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JOURNAL FOR May 2009 U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets FDA Bioresearch Monitoring Program Clinical Trials In Supportive Care of Cancer Patients Australasia A Stepping Stone to Markets Paediatric Trials Not Child’s Play for Insurers www.jforcs.com Contents KEYNOTE ADVISOR Mark A. Goldberg, MD MANAGING DIRECTOR 4 Martin Wright PUBLISHER WATCH PAGES 6 FDA WATCH Latest Developments in: FDA Enforcement Recalls Advertising Clinical Trials By Joe Pickett of EXPERTBRIEFINGS 8 Protecting Human Subjects in Clinical Trials: The FDA Bioresearch Monitoring Program The goals of the FDA’s BIMO Program are to support patient rights and safety and maintain data integrity in clinical trials. BIMO is facilitated by inspections of investigators, monitoring of studies, and laboratory validations throughout international sites. The four main areas of focus for inspections are sponsor, monitor or contract research organisations (CROs), the clinical investigators (CIs), institutional review boards (IRBs), and nonclinical laboratories. By Regina Ballinger of THOMSON REUTERS 10 Australasia Watch Australian Clinical Trial Notification (CTN) Scheme, as the preferred regulatory pathway, underpins the attractiveness of Australia to product developers both large and small. The CTN is a notification scheme, and over 95% of all trials conducted in Australia are approved via this route. By Russell Neal of Clinical Network Services (CNS) Pty Ltd. 12 Drug Development in China Related Regulations on Monitoring Period of New Drugs: The SFDA definitively stated the monitoring period of new drugs in the Drug Registration Regulation issued in July 2007, as well as introducing some relevant regulations. The SFDA can set up a monitoring period for the approved new drug. By Dr. Xunting Zeng of INCROM CHINA 14 Korea: New ‘Global Hub’ for Multinational Clinical Trials In recent years, Korea has grown up both nominally and virtually as the hub of multinational clinical trials. This can be seen as the fruits of the cooperative efforts made by Korea’s government, academia and industry to become a medical and healthcare power nation. By Kyung Won Jang, of the Korea Health Industry Development Institute Mark Barker MANAGING EDITOR Jake Tong EDITORIAL COORDINATOR Janet Douglas EDITORIAL ASSISTANTS Nick Love, Kevin Cross, Lanny McEnzie EDITORIAL ADVISOR KEYNOTE DESIGN DIRECTOR Sureka Dharuman RESEARCH & CIRCULATION MANAGER Dorothy Brooks ADVERTISING SALES Victoria Winward Zareen Monet ADMINISTRATOR Barbara Lasco FRONT COVER Inhouse – Design PUBLISHED BY: Pharma Publications www.pharmapubs.com Address: Diamond Key Building, Unit 4, Burwell Industrial Estate, Burwell Road, London E10 7QG, Tel: 0044(0)2085917584. Fax: 0014802475316. Email all correspondence to: [email protected] Journal for Clinical Studies – ISSN 1758-5678 is published bi - monthly by PHARMAPUBS. The opinions and views expressed by the authors in this journal are not necessarily those of the Publisher, the Consultant Editor and the companies named herein are not responsible for such opinions and views, or for any inaccuracies in the articles. The entire content of this publication is protected by copyright, No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form, by any means – electronic, mechanical, photocopying or otherwise – without the prior permission of the Publisher. 2009 PHARMA PUBLICATIONS www.jforcs.com JCS 1 Contents 16 18 The Global Crisis: An Advantageous Momentum for Latin America “Will Latin America continue to be seen as a region of opportunity for the global industry?” Will they (sponsors and CROs in the Northern Hemisphere alike) capitalise on the huge opportunities which are present here? An insight by Oscar Podesta of CHILTERN – Latin America. Paediatric Trials – Not Child’s Play for Insurers Chris Tait of Chubb Insurance Company of Europe SE, as an underwriter asked to insure sponsors' legal liability arising from clinical trials on children, examines the liability issues and asks; with regulations in place how do insurers go about assessing risks in paediatric trials? REGULATORY 20 Takeaways for Emerging Countries’ Clinical Trial Conduct Dr Nermeen Varawalla, reviews DIA Euro Meeting, Berlin 2009 26 Establishing of infrastructure for ethical review in Kazakhstan Modern development of science and technology is typically accompanied with increased public attention to ethical and legal aspects of scientific research. There is a systematic implementation of ethical principles in areas of science in Kazakhstan, as well as in other Central Asian republics. Prof. Bakhyt Sarymsakova evaluates the legal infrastructure in place. Donna Beardsworth of Beardsworth Consulting Group discusses the Supportive Care Trial challenges. 34 Interview with ACM Global Central Laboratory Dr. T.S. Jaishankar CEO of Quest Life Sciences & Member of the JCS Editorial Advisory Board talks with Elena Logan & Kathleen Murray of ACM Global Central Laboratory on the requirements from a Testing Laboratory in Oncology Studies 36 Interview with Medidata Solutions Worldwide Dr. Patricia Lobo, Senior Consultant of Life Science Business Consulting & Member of the JCS Editorial Advisory Board discusses with Steve Heath & David Quarm of Medidata Solutions, the application of data collection and analysis, for the early detection of Breast Cancer. Study Paper 40 QTc Prolongation in Patients with Chronic Renal Impairment Patients with end-stage renal disease are frequently associated with increased mortality rates due to sudden cardiac events. Ventricular arrhythmias are the major problems of cardiac origin in this population. Several attempts have been made to determine factors responsible for the occurrence of serious ventricular arrhythmias. This investigation was performed to elucidate a possible correlation between the status of renal impairment and QTc prolongation in patients with different stages of renal impairment and healthy controls. By Cornea N., Wadepuhl M., Tsvitbaum N.,Janik F., Eckl K.M. IT & LOGISTICS MARKET EVALUATION 28 Interview with Congenix Prof.Bakhyt Sarymsakova, Head of Department of International Cooperation National Research Center of Mother and Child Health & Member of the JCS Editorial Advisory Board discusses the present climate for conducting Clinical Trials in Russia & Eastern Europe with Irina Dobreva & Vladimir V. Novakovskiy of Congenix LLC – A CRO’s perspective 44 SUBSECTION THERAPEUTIC STUDIES Oncology Series 31 2 JCS Understanding and Addressing the Unique Challenges of Clinical Trials in the Supportive Care of Cancer Patients Researchers supported by government, academia and industry work diligently to develop safe and effective medicines to prevent and treat cancer, and to ameliorate side-effects of treatment. Although there are many research objectives, the primary goals are to increase survival, decrease side-effects, and maintain or recapture quality-of-life for cancer patients in all stages of their disease and treatment. Digital pen and paper help UN body fight disease in Africa The United Nations Food and Agriculture Organization (FAO), is using Digital Pen and Paper technology to virtually eliminate the need for ‘traditional’ data entry, enabling near-instant field reports to prevent or limit the effects of infectious diseases, drought and flooding in sub-Saharan Africa. Urban Fröderberg of Anoto Group AB explains. 49 Australasia - your stepping stone to market Australasia is frequently used as a term to describe the region of the world that encompasses Australia and New Zealand together with the many Asian nations immediately to the North. In this special sub-section, researchers and managers active in several organisations from Queensland, Australia, provide an insight into the clinical and translational research capabilities in Australia and New Zealand, with an emphasis on the former. Section Compiled by QCTN (Queensland Clinical Trials Network Inc.) www.jforcs.com Editorial Advisor Keynote By Mark A. Goldberg, M.D., Chief Operating Officer, PAREXEL International The theme for the 45th Annual DIA Meeting to be held in San Diego, California is “Better Medicines: Improving Safety with Every Step.” This seems an apt theme, particularly against the backdrop of the Obama administration’s likely focus on safety and comparative effectiveness in drug development. Safety will remain paramount in the global search for effective new therapies. With the knowledge that many potential adverse events will not emerge until much larger populations of patients are exposed, proactive pharmacovigilance planning is a growing focus for the biopharmaceutical industry. Voluntary reporting of adverse events is being replaced by registries and newer forms of non-interventional studies that will better characterise the profiles of marketed treatments. Technology has a key role to play in this area. An example is the potential that electronic medical records hold to mine data for safety signals, with the requisite protection of personal information, without having to use either specially designed studies or to rely on physician reporting. The approach to safety concerns is also evolving as companies implement new Risk Evaluation and Mitigation Strategies (REMS). In early phase studies, a goal will be to generate more comprehensive safety profiles of compounds. This will be facilitated by innovative trial designs, including the use of adaptive studies. In addition, the role of biomarkers will continue to evolve as a tool to better predict potential safety issues as well as efficacy. It is anticipated that medications that more specifically target the underlying mechanisms of disease will also have more attractive safety profiles. While the emergence of personalised medicine and the pairing of treatments and diagnostics may be progressing more slowly than some had expected, this area remains an inevitable evolution for the biopharmaceutical industry. This year’s Annual Meeting will bring representatives of the biopharmaceutical industry together at a time of heightened uncertainty. The industry faces pressures due to global economic challenges, patent expirations, and decreased R&D productivity among other factors. In the U.S., the direction of the new administration, beyond the safety considerations mentioned earlier, is still emerging and includes such considerations as drug importation, pricing, and reimbursement. With large mergers and acquisitions changing the landscape, the industry will likely experience additional shifts in drug development priorities. Combined with these market dynamics are a few key trends that continue to shape the biopharmaceutical industry, including increased globalisation of drug development, continued adoption of eClinical technologies, and the growing importance of strategic partnerships between CROs and pharmaceutical companies. • Increased globalisation of drug development is being driven by several factors, including the ability to access diverse patient populations and the lower cost of conducting quality clinical research in emerging geographies. Another major driver is the increasing importance of new end markets for biopharmaceutical products in a number of geographies, including India and China. • The use of technology has progressed from the adoption of a disparate set of tools from various vendors to the increasing availability of integrated technology suites. These suites offer the potential to meaningfully decrease cost and ease system interoperability. Combining these technology platforms with clinical expertise will help to bring greater productivity to development programs. • Evolving strategic relationships among service providers and sponsors will lead to new operating models and the emergence of best practices in partnering. These enhanced partnerships, which will create new expectations of CROs in the areas of expertise and relationship management, promise to bring greater innovation and efficiencies to the drug development process. Since change creates opportunities, it is likely that many of these emerging and ongoing trends will be favourable for the biopharmaceutical services industry, despite the current economic environment. The hope is that industry challenges will further drive innovation and enhance the performance of R&D investments. Service providers have an important role to play, in partnership with sponsors, to fulfil that promise. Given the many significant and evolving dynamics, this year’s meeting promises to foster an interesting dialogue among industry participants. Editorial Advisory Board Art Gertel, VP, Clinical Services, Regulatory & Medical writing, Beardsworth Consulting Group Inc. Hermann Schulz, MD, CEO, INTERLAB central lab services – worldwide GmbH Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP Bakhyt Sarymsakova - Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan Janet Jones, Senior Director, Strategic Patient Access, KENDLE Nermeen Varawala, President and CEO, ECCRO - the pan Emerging Country Contract Research Organisation. Catherine Lund, Vice Chairman, OnQ Consulting Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma. Board Member of the Drug Information Association. Chris Tierney, Business Development Manager, EMEA Business Development, DHL Exel Supply Chain, DHL Global Chris Tait, Life Science Account Manager, CHUBB Insurance Company of Europe Devrim Dogan–Guner, Medical Director, ENCORIUM Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics Jerry Boxall, Managing Director, ACM Pivotal. Patricia Lobo, MSc. PhD. Managing Director & Senior Consultant, Life Science Business Consulting. Peggy A. Farley, President and Chief Executive Officer of Ascent Capital Management Inc. Kamal Shahani, Managing Director of Cliniminds - Unit of Teneth Health Edutech Pvt. Ltd. Russell Neal, COO, Clinical Network Services (CNS) Pty. Ltd. Karl M Eckl, Co-founder, Executive and Medical Director, InnoPhaR Innovative Pharma Research Eastern Europe GmbH Rob Nichols, Director of Commercial Development, PHASE Forward Linda Zao, President and CEO, Draco Healthcare Consulting LLC. Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Liz Moench, President and CEO of Medici Global Stefan Astrom, Founder and CEO, Astrom Research International Georg Mathis Founder and Managing Director Appletree AG Mark Boult, Healthcare Market Sector Leader, DNV Ghassan Ahmed, Vice President, Medical & Regulatory Affairs, ClinArt International 4 JCS Steve Heath, Head of EMEA - Medidata Solutions, Inc Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation T S Jaishankar, Managing Director, QUEST Life Sciences www.jforcs.com Advertisement HELLO Our expertise lies in: I am Karl M. Eckl, In 2000, we specialised in the type of Phase I and IIa Clinical Studies which are critical and often delay clinical development because of difficult recruitment conditions. These studies are: • PK studies in the target population (e.g. Oncology Patients) • PK studies in patient populations used as pharmacological models like patients with renal and hepatic impairment • Proof of Concept studies in the target population (phase IIa) to speed up strategic decisions in clinical development of new medicinal products Cardiovascular CNS (including psychiatry) Endocrinology Infection disease Asthma and pulmonology Oncology Liver disease (alcohol and toxic cirrhosis and hepatitis B and C) Kidney disease (nephrology and urology) Gastroenterology Postmenopausal women Elderly population Gynaecology Rheumatoide arthritis Male and female healthy subjects Haematology Ophtalmology Pain patients Surgery and neurosurgery Why are these studies so difficult to perform? • No therapeutic benefit for patients increase reluctance to participate in such a study.Therefore it is necessary to have a panel of such patients whenever possible. • Reproducible boundary conditions are difficult to achieve in normal hospital settings. Therefore our own clinical sites are exclusively used for clinical research. I set up INNOPHAR to provide you with: • Patient populations which are the most critical ones to recruit for phase I and IIa studies (e.g. renal or hepatic impaired or oncology patients) • High quality services of our own clinical cites specifically tailored for these types of clinical studies • The service directly and not through any sub contractor • Own patient panels, we perform these studies frequently • Expertise, as phase I and IIa studies in these types of patients are our core business • We recruit patients in huge polyclinics which cover patient data from 50,000 patients or more each. We co-operate with 5 – 10 policlinics, and as a result we can give exact time windows for recruitment, which is a rare thing in this business. Our Formula for success can be yours. Just contact me or my colleagues at: INNOPHAR GmbH Innovative Pharma Research Eggersberg 4A. D-94375 Stallwang. Germany Tel: +49 (0) 9964 6010216 Fax: +49 (0) 9964 6010217 E-Mail: [email protected] www.ipr-ee.com Dr. Karl M. Eckl Managing Director INNOPHAR GmbH FDA WATCH ENFORCEMENT FDA announced on April 10 that it had obtained a permanent injunction barring Neilgen Pharmaceuticals Inc. of Westminster, MD., its parent company, Advent Pharmaceuticals, Inc. (Advent), of East Windsor, N.J., and two of their officers, Bharat Patel and Pragna Patel, from manufacturing and distributing any unapproved, adulterated or misbranded drugs. Both Neilgen, which does business as Unigen Pharmaceuticals Inc. (Unigen), and Advent are contract manufacturers and distributors of more than 25 different unapproved drug products each. The more than 50 unapproved drug products primarily include prescription cough and cold products. The unapproved drugs manufactured by Unigen and/or Advent include, but are not limited to: • • • • • • • • RE All 12 Suspension; BP Allergy Junior Suspension; PE Tann 20 mg/CP Tann 4 mg Suspension; BP New Allergy DM Suspension; D-Tann CT Tablets; B-Vex D Suspension; Histex SR; and Chlorpheniramine Maleate 12 mg/Pseudoephedrine HCl 120 mg LA Tablets. The unapproved drugs manufactured by these companies have not undergone the FDA's drug approval process, so their safety and effectiveness have not been established and the FDA has not reviewed the adequacy and accuracy of the directions for use and warnings on the labelling, FDA stated in its press release. For more information, please visit: www.fda.gov RECALLS FDA adopts interim plan to avoid shortage of opioid FDA on April 9 amended its March 30 action warning manufacturers to stop the production and distribution of certain unapproved prescription opioids, to allow the continued marketing and distribution of one particular type of opioid - a high concentrate morphine sulfate oral solution - on an interim basis. FDA took this action in response to concerns from patients and healthcare professionals in the palliative care community that the action taken on March 30 would cause a shortage of 20 mg/ml morphine sulfate oral solution, the agency stated in a press release. This product is widely used to alleviate pain in terminally ill patients. The agency has determined that this dosage form is medically necessary, and should remain on the market until an approved alternative becomes available to the patients that need it. “While the FDA remains committed to ultimately ensuring that all prescription drugs on the market are FDA approved, we have to balance that goal with flexibility and compassion for patients who have few alternatives for the alleviation of their pain,” said Douglas Throckmorton, M.D., deputy director, FDA’s Center for Drug Evaluation and Research. "In light of the concerns raised by these patients and their healthcare providers, we have adjusted our actions with regard to these particular products." For more information, please visit: www.fda.gov 6 JCS ADVERTISING FDA rules on drug ads cause confusion in web advertising FDA sent letters to 14 major pharmaceutical companies late last month with a strong warning: the companies’ search advertisements — the short text ads that run beside Google results — had to start including risk information about each drug or else be rewritten or removed, according to The New York Times on April 17. Just how the companies were supposed to comply was not so clear. In the 95 characters that Google allowed for search ads, there was no way to include all the required information, the companies argued. Now, as the companies change their search ads to comply with the letters, industry executives say the solution is worse than the problem: their ads are even more confusing and misleading now, they say. And they worry that regulators will enforce standards that were created for magazines and television, rather than making new rules that acknowledge how internet ads have evolved. The letters were sent to almost all of the major pharmaceutical companies, including GlaxoSmithKline, Pfizer, Merck and Eli Lilly. The letters said ads for widely prescribed drugs, including Celebrex, Propecia and Yaz, did not include the paragraphs of precautions the agency required. Though the texts of the ads varied, the agency’s objections to each ad were similar. One such ad was for Merck’s allergy drug Singulair. The ad read, “Allergy Medication Relief of Allergy Symptoms: Learn About a Treatment Option. www.SINGULAIR.com.” For more information, please visit: www.nytimes.com CLINICAL TRIALS FDA takes action against firm in human experiments Citing serious violations uncovered by a congressional probe, federal regulators on Tuesday imposed restrictions on a company that monitors testing of experimental drugs and medical devices on human beings, the Associated Press reported on April 17. The Food and Drug Administration sent a warning letter to Coast IRB, saying regulators identified "serious violations" of federal rules that protect human subjects, and are concerned about risks to patients. The Colorado Springs, Colo., firm agreed to stop reviewing new experiments and also halt enrolment in research trials already underway. Independent expert review of clinical trials is an integral part of the development of new drugs. But a congressional hearing last month exposed flaws in the system. Undercover investigators for the Government Accountability Office were able to get Coast IRB's approval for a fictitious testing protocol that supposedly involved pouring a litre of a product into a woman's stomach following surgery. Two other companies approached by GAO rejected the proposal. The FDA's action will affect some 300 human studies involving about 3000 researchers. Coast IRB will have to show regulators it is fully complying with all rules that govern experiments on humans before the restrictions can be lifted. Coast IRB did not respond immediately on April 14 to a request for comment. In the past, company officials complained the firm was "hoodwinked" by investigators, but said they have since made changes. I Joseph Pickett is Owner and President of Expertbriefings.com, a leading provider of regulatory teleconferences in clinical trials, pharmaceuticals, medical devices and biological products. For more information, please visit http://www.expertbriefings.com, or Email: [email protected]. www.jforcs.com PROTECTING HUMAN SUBJECTS IN CLINICAL TRIALS: THE FDA BIORESEARCH MONITORING PROGRAM Agencies under the purview of the United States (US) Department of Health and Human Services (HHS) have multiple initiatives to improve human subject protection (HSP). One such agency - the US Food and Drug Administration (FDA) - manages the activities of the Bioresearch Monitoring and Inspection Program (BIMO) mandated by the US Congress in 1976. The goals of the FDA’s BIMO Program are to support patient rights and safety and maintain data integrity in clinical trials. BIMO is facilitated by inspections of investigators, monitoring of studies, and laboratory validations throughout international sites. The four main areas of focus for inspections are sponsor, monitor or contract research organisations (CROs), the clinical investigators (CIs), institutional review boards (IRBs), and non-clinical laboratories.1 According to BIMO’s 2007 inspection records, the FDA conducted a total of 1024 inspections, half of which were minor.2 Minor inspection findings are classified as no action indicated (NAI) signifying that no objectionable conditions were noted during the inspection. About half of all violations occur at the investigator site. Of the more serious violations that did occur, 86% were in study protocol violations and record keeping.2 More serious violations are classified in one of two ways: 1. 2. A Voluntary Action Indicated (VAI) notes that objectionable conditions or practices were found during an inspection. VAIs will typically lead the FDA to generate a warning letter to indicate that corrective action is necessary. The most serious violation is an Official Action Indicated (OAI) which means that objectionable conditions or practices representing significant departures from the regulations were observed. An OAI finding on an inspection will generally result in a warning letter and/or administrative and regulatory sanctions. During BIMO inspections, there are several focus points that will provide clues to the presence of fraudulent data in clinical trial records. The FDA provides inspectors with guidance on identifying fraud during BIMO inspections:3 • • • 8 JCS Identify original source data and verify its existence and accuracy against what are reported to FDA. Missing records are a key indicator of potential fraud. Demand to see all the original source data and supporting data as identified from the protocol. Fabricated data will point in the direction of inconclusive results or results favouring test article. • • • • Observe if all documents are prepared or written by the same person and question whether others should have been involved. Notice the repeated pattern of data from a study. Identify departures from anticipated trends. Be alert to whether the firm has the expertise, capability, and equipment to perform the procedure or test associated with the data. Determine the sequence of events and amount of work related to generating the data and consider whether it was physically possible for the individual(s) performing the procedure to have done so in the timeframe and sequence indicated by the records. In 2006, the FDA launched the Human Subject Protection-BIMO Initiative to modernise the programme. A number of FDA regulatory actions have resulted including the publication of several more recent guidances to assist parties in understanding the BIMO program. I References: 1. US Food and Drug Administration Office of Invitro Diagnostics [Slide Presentation]. Building Quality into Device Clinical Trials. April, 2006. Available at: http://www.fda.gov/cdrh/oivd/meetings/041806agenda.html. Accessed February 14, 2009 2. Drug Information Association Annual Meeting 2008 [Presentation]. Compliance Trends in Clinical Research. 3. US Food and Drug Administration. Inspection Guide: Detecting Fraud in Bioresearch Monitoring Inspections. April 1993. 4. US Food and Drug Administration. Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting - Improving Human Subject Protection, 15January-2009. 5. US Food and Drug Administration. Guidance for Industry and Food and Drug Administration Staff; The Review and Inspection of Premarket Approval Applications Under the Bioresearch Monitoring Program, 8 January 2008. 