting in Dublin June 2009 13. Visser, J., 2009. Leading the way in biosimilar development, oral presentation on the 21th ESACT meeting in Dublin, June 2009 14. Heath, C., 2007. Circumventing the “pay now or pay later” dilemma: strategies for achieving process development with speed and long-term potential. Oral presentation on 20th ESACT meeting in Dresden, June 2007 15. De Jesus, M.J. et al., 2004. TubeSpin satellites: a fast track approach for process development with animal cells using shaking technology, Biochemical Engineering Journal, 17(3), pp.217–223. Fig. 3: Detail of the liqid handling systemin the CelloTM robotics system used at Recipharm Biologics.

equipment, there are significant maintenance costs, and special maintenance routines to ensure hygienic operation because cell line handling must be sterile. Given the complex nature of the system, speciallytrained operators and maintenance staff are needed. Breakeven calculations for this kind of investments typically show that a significant number (>6-10) of cell lines needs to be developed per year to match a depreciation timeline of typically 5 years. Using a contractor with all routines already established and a track record of developing production cell lines using different systems offers clear advantages to biopharmaceutical companies wanting to benefit from automated cell line development, but concerned about the investment and technical risks involved. An experienced outsourcing partner delivers benefits whether the biopharmaceutical company wants to outsource automation of their own proprietary system or buy a cell line made with a commercially available expression system. Conclusion: Biopharmaceuticals are becoming increasingly popular and the selection of mammalian cell lines to manufacture these products remains a key step their early development affecting the whole lifecycle and economy of the potential future drug. Automating large parts of early the cell line development process can radically increase the number of cell lines that a pharmaceutical company can develop without recruiting extra staff. This could have a major impact on the speed and cost of biopharmaceutical development programs as frontloading can be applied more widely and cell lines with better productivity, stability and other characteristics can be developed. Although the technology is attractive, it is only cost effective for biopharmaceutical 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY

companies with a significant portfolio of cell line development programs each year. Companies with a more modest pipeline may find it more cost effective to approach an outsourcing partner experienced in automated cell line development. By doing so, they can reap the benefits of this technology without the disadvantages and risks of buying, maintaining and routinely using a robotic system. References 1. Reichart, J, M. Tuffts Center for the Study of Drug Development March 11, 2008 2. Datamonitor, 2008. Monoclonal antibodies: Update 2008. Available at: www. 3. Pavlou, A K, Reichert J. M. N. 2004 Recombinant protein therapeutic- success rates, market trends and values to 2010. Nature Biotechnology vol 22, no. 12, pp. 1513-1519 4. HighTech Business Decisions 2007. Biopharmaceutical Contract Manufacturing 2007: Quality, Capacities and Emerging Technologies 5. Clarke, H.R.G. & Compton, B.J., 2008. Comparing mammalian expression systems. BioProcess International, Nov. Supplement 6. Bioprocess International Reader round table April 2008 7. Birch, J.R. & Racher, A.J., 2006. Antibody production. Advanced Drug Delivery Reviews, 58, pp.671–685 8. Carroll, S. & Al-Rubeai, M., 2004. The selection of high-producing cell lines using flow cytometry and cell sorting. Expert Opinion on Biological Therapy, 4, pp.1821–1829 9. Wurm, F.M., 2004. Production of recombinant protein therapeutics in cultivated mammalian cell lines. Nature Biotechnology, 22, pp.1393–1398 10. Mann, C. et al., 2006. Rapid and