6. US Food and Drug Administration. Draft Guidance for Industry: Protecting the Rights, Safety and Welfare of Study Subjects - Supervisory Responsibilities of Investigators, May 2007. Regina Ballinger, RN has been with Thomson Reuters for 6 years specialising in pharmaceutical regulatory affairs. She currently manages editorial content for the IDRAC regulatory database. She has been employed in the healthcare industry for over 15 years and has extensive experience in health education. Email: [email protected] www.jforcs.com AUSTRALASIA WATCH Welcome to our second Australasia Watch. This month I aim to shine a little light on the Australian Clinical Trial Notification (CTN) Scheme which, as the preferred regulatory pathway, underpins the attractiveness of Australia to product developers both large and small. The CTN is a notification scheme, and over 95% of all trials conducted in Australia are approved via this route, where the onus is on the Human Research Ethics Committee (HREC) to bear the responsibility for approving: • • • • the safety and efficacy of the medicine or device the ethical acceptability of the trial process approval of the trial protocol, and evaluating the scientific merit of the trial. One of the most common questions asked by sponsors considering using Australia is “Who completes the CTN submission?” As the Australia Therapeutic Goods Administration (TGA) does not review any data relating to the clinical trial under this scheme, one can consider the HREC as the regulator under the CTN scheme. In other words, when an investigator submits to their HREC, should they approve, typically within four weeks, and then if the HREC should raise questions going on to eight weeks, the investigator is getting both ethics and regulatory approval. The TGA does receive notification of the HREC approval via receipt a completed and signed CTN form, which they acknowledge in writing within 10 days of receipt of the signed CTN form and appropriate payment. Where the study is a first-in-human study, it is common for the TGA to request copies of the protocol and IB at some stage after issuing a letter of acknowledgement and on occasion it may request some additional information. The TGA is empowered to place an ongoing study on “Clinical Hold” should their concerns be significant. This is extremely rare and likely only to affect Phase I studies being conducted under a CTN. So who completes the submission and what does one need to submit? An HREC submission is prepared by each investigational site’s Principal Investigator, with of course appropriate assistance from the sponsor or CRO. The “standard” submission can vary slightly from site to site, but typically includes: • • A completed CTN form, signed by the Australian sponsor Completed HREC application form (increasingly the National Ethics Application Form, or NEAF, is used) • Final protocol • Current / up to date Investigator’s Brochure (IB) • Site-specific patient information sheet/informed consent form • Fully signed Medicines Australia Form of Indemnity • Copy of the Clinical Trial Insurance (CTI) with sufficient coverage to satisfy varying levels across Australia (check with your CRO or site to be sure. Note where a CRO is the Australian sponsor, many HRECs require that such parties are listed or named on the CTI • If the study is a first-in-human study, the HREC may request that an Independent toxicologist’s report, or similar, is also provided. It is worth emphasising here that we avoid a full regulatory submission such as an IND equivalent, but the quality of the submission, particularly the IB, should be of a standard that would be accepted by any international regulator. A separate CTN form must be completed for each potential trial site, and once the submission and payments have been posted to the TGA the trial may commence, though it is prudent to await the letter of acknowledgement before treating the first volunteer. By now you may have discovered the Australasian pull-out section in this month’s JCS, and hopefully I have added some supplementary detail to the articles featured and confirmed the simplicity and attractiveness of the Australian CTN Scheme. I Russel Neal With almost 20 years working in the healthcare industry, for the last 16 years Russell has been advising clients in clinical trial management in a career spanning Europe Asia and Australasia. He is currently Chief Operating Officer at Clinical Network Services (CNS) Pty Ltd, a privately owned, Brisbane based, full service contract research organisation (CRO) providing clinical management support and services to the healthcare community particularly during the early phase clinical development of their products. Email: [email protected] DRUG DEVELOPMENT IN CHINA Related Regulations on Monitoring Period of New Drugs The last issue mainly introduced the Special Approval Regulation on New Drug Registration, showing that the SFDA (State Food and Drug Administration of China) is determined to encourage innovation and strengthen risk control. Meanwhile, in order to protect public health, the SFDA definitively stated the monitoring period of new drugs in the Drug Registration Regulation issued in July 2007, as well as introducing some relevant regulations. The SFDA can set up a monitoring period for the approved new drug. The monitoring period is calculated from the approved date of new drug production and it must be within five years. Within the monitoring period, the SFDA will not grant approval to any other manufacturer to produce, change the form of or import the new drug. From the first day of the monitoring period, the SFDA will not accept same–type registration applications from other applicants; other applicants’ same-type applications that have been accepted but not approved for performing drug clinical tests will be returned. If the applications are approved for performing drug clinical tests, they can continue to be handled according to the Submission and Approval Procedures of Drug Registration. If the application meets the related requirements, the SFDA will approve the drug production or import, and then perform the monitoring along with all the other approved same-type drugs. Only after the monitoring period of new drugs can other applicants apply for imitation or import. Time Limit Table on Monitoring Period of New Drugs (Note: the monitoring period is only used for new drugs under the following conditions) 1.1 1.2 1.3 1.4 Drugs that have fewer components and are made from marketed multi-component drugs. 1.5 New compound formulations. 2 3.1 During the monitoring period of the new drug, the manufacturer’s duties are as follows: 3.2 1. 2 The drug manufacturer should inspect the production process, quality, stability, efficacy, adverse effects etc. of the drug, and should report annually to the local drug administration agency. The drug manufacturer should start to produce the new drug monitored within two years after the approved production date. Otherwise, the SFDA can approve other drug manufacturers’ applications for its production, and monitor it again. Formulations in which the APIs are made by synthetic or semi-synthetic methods. Formulations in which the new effective monomers are extracted directly or by fermentation from natural materials. Formulations that are optical isomers of known drugs and made by means of resolution, synthesis etc. 3.3 Formulations in which the administration routes are changed but not on the national and international markets. Internationally-marketed formulations, with or without changed drug forms, and with unchanged administration routes. Internationally-marketed compound formulations, with or without changed drug forms, and with unchanged administration routes. Internationally-marketed formulations with changed administration routes. 4 Marketed formulations in which the acid radicals, basic groups or metal elements are changed, but the APIs with pharmacological effects are unchanged. 5 Nationally-marketed formulations in which the drug forms are changed, but the special techniques on the drug administration route (such as targeted, slow-release and controlled-release techniques) are unchanged. Dr. Xunting Zeng has decades of experience in the field of Clinical Trials. Dr. Zeng received his PhD at Kansai Medical University, Osaka, Japan. Since then he worked as Special Investigator at International Medical Centre of Japan. Later he joined InCROM Group, a Japan based leading international Contract Research Organisation firm. Dr. Zeng is currently General Manager of InCROM China and heading up to elevate China clinical trial with global standard. Email: [email protected] 12 JCS www.jforcs.com KOREA: NEW ‘GLOBAL HUB’ FOR MULTINATIONAL CLINICAL TRIALS Clinical Practice) guidelines. In 2001, Korea expanded its clinical trials by introducing the IND (Investigational New Drug Application) in order to reach the required standards of other advanced countries. Also, the government established KoNECT (Korea National Enterprise for Clinical Trials) and selected 12 local clinical trial centres with three more to be selected this year, giving a total of 15 local clinical trial centres to manage. KoNECT will expend all its resources in supporting the facilities, equipment and human resources of the pharmaceutical companies. In addition, it helps the success of the local clinical centres by supporting management system and other bases for the specialisation and professionalisation of the centres. Various aspects can illustrate the competitiveness of Korea as the hub for clinical trials. Currently, the number of clinical trials in Korea exceeds 400, making it the 26th most active country in the world, 4th in Asia following Japan, India, and China. Including 215 multinational clinical trials performed in 2008, the total number of approved clinical trials in Korea leaped to 400, resulting in a 38.9% increase from the annual average. Number of Approved Clinical Trials: KFDA, 2008 A successful clinical trial is one of the most significant procedures in developing new drugs for the eradication of disease and the promotion of human health. Since clinical trials help confirm the safety and efficacy of the drugs, high-technology and well-designed protocols as well as cost-effectiveness and rapidity are all critical matters which should not be simplified. In recent years, Korea has grown up both nominally and virtually as the hub of multinational clinical trials. The number of multinational pharmaceutical companies promoting their multinational clinical trials in Seoul has been increasing exponentially. This can be seen as the fruits of the cooperative efforts made by Korea’s government, academia and industry to become a medical and healthcare power nation. These three powers have combined to instigate efforts to make Korea an advanced nation in regulatory science and operation systems, as well as to raise the level of skill and manpower for a successful clinical trial. Korea activated mandatory GCP (KGCP) in 1995 and introduced bridging trials for the domestic application of foreign clinical trials in 1999. In 2000, Korea’s standard for clinical trials was revised to conform to the ICH E6 (Good Korea has made dramatic advances not only in quantity, but also in quality, showing remarkable increases in Phase I and II trials compared to Phase III trials which used to be the dominant studies conducted in Korea. The early stage clinical trials, in which the first drug administration test is performed on the human body, is the most delicate and critical step in developing new drugs, thus, the increase in the early phase studies implies that Korea has enhanced its overall clinical trial reputation. The fact that multinational pharmaceutical companies have been continuously increasing the number of clinical trials in Korea testifies that they are paying attention to Korea, considering it as the potential hub for multinational clinical trials in Asia. In addition to its improvement in clinical trial performance, Korea is to establish the APEC Harmonization Center to contribute to global harmonisation of regulatory guidelines through educational workshops. Its initiative is expected to play a key role in the international harmonisation of the pharmaceutical development standard. The title “Multi-Regional Clinical Trials Seoul Workshop – Inaugural workshop of the APEC Harmonization Center” was given to the opening ceremony at the Seoul workshop, scheduled for June 15th, shows the efforts of Korea to be a true global clinical trial hub. KHIDI (Korea Health Industry Development Institute), which functions for the development of healthcare in Korea, has overseas branches in Beijing, Singapore and New York. In addition to inquiries regarding clinical trials, all cooperation and collaboration with the Korean healthcare industry and community will be taken care of through KHIDI and its branches. I Kyung Won Jang, PhD. Dr. Jang worked as head researcher at KHIDI (Korea Health Industry Development Institute), the government affiliated organisation established to promote Korea’s healthcare industry. Dr. Jang is currently the director of Center for Global Healthcare Business at KHIDI and also is associate director of APEC Harmonisation Center. Emails: [email protected] (US, Canada, Latin America); [email protected] (Asia and Pacific); [email protected] (China) 14 JCS www.jforcs.com THE GLOBAL CRISIS: AN ADVANTAGEOUS MOMENTUM FOR LATIN AMERICA As the books say, every crisis should be seen as an opportunity. It is also a fact that in times of uncertainty, innovation is a very important tool. During the last few months, everyone has been wondering what the future will be for our region and for the world. We have witnessed studies put on hold and budget-cutting everywhere. Of course, this is a major concern for us and with it comes the question, “Will Latin America continue to be seen as a region of opportunity for the global industry?” Will they (sponsors and CROs in the Northern Hemisphere alike) capitalise on the huge opportunities which are present here? As members of the clinical research industry in Latin America, we have the responsibility to do our best to make this happen, to show the world what we have done and are doing and, most importantly, to demonstrate how well we are performing. We must be proactive, have a strong commitment and willingness to grow - we need to actively pursue every chance to prove our worth. It is all too common to focus only our industry of clinical research and not recognise the impact that other industries have on our success and learn from their actions how best to approach such times as these. We need to take a step back and adjust our objectives (both as companies and as individuals) in order to make them compatible with the realities of every country. We must be self-evaluating. It is only through a systematic review and enhancement of our organisations that we will optimise our resources. This is not the first economic downturn experienced in recent years for Latin America – let’s use our experiences of overcoming adversity and adopt strategies which have proved to be successful in the past! Our region has been delivering first class services and data to support new products being brought into the market for many years now. We have proven what we are capable of - and we have handled - exponential growth. We should act accordingly. Can we add real value? Of course! Latin America is much more than a great 16 JCS cost-effective strategy to increase the number of patients. We need to expand our focus to the full reality that our services add much more to a study’s success, in addition to patient recruitment and monitoring. Finally, we must promote to our national governments the importance of the clinical research industry for local economies. This goal might seem too challenging, yet we have to face it because we need our governments to support growth and expansion of services long-term. We should not approach this as if the only items on our agenda are how to guarantee GCP compliance and faster approval for studies. We need them to strengthen the regulatory framework in every country towards harmonisation and predictability. And we must collaboratively work with our governments to discover opportunities for the common good. We all know the definition of a vulnerable population. It is obvious the financial situation will likely have an impact on our local health systems, medical institutions and, eventually, patients. We should take this opportunity to partner with our governments to discuss priorities, providing sound metrics and information to maximise transparency - ethical, legal, and economic. National administrations have a responsibility for the health of the population, and this is our overriding responsibility as well. We need to intensify our ties and strategies to enhance the success. There are ongoing efforts in several countries with sponsors and CROs working together to collect information. In fact, a few weeks ago the Argentinean government created the first clinical trial registry in the region, joining similar initiatives from other countries. We do have many common objectives and we should encourage dialogue to work side by side to make the most of this opportunity. I Oscar Podestá is General Manager for Chiltern, Latin America. Chiltern was established in 1982, and is a leading global Contract Research Organisation with extensive experience conducting and staffing international Phase I to Phase IV clinical trials across a broad range of therapeutic areas for a wide variety of clients. Chiltern has conducted trials in more than 40 countries and employs 1400 staff across 27 countries. Chiltern provides services including Early Phase, Global Clinical Development, Late Phase, Biometrics, Medical and Regulatory Affairs and Resourcing Solutions. E: [email protected] W: www.chiltern.com. www.jforcs.com PAEDIATRIC TRIALS – NOT CHILD’S PLAY FOR INSURERS It is common knowledge within the medical community that most drugs prescribed for children have not been approved for use in minors. Effectively they are being used in an off-label manner. This I am sure would surprise the man in the street, and whilst the expression “off-label” when used in medical circles is well understood not to mean inappropriate, improper or even illegal use, it does send a message to the general public that something is “wrong” and therefore the drugs may not be safe. To prove a drug’s safety requires the type of human clinical trial programme that drugs for general use are subjected to. Tests for safety, efficacy, dosage and contraindications would be required. In an ideal world, the assessment of a drug's effect on children would not be left to a rough calculation of relative body weight or skin surface area, along with empirical data from past years. However this has been the case until recently. This article will not drill deeply into the ethical issues surrounding clinical trials on children, but as an underwriter asked to insure sponsors' legal liability arising from such trials, it is important to be aware of these issues. Ethical issues are legion and the unique manner in which paediatric trials should be designed is legitimately part of the underwriting process. The EU has recently adopted a kind of halfway house in its attitude to the use of drugs on children. Accepting that an insistence of full separate paediatric trials on all new medicinal products is impractical, the EMEA introduced regulations stating that as of July 2008 marketing applications for new products not authorised in the EU prior to 26 January 2007 had to include the results of studies conducted in the paediatric population. These studies have to be in compliance with an agreed Paediatric Implementation Plan (PIP). The PIP is a development plan aimed at ensuring that the necessary data is obtained through studies on children (when safe) to support the authorisation of that medicine for children. PUMAs (Paediatric Use Marketing Authorisations) were also let loose in Europe, which enabled a medicine, already available on the market for adults, to be approved for children following the completion of a PIP agreed by the appropriate committee. There are various financial incentives available to reward the effort made by companies acquiring PUMAs. So, with this regulation in place how do insurers go about assessing risks in paediatric trials? First let’s define “Risk”: a good and succinct definition is: “The potential harm (real or theoretical) or potential consequence of an action”. Trials on children should be analysed for risks unique to the trial population. The foundation of everything must be the maxim that the child’s interest should always prevail over that of science and society, and risks must be set against the benefit that taking them might bring. It is the responsibility of the sponsor and investigator to make an assessment of the risks involved in a trial and to describe and explain this in the protocol, thereby enabling the ethics committee to make an informed decision. The risk assessment that insurers will undertake on the specifics of a trial itself includes: • The evaluation of the medicinal product tested and if relevant the control product • The risk of withholding active treatment where appropriate • The risk of the disease or condition being treated • The invasiveness or intrusiveness of the trial’s methodology • The reversibility of any adverse effect 18 JCS • • Age range of paediatric participants Other trials on the same population leading to possibility of an “overstudied” population Insurers’ assessment of the way a trial is managed will include: • Clarity of protocol’s risk assessment (see above) • Number of sites involved and communication between them (especially in multinational trials) • Age appropriate formulation (e.g. young children choking on tablets) and the risk of dosing errors or inaccuracy • Informed consent documentation and process. Informed consent is an ethical issue but also perhaps the most important aspect for underwriters as it is, so to speak, where the trial and the subject meet. Thus it is essential to have clear communication of information and risk as insurers realise that participants’ knowledge of the risk can mitigate the legal ramifications if litigation ensues. The latest version of the Declaration of Helsinki suggests that for a legally incompetent minor, the investigator must obtain informed consent from the child’s legally authorised representative in accordance with applicable law. However a “legally incompetent” minor may be able to give assent to decisions about participation in research and in such cases the investigator must obtain that assent in addition to the consent of a legally authorised representative. Of course the issue of childhood assent is contentious. An intellectual age of seven years has arbitrarily been recommended for including children in the assent process, but there is a body of professionals that consider that children under 10 years old will not fully understand the complexities of clinical trials and what they were being asked to assent to. Although parents are expected to sign the consent documents, underwriters will look to see that the child has been consulted to an appropriate level. These issues aside, information sheets should be separate for parents and children, should be concise in content, precise in language and age appropriate. That said, the number of age-specific variations of consent documents should be kept to a minimum, and the family as a whole should be given sufficient time and information to consider the pros and cons of their involvement. Knowledgeable insurers operating in this area appreciate the increased risks that are faced by all involved in this area of research. Premiums will tend to be higher for paediatric than other trials as insurers are taking on the risks of litigation following trials on children with the commensurately higher award potential, but the EU Trials Directive (rightly) insists that insurance be in place for all trials. Encouraging efforts have been made in Europe and in the United States to address the myriad issues surrounding paediatric trials. In the medical world it will require the combined efforts of paediatricians, manufacturers, bio-ethicists, medical societies etc to move the whole area of paediatric trials forward, and insurers, sharing in the risks all involved face, must be aware and proactive in helping to assess and mitigate risk in trial design, in addition, of course, to sharing in the financial consequences of these risks. I Chris Tait is the European Life Science Underwriting Manager for Chubb Insurance Company of Europe SE. Over the last 30 years Chris has gained a broad knowledge of the insurance industry. Chris has been instrumental in developing Chubb's expertise in the Life Science sector. He is a Chartered Insurer and Fellow of the Chartered Insurance Institute. Email: [email protected] www.jforcs.com DIA EURO MEETING, BERLIN 2009: TAKEAWAYS FOR EMERGING COUNTRIES’ CLINICAL TRIAL CONDUCT Venue 2009 marks the 20th anniversary of the fall of the Berlin Wall; this made Berlin an appropriate setting for the 21st annual DIA Euro Meeting, because the fall of the Berlin Wall heralding an age of improved East-West dialogue and understanding was an excellent metaphor for the deliberations and spirit at this recent DIA Meeting. The conference proceedings emphasised the ever more compelling need for affordable, safe, efficacious and quality medicines to be made promptly available across the world. There seemed to be universal recognition that countries in the “East”, which include Latin America and Africa, represent both challenges and opportunities as we endeavour to achieve safe, quick and affordable medicine access. Hence there is an imperative for East-West dialogue and co-operation which the Berlin Euro DIA Meeting facilitated in a stimulating and enjoyable manner. Attendees Happily the constraints of the present financial climate did not dampen attendance. There were over 1,600 attendees representing regulatory agencies, pharmaceutical sponsors, vendors, academics, patient groups and trade organisations. As has now become the norm, this DIA Euro Meeting was attended by senior representatives from the EMEA and most national regulatory bodies in Europe. In addition there was participation from representatives of the US FDA, Japan’s PMDA, Europe’s key pharmaceutical industry associations and patient groups. As a result delegates were able to access the latest high-level industry information and thinking; during formal presentations, audience discussion and via informal networking. Further pharmaceutical companies, particularly most of the leading ones and vendor organisations, were well represented. The exhibit hall had an international flavour with exhibits of numerous specialist CROs representing the emerging markets of India, Latin America and Eastern Europe. Notably the Queensland Clinical Trial Network had an exhibit to showcase the region’s considerable attractiveness for firstin-man clinical studies. Plenary Session The Architecture of the Future Governance System for Pharmaceutical Products in Europe was the subject for the plenary session, organised as a panel discussion, with panellists tasked with answering selected strategic questions. Panellists included the leadership of regulatory agencies, pharmaceutical companies and patient groups. The subjects discussed were the evolution of the European Regulatory Network and the role of National Competent Authorities, changing pharmacovigilance legislation, 20 JCS market access and pricing for new products and curbing the circulation of counterfeit medicines. Although the discussion was Eurocentric with a focus on Europe’s more developed pharmaceutical markets, each of the panellists emphasised the imperative to provide widespread access to affordable, safe and effective treatments. Clearly this imperative is a global one and in spite of the huge disparity in per capita healthcare expenditure between developed and emerging countries, the need for prompt access to affordable, safe medicines able to treat unmet medical need is universal. Panellists acknowledged the growing commercial value of emerging markets, their potential to accelerate drug development and the threats posed by fraudulent and poor quality practices. Programme Overview The main two-day conference programme was structured along 16 themes. Speakers with expertise in different functions representing key stakeholders featured in the 6-8 sessions that addressed key questions related to each of the themes. The programme structure was effective in enabling attendees to fully explore themes of interest and listen to the relevant perspectives. Not surprisingly difficult choices had to be made with multiple sessions vying for attendance. Below is a selection of topics with takeaways particularly relevant for emerging country clinical studies. Audits and Inspections This theme explored the evolution of Good Clinical Practice from adherence to a rule book into a holistic working approach and most recently to quality management. Inspections and audit have contributed, and continue to contribute, to this evolution and should be carried out as part of an ongoing quality management process. Experiences with inspection of e-CRFs, e-source data and data analysis were shared along with best practices for the delegation of sponsor functions to CROs and other third parties. A session describing experiences of European Competent Authorities with the handling of serious GCP breaches and fraud provided useful practical advice for industry, regulators, vendors and investigators. How regulators obtain information about serious GCP breaches, including falsification of data and fraud, was described. This was followed by a delineation of sponsor, investigator and patient responsibilities with recommendations on how to detect, report and avoid such cases. Issue escalation and tools for quality and risk management remain important and should be customised for an organisation’s needs. To enable extrapolation of clinical trial data generated in emerging countries for marketing authorisations in the USA and European Union www.jforcs.com (EU), there remains a strong need to harmonise quality standards across geographies. This is particularly true given the different clinical trial regulations in different countries and varying practices of GCP inspection. Pharmacovigilance and Risk Assessment Regulatory agencies face the challenge of balancing the facilitation of early access to affordable medicines with the requirement for long-term and thorough drug safety surveillance. Numerous initiatives including novel pharmacometric techniques and the identification and qualification of biomarkers are being undertaken to address this challenge. In addition there is a growing regulatory dialogue exploring conditional approvals and accelerated assessment with the definition of more specified treatment criteria and narrower patient sub-populations; these refinements do have implications for reimbursements. Regulatory agencies in the EU have substantially increased their focus on and investment in drug safety surveillance, both for their internal processes and for industry supervision. Failure to comply with pharmacovigilance regulations could result in seriously negative legal, regulatory and media consequences for the sponsor. Regulatory agencies have, or are soon to adopt, intelligent data mining tools for proactive and systematic oversight of pharmacovigilance processes and adverse event data. As regulators in India, China and Russia seek to strengthen their respective drug safety surveillance processes; there is a compelling opportunity for learning from and sharing best practices with the more experienced regulators. The opening of FDA offices in India and China and the EMEA’s investment in an international liaison function indicate that regulators on both sides recognise the need for enhanced co-operation. Furthermore the FDA and regulatory agencies in Europe more frequently need to evaluate marketing authorisation applications which include pivotal studies with an increasing proportion of subjects enrolled in emerging countries. Ensuring that these data have the quality, scientific applicability and ethical integrity represents additional regulatory responsibility. Paediatric drug development statements have been obligatory for marketing authorisation in the EU since January 2007. However practical issues regarding consent, recruitment, patient referrals and granting of waivers remain to be fully addressed. Further the ethics of conducting clinical research in a paediatric population are far from clear. Unusual trial designs that were discussed included an open, nonblinded clinical trial initiated by a patient group and driven by a steering committee with representation from participating patients. Following the unfortunate TGN 1412 experience standards for first-in-man studies for biologicals has substantially evolved. Emerging country CROs seeking to offer services in this segment are advised to understand this. Recent financial constraints in the global business environment have accelerated the rationalisation and consolidation of R&D departments within large pharmaceutical companies. The sale of Lilly’s pre-clinical research facility to Covance last summer remains a notable example of sponsor companies seeking to reduce their fixed R&D costs by forming strategic relationships with CROs. This has accelerated the trend for increased and more sophisticated utilisation of CROs with a move from transactional contracts that meet the sponsor’s short-term resourcing requirements to partnership based strategic outsourcing. Although small to mid-sized sponsors continue to utilise CRO services in a tactical, project-driven fashion, it is expected that soon they too will increase the breadth and depth of their CRO utilisation. “Unusual trial designs that were discussed included an open, non-blinded clinical trial initiated by a patient group and driven by a steering committee with representation from participating patients.” Increasing Clinical Trial Complexity Ken Getz, Senior Research Fellow from the Tufts Centre for the Study of Drug Development, Tufts University presented an analysis of 10,000 clinical trial protocols conducted between 1999 and 2006 to demonstrate that the complexity of clinical trial design has sharply increased. The number of unique procedures and the frequency of these procedures per protocol have increased at the rates of 6.5% and 8.7% per year, respectively. Protocol eligibility criteria have increased by over 12% per year and the administrative burden on investigative sites has increased by an estimated 10.5%. Furthermore, the number of protocol amendments, observed serious adverse events and length of the case report forms have all substantially increased. He recommended that sponsors develop processes to examine and limit protocol complexity, citing examples of initiatives undertaken by Genentech and Pfizer. Some of the drivers of clinical trial complexity are expanding global reach, adoption of novel technologies, increasing utilisation of patient reported outcomes (PROs) and the requirement to conduct paediatric studies. Best practices for the integration of PROs into the different stages of drug development and lifecycle management were shared; along with the use of electronic PROs and their acceptance by regulatory agencies. 22 JCS Clinical Trials in Non-ICH Countries A well-attended session discussing the implementation of ICH in non-ICH countries highlighted the increasing utilisation of emerging countries for global clinical development. The aims of harmonisation are to avoid duplication of clinical trials and to enable early access to new treatments. There remain strong ethical and economic reasons to avoid unneeded repetition within or prolongation of the clinical trial process. In order to achieve this, regulatory agencies worldwide should be able to extrapolate clinical trial results accrued from non-ICH countries. The ICH regions are the USA, EU and Japan; with the growth in emerging country clinical trial activity, harmonisation between ICH and non-ICH countries is becoming increasingly urgent. Dr Nermeen Varawalla, President, ECCRO described the Ethical and Scientific standards of ICH; namely, the protection of the rights, safety and wellbeing of trial subjects, and obtaining credible trial data acceptable by other regulatory authorities, respectively. A number of issues remain for emerging countries to fully meet these ICH standards. Socio-economic inequity, unmet medical need, cultural and linguistic variability and post-trial access are some of the issues that need to be addressed for the ethical standard to be met. Whilst the inexperienced clinical trial environment, nascent regulatory structures, unanswered scientific questions and variation in standards of care are factors that could influence meeting of the scientific standard. Kohei Wada, Co-Chair of the ICH Global Co-operation Group (GCG) described the group’s role to promote better understanding of ICH and its guidelines, by information sharing via brochures, websites and presentations at international meetings. More recently their remit has expanded to include facilitation of capacity building in non-ICH countries; within the industry and at regulatory agencies. The training of regulators and industry representatives continues to be a high priority; this is being achieved by frequently held and increasingly well attended workshops www.jforcs.com located in various emerging countries. He stressed the importance of a collective effort with a spirit of co-operation. Fergus Sweeney, Inspector, EMEA clarified that when assessing a marketing authorisation application, regulators do not place limits on the proportion of data accrued from a particular region; provided that the clinical data meets the quality, regulatory and ethical standards of that regulatory agency. Examples were cited, where for appropriate indications for example in a vaccine study, all the clinical trial data was accrued from emerging countries. Public Perception of Pharmaceutical Research There has been an erosion of public trust in pharmaceutical research with a tarnishing of the image of researchers, the industry and regulators. There was consensus that transparency about the methodology and results of drug research was the way forward to build public trust. Clinical trial registries, publication of trial results, public access to clinical trial data, clear definition of commercially sensitive information, elimination of ghost writing and full disclosure of funding arrangements between industry and researchers were all essential to create this transparency. The media has contributed to public mistrust and could potentially help reverse this. Speakers and members of the audiences voiced their views on how researchers, the industry, legislators and regulators can better work with the media, so that it can progress from being sensationalist and alarmist to providing society with a fair, more accurate picture of the drug discovery and development process. The Indian press was cited as an example of the media playing the role of a watchdog, protecting the exploitation of the lay public; by monitoring practices of the industry, clinical institutions and the Drugs Controller General of India. Although this is yet to build public trust it has succeeded in making industry and legislators more accountable. This theme also looked at the challenge of patient education and communication; recognising the advantages of a better-informed patient community able to understand the benefit-risk equation that is inherent in pharmaceutical research and usage of medicines. Educating patients to absorb and understand both the risks and effects of medicines remains complicated with significant cost implications. But engaging the users of medication is essential in order to achieve the goal of early affordable access to new medications. Finally a session examined the dilemmas of improving the informed consent process for clinical trial participants; seeking to find a balance between long and jargon-rich patient information sheets and effective communication able to fulfil ethical requirements. Results of a recent UK survey were disappointing, indicating that an alarmingly low proportion of clinical trial participants understood the main points of the informed consent materials. The discussion points of the public perception theme are a great example of how some of the most critical issues affecting pharmaceutical research are truly global in that they remain equally applicable in both the developed and emerging clinical trial settings. Adaptive Trial Design Adaptive or flexible trial designs allow for re-designing the study based on the results of interim analyses, by altering, for example, sample size, the randomisation ratio or the number of treatment arms. The statistical theory underlying these trial designs along with software tools allows for precisely controlling the type 1 error probability and hence the significance levels. The benefits of such a trial design could be acceleration of the clinical trial process, enhancement of trial efficiency and improved patient safety. Practitioners continue to await integrated tools and processes for patient allocation, drug supply management, clinical data management, study resource planning and practicalities of statistical analysis. The regulatory perspective on midstream adaptations of a clinical study is 24 JCS discussed in EMEA’s Reflection Paper, 2007 and FDA’s draft guidance, 2009. Importance of Health Economics The worldwide healthcare budgetary constraints could limit market access of new products and technologies. Health economics has the potential to help achieve the goal of sustainable and equitable access to biomedical innovation for all global societies. A decade after the formation of NICE in the UK, almost all EU countries have established processes and standards for Health Technology Assessments and economic appraisal. Evidence of product value is needed to satisfy questions posed by reimbursement agencies, clinical guideline committees, prescribing physicians and self-paying patients. Thus endpoints able to demonstrate product value have become essential clinical trial objectives alongside those for safety, efficacy and quality. Furthermore product value data can have a profound influence on product pricing. PROs are increasingly used to capture the patient’s view and experience regarding the value that they perceive they have received from the product. Also post-marketing data from patient registries and observational trials has an important role. Health economic analysis has been particularly relevant for facilitating the launch of orphan drugs. Extrapolation of health economic data from emerging country clinical trials is difficult given the variation in standard of care and patient expectations. Personalised Medicine The holy grail of the discipline of personalised medicine is to deliver targeted, individualised medicines with improved efficacy, safety and value. Better understanding of individual responses to disease and disease response to a particular drug; namely, prognosis and prediction, respectively, remain the foundation for personalised medicine. The integration of biomarkers into the clinical process, clinical validation of biomarkers, health economic outcome evaluation, benefit-risk assessment and co-development of drug-diagnostic combinations are some of the key tools and techniques that are being actively explored. This is a discipline with much promise, hence one to watch. Continuing the Dialogue The 21st DIA EuroMeeting successfully showcased the latest thinking across many key areas affecting the development and use of medicines. The forthcoming annual DIA Meeting in San Diego, which is expected to attract many more worldwide attendees, with a greater proportion engaged in emerging country clinical development, will no doubt provide an opportunity to re-visit some of these themes with a US-centric and global perspective. The 3rd Annual DIA Clinical Forum to be held in Nice in October this year will bring together the disciplines of clinical data management, validation and statistics with clinical trial operations to encourage cross-functional dialogue and closer collaboration. The programme highlights a strong focus on sharing experiences, case studies and best practices. Readers are encouraged to attend both meetings, and if unable to do so, they should look out for coverage of these and other key industry meetings in forthcoming issues of Journal for Clinical Studies; the industry’s only publication focused on emerging country clinical trials. I Dr Nermeen Y. Varawalla, MD, DPhil (Oxon), MBA recognised to be an industry expert in the utilisation of emerging countries for global clinical trials and leads ECCRO – the pan Emerging Country Contract Research Organisation. She was awarded the Rhodes Research Fellowship to the University of Oxford where she conducted her doctoral research in Molecular Genetics. In recognition of her expertise in the globalisation of clinical trials, Dr Varawalla is frequently invited to speak at industry conferences. In addition she is a regular contributor to industry trade and peer reviewed publications and serves on the editorial board of the Journal of the Institute of Clinical Research, India and the Journal for Clinical Studies, UK. Email: [email protected] www.jforcs.com ESTABLISHING OF INFRASTRUCTURE FOR ETHICAL REVIEW IN KAZAKHSTAN Modern development of science and technology is typically accompanied with increased public attention to ethical and legal aspects of scientific research. There is a systematic implementation of ethical principles in Kazakhstan. Regulatory framework Kazakhstan citizens still do not have an important legal instrument to protect their rights in the increasingly important area of application of modern biotechnology. Kazakhstan Constitution Article 29 notes: Citizens have the right to healthcare; have the right to free and guaranteed medical care; Paid medical care at state and private medical facilities as well as from persons engaged in private medical practice shall be rendered in the terms and procedures. Article 31 goes on to note; Suppression of facts and circumstances endangering people’s life and health by officials shall bring about responsibility as provided by the law. Article 39 states; the rights and liberties of man and citizen can be limited only by laws and only to the extent necessary to protect the constitutional system, maintenance of public order, rights and liberties of man, health and good morals of the population. In addition, Law No. 170 ‘Health Protection of Citizens in the Republic of Kazakhstan’, provides for the procedure of application of new prevention techniques, diagnostics, medications, immuno-biological drugs, disinfectants, biomedical research, preclinical research, medical and biological testing, clinical studies, application of new techniques and methods of prevention, treatment and rehabilitation. ● Preclinical research… shall be conducted on animals. ● Clinical tests on humans may be conducted only upon receipt of his written consent thereto… Clinical testing shall be terminated at any stage thereof at request of the person under test as well as in cases of a threat to his life and/or health. ● Application of new methods and preventive measures, diagnostics and medical rehabilitation shall be possible upon positive results of clinical studies. Conclusion The principle of voluntary and informed consent has been legally set forth. This article of law is pretty much declarative, and although some rights of citizens taking part in biomedical research are established, it does not contain any enforcement and remedy mechanisms. Nothing is provided in terms of necessary preliminary ethical evaluation of research applications. RK Law No. 522-2 ‘On Drugs’ (2004) details the regulation of testing of new medications; ● The aim of the clinical studies and testing of pharmaceuticals is to evaluate and prove, using scientific methods, that such pharmaceuticals and medications are safe and effective. ● Decisions on clinical studies and testing of pharmaceuticals shall be made by the state authority. ● A written consent shall be taken from the voluntary participants of clinical studies and/or testing of pharmaceuticals. ● Prior to clinical studies, the patient shall be provided with information on: i) the medication; ii) safety, effectiveness and risks to health; iii) actions in case of unforeseen health events; iv) terms and conditions of his health insurance. ● The patient has a right to refuse to participate in clinical studies and/or testing of a pharmaceutical or medication at any stage of the testing. 26 JCS ● It is prohibited to conduct clinical studies and/or testing of pharmaceuticals and medications on: i) children up to 16 years old; ii) pregnant women; iii) military personnel; iv) persons serving sentences in detention centres and persons at pretrial detention centres; v) persons recognized as disabled. Unless the medical products concerned are only intended for the above-mentioned groups. This law has been drafted based on the assumption that ethics committee expertise shall precede each testing. However, the status of an ethics committee, its authorities, its establishment and the composition of the ethics committee are not defined in the law. Although constantly violated, this article includes a statement that children under 16 may not participate in testing of new medication, treatment methods. It should be noted that contemporary international norms allow testing involving children and other vulnerable groups provided that certain clearly defined terms have been met. Instruction on Clinical Studies &Testing of Pharmaceuticals and Medications in the Republic of Kazakhstan, as approved in 2005; Instruction was adopted in addition to the Law. • • • • Attachment 4 – Instruction on Cooperation with the Commission on Ethics and Ethical Evaluation of Clinical Studies. Attachment 5 – Application for Ethical Evaluation of Materials of Clinical Testing. Attachment 6 – Opinion of the Commission on Ethics Re: Results of the Ethical Evaluation of the Materials of Clinical Testing. Attachment 11 – Instruction on Provision of the Person Under Test with Information on the Clinical Study and Receipt of a Written Informed Consent from Him. At the same time ‘Good Clinical Practice’ (2006), the departmental regulative act representing the standard of the RK branch, has been developed. It set forth obligations of all the parties involved in the research, as well as the procedure and activities of ethics committees during studying of the effects of a medication on human subjects. Today biomedical research has actually become a whole industry in which the interests of various parties intersect and often come into conflict. The absence of due legislation does not allow protection of persons bring tested, while the absence of legislation makes the status of all other persons involved insecure. Further, it appears as if Kazakhstan does not have a reliable legislative barrier against the “import” of such research that might be dangerous to our citizens. The absence of developed structures and tools of ethical expertise obstructs the promotion of local biomedical achievements to the world market. To date there is no clear system to regulate ethics committees that conduct ethical expertise of any research involving human subjects. Although, Ministry of Health Care has initiated the establishment of a Central Ethics Commission at the MoH, and local ethics committees at all scientific institutions under the MoH administration, to carry out clinical studies for ethical expertise of the research involving humans. I Prof. Bakhyt Sarymsakova MD, PhD. Position: Head of Department of International Cooperation, Astana Medical University. Prof. Sarymsakova is Executive Secretary of National Ethics Committee and has been working in public health sector for many years. Research interests are in bioethics and public health. She served as a PI for several projects with COHRED (Geneva), AHPSR (WHO), UNESCO. Email: [email protected] www.jforcs.com Advertisement Conres is a Contract Research Organisation established in Capacity & Capability: 2004 covering Slovenia, Croatia, Serbia and Bosnia & Herzegovina. We maintain local ofices and are working with local staff familiar with local habits, language and culture. We are able to register your trials quickly with the local authorities. Our standard operating procedures are equal for all countries, and it is possible to contract us centrally for all countries and use sponsor SOPs. Unique Feature from CONRES: CCRMS – Conres Clinical Research Management System We guarantee the sponsor high recruitment rates thanks to our Conres Clinical Research Management System (CCRMS). You can eliminate the need for spreadsheets updated by different people in different versions with a central online overview of patient visits source data veriied. Connected to the CCRMS is a unique system to provide the study team with fees on a monthly basis if requested, and only after all agreed tasks are performed. The CCRMS is also a reporting and tracking system, which means that every Conres employee can answer sponsors’ questions in a matter of minutes. Sponsors are invoiced with a detailed and transparent speciication of the activities performed. We also use an Electronic Filing System which guarantees fast access and data safety. Employee and CRA Qualiication: All Conres employees are carefully recruited having previous experience in working with medical staff and are familiar with the needs of the corporate environment we operate in. New CRAs with medical degrees are trained for three months before they can work independently. We manage Phase II, III and IV trials. Our Clinical Research Associates actively cooperate with the sponsor in the presentation of the study protocol to the study teams. We also organise investigator meetings for the sponsor and work closely together with the sponsor. Our CRAs always make presentations alongside sponsor representatives at investigator meetings. All personnel are luent in English. Company car, laptop, mobile internet access and lexible working times are a standard for us. If you are looking for the advantages and lexibility of a local CRO, a serious partner with high quality and guaranteed patient recruitment, we kindly invite you to become a partner of Conres. For inquiries and references please contact: GM and Business Development Manager Ivo Kalshoven Conres Koseska cesta 8 SI1000 Ljubljana, Slovenia tel: +386 1 5819229 fax: +386 1 5819230 email: [email protected] website: http://www.conres.si INTERVIEW: INVESTIGATING THE RUSSIAN AND EASTERN EUROPEAN CLINICAL TRIAL MARKETS 1. Let us start with a little bit about Congenix. What are your company’s special features? What is your present position in the market? What countries of the CIS region does your CRO work in? Congenix was established in 2004. Before the company’s creation its founders spent years working at different CROs, both international and local, and also in the Ministry of Health of Russia. This background has allowed us to form our own vision of what is necessary to begin. As opposed to the majority of companies which are represented in the market, we have invested time and funds in the installation of quality systems. We would like to express our gratitude to Quality and Compliance Consulting, Inc. and Verdandi AG for their help in this. The results of independent audits have completely proved the benefits of such an approach. Besides, compliance with high quality standards is one of the important factors helping us to successfully win tenders. For example, in 2008 Congenix won the right to organise and conduct a big 600-patient clinical trial sponsored by a pharmaceutical company which is a member of the top 5. Since all Congenix staff involved in projects have a medical education, Congenix does not have any therapeutic specialisation. We have knowledge and experience wide enough to start a project from the zero point, for example in both cardiology and in oncology. At the same time we are quite flexible, and the reason is that the company is managed by its founders, who are directly interested in results. All important decisions can be made easily without loss of time. Often we organise and conduct the local part of a clinical trial as a sub-contractor for other middle size CROs. With one such company we have a long partnership, and altogether our companies are able to conduct projects in most parts of Eastern and Central Europe. At the same time we also hope to appear in the US market through developing partnership with one of the leading American CROs. This company is the pioneer in conducting adaptive clinical trials. Its unique technology is designed to save time, reduce costs and provide real-time information and