THOMAS ELDERED IS CHIEF EXECUTIVE OFFICER OF RECIPHARM AB, one of the world’s top ten contract biomanufacturing companies, where he is responsible for its day-to-day business and management. Before becoming CEO in 2008, he served as the company’s co-executive vice president for 13 years. During his career he has held senior positions in a range of pharmaceutical companies including head of operations and director of logistics and planning at Kabi Pharmacia AB, factory manager at Pharmacia AB and international production coordinator for Fermenta. He holds an M.Sc. in Industrial and Management Engineering from the Institute of Technology, Linkoping University, Sweden. CHRISTEL FENGE IS MANAGING DIRECTOR OF RECIPHARM BIOLOGICS, a newly formed subsidiary of Recipharm AB offering contract development services for monoclonal antibodies and recombinant proteins expressed in mammalian cell culture systems. Part of this business is the development of production cell lines either by automating customers’ own expression systems or using CHO DHFR- based technology. Before joining Recipharm, she worked in different biopharmaceutical process development roles at AstraZeneca, Astra, Pharmacia & Upjohn and Kabi Pharmacia. Christel holds a Ph.D. in biochemistry from the University of Hannover, Germany.

Contract Manufacturing of Biopharmaceuticals

Biovian cGMP services Microbial fermentation Mammalian cell culture Protein purification Gene therapy vector production Formulation Fill & Finish Lyophilisation Analytical quality control Cell bank preparation and storage


New Models for Cost Coverage of Drugs call for Improved Patient Compliance In a recently published study (Sept 4, 2009) on the future of the pharma industry Roland Berger Strategy Consulting, one of the world’s top ranking business consulting agencies describe new models of medication reimbursement as the health care payers will no longer be able to cover the cost of medicines which quite often don’t work. These new models will include guaranties for the effectiveness of a drug or it will not be paid for. The classical way by which the health care system pays the price once negotiated with the pharma company will become the exception in a few years time. In Canada a top tier pharma company returns the cost for an Osteoporosis medication if it fails to provide the desired effect already today. The company even pays the surgical intervention that may become necessary as the consequence of bone fractures. Such drastic changes in cost coverage emphasize once more one of the main factors if medicines fail to work. Medicines which are not taken cannot be effective. It is common knowledge that patients’ compliance/adherence to their therapy plays a crucial role in achieving a positive outcome or as R.B. Haynes put it: “Increasing the effectiveness of adherence interventions might have a far greater impact on the health of the population than any improvement in specific medical treatment” . And Heneghan CJ, Glasziou P, Perera R 2 found in their study about the role of packaging with regard to long term medicinal treatment that: ”People often miss taking prescribed medication, because of forgetfulness, changing medication schedules or busy lifestyles. It is estimated that between 40% and 60% of people do not take medication as prescribed, which can lead to worse health outcomes. Packaging of medications with reminder systems for the day and/or time of the week is an attempt to help people take long-term medications.” HCPC-Europe, a not for profit organisation, who’s mission is to assist and to educate the healthcare sector in the improvement of patient compliance through the use of packaging solutions 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

organises an annual conference which this year will take place in Basel Switzerland on November 10. An essential element of the conference is awarding novel pack design for supporting patients’ adherence to medicinal therapy. The jury consisting of members of HCPC-Europe’s advisory board and board will have to decide between a large number of entries ranging between creative low cost solutions and most sophisticated high tech drug delivery systems/packaging. “The global growth of the pharmaceutical industry will increasingly require financing from beyond health insurance companies” says a recently published study (Sept. 4, 2009) from Roland Berger Strategy Consulting one of the world’s top ranking business consulting agencies, on the future of the pharmaceutical industry and it continues “innovative partnerships with payers have sprung up in the established markets as well, particularly in light of increasing cost pressure: Survey respondents are placing priority on valueadded models (43%) and risk-sharing models (38%).” What this means is best described by a cost coverage agreement between a top tier pharma company and the health insurance in Canada for a new osteoporosis medicine. The insurance company pays the price this company ask for this novel medicine. If, however, the drug fails the company not only has to return the expense for the medication but even has to cover the cost of surgical interventions as they may become necessary as the consequence of frequently occurring complicated bone fractures with patients suffering from this disease. Another model by which the pharma company guarantees the effectiveness if its drug was negotiated between two drug producers and the Italian Servizio Sanitario Nazionale. During the first three months of treatment the pharma companies only get half of the negotiated price for their cancer medication. In the case the treatment provides the desired effect the pharma companies are paid the full price. If, however, the drug has no or insufficient effect it will no longer be applied. While in clinical trials the outcome decides over the