decisionmaking capability for the sponsors. In spite of the fact that we mainly have experience in conducting Phase I/II and II clinical trials, it should be pointed out that Congenix also has its own resources, including human resources, to conduct an international multicentre Phase III project. To sum up, Congenix is not a big company, but we have experience, wide opportunities and flexible approaches which allow us to successfully operate as an expert CRO in our geographic area. 2. What are the most common challenges faced by a CRO like yours in its respective regions? We would like to highlight the widespread points to be considered before 28 JCS setting up a clinical trial in Russia and the countries of Eastern Europe: regulatory details; staff availability; availability of comparator; standard therapies; validation of study tools, e.g. patient questionnaires; laboratory samples logistics; communication and language barriers. First of all we would like to highlight briefly the regulatory details in Russia and some countries of the CIS where we operate. The legal basis to conduct clinical trials in Russia is the 1998 Federal Law on Drugs. The regulatory basis for conducting clinical trials in Russia is the 2005 National Standard of the Russian Federation 52379-2005 Good Clinical Practice, a translation of the GCP E6 guideline. The Russian Ministry of Health and Social Development also regulates the process by means of various Orders and Instructions, all of which have been developed in correspondence with the law and national standards. The next promising country for conducting clinical trials is Ukraine. Clinical trials are regulated here by state law ‘On medicinal products’, effective from 1996, and the regulations approved by the Ukrainian Ministry of Health in 2006. The latest documents were developed taking into consideration the requirements of Directive 2001/20/EC. At present, a regulatory basis is being formed in Kazakhstan for the clinical research market in this country. The following local laws are applicable for conducting clinical trials: instruction for conducting the clinical trials approved by Ministry of Health of Kazakhstan in 2005; Drug Law approved in 2004. The law regarding approval of clinical trials in Byelorussia became effective in 1993. The revision of regulations for conducting clinical trials is ongoing in Byelorussia. The role of local ethics committees is very important, and informal, international insurance is accepted in this country. In Moldova the approval process for clinical trials is regulated by the drug law about pharmaceutical activities, effective from 1997, and the law about rights and responsibilities of subjects effective from 2005 in parallel with international regulations. Thus the main countries with significant recruitment potential have structured and well organised permit systems and regulations which satisfy the requirements of ICH GCP guidance. Concerning the availability of study staff, it is necessary to note that Russia ranks highly among other Eastern European countries in the availability of basic medical resources for conducting clinical trials. At present, most clinical trial work is conducted in Moscow and St. Petersburg owing to the better infrastructure, large populations and the presence of major research centres in these two cities; the well-equipped academic sites located to the east - from the Ural Mountains in Siberia to the Far East, which is rich in natural gas and oil resources - remain largely underused. While many medical procedures that in the West might be performed in an outpatient setting, in Russia call for a stay in hospital, hospital costs do not add www.jforcs.com Great Bridge of St Petersburg, Russia significantly to the trial expenses. Moreover, this additional level of attention is helpful in informing the subjects of their obligations and providing the opportunity to closely monitor and instruct them early on, thus helping to facilitate compliance. At the same time we meet situations when the comparator(s) are not available at the clinical sites or the standards of treatment are significantly different from what is conventional in Western countries. This is a so called “fly in the ointment” decreasing the number of trials which could be potentially conducted in Russia and the countries of Eastern Europe. We also would like to touch briefly upon the issue of laboratory samples logistics. During the study course all laboratory samples run freely between study sites and central labs. All the main international courier companies are present in our region. In some cases we prefer to use the local courier companies since they are more flexible and able to perform difficult tasks. But sometimes unexpected events can happen. For example, a ban on the export of biological samples which lasted for two weeks in June 2007 impacted on clinical trials conducted in Russia, despite its brevity. This fact led to a decrease in the numbers of international clinical trials conducted in Russia compared to the second quarter of 2006. At the same time this event highlighted the opportunities for local laboratories to serve as central laboratories. Our company has a very positive experience working with the laboratory INVITRO. Communication lines are also very important. We understand that our company is not positioned in a closed space, but is in close connection with the sponsor and local regulatory bodies, as well as with the clinical site’s study team. It is not a secret that clinical trials are not the main activity for physicians. And sometimes our company faces a challenge when the investigator and his/her study team do not give enough attention to the trial. In this situation only close interaction between the CRO and the site study team, and competent site management, help to resolve the issue. Concerning the communications with competent and expert bodies, our company also prefers an active position. Practice has shown that the CRO should be not only an intermediate link between competent authorities and the sponsor, but also should be actively involved, for example, in the discussion process at the stage of obtaining clinical trial authorisation. For example, the involvement of our regulatory experts has led to a positive outcome, an exit from no-win and obtaining clinical trial authorisation for an early phase clinical trial dedicated to treatment of rheumatoid arthritis. 3. What strategies have you put into place to improve the quality and safety of the clinical trials in the CIS regions? We would like to note that quality management is the key component of our work, as well as compliance with all applicable regulations. It is critical that our project managers develop a QC plan for each significant operational stage of the study, including investigator selection and qualifications; study monitoring and source documents verification; query resolution, etc. Congenix establishes annually an audit program to verify conformance to contractual requirements, sponsor needs, contractual obligations and regulations, to obtain and maintain confidence in its capability to deliver quality services and to improve existing processes. The Congenix QA department performs trial-specific audits to evaluate 30 JCS the trial conduct and compliance with the protocol, SOPs, GCP and applicable regulatory requirements. Depending on the audit type, trial-related audits may be conducted at Congenix, investigator sites managed by Congenix or other locations. Our QA department also performs system audits to assess strengths, deficiencies, weaknesses and areas of potential improvement of systems related to the conduct of clinical trials. We strive to continuously improve the quality of the services provided to sponsors. Congenix welcomes suggestions for improvement, in particular feedback from audits, e.g. in formal audit reports or discussion with QA auditors. 4. Could you please give us an example of best practices of ethical review in the region? Since the clinical trial approval system in Russia is well developed, the central ethics’ committee review is very likely an example of best practices. The process of obtaining the approval of the regulatory authorities for clinical trials in Russia much improved in 2008. The work of the Central Ethics Committee was reorganised in the last year and the process now flows faster. An Ethics Committee provides us with its final approval within two weeks. In the height of summer we submitted documents for one of the projects, they were reviewed in the next meeting of the Central Ethics Committee four working days later and received final approval in less than one week. 5. What kind of educational programmes do you have which can be offered to the sites? Congenix provides investigators with its own developed training which gives an idea of the drug development process and describes all investigator responsibilities in the course of a clinical trial. In particular, we recommend this training for investigators who are only starting to work in the area of international clinical trials. 6. What is your vision for the future and where do you see Congenix in the next five years? From our point of view the company’s success will be based on the following key elements: the maintenance of the company’s flexibility; Congenix’s strengthening in our geographic region; acceleration of our business development efforts; and taking on board the new unique services which will significantly single us out among the others. Without any doubt Congenix will remain the foremost reliable and client-oriented company providing professional services in the field of clinical trials. I Irina Dobreva is Chief Executive Officer and co-founder of Congenix LLC, a Russian CRO established in 2004. Irina has extensive experience in clinical trials, not least starting as an expert at the Russian Ministry of Health. She qualified in Medicine from Ural State Medical University and trained in Oncology. Email: [email protected] Dr Vladimir Novakovskiy is Managing Director, Clinical Operations and Regulatory Affairs at Congenix. Dr Novakovskiy holds a medical degree from St Petersburg Medical University. He has also got a PhD in medicine, specialising in oncology and immunology. Email: [email protected] www.jforcs.com UNDERSTANDING AND ADDRESSING THE UNIQUE CHALLENGES OF CLINICAL TRIALS IN THE SUPPORTIVE CARE OF CANCER PATIENTS It has been widely reported that only 2 to 4 per cent of new adult cancer patients in the United States participate in clinical trials. Representation is known to be especially low from elderly and minority populations.1,2,3 Data from the National Cancer Institute reveal that 1.4 million Americans received a diagnosis of cancer in the 12-month period from January through December 2006 (most recent data available).4 That number will be higher for 2008. Given those statistics, one could reasonably estimate that in 2008, only 48,000 to 50,000 patients will participate in the thousands of cancer trials open to enrolment in the United States. A small portion of those will consent to participate in a supportive care trial. We can take steps to improve the rates of enrolment into cancer trials overall and supportive care trials in particular. Researchers supported by government, academia and industry work diligently to develop safe and effective medicines to prevent and treat cancer, and to ameliorate side-effects of treatment. Although there are many research objectives, the primary goals are to increase survival, decrease side-effects, and maintain or recapture quality-of-life for cancer patients in all stages of their disease and treatment. Pre-clinical and clinical trials are on the critical pathway to conquering cancer, and patient volunteers are required to win that fight. The NCI, which sponsors more than 8,000 active trials as of this writing, reports that less than 2 per cent of the adults diagnosed with cancer in the United States each year receive treatment through enrolment in an NCI Cooperative Group clinical trial.5,6 That means that only another 1 per cent (~16,000 patients) of those newly diagnosed are enrolled in trials outside of the NCI purview. The low rate of clinical trial participation lengthens the time required to meet patient accrual targets for trials and therefore lengthens the time required to complete clinical trials, slowing the pace of progress in improving cancer treatments. Every cancer patient is a potential subject in a clinical trial. But where do the volunteers come from? Which patients tend to be enrolled in clinical trials and which populations do not? And why? Researchers from University of Wisconsin reported in May 2008 at the American Society of Clinical Oncologists that data from a 1900 patient study revealed that 60% of newly diagnosed cancer patients say they were never told of trial options.7 The same report also indicates that patients satisfied with care are more likely to enroll in trials and that patients in rural settings and those involved in support groups and even those who travel relatively far distances to receive care are more likely to enroll. In 2002, researchers from UC Davis Cancer Center reported a much higher rate of trial participation than the average. They defined five broad categories of potential barriers to participation, including lack of resources on the part of the patients; health insurance restrictions; confusion about the differences between research and medical care; confusion about the procedures of the trial itself; and misunderstandings about the illness and its severity. www.jforcs.com Those patients who do volunteer to participate in a clinical study do so, perhaps, for very different reasons. Even within a single individual, the decision to volunteer or not may change several times over the course of his or her post-diagnosis lifetime. Careful consideration of the various motivations and deterrents to clinical trial involvement of the cancer patient is critical to the success of any clinical trial in this arena. Treatment trials are often more attractive to both investigators and to their patients, and the reasons are obvious – patients and their physicians will go to extremes to preserve life. It follows that, if enrolling patients into treatment trials is difficult, enrolling patients into trials designed as supportive care is often many times more arduous. Consider the choice of enrolling in a trial to treat your cancer or to treat the side-effects of your life-saving treatment - nausea, neuropathy, anemia, or depression. Which would you choose? Would your choice change under varying circumstances? Consider the overwhelming odds against a patient even finding a supportive care trial when NCI posts 29 trial results in supportive care while listing more than 8,000 NCI-supported treatment trials. Enrolling patients into any particular clinical trial is difficult, especially in the regions of the world where healthcare is relatively available, options for treatment are many, and there are many clinical trials open to enrolment at any given time. To anyone working in the universe of clinical research today, it is evident that: • the number of trials seeking to enroll volunteers with cancer is huge and on the rise; • the competition for patient-volunteers is increasing; • patients may be presented with many potential trial choices or may not know of a single one; • the importance of clinical trial participation is not well-known in the population; • patients are fearful about trial participation; • the need to seek clinical trial subjects in other parts of the world continues to be important and increasingly so; • information is increasingly available to patients via the internet and patients are, therefore, capable of becoming very well-informed regarding their treatment options and the trials seeking enrolment; • communities of patients, both real and virtual, are powerful forces for support, communication, and influence; they can drive patients to trials or away from them. The keys to success in enrolling into any clinical trial include: • a feasible protocol; • committed physicians and study coordinators experienced in clinical research; JCS 31 • • • • patient education and outreach; appropriate educational materials; advertising and trial awareness campaigns including trial branding and promotion; MD-to-MD outreach involving other community physicians outside the trial construct. critical. Appropriate materials in cancer clinics and on the web can engender conversation and increase comfort in the clinical trial option. The altruistic act of trial participation is highly motivating for some patients but requires understanding and support of their family and support network. How then can the important clinical trials of therapies used to treat the side-effects of chemotherapy - the supportive care trials - enroll the subjects required? The universe of potential subjects is large; the participation of adults is small; the preference for participation in a treatment trial is often overwhelming. Can clinical trials in supportive care be done within reasonable timeframes? What does including ex-US sites add to the mix, and why? Cancer-community involvement and support. Investigators can do only so much. They can speak to patients as they return to the clinic for treatment and suggest clinical trial participation at that time. They can mount a call-out to qualifying patients in their practice. But better still is to have the community of cancer patients at large (or the community of a specific diagnostic subgroup) drive conversation and consideration of trials from the patients (the many) to the investigators (the relative few). Industry support in the community forums is critical here. The keys to enrolling subjects into supportive care trials include all of the above AND: Where possible, trial design should facilitate the enrolment of patients whose treatment regimens are already defined and include current, approved therapies. The advantage to participation in a supportive care study is to optimise treatment, whether in increasing a patient’s ability to tolerate the sideeffects of their treatment, thus allowing them to complete their scheduled regimen, or to allow them to maintain a higher quality-of-life while undergoing treatment. Inclusion of a large number of sites in the trial. Given the unique challenges to enrolment, trials in the supportive care area will likely require more study centres than might reasonably be estimated. Although many patients may qualify for entry, and although the population at a study site may appear to be more than adequate, enrolment goals will only be met with a very large number of approaches to patients – many patients and perhaps several approaches over the course of treatment. Selection of Principal Investigators and study centres with a focus on community, patients, and even supportive care and an understanding of the barriers to enrolment. Smaller, community-based, rural practices may be the ideal, as they pull patients from a large area to a centralised, focused community practice. Patients feel comfortable and participatory, and not lost in a huge bureaucracy. Investigators who are highly involved in their community and whose patient population is drawn from a large area have been very successful in past trials. A patient might travel monthly to New York City for cutting-edge treatment of their disease, but they are less likely to do so as required for a supportive care trial. Education and outreach to minority and elderly patients can increase participation into the trial. Careful and considerate timing of the request of a patient to consider a supportive care trial. Has the patient chosen a standard of care treatment option to which a supportive care trial could be adjunct? Does the patient understand the benefits of ameliorating side-effects so that chemotherapy regimens might be continued without suspension? Or, is the patient seeking ‘cutting edge’ experimental treatment for their disease in a clinical trial setting? The latter would preclude many other supportive care trial options. Repeated approaches to patients discussing trial considerations during the course of their chemotherapy treatment. Patients who may be willing to volunteer may be interested in a trial after their first course of chemotherapy once they understand what is going to happen to them in the administration of a cycle of their treatment. Patients may be willing to participate in a supportive trial if they have chosen a standard-of-care treatment regimen with their physicians. Patients may choose a supportive care trial when they are being treated for recurrence of their disease rather than when receiving first-line therapy. Family and caregiver education. Families are hugely influential in the patient decision-making process and many decisions are required of the cancer patient. An understanding of the clinical trial process, trial options, and human subject protections, is 32 JCS Adding sites outside of the United States. Ideally, the volunteer rate for patients into clinical trials will increase over time in the US. However, it is increasingly important to expand the search for qualified and interested subjects into other parts of the world. Much success has been documented in the conduct of clinical trials in emerging markets, where patients benefit greatly from the basic care provided in any trial – treatment or supportive care – and their choice of either one has an important and positive outcome in the healthcare they receive. Those of us in the business of clinical research and, specifically, those conducting trials in supportive cancer care need to work to deliver all of the requirements for trial success in the supportive care arena, if we are to adequately serve the growing population of cancer patients through cancer trials in the coming years. I References: 1. Joseph R. Viewpoints and concerns of a clinical trial participant. Cancer. 1994;74:2692–2693. 2. Trimble EL, Carter CL, Cain D, Freidlin B, Ungerleider RS, Friedman MA. Representation of older patients in cancer treatment trials. Cancer. 1994;74(7 suppl):2208–2214. 3. Kaluzny A, Brawley O, Garson-Angert D, et al. Assuring access to state-of-the-art care for U.S. minority populations: the first 2 years of the Minority-Based Community Clinical Oncology Program. J Natl Cancer Inst. 1993;85: 1945–1950. 4. Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, Altekruse SF, Feuer EJ, Huang L, Mariotto A, Miller BA, Lewis DR, Eisner MP, Stinchcomb DG, Edwards BK (eds). SEER Cancer Statistics Review, 1975-2006, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2006/, based on November 2008 SEER data submission, posted to the SEER web site, 2009. 5. Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: Race-, Sex-, and Age-Based Disparities. Journal of the American Medical Association 2004;291:2720-2726. [Abstract] Last accessed July 6, 2005. 6. Christian MC, Trimble EL. Increasing participation of physicians and patients from underrepresented racial and ethnic groups in National Cancer Institute-sponsored clinical trials. Cancer Epidemiology, Biomarkers & Prevention 2003 (suppl.):12:277s-283s. [Abstract] Last accessed July 6, 2005. 7. Wassenaar TR, Walsh MC, Cleary JF, Remington PL and Trentham Dietz, A. Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 26, No 15S (May 20 Supplement), 2008: 9524 8. UC Davis News Release May 20, 2002 Donna E Beardsworth is the founder and Chief delivery Officer of Beardsworth Consulting Group, Inc and currently serves as the Chief Delivery Officer for the organisation. Beardsworth is a full-service CRO with a 23-year history of delivering quality clinical research projects. Beardsworth specialises in the conduct of complicated trials in difficult therapeutic areas such as cancer. Their experience is in both treatment and supportive care trials in the cancer patient. Email: [email protected] www.jforcs.com INTERVIEW: A GLOBAL CENTRAL LABORATORY PERSPECTIVE ON ONCOLOGY STUDIES 1. Let us start with the core competencies of ACM Global Central Lab. What are your key offerings to the Global Clinical trials Industry? ACM Global Central Laboratory is a full service reference and Clinical Trial Central lab. We offer not only a broad menu of assays including safety, esoteric, microbiology and anatomic pathology and the expertise in our personnel that perform them but also project management, data management and study kit building. 2. What are the main requirements from a testing lab? What is being asked from you now days? Laboratories are expected to provide results that impact people's lives. Accurate, repeatable assays implemented after rigorous validation are required. Molecular diagnostic testing has become a standard request in protocols. Flow cytometry, PCR and IHC are a routine offering in our laboratory. 3. How does a testing lab meets high quality standards? Clinical Trial laboratories are always under the microscope. From formal regulatory/certifying (CLIA, CAP and NGSP to name a few important to our clients) agencies to the many client audits requiring adherence to established industry standards and regional Standard Operating Procedures (SOP). Participation in various proficiency programs in conjunction with daily quality control testing demonstrates lab and assay performance. 4. Whether the method used in the laboratory is sensitive or not? Validation and initiation of an assay in a lab can depend on the intent of the evaluation. Validation covers assay, sensitivity, reproducibility, stability and interference assessments. All must be documented and approved by the medical director prior to being introduced to the menu of assays provided by ACM. 5. Is Method having specificity and reproducibility? It is important that during an assay validation, we accurately determine the specificity of our assay so as to provide reliable results. Determining the reportable range is also a key element so as to determine if the assay meets the clients need for the target population. 6. How do you meet Time deliverable? Dedicated departments address the specific requirements from request for proposal and contract to a dedicated laboratory protocol set up team that work in concert with the project management team to define, validate and implement study requirements. Due to the level of automation used in our facilities, and the volume of testing performed on a daily basis, we are able to maximize the use of our lab. Overall however, our seasoned Project Managers are responsible for ensuring all key deliverables are met. 34 JCS 7. Do you have have automated testing platform? Yes we have the Siemens Work Cell with 3 Siemens Advia 1800, 3 Centaurs with the option to connect the hematology analyzers. All instruments have back up and are interfaced to the Lab Information System (LIS). This allows for high throughput making TAT a non issue, scalability for additional large sample numbers, and reduced specimen volume- always a key concern for IRB evaluation of new trial approval. The automation allows our scientists to be utilized in a productive fashion working to implement assays important to our clients.. 8. Do you provide cost-effective solutions? Yes, ACM Global Central Lab offers a number of cost-effective solutions. We continually implement state of the art technology, which lowers the cost to perform testing. For example, we utilize the Siemens WorkCell robotic line which is interfaced with all our analyzers. Since ACM provides comprehensive testing such as pathology, microbiology, PGx along with safety testing, 99% of the testing is performed in one location. When specimens are parsed out to various labs for testing, there are additional shipping costs as well as operational costs. Another critical component is staffing, with a turn over rate of less than 4%, we are able to minimize the cost associated with hiring and training. As part of a health organization, we have significant buying power on couriers, collection supplies, etc., which enables us to pass along additional savings to our clients as well. I Elena Logan, Vice President, Clinical Trials, US. Elena's experience is comprised of project management for a major pharmaceutical company, clinical operations and business development in the CRO industry and currently as VP, Clinical Trials for ACM. Email: [email protected] Kathleen Murray, Executive Director, Global Technical Affairs, US Kathy has spent over 25 years in the clinical laboratory with experience in all areas of general laboratory testing. Kathy’s focus is to expand the ACM’s presence around the globe while ensuring data harmonisation and standardisation of process. Email: [email protected] www.jforcs.com INTERVIEW: DATA COLLECTION AND ANALYSIS FOR THE EARLY DETECTION OF BREAST CANCER 1. Let us start with the core offerings of Medidata Solutions. What are your core objectives? Medidata Solutions’ mission is to provide hosted clinical development solutions that enhance the efficiency of customers’ clinical development processes, and optimise their research and development investments. We strive to facilitate operational excellence in our customers’ clinical research processes. We provide software and services designed to eliminate redundant processes and to increase agility through insightful decision-making. Our products improve information flow through the study lifecycle, study design, planning, execution and study close. Medidata products and services are designed to allow customers to achieve clinical results more efficiently and effectively by streamlining the design, planning and management of key aspects of the clinical development process: protocol development (Medidata Designer™), investigator benchmarking and budgeting (Medidata Grants Manager™), contract research organisation (CRO) benchmarking and budgeting (Medidata CRO Contractor™), and the capture, management, analysis and reporting of clinical trial data (Medidata Rave®). Protocol development: Medidata Designer™ is a protocol authoring and trial design tool that helps guide clinical research teams through the protocol creation process, also automatically populating downstream trial applications, such as electronic data collection and data analysis systems and including clinicaltrials.gov. Investigator benchmarking and budgeting: Medidata Grants Manager™, an investigator site contract benchmarking tool, helps trial managers optimise investigator grants by establishing fair and consistent site payments and mitigating compliance risks. CRO benchmarking and budgeting: Medidata’s outsource planning and contracting solution, Medidata CRO Contractor™, puts data-driven analytic tools in the hands of research sponsors to efficiently plan, budget and manage CRO relationships. Capture, management, analysis and reporting of clinical trial data: Medidata Rave® is an industry-leading electronic data capture, management and reporting solution that enhances clinical trial productivity and provides early visibility to reliable clinical data. Focusing on user experience and functionality, Medidata Rave provides site investigators as well as sponsor and CRO study teams with intuitive interfaces, advanced eLearning tools and accessibility from any internet-ready computer. Built on industry standards, including CDISC ODM, and offering a web-based API, Medidata Rave has been seamlessly integrated with a wide range of clinical trial applications. Recently, Medidata introduced an extension to Medidata Rave, Rave Monitor. Rave Monitor offers visit report functionality as an integral part of the EDC/CDM 36 JCS system, providing sponsors and contract research organisations with a more efficient, compliant and cost-effective way to manage site visits. 2. How did you get involved with U-Systems? Did you make the initial contact? What were the project guidelines? Why were you chosen? U-Systems was looking to replace its paper-based data collection with an affordable electronic data capture (EDC) system that would increase efficiencies across its clinical trial process, improve data quality and maintain a ready audit trail for submission of study data for post-market approval. Medidata was chosen for our flexible and affordable implementation and eLearning capabilities. Additionally, U-Systems was attracted to our focus on small to mid-sized companies and its ability to deliver fast implementations while collaborating with our sponsors and addressing their needs. With Medidata’s help, U-Systems was able to launch it’s first-ever EDC trial in just six weeks. Medidata Rave’s built-in eLearning functionality was critical for U-Systems to quickly train site staff to become proficient in Rave, saving both time and cost in study start-up. Medidata’s eLearning tool also enabled U-Systems to easily certify that all study coordinators completed training before entering study data, as access to the study is blocked until successful completion of the training – a key enabler of audit trail documentation. With the potential for this initial study to grow to nine sites, U-Systems expects to continue to rely on Medidata Rave’s ability to quickly train site personnel in order to achieve timely and accurate data entry and review. 3. Coming to the operational procedures, is there any facility to check for out of range values when data validation happens automatically when data is entered in to the eCRF online? One of the prime benefits of Medidata Rave is its automatic flagging of “out of range” values as soon as a site enters in the eCRF. Rave can handle both local and centralised laboratory limits, and also check for multiple data dependencies. For example, this can allow for range checking based on age or physiological status (e.g. fasting) or using multiple analytic unit conversions. In addition, the edit check engine can reference both data entered through eCRFs or loaded data such as lab, serologic or pharmacokinetic data. 4. Is there automatic reminder for a subject’s next visit? Medidata Rave’s built-in tools can provide a clear visual cue to the end user to alert them to the need to follow up on overdue visit data. In addition, Medidata Rave features an edit check triggered messaging functionality www.jforcs.com of the clinical development process. Below are some examples of features that are particularly useful in oncology trials. Nesting of folders/events within a study outline This feature supports concepts like treatment cycles within time periods. This facilitates downstream processing such as edit check and reporting comparisons. Dynamic fields, forms, visit schedules Fields, forms, and cycles can be added manually or based on an event or trigger. For example, a schedule can be added for a new course of treatment if the previous treatment failed or a new cycle can be dynamically created based on a lab result for white blood cell count. Imaging support Medidata Rave supports the ability to upload different types of images so that they can be viewed and compared on a visit by visit basis alongside things such as tumour measurement data. which can be used to send predefined alerts to end users concerning upcoming events such as visits. Medidata Rave can also be interfaced with systems from organisations that provide mobile-based medical alerts to patients to remind them of upcoming visits. 5. Will the system provide automated support for generating invoices when certain milestones are met for each subject? Medidata Rave can be integrated with other systems to trigger messages or activities based on study events or milestones. For example, Medidata Rave has been integrated with financial and CTMS systems to produce invoices based on the achievement of specific milestones and events within a study. Medidata Rave does not produce such invoices from within the system. 6. Will the system ensure agency-specific document formatting and publishing? Medidata Rave provides a sponsor with submission-ready PDFs, formatted in accordance with agency-defined formatting specifications for electronic submission of clinical study data. In addition, the PDF outputs include full audit information which can be used for the site and sponsor archival of the study data. 7. Will the system perform as liaison between regulatory bodies and the sponsor company? Medidata is available as a resource for guidance on local, national and international regulatory requirements, when working with sponsor and CRO organisations. Medidata does not get directly involved with inspections by a regulatory authority; however, when sponsors are being inspected, Medidata makes itself readily available to support the sponsor and to help them respond to regulatory questions and requests. 8. What is Medidata's next big project? Any more innovative data collection and analysis tools on the oncology front? Medidata continues to develop new ways to help our clients fulfill their clinical research objectives. We provide robust tools which enable our oncology customers to conduct faster, more efficient trials. Approximately 34% of the studies currently conducted in Rave are in the oncology therapeutic class. Rave is highly configurable and we continuously seek to add functionalities to streamline the design, planning and management 38 JCS Sophisticated lab system Medidata Rave has robust capabilities in both central and local labs. This allows the ability to monitor lab data alongside hand-entered data, including tracking against reference and alert ranges. Ranges are time sensitive and can utilise any data points in the study. The central lab upload tool has to the ability to ensure data is matched to the proper patient and visit, and if it is a new or incremental update. Sophisticated security engine Medidata Rave utilises a single security engine for all inputs, outputs and reporting. This also allows for sophisticated blinding and unblinding of efficacy data by study phase and can be very useful in adaptive trials. Configurable patient statuses Beside the statuses of enrolled, screening, and failed, any other status can be created. Examples may be “completed cycle 1, completed cycle 2.” This facilitates outputs and reporting. “Snowbird” support Within Rave, we have the ability to transfer or share patient records between clinics and sites. This is very useful in areas such as patient relocation i.e. to warmer climates for the winter or when an investigator moves from one institution to another and the patients follow. Included in this support is a complete audit trail of all movements and activities. Global Library and Architect Loader These utilities provide the ability to rapidly deploy studies based on standards. They also provide the ability to easily share study designs across related areas. All our customers, including some of the largest players in the field of oncology, play a key part in the ongoing development of Medidata Rave. This has enabled us to take into account key data collection and analysis needs in the field of oncology. I Steve Heath, VP and Head of EMEA. Steve is responsible at Medidata for commercial and operational activities within EMEA. Steve has wide familiarity of selling and implementing EDC (electronic data capture), CDM (clinical data management) and ePRO (electronic patient reported outcomes) systems as well as LIMS, clinical project management, safety and adverse drug reaction reporting systems. David Quarm, Senior Business Consultant, Medidata Solutions www.jforcs.com QTC PROLONGATION IN PATIENTS WITH CHRONIC RENAL IMPAIRMENT Introduction Patients with end-stage renal disease are frequently associated with increased mortality rates due to sudden cardiac events (1-8). Ventricular arrhythmias are the major problems of cardiac origin (9) in this population. Several attempts have been made to determine factors responsible for the occurrence of serious ventricular arrhythmias (7, 10, 11). It was shown in previous clinical studies that prolongation of QT interval and changes in the QT dispersion on the surface electrocardiogram may correlate with the onset of serious cardiac arrhythmias (12, 13). This investigation was performed to elucidate a possible correlation between the status of renal impairment and QTc prolongation in patients with different stages of renal impairment and healthy controls. Material and Methods Screening data of 43 patients with different stages of renal impairment and 28 healthy subjects from three clinical studies were analysed. Table 1 summarises the demographic data. All studies were approved by the central ethics committee in Chisinau, Moldova and the studies were performed in the clinical site of INNOPHAR at the National Institute of Cardiology. Renal impairment was documented by creatinine clearance (CLCR) calculated according to the formula of Cockcroft-Gault. Patients with clinically relevant cardiac diseases were excluded. Patients with controlled hypertension were only included if they did not take any medication which might have an effect on QT interval. Table 1: Demographic Data H RI H RI H Results Table 1 shows that the demographic data of both groups were comparable. In particular, heart rate (HR) was not significantly different in both groups (p = 0.679). Also the gender distribution was comparable in both groups (57% and 58% females, and 43% and 42% males in the group of healthy and renal impaired patients respectively). There was a statistically significant difference in the CLCR between the healthy controls and the renal impaired patients (p << 0.001). Figure 1 presents the arithmetic mean values for CLCR. Figure 1: Mean CLCR (mg/ml) (H=healthy, RI=renal impaired) H 43 28 43 28 43 Minimum 23,00 22,00 52,00 46,00 54,00 49,00 Maximum 64,00 68,00 100,00 92,50 90,00 91,00 Median 48,00 47,00 72,70 70,00 66,50 67,00 Mean 47,07 46,19 73,75 69,47 68,50 67,51 SD 10,25 11,99 12,24 12,33 9,05 10,80 There was also a statistically significant difference in the arithmetic mean of QTc (p << 0.001) between healthy controls and patients with renal impairment (refer to Fig 2). Figure 2: Mean QTc in ms (H=healthy, RI=renal impaired) H After a comprehensive physical and laboratory investigation, rest ECGs with 12 lead standard deviations were recorded according to the standards published previously (14). QT was calculated as the mean value from 10-second ECG recordings as the difference from beginning of the Q-wave and the end of the T-wave by using the Dr. Vetter PC-ECG (Dr. Vetter GmbH, Germany). All subjects were investigated in a supine position in the fasting state after a resting period of at least 15 minutes. The room for ECG recordings was noise-protected and the temperature was kept constant at 22±2°C. QT was corrected according to the Bazet Formula QTc = QT*(60/HR)-1/2. As the last phase of the repolarisation process is potassium-dependent serum potassium was also investigated. CLCR data were log-transformed because there is a bottom effect like in other laboratory data, and the data are left skewed and therefore deviate from normal distribution. All metric data were analysed by t-test, and categorical data were submitted to a Pearson-Chi-Square-Test. The critical statistical 40 JCS RI RI 28 N level was defined as 5% in general. A regression analysis with a linear model (ANCOVA) was performed to investigate whether age, weight and gender have an influence on the correlation of CLCR and QTc. RI The scatter plot in Figure 3 confirms the correlation between CLCR (on log-transformed axis) and QTc. Figure 3: QTc (ms) vs CLCR (in log-scale) www.jforcs.com The regression analysis reveals a statistically significant correlation between CLCR and QTc (p < 0.001). The ANCOVA analysis confirmed that there was no statistically significant influence of age and weight on the correlation between CLCR and QTc (p > 0.05). A statistically significant difference (p = 0.05) in QTc was observed between males and females (428,20 ms for males and 442,94 ms for females). Figure 4: QTc (ms) in Females and Males F M There was also a statistically significant difference in serum potassium between healthy subjects and renal impaired patients (refer to Table 2). Table 1: Serum Potassium (mmol/l) Healthy 28 4.262 0.558 Renal Impaired 41 4.878 0.751 <0.001 The scatter plot in Figure 5 reveals that the slope in the correlation between heart rate and QT is different in healthy subjects and in renal impaired patients. Figure 5: Correlation heart rate (HR; b/min) vs QT-Interval (QT; ms) Discussion This investigation was performed to analyse the possible correlation between renal impairment based on CLCR and QTc prolongation in patients with different degrees of renal impairment in comparison to healthy subjects. The data revealed a statistically significant correlation between CLCR and QTc corrected according to Bazet. This result is consistent with previous investigations (15) in which significant QTc prolongation was described in chronic renal impaired patients who had recently started hemodialysis. The mechanisms responsible for QTc prolongation in patients with chronic renal impairment are not completely understood. There are controversial results published. The investigation of Voiculescu et al. (16) revealed that QTc prolongation was not correlated with the stage of renal impairment but with the duration of renal impairment. There were speculations on the influence of autonomic neuropathy (17, 18) on the development of QTc prolongation because it was found not only in patients with renal impairment but also in patients with diabetes mellitus (19-24) or hepatic impairment (25-28), which seems to confirm that QTc prolongation is triggered by autonomic neuropathy of different origin. Reports on hepatic impaired patients who underwent liver transplantation reveal that QTc normalises in most cases within one month (29, 30) whereas autonomic neuropathy is not reversible in all patients (29). Autonomic neuropathy if present may contribute to the QTc prolongation but there must be other factors which are more important. As can be seen from the scatter plot (refer to Figure 5) the slope is different 42 JCS between healthy subjects and renal impaired patients. This may be an indicator that the correlation between HR and QT is changed by renal impairment. Electrolyte imbalance which is commonly present in renal impairred patients may have an impact on the electrophysiological correlation between HR and QT. A significant difference in serum potassium observed in the investigated population confirms this hypothesis, but further investigations will be necessary to come to a final conclusion. The differences in QTc for gender were already described in a previous investigation (31) and may be taken as confirmation that the present investigations were performed to a good quality standard. I References: 1. Morris KP, Skinner JR, Wren C, Huner S, Coulthard MG. Cardiac abnormalities in end stage renal failure and anaemia. Arch Dis Child 1993; 68: 637 – 643. 2. Shpira OM, Bar-Khayim Y. ECG changes and cardiac arrhythmias in chronic renal failure patients on hemodialysis. J Electrocardiol 1992; 25: 273 – 279. 3. Thomson BJ, McAreavery D, Neilson JM, Winney RJ, Ewing DJ. Heart rate variability and cardiac arrhythmias in patients with chronic renal failure. 4. Ramirez G, Brueggemeyer CD, Newton JL. Cardiac arrhythmias on hemodyalisis in chronic renal failure patients. Nephron 1984; 36: 212 – 218. 5. Weber H, Schwarzer C, Stummvoll KH et al. Chronic hemodialysis: high risk patients for arrhythmias? Nephron 1984; 37: 180 – 185. 6. Singh JP, Sleight P, Kardos A, Hart G. QT interval dynamics and heart rate variability preceding a case of cardiac arrest. Heart 1997; 77: 375 – 377. 7. Nakamura N et al. QTc dispersion in haemodialysis patients with cardiac complications. Nephrology 2005; 10: 113 – 118. 8. Raizada V et al. Renin-angiotensin polymorphsisms and QTc interval prolongation in end-stage renal disease. Kidney International 2005; 68: 1186 – 1189. 9. Kocak G et al. QT/corrected QT (QTc) intervals and QT/QTc dispersions in children with chronic renal failure. International Journal of Cardiology 1999; 70: 63 – 67. 10. Ichikawa H, Nagake Y, Makino H. Signal averaged electrocardiography (SAECG) in patients on hemodialysis. J Med 1997; 28: 229 – 243. 11. Goldner B, Brandspeigel HZ, Horwitz L, Jadonath R, Cohen TJ. Utility of QT dispersion combined with the signal-averaged electro-cardiogram in detecting patients susceptible to ventricular tachyarrhythmia. Am J Caridol 1995; 76: 1192 – 1194. 12. Kirvela M, Yli-Hankala A, Lindgren L. QT dispersion and autonomic function in diabetic and non-diabetic patients with renal failure. Br J Anaseth 1994; 73: 801 – 804. 13. Örincz I, Zilahi Z, Kun C, Natyus J, Kakuk G. ECG abnormalities in hemodialysis. Am Heart J 1997; 134: 1138 – 1140. 14. Eckl KM, Sydorchuk L, Biletski S, Tsvitbaum N, Wadepuhl T, Thomsen T, Darius H. The reliability of QTc interval assessment. AGAH annual meeting, 23-25 February, Bonn, Germany. 15. Beaubien ER, Pylypchuk GB et al. Value of Corrected QT interval dispersion in identifying patients initiating dialysis at increased risk of total and cardiovascular mortality. Am J of Kidney Diseases 2002, 39(4): 834. 16. Voiculescu M, Ionescu C, Ismail G. Frequency and prognostic significance of QT prolongation in chronic renal failure patients. Rom J Inern Med 2006, 44(4): 407 – 417. 17. Kirvela M, Yli-Hankala A, Lindgren L. QT dispersion and autonomic function in diabetic and non-diabetic patients with renal failure. Br J Anaesth 1994, 73: 1814. 18. Kurosu M, Ando Y et al. Factors related to the QT prolongation in chronic renal failure. Nippon Jinzo Gakkai Seri 1999, 41(2): 70. 19. Brown DW et al. Impaired fasting glucose, diabetes mellitus, and cardiovascular disease risk factors are associated with prolonged QTc duration. Results from the third national health and nutrition examination survey. J Cariovasc Risk 2001, 8(4): 227 – 233. 20. Sawicki PT, Dahne R, Bender R, Berger M. Prolonged QT interval as a predictor of mortality in diabetic nephropathy. Diabetologica 1996; 39: 77 – 81. 21. Ewing DJ, Boland O, Nielson JM, Cho CG, Clarke BF. Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients. Diabetologica 1991; 34: 182 – 185. 22. Kahn JK, Sisson JC, Vinik AI. QT interval prolongation and sudden death in diabetic autonomic neuropathy. J Clin Endocrinol Metab 1987, 64: 751 – 754. 23. Belavere F, Ferri M, Guarini L, Bax G, Piccoli A, Cardone C, Fedele D. Prolonged QT period in diabetic autonomic neuropathy: a possible role in sudden cardiac death? Br Heart J 1988; 59: 379 – 383. 24. Page MM, Watkins PJ. Cardiorespiratory arrest and diabetic autonomic neuropathy. Lancet 1978; I: 14 – 16. 25. Thuluvanth PJ, Triger DR. Autonomic neuropathy and chronic liver disease. Q J Med 1989; 72: 737 – 747. 26. Hendrickse MT, Triger DR. Peripheral and cardiovascular autonomic impairment in chronic liver disease; Prevalence and relation to hepatic function. J Hepatol 1992; 16: 177 – 183. 27. MacGilchrist AJ, Reid JL. Impairment of autonomic reflexes in cirrhosis. Am J Gasroenterol 1990; 85: 288 – 292. 28. Oliver MI, Mirales R, Rubies-Prat J, Navarro X, Espadaler JM, Sola R, Andreu M. Autonomic dysfunction in patients with non-alcoholic chronic liver disease. J Hepatol 1997; 26: 1242 – 1248. 29. Mohamed R, Forsey PR, Davies MK, Neuberger JM. Effect of liver transplantation on QT interval prolongation and autonomic dysfunction in end stage liver disease. 30. Finucci G, Lunardi F, Sagerdoti D, Volpin R, Bortoluzzi A, Bombonato G, Angelli P, Gatta A. QT interval prolongation in liver cirrhosis. Reversibility after orthotopic liver transplantation. Jpn. Heart J 1998, 39 No 3: 321 – 329. 31. Moss AJ. The QT interval and torsade de pointes. Drug Safety 1999, 21(1): 5 – 10. Contributed By: Cornea N., Wadepuhl M., Tsvitbaum N.,Janik F., Eckl K.M. Natalia Cornea worked as a Nephrologist in the Dialysis and Kidney Transplantation Center of Clinical Republican Hospital. During these years she also participated in many scientific conferences, courses and symposia in Moldova, Romania, Hungary, Ukraine and Poland. Natalia took an active part in carrying out the “IV Congress of Urology, Hemodialysis, Transplantology with international participation” Chisinau, Moldova being on the scientific and organizational board. Email: [email protected] www.jforcs.com DIGITAL PEN AND PAPER HELP UN BODY FIGHT DISEASE IN AFRICA The United Nations Food and Agriculture Organization (FAO), is using Digital Pen and Paper technology to virtually eliminate the need for ‘traditional’ data entry, enabling near-instant field reports to prevent or limit the effects of infectious diseases, drought and flooding in sub-Saharan Africa. Since its foundation in 1945, the UN’s FAO has focused special attention on developing rural areas – home to 70 per cent of the world’s poor and hungry people. Its role is to lead international efforts to defeat hunger, and it serves as a knowledge network to help developing and transitional countries modernise and improve agriculture, forestry and fishery practice, to ensure good nutrition for all. Most of the FAO’s missions are in remote regions with little or no access to electricity, computer facilities or telecommunications infrastructure. This severely restricted the availability of timely information from the various collecting sources to enable appropriate decision-making and efficient, well-timed action. Hand-written information gathered by local veterinary assistants and FAO staff in the field could end up being stored for weeks or months before it reached District Veterinary Offices and FAO analysts based in Rome, Italy. The result was frustration at all levels. By the time FAO headquarters had made their analyses, a disease outbreak may already have wiped out livestock for example. In rural sub-Saharan Africa, such events are particularly devastating, as a big part of the population – as much as two-thirds of the population – depends on livestock for its living. The importance of livestock health Livestock is an important sector of agricultural production in the countries of the Southern African Development Community (SADC), accounting for 20 to 40 per cent of the agricultural gross domestic product, and holds a high social value for rural communities in the region. Moreover, there is ever-increasing demand for livestock and livestock products in the region. Estimates by the SADC indicate that over the next 10–15 years, the average annual consumption of meat and milk will more than double from 7kg to 15kg of meat and from 20 to 50 litres of milk per person in the region. Ambitious export strategies have been developed to alleviate poverty in sub-Saharan Africa. However, severe drought since 2000 has limited grazing and water points. A chronic shortage of resources, land disputes and a crippling HIV/AIDS epidemic has severely limited communities’ ability to cope with outbreaks of trans-boundary animal diseases (TADs), which are the most important barrier to market access for livestock and livestock products. Outbreaks of TADs in previously disease-free areas of SADC countries over the past few years have endangered the animal health status of the entire region and threatened the livelihoods of more than half of the population. Outbreaks of disease can result in massive animal and economic losses. For example, an outbreak of Foot and Mouth Disease (FMD) in 2001 led to the suspension of beef exports from Zimbabwe to European countries. In Botswana, thousands of cattle had to be slaughtered following an 44 JCS outbreak of Contagious Bovine Pleuropneumonia (CBPP) in 1995, and subsequent control of the disease and restocking has been a costly exercise for the government. This is why the FAO places such emphasis on its programme to eliminate or alleviate the damaging effects of disease, and sudden drought or flood. In 2004, the FAO began a project in to implement emergency control of epidemic FMD, CBPP and other dangerous animal diseases, such as Anthrax, in southern Africa. An ‘almost revolutionary’ solution To help streamline the work of the FAO, South African IT company Xcallibre developed a new real-time data collection application based on Anoto’s digital pen and paper technology. This works in combination with mobile handsets and networks – increasingly widely available in Africa – to get field data to the people who need it fast. Field agents can register data with the digital pen on to a special form. The information is saved in the pen’s