future of a medicine the assessment of the effectiveness of a treatment in “real life” is left to the patients and their doctors, who, in most cases ignore whether the drugs were applied in the correct way, the correct quantity at the correct time; and drugs that are not taken cannot work. Under these circumstances pharma companies will struggle to guarantee for their products. And they will have to make all efforts to help patients to be as compliant as possible as non-adherence to medical treatment remains a persistent and still underestimated problem. “In spite of many advances made in adherence research, non-adherence rates have remained nearly unchanged in the last decades.” Statements like these suggest that efforts to improve patients’ adherence have been insufficient and/or ineffective. With these new models of cost coverage for medicines this matter is to be seen from a new, different angle. Profitability of medicines will more than ever before depend on patients’ compliance/ adherence. The reasons for non compliance are well known. Numerous studies have looked into the matter and show that most patients will be non-compliant some of the time and there are various patterns of compliance or rather non-compliance according to which the likely reasons and causes can be linked. “People often miss taking prescribed medication, because of forgetfulness, changing medication schedules or busy lifestyles. It is estimated that between 40% and 60% of people do not take medication as prescribed, which can lead to worse health outcomes.” Omissions of doses are mostly linked with forgetfulness or with the complexity of the therapy. Underdosing is mostly caused by fears of side effects. Overdosing frequently happens when the desired effect of the medication does not happen within the expected time frame. Medication holidays are mostly the result of temporary improvement of the condition (symptoms less apparent) and happen particularly frequently with antihypertensives. Incorrect timing is likely to be caused by forgetfulness. While it will be difficult to influence




HCPC-Europe Compliance Enhancing Drug Packaging Award 2007 – ZacPac

HCPC-Europe Compliance Enhancing Drug Packaging Award 2008 – Stora Enso Pharma DDSi

some of the causes for non compliance/ adherence, the main factor –forgetfulness– can rather easily be dealt with. Calendar drug packages (such as ZacPac) or innovative packs incorporating a chip with reminder functions, capable of communicating with a central database (like Stora Enso’s DDSi) are commercially available and designed to help patients to adhere to their therapies. HCPC-Europe, a not for profit organisation, who’s mission is to assist and to educate the healthcare sector in the improvement of patient compliance through the use of packaging solutions was set up between the pharmaceutical, the packaging and the machinery industries with the assistance of patient organisations, driven by the awareness that health care systems are loosing enormous sums of money through medication that is not taken properly or not at all. Thoughtful packaging of medicines, the founders and members 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of HCPC-Europe argue, can in itself play a significant part in patient compliance and that, by organizing as a body, HCPCEurope can be effective in promoting packaging-related initiatives which will help improve patient compliance. One of HCPC-Europe’s initiatives is their yearly conference at which innovative pack design is awarded with a trophy representing Colubus’ egg. (“Columbus´ Egg is a turn of phrase that describes a stupefying simple solution for what might appear to be a complex unsolvable problem. Anecdotal - folklore suggests that when Christopher Columbus returned from his voyage of discovery of the Americas in the year 1493 he was having dinner with Cardinal Mendoza who commented that it had not really been such a big deal to discover the Americas - in fact anyone could have done it. In retaliation Christopher Columbus challenged all persons present to stand an egg on end.