memory, before it is transmitted via a mobile or fixed internet connection. Next, the data is processed and sent by e-mail to the appropriate people at the local District Veterinary Office or FAO headquarters – who can then return instructions to field staff on what steps to take. This digital pen and paper application is now being used by regional and national authorities in Namibia, Zambia, Mozambique, Malawi, Tanzania and Zimbabwe. ”The pen is an almost revolutionary way to overcome a big problem with gathering data from the field and making timely decisions in case quarantine needed to be imposed,” says Fred Musisi, the FAO’s Regional Emergency Livestock Officer. “If there is a case of rabies or an outbreak of a deadly disease, a field worker can send the detailed surveillance data immediately only using a mobile phone. In the worst case, if there is no mobile network nearby, the field worker simply moves to a location with mobile coverage or finds the nearest fixed internet connection. But no longer do they have to drive hours back to a capital city before the information can be confirmed.” Simplicity and speed Other mobile-based computers (such as PDAs) were initially considered as an alternative information tool, but this idea was discarded for a number of reasons: the need for batteries, the length of the questionnaires and a legal requirement for signatures on the forms. The adoption of the digital pen and paper as a data capture tool was relatively easy, and overcame the challenges of PDA-type solutions. Xcallibre and Anoto developed a non-technical ‘train the trainer’ approach for the roll-out. FAO country representatives now implement the solution on their own as more users come on board. Ease of use was a key consideration in the design of the forms. With the help of digital pen and paper, information transfer is accelerated and all relevant users and offices can simultaneously receive secure and controlled access to the information collected. The solution has www.jforcs.com also improved the information management capacity, since the data collection methods can now be standardised throughout the sub-region. The ability to gather and analyse data in virtually real time leads to significant benefits for the FAO’s monitoring and early warning systems. These include improvements in disease surveillance and information flow, both at national and regional levels; the establishment of active surveillance programmes to monitor situations in different ecosystems; and impact assessment and risk analysis as part of the effective control of TADs. Wider benefits Overall, the FAO has greatly improved the collection, processing and distribution of information on TADs across the participating countries. It has reduced the time it takes to get a form to regional or national offices for capture down from one to three months to a matter of minutes in areas with mobile phone coverage. With this near real-time data, the FAO is able to represent outbreak patterns spatially and use spatial analytic techniques to develop response mechanisms. A web-based editing and reporting tool gives all users and offices simultaneous, secure and controlled access to the information collected. The main beneficiaries of FAO’s TAD control projects are the owners and keepers of 2.14 million head of cattle in target areas in Malawi, the Caprivi Region of Namibia, Tanzania, Zambia and Zimbabwe. The spread of dangerous livestock diseases within and across international borders has been successfully contained in all five countries. No new cases of FMD have been reported in intervention areas in Malawi. No new cases of Anthrax have been reported in the Caprivi Region of Namibia since January 2005, and reporting of new cases of CBPP has continued to decline substantially in southwest Tanzania. The FAO helped successfully control the CBPP epidemic in Zambia and contributed to completion of the first phase of progressive elimination of FMD in Zimbabwe. In addition, the FAO helped Zimbabwe to reclaim part of the beef export zone, as well as minimise losses in national milk production. The FAO is now considering using the application as standard procedure in its field missions in Asia and Latin America as well. In addition to this, they are also considering new areas of application, for example as a tool to combat HIV/AIDS. For the Xcallibre and Anoto team, the next challenges are to find alternative transmission methods – such as satellite phones – where mobile cellular coverage or fixed internet access is poor or unavailable. Other possible developments include the use of solar chargers for charging digital pens, mobile phones, laptops and satellite phones. The team is also considering the use of Bluetooth® GPS devices to capture the pen’s location for browser-based mapping and analysis. Thanks to the efforts of the FAO, and their creative use of Digital Pen and Paper technology, the people of sub-Saharan Africa can look forward to a more secure and prosperous future. How DPP technology works Digital Pen and Paper technology works by remembering what has been written or drawn on special, dotted paper, and transmits this data back to a PC or server. The digital pen writes just like a normal ballpoint pen, but has a tiny infrared camera at its tip, which reads and records the movements of the pen relative to a pattern of grey dots printed on normal paper. The dot pattern can be generated using a standard printer. For mobile staff, digital pen and paper allows them to fill in forms on the move without the need to return to the office and type them up later in the day. Users can either send the data back to the office via Bluetooth and a mobile phone – or wait until they return to their desk to dock the pen and instantly transfer the information. 46 JCS The FAO’s field agents register data with an Anoto Digital Pen into a customized form, then the informa¬tion is saved in the pen’s memory, awaiting transmission using GPRS or internet. Next, the data is processed and sent by e-mail to the relevant actors (District Veterinary Office, FAO headquarters), which can return instructions to field staff on what steps to take. Figure 1: Digital Pen and Paper Technology (DPP) Partner Profile: Xcallibre The South African company Xcallibre is a new-age global technology services company, which sets out to deliver end-to-end business solutions to its clients. It comprises highly-skilled people and a network of strategic partners, all specialists in their respective fields. Xcallibre brings together a unique combination of mobility technologies and highly advanced service infrastructure, to create a forms/document processing solution with the ability to transfer handwritten and/or digital notes and forms to your back-office, as graphical images and fully loadable data files. Xcallibre delivers a wide portfolio of innova¬tive business process systems to its clients in a number of sectors, including insurance & banking and healthcare. Customer Profile: The Food and Agriculture Organization (FAO) The FAO is a United Nations organization that leads international efforts to defeat hunger. FAO also helps developing countries and countries in transition to modernise and improve agriculture, forestry and fishery practices and to ensure good nutrition for all. Since its foundation in 1945, FAO has focused special attention on developing rural areas. I Urban Froderberg. After his education at Uppsala University, Sweden, Urban Froderberg started his career in the pharmaceutical business at German Boehringer Ingelheim. He joined Swedish Astra in 1988 where he held several successful positions within Marketing & Sales. He has worked with business development etc. at AstraZeneca, in all a twenty years experience within the pharmaceutical business. Since August 2007 Froderberg serves as Business Area Manager, Healthcare, at Swedish Anoto AB the company, leading in the unique technology for digital pen and paper. Email: [email protected] www.jforcs.com JOURNAL FOR U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets London, UK, April 16, 2009: Chiltern International Limited (Chiltern), a global Clinical Research Organization (CRO) providing clinical development and staffing services in Europe, the Americas and India, today announced the acquisition of Vigiun, a full service Clinical Research Organization located in São Paulo, Brazil. Established in 1999 by Eduardo Forleo, MD, and Elisa Halker, BSN, Vigiun has extensive experience conducting clinical trials in a variety of therapeutic areas, in particular infectious disease, oncology, and respiratory. “We warmly welcome Vigiun to the Chiltern team,” stated John Vann, Executive Vice President, Americas. “The acquisition of Vigiun enhances Chiltern’s growing presence in Latin America, which was established nearly a year ago when we began operations in Argentina under the leadership of Oscar Podestá, our General Manager for Latin News America. The knowledge and experience of Eduardo Forleo and Elisa Halker, and all of the Vigiun staff, will further strengthen our ability to serve our clients and continue our strategy for growth in the region.” Dr. Forleo has been appointed Chiltern’s Country Manager for Brazil and Medical Director for Latin America. Ms.Halker will serve as Director of Clinical Operations for Brazil. Said Dr. Forleo, “This is an exciting time to become a part of Chiltern. Our business has grown to the point that it makes sense to join forces with a global CRO whose mission and values align with ours. I look forward to contributing in very positive ways to the company’s ongoing and future success.” “I am very pleased to have Vigiun join Chiltern,” said Glenn Kerkhof, Chiltern’s CEO. “Vigiun is an ideal complement to our existing Latin American operations and Chiltern’s presence in 27 other countries as we serve the pharmaceutical and biotech industries globally.” Latin America has a population of 503 million people, of which 192 million are in Brazil. This vast population provides a significant number of potential patients in all disease areas. Latin America is rich with experienced investigators and is known for high quality data and excellent patient retention in clinical trials. For More Information Contact: Mac McElroy Stuart McGuire Chiltern International Inc. Chiltern International Ltd. 1241 Volunteer Parkway 171 Bath Road Suite 950 Slough Bristol, TN 37620 Berkshire SL1 4AA USA UNITED KINGDOM Tel: +44 (0) 1753 512 000 Fax: +44 (0) 1753 511 116 Email: [email protected] AUSTRALASIA Your Stepping Stone to Market JOURNAL FOR U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets Compiled by Contents Overview of Australasia Early Phase Clinical Trial Environment 54 Australia and New Zealand offer medicinal product developers much more than just an efficient regulatory framework. Of paramount importance to those planning clinical trials are the availability, suitability and interest of clinical researchers together with volunteer populations, whether that be healthy people or patients with the indication being researched, that are motivated and accessible within ever decreasing timelines. Russell Neal of Clinical Network Services (CNS) explains why Australia and New Zealand offer an increasingly attractive “one-stop shop”, in terms of time, delivery and cost, in early phase research. Conducting Early Phase Clinical Trials in Australia. 56 Phase I clinical trials are a critical stepping stone in product development pipelines for biotechnology and pharmaceutical industries. These trials are crucial because they are used to establish the safety and tolerability of new products in humans and thereby determine if they are safe to proceed into further clinical testing. Nathan Martinez, Executive Officer of Q-Pharm, shows how Australia offers an attractive proposition for conducting early phase clinical trials from quality, efficiency and economic perspectives. Australia says G’day to Clinical Trials! 60 Australia offers a number of significant advantages as a site for clinical trials one of which is a clear, affordable and uncomplicated regulatory environment. There is a straightforward and rapid regulatory process for the approval of clinical studies for most investigational medicinal products, including biologics in some cases. Dianne Jackson-Matthews, Director of ERA Consulting’s Australian office outlines the regulatory pathways for clinical trials in Australia. Australian Bioanalytical Expertise for Preclinical and Clinical Studies 63 Australia has a rich history of success in the drug development and clinical trial industries. An essential part of that process is the provision of quality bioanalytical services to meet the needs of both the preclinical and clinical stages of development. Russell Addison of TetraQ analyses Australia’s significant capabilities and expertise in providing bioanalytical services for preclinical and clinical studies for the international pharmaceutical and biotechnology industries. Translational Research – the Bioinformatics Challenge 66 The discovery and development of effective new and modern therapies can be achieved using a translational research approach. Translational research draws on the expertise of the biological researcher, clinician, biostatistician and computer scientist to discover the basis of disease and to translate that knowledge into therapies. Jeremy Barker and Dominique Gorse of QFAB highlight the following case studies: KOALA Childhood Obesity Program, Nuclear Receptors in Breast Cancer, Australian Prostate Cancer Research Centre, Innovative Wound Management. Queensland Biotechnology – Ripe for the Picking 70 There are many regions around the world jockeying to become local biotechnology powerhouses. Few, however, possess Queensland’s unique environment for biotechnology growth according to Professor Peter Andrews, Queensland Chief Scientist. Enabling a Networked and Collaborative R&D Environment 73 Biopharmaceutical companies are looking at new R&D business models by compartmentalising, outsourcing and networking their R&D activities with a multitude of research organisations. Given the explosive development in the application of high-end computing, laboratory automation and molecular science, QCTN has pulled together a cluster of Australian R&D service providers with excellent and mutually complementary capabilities in the fields of translational and clinical research, supported by a robust bioinformatics and biostatistics infrastructure. Otto Damsma of QCTN explains QCTN’s role in coordinating and facilitating national and international sponsors and its members - Australian R&D service providers. Facilitating Genomics and Translational Research 77 As a result of the mapping of the human genome, along with recent significant advances in technologies used to study genomes, genomic research is now yielding increased amounts of information and understanding about the role and function of genes in human disease. Tony Feneziani of Australian Genome Research Facility Ltd explains the role of AGRF in supporting translational research. www.jforcs.com JCS 51 Editor’s Note Australasia: a Stepping Stone to Markets Australasia is frequently used as a term to describe the region of the world that encompasses Australia and New Zealand together with the many Asian nations immediately to our North. In this special supplement, researchers and managers active in several organisations from Queensland, Australia, provide an insight into the clinical and translational research capabilities in Australia and New Zealand, with an emphasis on the former. Queensland is known in Australia as the ‘Smart State’ and it is experiencing the most sustained period of growth and prosperity ever recorded in the State’s history. While Queensland continues to grow, in spite of the global economic downturn, it has established a position with the best in the world in pharmaceutical and biotechnology research and development and is fast becoming an important international hub for translational medical research and the biotechnology industry. In his article “Queensland Biotechnology – Ripe for the Picking”, Prof. Peter Andrews, Queensland Chief Scientist, provides a bird’s eye view of more than a decade of strong and focused investment by the Queensland Government in both academic and industrial players in the fields of life sciences, biotechnology, tropical sciences and other sectors. Mario Pennisi Chief Executive Officer Queensland Clinical Trials Network Inc. (QCTN) Attractive landscape Australia is renowned for its beautiful and unique flora, fauna, landscape and shores. In his overview article, Russell Neal of CNS Pty Ltd describes the clinical trial landscape in Australia and New Zealand, the rise of specialised early phase clinical research units and practical aspects and considerations for undertaking clinical research in Australia. The reasons why one would choose Australia for early phase clinical trials, and the advantages of Australia’s regulatory system, are further highlighted in the article by Nathan Martinez of Q-Pharm Pty Ltd, a phase I/II unit based in Brisbane, as well as by Dianne Jackson-Matthews of ERA Consulting (Australia) Pty Ltd. In her informative article, Dianne Jackson-Matthews provides case-studies concerning the regulatory pathways for clinical trials involving biologicals, cell therapy and small molecules. No preclinical or clinical studies can be performed without bioanalysis of samples and ADME analysis. TetraQ is a provider of bioanalytical services, as well as offering efficacy investigations using disease models (pain, Alzheimer’s and others), toxicology and pharmaceutics services. TetraQ is accredited by Australia’s National Association of Testing Authorities in the field of R&D and is compliant with the OECD principles of Good Laboratory Practice. Refreshing The clinical playing field will be familiar to many readers, but the way clinical research is undertaken in Australasia and the breadth and depth of opportunities that exist in the fields of translational medical research and bioinformatics will be both remarkable and refreshing. Remarkable in terms of the technical resources and expertise available in Australasia to conduct genomics and other “omics” research, and refreshing in the way a coordinated network of industrial and academic R&D service providers can be identified and accessed through the facilitation of an independent industry group QCTN. QCTN is to a large degree the result of the foresight of the academic and industrial life sciences community with the strong support of the Queensland Government. They realised that a coordinated response was necessary to assist the biopharmaceutical industry in its search for new R&D business models in order to increase their productivity and efficiency in product development, and established QCTN in 2005. As explained in the article by Otto Damsma, at QCTN, outsourcing R&D activities is one of the solutions that biopharmaceutical companies need to explore, but the way in which this is aligned with the R&D strategies and the way it is set up and managed are success-determining factors that need new consideration in the era of internet, high-throughput screening, bioinformatics and genetic profiling. Jeremy Barker, CEO, and Dominique Gorse, Technical Manager, of the Queensland Facility for Advanced Bioinformatics, and Tony Feneziani, Manager at the Australian Genome Research Facility Ltd, whose contributions can be found in this journal, represent just two of the many research institutes active in the translational field. Capacity for more While Queensland-based organisations are highlighted in this issue, the reader should consider these organisations to be representative of the preclinical, clinical and translational research facilities and capabilities available in Australia and New Zealand. Both countries have modern Western societies and healthcare environments. Nonetheless, the cost of R&D is still relatively low compared to other Western countries and Japan. Information provided by respected market analysis companies suggest that there is a potential for doubling the value of R&D work undertaken in Australia. The extra capacity for both translational and clinical research in Australasia represents a wonderful opportunity for Asian and Western biopharmaceutical and medical device companies to access quality researchers and reduce time-to-market, and will be on show later this year at the TRX09 symposium in Brisbane. Australasia can serve as a stepping stone to these markets, since data generated in preclinical and clinical studies in Australia and New Zealand are generally well received by the American and European regulators. 52 JCS www.jforcs.com OVERVIEW OF AUSTRALASIAN EARLY PHASE CLINICAL TRIAL ENVIRONMENT Much has been written describing the virtues of the Australian regulatory system and how it can offer an attractive alternative to well-prepared product developers, especially during the early part of their clinical development programme. Indeed, ERA Consulting provide some illustrative case studies in this pullout that will assist the reader in understanding the advantages that the local regulatory structure can make available. However, Australia, and indeed New Zealand, offer medicinal product developers much more than just an efficient regulatory framework. Of paramount importance to those planning clinical trials are the availability, suitability and interest of clinical researchers with volunteer populations, whether that be healthy people or those patients with the indication being researched, that are motivated and accessible within ever decreasing timelines. Australasia Australasia is sometimes used as a term for New Zealand and Australia together, in the absence of another word limited to those two countries. Sometimes Papua New Guinea is encompassed by the term. Australasia, with a combined population of around 25 million people of predominantly European descent, but with sizeable Polynesian and Asian populations, is ageing at a rate comparable to other developed countries. This means that Australasia has a similar disease profile and incidence as those countries from where the majority of clinical trial therapies are generated. This is a broad conclusion and indeed there are several indications that do differ in incidence, such as higher levels of respiratory disease - with asthma being the highest in the world - or climate influenced conditions such as melanoma. On the other hand, such prevalent illnesses do tend to be better managed as well, thus sometimes limiting the size of a suitable trial population. Infectious diseases are geographically distinct with conditions such as Ross River Fever being mainly a local (i.e. Australian) disease. Indeed seasonal disorders such as infectious disease, allergies, etc often mean that the southern hemisphere can offer the developer an all-yearround trial opportunity when conducted in series with northern hemisphere season. Australasia is a small market with Australian Pharma accounting for approx $9.4 billion (which includes complementary medicines and medical devices) and represents only about 1.3% of the world market. This can mean that the local patient population may not always get access to new, early development stage products, such as might be available in larger markets such as the US or Europe. This does create a genuine interest and enthusiasm from clinicians and patients alike wanting to get access to cutting edge treatments or, at a minimum, be part of finding a solution for those conditions they may suffer from. This view is widely supported as evidenced by many companies reporting good enrolment across all phases of clinical trials where Australasia was part of their clinical trial programmes. Early Phase Clinical Research Units Of particular note is the recruitment success seen across the spectrum of 54 JCS phase I-II trials conducted in the region over the last five to six years. Typically, many such studies have focused upon healthy volunteers, with six of the established Australian and New Zealand phase I units having, as you would expect, significant databases of healthy male and female volunteers, including sub-groups based on, for example, age and ethnic origin. This is made easier with most units being centrally located in the major Australian or New Zealand cities and close to higher education facilities, tertiary hospitals and in some cases, access to large local General Practitioner networks. Indeed a 2007 review of the phase I units suggested that there were around 170 beds in specialised, dedicated Phase 1 units accounting for an industry revenue of over A$50million per annum with over 75-80% of their business coming from the US, Europe and Japan, of which over half was considered repeat business. The Q-Pharm article elsewhere illustrates in more detail the type of expereince and capabilities demonstrated by these units. As well as such professional units, there is clearly an emerging second tier group of units across Australia and New Zealand with good experience in phase I studies but without the dedicated facilities of the main phase I units. These units, predominantly part of tertiary teaching hospitals and associated private clinics, are well positioned to contribute wholly or partially to early phase studies, especially where subject confinement is not a requirement, as this is one common restriction at such facilities. Indeed, many do work co-operatively with local phase I units to which they are comfortable to refer their patients when study designs may be too demanding or labour intensive for them to run in their own clinics. With their close relationships with their day-to-day patient populations this often leads to a more personal service for patients thus better recruitment, retention, and quality. Such groups offer sponsors more direct and efficient access to educated and motivated patient populations. Therefore, with the recent trend for more and more early phase studies to be conducted in target patient populations, the strength of such an active researchorientated, second tier of investigational sites ably positions Australasia as a proven option for sponsors in their early phase of development. Clinical Network Services (CNS) notes that almost a third of its phase I/II studies are patient studies and is a strong advocate of using these specialist, niche therapeutic research groups that include respiratory groups such as P3 in New Zealand and the Mater hospital, Brisbane, the Pain and Anaesthesia Research Clinic (PARC) in Adelaide, numerous oncology groups across the entire region, Queensland Paediatric Infectious Diseases (QPID) Laboratory, Brisbane and the newly launched Prostate Cancer Research Centre at the Princess Alexander Hospital, Brisbane, to name but a few. For international sponsors having access to such a wide variety of site and patient resources, but may have not conducted studies in Australasia previously, distance and time differences can be a worry and may in some minds mitigate the many obvious advantages of the region. However, it would be fair to say that where the decision was taken to use Australiasia, many companies return with Australasia forming a core component of much of their development strategies supported by investment in forward planning and feasibility of studies working with trusted affiliates or www.jforcs.com specialist CROs. The value of local expertise cannot be understated and is a key component in managing anxiety driven by distance and timezone. Local Partnering Essential Using a trusted local partner is also of great value when one considers the options available in Australasia as described earlier in this article. It is to be expected that local specialists will know their local market better than many internationally located sponsors. Specialists such as local niche CROs depend upon knowing the capabilities and performance of phase I units or the plethora of therapeutically focused investigational sites. Clinical Network Services (CNS) is one such organisation, who with over 10 years advising clients on which sites best suit their needs, including populations, resources, timelines, etc, are experts in liaising with local sites and preparing effective site strategies to meet ever decreasing product development timelines and budgets. CNS is an Australia-based, full service contract research organisation (CRO) providing clinical management support and services to the healthcare community, particularly during the early phase clinical development of their products. CNS has established itself as Brisbane’s only headquartered clinical management company working both nationally with dedicated phase I units and hospital groups, as well as internationally with its strategic partners, particularly in New Zealand. Over the last five years of its 10 year history, CNS has expanded its services from traditional core CRO activities such as study management and clinical monitoring to providing a full range of services from initial protocol/IB development, through study startup and third party management, such as analytical laboratories, selection of sites with capacity to run early phase (0 – 2a) and proof of concept studies, monitoring and over study management concluding with full Data Management/Biostatistics and Clinical Study Report writing. of infectious and non-infectious samples for transit must be performed by properly trained and certified staff and though many international shippers are experienced in shipping such products, unpredictable transport issues can be avoided by using local laboratories. Indeed, most laboratories have their own national courier networks which ensures appropriate packaging and timely delivery of samples to the assessing laboratory. Also when considering the analytical capabilities in Australia, and where the sponsor is still in the pre-clinical phase, several groups have internationally accredited pre-clinical services that may be attractive to sponsors where their local partners may have timeline delays or where cost is an issue. This is discussed in more detail in the article here by TetraQ. Data Capture In regards to fast data access, especially where go/no-go decisions in ascending dose studies are required, Australia is very familiar with the international electronic data capture systems commonly used. Indeed, recent surveys have shown that upwards of 98% of Australian sites have good internet access and have used such EDC systems. That said, many single site phase I studies rarely require this complexity of live data reporting and many of the phase I units and CROs are very familiar with timely collection of safety data and providing necessary tabulations to Data Safety Monitoring Committees or similar. Furthermore, Australia has also responded to early phase data management needs where groups such as CPR Pharma have great experience in meeting sponsors’ data and analytical needs in these small specialist studies. Continuing broadly from data capture and management, it would be remiss not to mention Australasia’s standing at the front line of technological applications in research. The convergence of many new and evolving disciplines in medicine, IT and science is bringing about a fundamental paradigm shift in the way medical research, drug research and, ultimately, patient care is undertaken. Translational medicine and in particular bioinformatics has become a leading capability in Australia and again, support services in this area are emerging as highlighted by QFAB in these pages. “Continuing broadly from data capture and management, it would be remiss not to mention Australasia’s standing at the front line of technological applications in research.” Ancillary Services Another consideration for international sponsors is how to manage theancillary activities that are critical in the success of the trial itself. To some, this may add a level of complexity to conducting studies so far away. Considerations include where to package product; how to handle frozen samples and their shipment to analytical laboratories; how to access safety data and analyse in a timely manner (even more so when assessing Dose Limiting Toxicities (DLTs) in a single ascending dose (SAD) phase I study) and many more. It should not be surprising to the reader that as well as a growing group of early phase sites, there has also been an accompanying growth in those support groups, many of whom also write here. Secondary Manufacturing for Clinical Studies Whilst initial manufacturing tends to be more locally managed and outsourced by sponsors, there are secondary manufacturing capabilities in Australia. This can be useful where products have a short shelf life, such as some biologicals, or where local labelling needs cannot be cost-effectively met at the primary manufacturing sites. However, there is an emerging drug manufacturing industry in Australia as described in BPA’s article elsewhere in this pullout. Laboratory Management Australia’s local and central laboratories are strongly preferred by Australian investigators in order to avoid loss of or damage to test samples and reduce wastage of time and sample tissue. Such preferences may be more prevalent in more specialist indications such as microbiological testing in Cystic Fibrosis patients, where investigators are used to the quality and reporting of their local laboratories. Furthermore, packaging www.jforcs.com Conclusion Australasia has been a key contributor to global phase IIb – IV studies over the years. The region has also emerged as a responsive and innovative option in earlier phase studies as well, not only with respect to the number of experienced and highly capable phase I units such as Q-Pharm and ACRO, but also as seen by the enthusiasm of key opinion leaders, specialist research groups and most importantly their patient populations. Where sponsors partner with knowledgable and capable partners, efficient and reliable strategies are available in Australasia to sponsors of all types, and when local ancillary services are also considered, Australia and New Zealand offer an increasingly time, delivery and cost attractive, “one-stop shop” in early phase research. I Russell Neal has almost 20 years' experience in the healthcare industry. He moved with Quintiles UK to Sydney in 1994 before moving to Singapore in 1999. In 2003, Russell returned to Australia following three years as a Regional Training Manager Asia Pacific and is currently Chief Operating Officer at Clinical Network Services (CNS). JCS 55 CONDUCTING EARLY PHASE CLINICAL TRIALS IN AUSTRALIA Phase I clinical trials are a critical stepping stone in product development pipelines for biotechnology and pharmaceutical industries. These trials are crucial because they are used to establish the safety and tolerability of new products in humans and thereby determine if they are safe to proceed into further clinical testing. As such, phase I clinical studies are the first point in clinical development where biotechnology and pharmaceutical companies make the crucial ‘go/no go’ decision. Given the importance of this decision and the high costs associated with continued clinical development, it is imperative that phase I trials be conducted in an efficient and cost effective manner without compromising quality. Fortunately, as will be shown in this article, Australia offers an attractive proposition for conducting early phase clinical trials from quality, efficiency and economic perspectives. Why choose Australia for early phase clinical trials? Australia has an established, professional and world-class industry for the conduct of early phase clinical trials. Importantly, the early phase clinical trial industry in Australia offers a number of competitive advantages including: • • • • • Low average cost (very cost competitive compared to U.S. and Europe based providers) High quality of work Fast regulatory times / efficient regulatory system High percentage of clinical trials completed on time Highest standards of care and medical infrastructure Australia has also been recently recognised as a safe location for contract research services outsourcing. In particular, Australia has: • • • High levels of IP protection Low risk destination with respect to - Infrastructure - Legal system - Economic stability - Human Capital - Geopolitical factors Mature pharmaceutical market Importantly, trials conducted in Australia meet international standards, such as those of the US FDA. This is because Australia’s early phase clinical research centres conduct their studies according to ICH-GCP guidelines. It is important to note that ICH-GCP guidelines were originally developed with consideration of the current good clinical practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries, and the World Health Organization. As such, Australia has a longstanding history of recognised and respected good clinical practices. As a result, many clinical studies conducted at Australia’s early phase clinical research centres, have been accepted internationally for submissions to regulators. 56 JCS The regulatory pathway in Australia – efficient and thorough. Early phase clinical trials conducted using “unapproved therapeutic goods” in Australia, that is, goods which have not been evaluated by the Therapeutic Goods Administration (TGA) for quality, safety and efficacy and entered into the Australian Register of Therapeutic Goods for general marketing, are required to make use of the Clinical Trial Notification (CTN) or Clinical Trial Exemption (CTX) schemes. This is because such products are considered experimental, and do not have general marketing approval. Such goods also include medical devices. There are a number of avenues in the Therapeutic Goods Legislation via which “unapproved” goods may lawfully be supplied. The CTN and CTX schemes provide two of these avenues for access. The choice of regulatory path, CTX or CTN, is the sponsor’s selection and will determine the type of review process to be undertaken. CTX involves review by the TGA of ‘information’ about the product provided by the sponsor and can occur concurrently with the review of the protocol by the local Human Research Ethics Committee (HREC). The ‘information’ includes the overseas status of the investigational product, proposed usage guidelines, a pharmaceutical data sheet, a summary of the preclinical data and clinical data. CTX is the pathway by which some novel new products (especially biological agents) may proceed, particularly if they have not been previously reviewed by a competent Regulatory Agency (e.g. FDA, EU). In general, sponsors prefer CTN, but several trials are processed through the CTX route. For clinical studies being submitted by the CTN route, the local HREC is responsible for assessing the scientific validity of the trial design, the safety and efficacy of the medicine or device and the ethical acceptability of the trial process, and for approval of the trial protocol. For phase 1 clinical trials being submitted by the CTN route at Q-Pharm, the HREC require review of the toxicology and Investigational Brochure by a demonstrably independent reviewer. This review can occur in conjunction with the submission process however the report must be available to the Clinical Trials Protocol Sub-Committee (Scientific sub-committee of the HREC) by the time it meets. Toxicology in this instance means the standard array of preclinical testing. It is sufficient to provide the IB to the HREC, but some independent evaluators may request additional details on the preclinical data, especially if there are concerns. The independent reviewer can be chosen by the sponsor, and is not required to be an Australian. Providing the HREC were willing to review the protocol under the CTN system, they would make a decision as to whether or not the trial was ethically acceptable, and it is this advice that is communicated to the TGA through the CTN form. Following acknowledgement of receipt of the CTN form by the TGA, the trial may then commence. Finally, clinical trials must be sponsored by an Australian entity (company, institution or individual). If clients don’t have an Australian subsidiary or affiliate, the sponsor can be a CRO that is contracted for the purpose. Q-Pharm recommends that foreign clients engage an independent CRO to fill the role of sponsor because under GCP there are distinct obligations and responsibilities for the Sponsor’s representative and the Investigational Site. www.jforcs.com The value of dedicated early phase clinical centres? In Australia, early phase clinical trials are normally undertaken in dedicated centres that are appropriately equipped for the specialised monitoring and the high degree of surveillance required. As Phase I studies are normally the first time the drug has been exposed to humans, the potential associated risks mandate a high degree of surveillance of study volunteers (as shown in Table 1). Given the intensity of monitoring and subject surveillance required, it is easy to see why phase I studies are best conducted in dedicated centres that are appropriately experienced, staffed and equipped. These clients come from the Pharmaceutical, Biotechnology and Device Industries (Figure 2). This is why Australia’s early phase clinical research centres have a broad base of experience with different investigational product types. While the majority of clients approach providers directly for clinical trial services, a significant number of projects are also brought to these sites via clinical research organisations, as shown by the breakdown of clients by sector for Q-Pharm (Figure 2). Figure 2: Clients by industry sector for Q-Pharm Table 1. Typical schedule of events for assessment of a volunteer in a Phase 1 study (not including pre-dosing assessments or assessments after 6 minutes postdose). Event/Assessment Design commenced Time post dose t=0 PK sample - 1 minutes post-dose 1 min Post-dose Observations (ECG, Temp, Pulse, Blood Pressure, Resps, sO2) 1 min Adverse Event check 1 min PK sample - 2 minutes post-dose 2 mins Post-dose Observations (ECG, Temp, Pulse, Blood Pressure, Resps, sO2) 2 mins Adverse Event check 2 mins PK sample - 4 minutes post-dose 4 mins Post-dose Observations (ECG, Temp, Pulse, Blood Pressure, Resps, sO2) 4 mins Adverse Event check 4 mins PK sample - 6 minutes post-dose 6 mins In order to meet the demanding requirements of early phase clinical trials, Australia’s early phase clinical research centres have specialised facilities. By way of example, the Q-Pharm facility includes an 18 bed Phase 1 clinic with telemetry, dedicated subject recruitment and outpatient facilities, a 24 bed clinic for Bioequivalent/Bioavailability studies (which can also be used for Phase 1 or 2 studies), data management & QA units, secure pharmacy, PC2 laboratory, minor procedures room, an extensive database of volunteers, and a comprehensive network of clinical associates. Client base of Australia’s early phase clinical research centres Australia’s early phase clinical research centres service a truly international market. In 2007, the industry generated annual revenue in excess of $AUD50 million. The majority of these earnings were from overseas sources and this international market share is increasing each year. For example, during Q-Pharm’s years of operation, it has grown from a company servicing Australian clients only, to a company whose majority of clients are based overseas (Figure 1), and Australia’s other early phase clinical trial service providers have reported the same business mix with many international clients returning for repeat business. Figure 1: Clients by location for Q-Pharm www.jforcs.com Experience and Capabilities of Australia’s Early Phase Clinical Research Centres – Q-Pharm as an example. Q-Pharm specialises in the conduct of early phase clinical trials and bioequivalence and bioavailability studies. The company has more than seven years experience in healthy volunteer and patient studies and during that time its personnel have been responsible for the conduct of over 170 studies (and over 300 studies as Q-Pharm or its progenitor organisation). Many of the clinical studies conducted at Q-Pharm have been accepted internationally for submissions to regulators in Australasia, Europe and the Americas. Like Australia’s other early phase clinical research centres, Q-Pharm has a history of successful regulatory inspections and many client audits. Inspections have come from North America (FDA inspection in 2007), South America (ANVISA in 2003, 2006 and 2008) and Australia. For all early phase clinical research centres in Australia, alliances and affiliations are key to a sites ability to successfully conduct these crucial studies in a safe operating environment. For example, Q-Pharm is located on the campus of one of the largest tertiary care teaching hospitals in the Southern Hemisphere providing crucial access to emergency care, specialist clinicians and potential volunteers. Q-Pharm also enjoys a strategic alliance with TetraQ, providing the facility to undertake bioanalytical services. CASE STUDIES First-time in human studies Australia’s early phase clinical research centres are well experienced with conducting pivotal ‘first time in human’ (FTIH) clinical studies. Some examples of FTIH studies conducted at Q-Pharm are provided in Table 2. While the majority of these studies have proceeded via the CTN pathway, some higher risk agents, particularly biologicals, have utilised the CTX pathway. Of those studies processed via the CTN pathway, most have been approved in a single round of HREC review, however some have required multiple reviews in order to obtain ethical approval. These examples highlight the notion that even though the regulatory pathway in Australia can be efficient, it still operates at the highest standard (in line with international and local requirements) in order to ensure the safety and well-being of potential study volunteers is protected. JCS 57 Table 2: Examples of experience with First Time in Human Clinical Trials at Q-Pharm Client Study type/ Subject type Product type/ Route of administration Regulatory Pathway (No. of HREC review rounds required) Outcome AU biotech Dose Escalation / HV Biological + radiolabelled / IV CTX To Phase 2 AU biotech Dose Escalation / P Small molecule / IV CTN (1) IV to Oral US biotech Dose Escalation / P New class biological / IV CTN (3) M&A deal executed US academic Dose Escalation / HV Vaccine / IM CTN (+IND*) (1) To next phase UK pharma Dose Escalation / HV Small molecule / Oral CTN (4) Trial suspended AU academic Dose Escalation / HV Vaccine / IM CTN (1) To next phase US pharma Dose Escalation / HV Small molecule / Oral CTN (1) Single Ascending Dose to Multiple Ascending Dose US pharma Dose Escalation / HV Peptide / SC CTN (1) Current US pharma Single dose / HV Small molecule / Oral CTN (1) To next phase US pharma Dose Escalation / HV Biological / IV CTN (1) Current # - CTN path only with Expert, Independent Toxicology Review KEY: AU = Australia US = United States UK = United Kingdom HV= Healthy Volunteer P = Patient IV = Intravenous IM = Intramuscular SC = Subcutaneous Japanese Bridging studies Q-Pharm recently identified the area of Japanese - Caucasian bridging studies as a niche area for Australia’s early phase clinical trial industry. As such, the company has conducted bridging studies for a client that operates in the Japanese pharmaceutical market where Japanese subjects were matched to Caucasians for gender and body weight. To ensure these studies were successful, Q-Pharm put specific measures in place including: • Established large subject database of Japanese volunteers • Employed specific support staff -Japanese nurses -Nurses fluent in Japanese -Japanese support officer providing interpretation service which is available for volunteers • Designed Japanese specific menus This case-study highlights the reality that many early phase clinical studies require unique measures to be put into place in order for them to succeed. However, it is normally only in the context of a dedicated phase I centre that such measures can be accommodated. Patient studies - Oncology Q-Pharm has experience in conducting early phase clinical studies in patients such as in the oncology setting. These studies are performed in collaboration with local specialist clinicians from whom the patients are recruited. Close collaboration with these clinicians is crucial to the success of these types of studies given the health status of the patient volunteers and their already established relationship with their treating clinician. As such, sharing of trial related activities between the dedicated early phase clinical research centre and the hospital clinic is standard practice. For example, in a recent oncology study in patients with advanced solid malignancies, the hospital clinic conducted recruitment, screening (e.g. pathology, radiology), and outpatient activities (eg follow up visits). To complement this, Q-Pharm conducted trial activities such as confinement 58 JCS CTN = Clinical Trial Notification CTX = Clinical Trial Exemption (scheduling), pharmacy (study drug preparation), dosing, laboratory (pathology, study specific pharmacokinetic sampling and analysis), and after hour medical coverage. Summary Due to the current global financial crisis, sponsors are now more than ever looking to conduct clinical trials in a cost effective manner without compromising quality. Fortunately for these clients, sites such as Q-Pharm in Australia offer an attractive proposition from both a quality and economic perspective. Quality-wise, Australia’s regulatory processes ensure studies are set up and conducted in an appropriate and recognised setting to the highest standards of clinical practice. The regulatory pathway in Australia is efficient and very well established which ensures that the data generated from these studies is acceptable for submission to regulatory agencies worldwide. For example, studies conducted in Australia have been used to support marketing licensing applications in the United States (FDA) and Europe (EMEA). When this quality advantage and timeline efficiency is combined with the cost-effectiveness of conducting clinical trials in Australia, it is not difficult to see why Australia is becoming a key provider of contract early phase clinical research services to the international market. I Nathan Martinez, PhD, is Executive Officer at Q-Pharm and is responsible for business and corporate development activities. Dr Martinez has numerous years experience in drug development from product design and pre-clinical testing through to managing Phase III studies. He gained his PhD in medical immunology at the Walter and Eliza Hall Institute of Medical Re search, has a post-graduate qualification in drug development, and is ACRP CCRC certified. Prior to joining Q-Pharm, he worked as a post-doctoral scientist in vaccine design and pre-clinical testing, managed cell-therapy based clinical trials and associated basic research, and also worked as a project manager and group leader at a GMP facility. www.jforcs.com AUSTRALIA SAYS G’DAY TO CLINICAL TRIALS! Australia offers a number of significant advantages as a site for clinical trials one of which is a clear, affordable and uncomplicated regulatory environment. There is a straightforward and rapid regulatory process for the approval of clinical studies for most investigational medicinal products, including biologics in some cases. Also, for initial ‘first-in-man’ studies there is no requirement for the trial material to be made under current Good Manufacturing Practice (cGMP). All clinical research in Australia is conducted in accordance with current international standards of Good Clinical Practice. Through a series of scenarios this article will outline the regulatory pathways for clinical trials in Australia. Although these examples are hypothetical they do reflect the established experience of companies operating in Australia and serve to illustrate regulatory requirements in a number of different situations. For an overview of the regulatory steps toward gaining approval to conduct clinical research in Australia, refer to the schematic in Figure 1. Figure 1. Schematic of the regulatory pathways governing clinical trials in Australia (see Table 1 for abbreviations) Table 1: Abbreviations cGMP CTA CTN CTX DNIR FDA HREC IB IBC MHRA NLRD OGTR TGA 60 JCS Current Good Manufacturing Practice Clinical Trial Application Clinical Trial Notification scheme Clinical Trial Exemption scheme Dealings NOT Involving Intentional Release Food and Drug Administration [US] Human Research Ethics Committee Investigators Brochure Institutional Biosafety Committee Medicines and Healthcare products Regulatory Agency [UK] Notifiable Low Risk Dealing Office of the Gene Technology Regulator Therapeutic Goods Administration SCENARIO 1: SMALL-MOLECULE PHARMACEUTICAL IN LATE STAGE DEVELOPMENT A small-molecule pharmaceutical is in the late stages of development. The US Company wishes to include several Australian sites in a pivotal, phase III clinical trial. The appropriate regulatory pathway for this clinical trial is the Clinical Trial Notification (CTN) scheme. Under this scheme the approving authority is the Human Research Ethics Committee (HREC) of the institution or organisation at which the clinical trial will be conducted. HRECs are independent committees affiliated with hospitals and other organisations conducting clinical research. The agency responsible for regulating medicines in Australia, the Therapeutic Goods Administration (TGA), is notified under this scheme but no approval is required. The sponsor of the trial must be an Australian entity so the USA-based Company without an affiliate in Australia must retain an Australian CRO or other such organisation to submit the application and sponsor the trial on their behalf. The application package consisting of information on the product, the trial, the trial site, various certifications and the Investigators Brochure is submitted to the HREC in advance of a planned HREC meeting date. A scientific/technical sub-committee usually performs a review of the quality and non-clinical data of the proposed study and then passes a recommendation on to the HREC. The HREC then meets to conduct a formal independent ethics review, to generate queries to the investigator if necessary, and finally to grant an ethics approval. A [current] fee of 260 AUD is paid to TGA as the notification is filed for each of the trial sites. Acknowledgment of notification is provided by TGA within 10 days but there is no requirement for the Company to wait and the trial can commence once the fees are paid. Under the CTN scheme the TGA is only notified regarding the clinical trial however, TGA has the authority to put a hold on clinical trials in Australia due to safety or other concerns. Summary: The CTN scheme provides a relatively rapid and simple path to clinical trial approval. Providing scientific and ethical review, institutional HRECs are responsible for approving clinical trials. The TGA collects a modest fee for the notification and would normally take no action regarding the trial information. SCENARIO 2: NON-CGMP BIOLOGICAL IN ‘FIRST-IN-MAN’ PHASE I TRIAL A small biotech company is developing several related biological medicines. Pilot-phase manufacturing of the candidates is to a high quality but in a facility that is not GMP certified. The Company requires some initial clinical data to narrow the field of candidates and secure and extra round of funding. In Australia there is a provision for initial “first-in-man” clinical studies to be conducted with material that is not manufactured according to cGMP. This is in recognition that at early stages of development manufacturing processes are not fully developed and validated. It is especially pertinent to biological medicines where significant manufacturing changes are expected to occur during development. Of course, to be used in a clinical trial, the investigational material must be of documented quality and appropriate non-clinical data must be available. This approach to manufacturing requirements is significantly different to that of Europe where EU legislation mandates that all investigational www.jforcs.com medicinal products are manufactured according to EU cGMP. There may be some flexibility pertaining to the manufacturing process but the facility is absolutely required to be GMP licensed. In the US, FDA allows a somewhat flexible and less onerous approach for phase I products, but cGMP still applies. As with 95% of applications in Australia, this clinical trial could be approved through the CTN scheme. If the institutional HREC determines that it has sufficient expertise to assess the quality and non-clinical data supporting the application then it can approve the trial. Alternatively, if the HREC determines that it does not have sufficient expertise or that the trial would be ‘high-risk’ then it can defer reviewing the application to the TGA through the Clinical Trial Exemption (CTX) scheme. If the information in the Investigators Brochure is comprehensive then the application has a better chance to be reviewed by the HREC under the CTN scheme. Summary: In Australia, “goods prepared for the initial experimental studies in human volunteers” are not required to be manufactured according to cGMP. There is also the possibility of clinical trials involving somewhat complex medicines such as biotech products to be approved through the rapid CTN process. SCENARIO 3: CELL THERAPY A UK company is developing a human cell therapy product. Scientific Advice Appropriately, an early step in seeking approval for a clinical trial involving an advanced medicine such as a cell therapy is to seek scientific advice from the pertinent regulatory agency. The TGA is open to meeting with companies to discuss scientific and regulatory issues, and provides this service free of charge. In contrast, for example, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK charges up to £4,542 for providing scientific advice. The Clinical Trial Exemption (CTX) scheme In Australia, the regulatory pathway for a clinical trial involving a ‘high-risk’ product, an advanced therapy or a gene therapy is the Clinical Trial Exemption (CTX) scheme. An application consisting of summaries of quality, non-clinical and clinical data along with the information on safety (adverse event experience) and on proposed usage of the product, and the Investigators Brochure is submitted to the TGA. The applicant must wait until written approval is provided from the TGA, as well as HREC approval, before starting the trial. TGA first evaluates the application and determines if there are any issues with the proposed use (“usage guidelines”). The CTX review period is 30 or 50 business days depending on the content of the package submitted. Where there are no clinical data the 30 day review may apply. The fee for the 30 and 50 day CTX review is currently 1,240 AUD or 15,300 AUD respectively. During review of the CTX dossier questions and clarifications are addressed to the applicant through one or more requests from TGA with stipulated times for the applicant to respond. The evaluation clock stops until a full response to the request is received by the TGA. Any requests that have not been answered completely may appear in the assessment report generated by the TGA at the end of the evaluation period. Any outstanding questions must be satisfactorily answered by the applicant. The applicant must wait until written approval is provided from the TGA before starting the trial. A hallmark of the CTX application process is the flexibility of the TGA in addressing objections and working with the applicant to develop solutions. As an example, at the TGA’s discretion, an applicant can be allowed additional time in which to address issues regarding an advanced therapy product without termination of the review of the procedure. 