Everyone tried but failed. Christopher then took the egg - he tapped it gently on the table breaking it slightly and, with this, the egg stood on its end. Hence the Egg of Columbus. Allegedly the other persons did protest that they too could have done this but Christopher simply responded that yes they could have done it but he actually did it.) The new models for cost coverage of medicines underline the importance of HCPC-Europe’s initiatives. At this year’s conference which will take place at the Basel-City facilities of the Institute of Pharma Technology at the FHNW School of Life Sciences, Basel Switzerland on Nov. 10th, 2009 speakers from all sectors of healthcare will give an insight into their findings regarding the relation between compliance enhancing drug packaging, outcomes and the respective return on investment. In addition Nicola Bedlington, Executive Director of the European Patients’ Forum and HCPC-Europe will present the results of their Voice of the Patients Surveys on the subject. Like in the years before the pharma industry as well as other industries and private individuals have participated in the contest for the Drug Packaging Design Award and made exciting innovative entries. Again, they range from low cost solutions using conventional technology combined with clever design to most sophisticated electronically assisted drug delivery systems.

TASSILO KORAB MSC started his career as an international Sales Manager, and has been in the packaging industry for more than 20 years. As a recognised expert in flexible packaging, he holds an MSc in Healthcare Economics, as well as having written several publications on patient compliance, standards and regulations for child resistant packaging and the war against counterfeits. Tassilo Korab is Managing Director of TKM Handelsg.m.b.H., Vienna, Austria, a consulting company in the sector of Flexible Packaging for the pharmaceutical and healthcare industries. He was one of the co-founders of HCPC-Europe, the Healthcare Compliance Packaging Council, a not-forprofit organization uniting the pharmaceutical industry, packaging materials suppliers, packaging machine manufacturers and patient organisations in their common endeavour to improve drug packaging design in the interest of the patients. He has been representing the organization first as funding member and member of the board and, since September 2005, as Executive Director.

Compliance Packaging extending supply chain security beyond the pharmacy to the patient The pharmaceutical sector remains fairly well unchallenged as one of the world’s most regulated industrial sectors and the intense focus of recent months and years on securing the supply chain serves only to reinforce this. Without exception, promoters of the various schemes cite patient protection as a key driver - in its simplest expression, this means ensuring that the correct product reaches the patient. However, the economic imperatives cannot be ignored: healthcare providers and governments in the developed world face spiralling care costs as the age profile of the population increases, reimbursement fraud is ever-present and the global trade in counterfeit medicines continues unabated. It’s impossible to be exact about on the level of counterfeit products in the supply chain but it is claimed that in some developing countries, it is a staggering 70% and that over half these products contain no active ingredient whatsoever. Adamos Adamou, the EU Minister responsible for steering the Counterfeit Medicines Directive through the European Parliament, has said, “Today, there is no guarantee of buying safe medicines. Counterfeit medicines are a form of terrorism against human health. It doesn’t matter whether a pill contains sugar or poison: if the safety is compromised, so is our health.” No surprise, then, that the entire community is focused on devising and implementing measures to secure the supply chain, including e-pedigree authentication through Track and Trace strategies based on mass serialisation at unit of sale level. The objective is to ensure that, however convoluted the supply chain, the pack reaches the pharmacy exactly as it left the manufacturer. The principle is a laudable one but what many of the legislators appear to overlook is that the supply chain doesn’t end at the pharmacy – it ends with safe administration of the medication to the patient. And if the patient doesn’t take it correctly, or indeed, if he doesn’t take it at all, the huge investment and effort involved in developing, manufacturing, packaging and authenticating the product is compromised or even obviated. One half of the patients for whom appropriate medication is prescribed fail to receive the full benefits because of inadequate adherence to treatment. In our view, then, the addenda to any supply chain security scheme should include: • Safe delivery to the patient • Safe storage to the patient • Proper use by the patient There is, of course, a huge difference

between medicines dispensed from pharmacies in hospitals or other institutions for in-patient care and those dispensed from high street outlets for administration in the home. In the former scenario, hospital regimes generally dictate timely administration and correct dosage, backed by appropriate record keeping. In the US, the FDA’s mandates requiring barcodes at unit dose level has prompted a shift to electronic records, extending the e-pedigree right to the patient. The story in the home, though, is altogether different: professional liability doesn’t apply where a medicine is self-administered or where the care provider is a family member, routines are rather less rigid and record keeping is not a requirement. As health care costs continue to hit alltime highs, governments would do well to take a closer look at patient non-compliance, which has been shown to be a significant contributing factor. It’s a complex and multifaceted issue but studies in the US show that poor adherence to medications causes an estimated 125,000 deaths annually and accounts for 10-25% of hospital and care home admissions. ‘Side effects’ of non-compliance can include unnecessary disease progression, complications requiring additional treatment, prescriptions or hospitalisation, reduced patient functionality and quality of life – all of which have significant economic implications. Some of the common causes of noncompliance include • Failing to collect or fulfil a repeat prescription • Over- or under dosing • Taking the wrong medication • Prematurely discontinuing a medication • Taking a dose at the wrong time • Taking a medication prescribed to someone else • Taking a dose with prohibited foods • Storing a medication incorrectly • Incorrect use of medical devices such as inhalers Elsewhere in this issue, my fellow HCPCEurope board member Tassilo Korab has highlighted the trend for pharmaceutical manufacturers to underwrite the cost of medicines by reimbursing healthcare providers for the cost of treatments that are deemed ineffective. Yet with non-adherence rates typically ranging from 30-60% , the potential commercial risk to manufacturers is

huge. While manufacturers cannot be held solely responsible for non-compliance, the scenario above demonstrates how vital it is – from both ethical and commercial perspectives – that they take every possible step to facilitate compliance. Packaging has a significant role to play here: correctly executed, compliance-enhancing packaging offers visual confirmation of daily doses taken, gives a clear indication of when a new course is required and serves to remind the patient of the reasons for treatment and the importance of the drug in his care plan. Brecon and its sister companies in the ABC Packaging Group have been working with leading manufacturers over many years to develop compliance-enhancing packaging – in addition to our wide experience of packing commercial products, there is much we can add thanks to our particular expertise in clinical trials supplies, where compliance is both essential and closely monitored. A key challenge for the industry is that compliance rates vary greatly according to the condition being treated. The origins of compliance-enhancing packaging can be traced to the introduction of the birth control pill almost 50 years ago: to day, this category of product boasts the highest rate of compliance, over 95% for any product. Why? Because users understand that noncompliance can have a very rapid and tangible impact on their lives. At the other end of the scale, compliance rates for chronic conditions such as congestive heart failure, diabetes and glaucoma, where disease progression may be more insidious, languish at around 42% - although in the case of glaucoma, this increases to 58% once sight has been lost in one eye.


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The calendar blister pack developed to aid compliance for birth control pills is still the ‘front line of defence’ in compliance packaging, providing a straightforward yes/no indication of whether a medication has been taken on a particular day or at a particular time. And studies repeatedly show that the blister – with or without calendar – delivers greatly improved compliance for solid dose products as compared to alternative pack forms such as bottles. Typical of these is a 2005 study which measured the relative compliance and effectiveness of the ACE inhibitor lisinopril supplied in walleted blister packs as against bottles. Results of the study showed that 48% of patients receiving blister packs saw improved blood pressure, compared with less than 20% for those receiving bottles. This study also underlines how the compliance-enhancing benefits of the blister can be complemented by combining it with other pack strategies. As referenced above, patients are far more likely to comply with their regimen if they understand what they have been prescribed and why. Yet how many times do we receive a medicine, either by prescription or by purchasing it over the counter, and discard the accompanying product information after a cursory glance at best? The wallet pack used in the lisinopril study served to ensure that product and dosage information remained visible and attached to the blister at all times. One of the latest and most effective demonstrations of this philosophy is Burgopak’s unique sliding blister pack for pharmaceuticals. The patented pack design ensures that patient information is never separated from the product and it was recently awarded the top US rating for its CRSF properties. This is one of the most important innovations we’ve seen in pharmaceutical packaging for many years. Key to its appeal is the fact that the integrity of the pack is maintained at all times: this has already been seized on by the pharma marketing community as an excellent means of reinforcing brand messages in the highly competitive OTC sector. However, its compliance-enhancing capabilities are arousing significant interest from the Rx sector too, particularly since its distinctive and patented design is in itself an effective deterrent for the counterfeiters. What Burgopak and other complianceenhancing pack formats pre-suppose is that the pack will be delivered to the patient

exactly as it leaves the manufacturer. Original Pack Dispensing (OPD) was a key issue in the UK and many other markets some 20 years ago and was encouraged or enforced by legislatures as a means of improving patient safety. OPD continues to be cited as good practice as compared with the previous method of prescription fulfilment that typically involved a pharmacist dispensing the appropriate number of tablets from bulk containers. And

with good reason: eliminating repackaging in the pharmacy reduces the potential for cross-contamination, it enhances product stability and it means that all the security measures employed during manufacture and packaging – designed to ensure the correct product at the correct strength is collated with the correct product information and pack remain uncompromised. It’s somewhat ironic, that in recent years, the need to control prescription costs has become evident in a new practice, whereby the pharmacist supplies a full or partial blister in a generic carton, and frequently with little or no product information. While this achieves some of the goals associated with OPD, its implications for compliance are alarming. Governments may well argue that saving a few pennies per prescription adds up to a significant annual saving overall, the hidden and long-term costs of non-compliance are huge. To paraphrase Mr Adamou: “It doesn’t matter whether a pill is good or bad: if the patient doesn’t take it, or takes it incorrectly our health is compromised.” (PAGB code of practice) Over the counter medicines are designed for the public to choose and use without medical intervention for a range of illnesses. Good consumer information is essential to

ensure that people can safely self medicate and the most important place for this information is with the product itself. Many OTC medicines contain ingredients which were previously available only in prescription products but which have been evaluated as suitable for use in self medication. As a condition of this change of availability, a great deal of emphasis is placed on the provision of detailed information on the pack to ensure it can be used safely. Such medicines can be purchased only in pharmacies but with continued evidence of safety in use they can be made available for sale in general sales outlets and can be on self selection in pharmacies. With this high level of self selection it is essential that the label and leaflet information supplied with the product helps people to choose and use medicines safely. While labelling regulations establish the information which must be on a product label and for some items the order in which they are to be set out, every medicinal product has its own information requirements linked to its active ingredient and formulation. The

Summary of Product Characteristics is the blue print for packaging information and each piece of information on the label must be supported by information in the SmPC. Interesting that this applies to POM-P medicines but many prescription meds are not subject. (e.g. Zopiclone, Tramadol, supplied to R.Alt with no info. STEVE KEMP has 15 years’ experience of pharmaceutical packaging. He is Business Development Director at Brecon Pharmaceuticals, a post he has held since joining the company in 2001. Prior to joining Brecon, he was Commercial Services Director at PCI/Unipack, subsequently Cardinal Health. Since 2008, Mr Kemp has served as Vice-Chairman of the European Healthcare Compliance Packaging Council (, whose mission is to assist and educate the healthcare sector in the improvement of patient compliance through the use of packaging solutions. Email:


Intelligent Packaging: 21st Century Secret of Patient Compliance? As Protomed’s founder Norman Niven prepares to bring together pharma’s key opinion leaders at a pioneering industry seminar this month, Mark Barker of IPI finds out why ‘smart packaging’ could be the future of improved patient care. IPI: How big an issue is patient compliance? Medication compliance has burdened the healthcare system for years. It’s estimated 60 per cent of patients don’t follow the instructions on their prescription, and this is even more common in the over-65s. As a result, around 15 per cent of all hospital admissions are due to medication mismanagement. IPI: You’ve arranged a seminar to tackle this issue in more detail – tell us more. Non-compliance costs the healthcare industry dearly, both financially, and in terms of patient wellbeing. At a time when the health service is suffering a mass resource shortage, and patients are losing faith in traditional medicine, it’s critical we employ all the tools available to counter the compliance problem. We’re bringing together thoughtleaders from all corners of the pharma and healthcare landscape to focus on bringing this issue to the fore. With speakers such as David Pruce of the RPS (Royal Pharmaceutical Society) joining us, we’ll be examining how we can bring about change in the industry’s approach to managing medication. IPI: How can technology improve compliance? Isn’t it just a matter of human error? Technological innovation has advanced tremendously over the last decade, but the pharma industry has been a relatively late adopter. More recently though, pharma companies have recognised that mobile and packaging technologies could hold the solution to patient compliance. Innovations like Biodose® minimise human error by packaging oral medication in pre-measured pods personalised with patient data, making it possible to trace electronically when and whether it is taken. IPI: And how can systems like this make a difference? Pharma companies have used this approach in clinical trials to ensure medication is taken at the right time and dosage to minimise inconsistencies that could invalidate the results. Also, care homes can source premeasured patient packs to speed up round 102 INTERNATIONAL PHARMACEUTICAL INDUSTRY

times, freeing up caregivers’ time to focus on patients’ wellbeing. Many pharmacies provide the Biodose system to customers taking multiple prescriptions, which reduces error and accelerates recovery. IPI: What’s the incentive for pharma companies to move towards more hi-tech packaging? In this crowded marketplace, compliance monitoring programmes offer pharma companies a valuable USP. Rather than launching a new product, they can reinvigorate existing brands by offering the added value of pre-measured packaging and a compliance tracking system. To increase brand loyalty when a product’s patent is nearing expiry, pharma companies can offer this as a complementary service to pharmacists and medical professionals prescribing a particular brand. This enables pharmacists to offer added benefits to their patients and also reduces brand switching. By adopting this technology, pharma companies can demonstrate they care that their products are helping patients and that the government gets maximum value for its investment in medication. Switching brands when medication appears not to work is an enormous expense for the NHS. But if the drugs don’t work, it’s usually because patients are not taking them correctly – something they’ll rarely admit to their doctor or pharmacist. Our compliance-tracking technology helps medical professionals evaluate the true effect of a given drug, minimising the need to switch brands or increase dosage unnecessarily. IPI: Is intelligent packaging the future of patient compliance? We’re constantly developing technologies that increase the likelihood of patients taking medication as instructed, which is a huge step forward for the whole industry. The next stage is to identify non-compliance by tracking patient activity, and technology now gives us the tools to do this. We’ve recently enhanced the function of Biodose, enabling it to monitor electronically when patients are taking medication. A microchip embedded in the container is programmed with the time medication should be taken. The package then emits a reminder if the seal on each day’s medication isn’t broken. The data can also be transmitted to the PC or mobile phone of a GP, carer or family member to monitor whether medication has been taken

correctly. This has major potential for reducing deliberate non-compliance – a widespread trend with considerable financial implications for the NHS. And for all those with an interest in increasing the efficacy and efficiency of modern healthcare, using technology to eliminate error and improve recovery can only be a positive progression. Sources: Safety in doses: medication safety incidents in the NHS, NHS National Patient Safety Agency (2007) Research by Medco Health Solutions on drug error rate among elderly patients (2006)

NORMAN NIVEN has thirty years’ experience of primary and secondary healthcare as former director of BUPA Care Services. From his roots as a pharmacist, Norman has applied his industry knowledge and entrepreneurial streak to develop the total medication management system Biodose. As a member of HCPC Europe (Healthcare Compliance and Packaging Council), he now helps raise awareness of the role of packaging technologies in patient compliance. Norman Niven, creator of medication management system, Biodose, works with HCPC Europe (Healthcare Compliance and Packaging Council) to highlight the challenge of patient compliance

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