62 JCS The flexible approach of the TGA can be contrasted with that of the MHRA, which allows only 30 days to respond to any deficiencies in a clinical trial application (CTA). If the applicant cannot address the deficiencies within this timeframe the application is rejected and this rejection is recorded in the pan-European EudraCT database. In addition, the situation in Australia contrasts with that in the US, where deficiencies in an IND application that cannot be addressed rapidly can lead to a “clinical hold” being issued. Assuming that any objections have been resolved the TGA will provide written authorisation for the CTX. The applicant must in parallel secure HREC approval for the institutions where the trial will be conducted; in some cases the TGA will provide comments to assist the HREC(s) in coming to a decision. SCENARIO 4: GENETICALLY MODIFIED CELL THERAPY A company is developing a genetically modified cell therapy product. As a genetically modified viable cell therapy in Australia the product would also fall under the category of a genetically modified organism (GMO). Thus the product and clinical trial information would need to be reviewed by an Institutional Biosafety Committee (IBC), and would require a licence from the Office of the Gene Technology Regulator (OGTR). As with other advanced therapies, the appropriate regulatory pathway for this product is a CTX application to the TGA, as well as approval from the relevant HREC(s). Clinical trials involving genetically modified cells or involving gene therapy must be reviewed by a properly constituted and accredited IBC. These independent committees composed of experts and lay people are associated with research organisations and generally meet 4 - 12 times per year. The applicant wishing to conduct the clinical trial must submit a package describing the GMO to be used in the trial as well as the trial itself. The application must also include a biosafety and environmental risk assessment and management plan. The application package should be submitted several weeks ahead of a scheduled IBC meeting. The length of time to evaluate the submission varies substantially depending on the particular IBC and the complexity of the application. The IBC can also request additional information from the applicant in order to come to a decision. A GMO product intended for use in humans in a clinical trial constitutes a “Dealings NOT Involving Intentional Release” (DNIR). In this case the applicant must obtain a licence from the OGTR before commencing the trial. The OGTR has 90 working days to reach a decision on the application, which includes the assessment made by the IBC. In common with other reviewing bodies, additional information may be requested and this stops the evaluation period until the applicant responds. The OGTR has a broad remit to seek advice from experts and other bodies including the TGA in order to reach a decision. If a positive decision is made, the applicant will be issued a licence for up to five years covering the use of that GMO. With the licence from the OGTR, the CTX authorisation from the TGA and the HREC approval, it would be possible to commence the clinical trial. Conclusion As described in the above scenarios, Australia has a streamlined regulatory system suitable for investigation of small molecules up to complex genetically modified cell therapies. This well-defined landscape can welcome clinical studies ranging from “first-in-man” phase I trials to multi-center phase IV trials. Come down and say G’day! I Dr Dianne Jackson-Matthews, Director of ERA Consulting’s Australian office, was formerly Director of ERA’s Washington DC office having spent 25 years in the US including senior positions within the biotech industry. www.jforcs.com AUSTRALIAN BIOANALYTICAL EXPERTISE FOR PRECLINICAL AND CLINICAL STUDIES Australia has a rich history of success in the drug development and clinical trial industries. An essential part of that process is the provision of quality bioanalytical services to meet the needs of both the preclinical and clinical stages of development. The requirement to conduct bioanalysis to a standard which will satisfy stringent performance limits, such as those set out by regulators like the US FDA, dictates that such providers must have significant expertise in the field. Such laboratories are not only required to accurately analyse large numbers of samples generated from clinical trials in a reasonable timeframe, but must also be expert in bioanalytical method development and validation. Bioanalysis in Preclinical Testing Preclinical drug development brings with it a whole set of bioanalytical challenges and requirements. Many companies at early stages of drug development are seeking indicative results for their lead compound and they do not require, nor will they fund, extensive bioanalytical method validation prior to sample analysis. For example, the result required from a preclinical pharmacokinetic study conducted in rodents might simply be an indication of whether the in vivo half life of the candidate drug is in the order of “hours, days or weeks”, or preliminary information on the bioavailability of the compound following an oral or other extravascular dose. Of course, even at early stage drug development, sponsors still need to have confidence in the data provided to them. However, how can this be attained without conducting extensive pre-study validation of the bioanalytical method involved? Quite simply, the sponsor must have confidence in the bioanalytical service provider and in the work conducted by them. Contracting bioanalytical work to specialist laboratories that are well equipped, have experienced staff and are suitably accredited, with appropriate quality systems in place, allows sponsors to have a reasonable degree of confidence in the results provided to them, and allows those results to be used as the basis for further decision-making in the drug development process. TetraQ is a preclinical service provider based in Brisbane, Australia. The ADME/Bioanalytics laboratory of TetraQ is a recognised leader in bioanalytical assay development and validation and is well equipped with chromatographic equipment (LC-MS/MS, HPLC). The TetraQ ADME/Bioanalytics facility was the first laboratory in Australia to gain accreditation with the National Association of Testing Authorities (NATA) in the field of Research and Development, with a quality system that complies with ISO/IEC 17025 (2005). It is also recognised for compliance to the OECD Principles of Good Laboratory Practice (GLP), which allows its bioanalytical results to be accepted internationally for regulatory review and provides a high degree of assurance for TetraQ’s clients. TetraQ’s R&D accreditation allows the flexibility to provide varying www.jforcs.com levels of analytical method validation depending on clients’ needs, from screening assays (as might be required for early-stage preclinical pharmacokinetic studies such as those described above), to comprehensive validation for regulatory purposes. Method Development and Validation TetraQ has extensive experience in the development of chromatographic assays for new and existing pharmaceutical and biotechnology products (including peptides), and has an extensive list of validated assays on hand. TetraQ conducts validation as necessary for preclinical studies; however assays intended for use for the analysis of samples from human clinical trials invariably require comprehensive validation prior to use. For such studies, validations conducted by TetraQ meet the requirements of the FDA Guidance for Industry on Bioanalytical Method Validation (May 2001). Detailed reports are prepared for all comprehensive method validations. Bioanalysis Using ELISA Methodology The development of new biological and antibody-based pharmaceuticals has led to an increasing requirement for the quantitation of these compounds in plasma as part of preclinical and clinical experimentation. These compounds are frequently not suitable for analysis by chromatographic or LCMS/MS techniques, and are often quantitated by Enzyme-Linked Immuno Sorbent (ELISA) Assays. Validation requirements for ELISA assays differ from those for chromatographic methods, in that additional specificity testing must be carried out to ensure the correct molecule is being quantitated and the assay is free from interference due to cross-reactivity of the antibody with other endogenous compounds. The acceptance criteria for accuracy and precision of ELISA assays also differ from those for chromatographic assays; the FDA Guidance on Bioanalytical Method Validation outlines the specific requirements for ligand-binding assays such as ELISAs, and these require careful interpretation by the analytical laboratory responsible for the validation and conduct of these techniques. The TetraQ ADME / Bioanalytics facility is one of the few laboratories in the Australia-Pacific region that is accredited to conduct bioanalysis using ELISA methodology. TetraQ has successfully transferred preestablished ELISA assays into their laboratory and performed appropriate levels of validation to ensure optimum assay performance. TetraQ can also assist with the development of new ELISA assays, as long as an antibody against the test compound is available. Immunogenicity ELISA assays, such as those testing for the presence of human anti-human antibodies (HaHa) in plasma samples following the administration of biological pharmaceuticals such as humanised monoclonal antibodies, have also been transferred into the TetraQ laboratory and used for the analysis of samples from clinical trials conducted both within Australia and overseas. Inflammatory markers such as interleukins are also often required to JCS 63 be quantitated in plasma samples from clinical trials involving the administration of biological or antibody-based compounds. These markers are measured by TetraQ using ELISA methodologies; in these cases TetraQ procures commercial assay kits from reputable suppliers and conducts pre-qualification of the methods, using quality control samples prepared in-house, to ensure optimum assay performance and compliance with international regulatory requirements. Industry Affiliations TetraQ has a strategic alliance with Q-Pharm Pty Limited, a clinical trial provider also based in Brisbane (indeed housed in an adjacent building to the TetraQ ADME / Bioanalytics laboratory) and which specialises in the conduct of early phase (Phases I and II) clinical trials, and human bioequivalence and bioavailability studies. TetraQ provides all of the bioanalytical and pharmacokinetic services required by Q-Pharm, and works closely with them to formulate the development and validation of new bioanalytical methods as required. Pharmacokinetic Analysis TetraQ conducts pharmacokinetic analysis of concentration vs time data from preclinical and clinical studies, on data generated in-house or by other service providers. Analysis is conducted using WinNonLin software that has been extensively validated using the comprehensive validation suite purchased from the software supplier. Statistical analysis of the results of bioequivalence studies is also available, with confidence interval determinations conducted on pharmacokinetic parameters. complete toxicological assessment of new drug entities must be conducted and the compound shown to be safe enough for human administration before their use in clinical trials. TetraQ provides these and many other services to the Australian and international pharmaceutical and biotechnology industries. The table below lists some of the preclinical services offered by TetraQ. Who are TetraQ’s Clients? TetraQ’s clients are Australian biotech and pharmaceutical companies (both ASX listed and private), universities and research institutes. TetraQ also has international clients that are based in Japan, USA, Europe, UK and Asia. As well as attracting new clients TetraQ has repeat business from many established clients which indicates strong client satisfaction. Conclusion In conclusion, Australia has significant capabilities and expertise in providing bioanalytical services for preclinical and clinical studies for the Australian and international pharmaceutical and biotechnology industries. TetraQ is a leading Australian provider of high quality bioanalytical and preclinical services and is a ‘one stop shop’ for early stage drug development. With world class facilities, state of the art equipment, a strong commitment to quality and a highly skilled scientific and commercial team, TetraQ is focused to provide tailored solutions to meet clients’ bioanalytical and preclinical needs. I Russell Addison is the Senior Manager of the ADME / Bioanalytics laboratory of TetraQ. He has a PhD in human steroid metabolism and analysis and has extensive experience in drug metabolism, pharmacokinetics and bioanalysis. Other Preclinical Specialities Of course, bioanalysis is only part of the overall preclinical pharmaceutical development process. All new drug candidates require extensive testing in a number of areas to demonstrate that they are effective and safe enough to be progressed into human trials. For example, potential treatments for pain or other neurological disorders require efficacy testing to ensure the effectiveness of the compound in an in vivo animal model. In addition, ADME/ Bio-analytics Efficacy Toxicology Pharmaceutics Contract Bioanalytics - Bioanalytical method development, validation and sample analysis in human and animal biological samples -LC-MS/MS, HPLC, ELISHA, PAMPA assays Proof of concept studied in animal models of human disease Genotoxicity assays - Ames Test, Micronucleus Test, Mouse Lymphoma Assay Physicochemical characterization In vitro drug metabolism studies - Cyropreserved hepatocytes, hepatic microsomes CYP450 screening, metabolic stability and metabolite identification Pain models - nociceptive, inflammatory and neuropathic Dose escalation and dose range finding studies Solubility studies In vivo bioavailability and pharmacokinetics studies CNS models - Multiple Sclerosis, Parkinson’s disease Acute and repeat dose (chronic) toxicity studies Stability trials Toxicokinestics Other models - diabetes, obesity, allergic rhinitis, pheblitis, cancer (through partner) In vivo safety pharmacology (including hERG, respiratory and CNS) Dissolution studies Tissue distribution, plasma protein binding and plasma stability studies Both the ADME / Bioanalytics and Toxicology laboratories are recognised for compliance with the OECD Principles of Good Laboratory Practice. 64 JCS www.jforcs.com TRANSLATIONAL RESEARCH: THE BIOINFORMATICS CHALLENGE The Queensland Facility for Advanced Bioinformatics, QFAB, (http://qfab.org) is a Queensland Government Smart State-funded initiative to provide advanced capability and facilities in data management, integration and analysis for Australia’s growing biotechnology and health sectors. Founded in early 2007, QFAB is providing high-end data integration and analysis for its partners and a growing base of clients. Its partners are The University of Queensland, Queensland University of Technology, Griffith University, Australian eHealth Research Centre (a joint venture of CSIRO and Queensland Government), Queensland Department of Primary Industries and Fisheries, Queensland Cyber Infrastructure Foundation, and the Australian Partnership in Advanced Computing (the latter now incorporated into NCRIS). The discovery and development of effective new and modern therapies can be achieved using a translational research approach. Translational research draws on the expertise of the biological researcher, clinician, biostatistician and computer scientist to discover the basis of disease and to translate that knowledge into therapies. The collective interchange of ideas, concepts, language and data represents a significant challenge which is being addressed through the application of sophisticated bioinformatics and integrated computational environments. Translational Research The drive to understand the mechanisms of disease is fundamental to biomedical science, health practitioners and the pharmaceutical industry. Not only does this hold the promise of the discovery of better drugs but also the potential for more personalised medicine. Approaches to drug discovery are being accelerated through the application of a methodology known as translational research. This approach aims to understand the molecular basis of disease linking together experimental approaches such as gene expression, Genome Wide Association studies (GWAS) and proteomics, with data from clinical trials and general patient information [1]. The NIH Roadmap for Medical Research outlines one of its objectives as transforming the way biomedical research is conducted [2]. One of the Roadmap initiatives, Biomedical and Computational Biology, is funding the development of software and tools to link the clinician’s observations with the discoveries of the researcher [3, 4]. Other groups around the world are aiming to do similarly with specific software applications or through software such as interactive workflow packages, for example Inforsense [5] or IO Informatics [6], which link the various data and analytical components. Translational research faces two primary areas of challenge: at the technical level, linking and visualising disparate data which may use different or no ontologies and, at the social and regulatory levels, with the need to maintain patient confidentiality through compliance with clinical records privacy laws. The Queensland Facility for Advanced Bioinformatics (QFAB) QFAB is a Queensland collaborative initiative with a commitment to help life science researchers unlock the full value of their research data through the application of bioinformatics. It delivers advanced bioinformatics solutions to enable the global efforts of biotechnology, research biology, drug discovery and translational medicine. Contributions from QFAB partners often leverage other initiatives including the ARC Centre of 66 JCS Excellence in Bioinformatics at UQ or the Microsoft QUT eResearch Centre. As represented in Figure 1, QFAB provides specialised bioinformatics tools, workflow technology, health data integration software, computational resources and ICT experience. QFAB also operates mirrors of the UCSC Genome Browser and ENSEMBL, and hosts public and proprietary datasets federated via SRS. With transparent access to data and applications, project-dedicated computation and storage, and the required confidentiality, privacy and security, partners and clients carry out secure in-silico discovery both on-site and remotely. In this article we will illustrate by way of example some of the initiatives in translational research that the Queensland Facility for Advanced Bioinformatics is involved in. Figure 1: QFAB platform is built around a web service workflow engine that integrates disparate data (top right) and tools (top left). The Health Data Integration software (HDI) developed by the Australian e-Health Research Centre provides linkage to patient records in different hospital data repositories while maintaining privacy and providing private and secure access to an integrated virtual data repository. This enables research and analysis on a larger scale than would be possible on the individual data repositories alone. CASE STUDY - KOALA CHILDHOOD OBESITY PROGRAM The KOALA Childhood Obesity Program is led by Dr Gary Leong, a paediatric endocrinologist and researcher who divides his time between the Institute for Molecular Bioscience (IMB) and the Mater Children’s Hospital. The Program is designed to improve the understanding of the basis of childhood obesity and its metabolic complications in order to develop effective interventions. This will be achieved by the integration of studies in metabolism, genetics, environment (family and lifestyles), www.jforcs.com community influences and behaviour management. The understanding of the genetic interactions with the environment will aid in targeting the intensity of lifestyle-based interventions for children and families with low-, medium- or high-risk genetic, clinical and/or community profiles for obesity and its major complications, including type 2 diabetes, cardiovascular disease and fatty liver disease. The research outcomes will be translated into improved clinical practice for children with obesity. The KOALA program brings together researchers from the University of Queensland and a multidisciplinary clinic at the Mater Children’s Hospital that includes medical, nursing, psychological and allied health professional team members. The KOALA program is currently in a one-year pilot study, with general practitioners from the Queensland South East Alliance of General Practice referring 100 overweight children to the program. QFAB has developed a web portal [7] to capture data from participating families, health professionals and researchers, and continues to work with the project toward its goal of identifying biomarkers for the future onset of obesity-related illnesses. CASE STUDY - NUCLEAR RECEPTORS IN BREAST CANCER Therapies that target the estrogen receptor have shown great success in treating breast cancers that express this nuclear receptor [8]. Despite the success achieved through targeting the estrogen receptor, the significance of other nuclear receptors in breast cancer management has received little attention to date. The Nuclear Receptors in Breast Cancer (NRBC) project is focused on studying signalling pathways of all the nuclear receptors that are expressed in breast cancers. The objectives of this discovery research program are to identify the nuclear receptor networks active in breast cancers and from these to select receptors that may be targeted for treatment in patients whose breast cancer does not express the estrogen receptor and for whom current treatment options are severely limited. Since many nuclear receptors have currently approved therapeutic drugs available to modulate their activity, these potential targets may be readily explored in the clinic to determine if current drugs can be combined with existing breast cancer treatment options to improve outcomes for underserved patient groups. The Chief Investigators of the NRBC project are drawn from virtually every State in Australia and contribute complementary expertise in hormone research, bioinformatics, high throughput analyses, human tissue research, animal models and clinical endocrinology. With Professor Mark Ragan, who leads the ARC Centre of Excellence in Bioinformatics [9] and the Division of Genomics and Computational Biology of the Institute for Figure 2: An example of a protein-protein interaction network built around the pregnane X receptor (PXR). Visualisation of the network is performed using the Cytoscape software [18]. The shapes represent different classes of proteins, the colour relates to the differential gene expression between two clinical cohorts. www.jforcs.com Molecular Bioscience at the University of Queensland, QFAB is currently building one of the most comprehensive collections of protein interaction networks around Nuclear Receptors and their co-regulators to visualise gene expression data and facilitate decision support (Figure 2). CASE STUDY – AUSTRALIAN PROSTATE CANCER RESEARCH CENTRE (QUEENSLAND) A new initiative to establish the Australian Prostate Cancer Research Centre - Queensland has the vision of developing a hub of prostate cancer research in Brisbane focused on new therapeutics, predictive biomarkers and treatment response indicators to inform and drive improved clinical practice. Headed by Professor Colleen Nelson, the Centre’s partners span several disciplines, employing high-throughput genome-wide bioprofiling of prostate cancer tissues to discover and characterise molecular mechanisms underlying prostate cancer progression and therapeutic resistance. Validation of the relevance of potential targets through evaluation of expression of candidate genes on tissue microarrays will be carried out. Pathways and networks will be elucidated using advanced informatic approaches and laboratory investigation to characterise the function of candidate genes associated with treatment resistance. These findings will be used to identify potential targets for intervention, with creation and evaluation of new therapeutics. To achieve this vision requires a collaborative multi-disciplinary translational team-based approach (spanning discovery science to clinical evaluation), underpinned by leading edge technology. QFAB will be providing a stabilised point of data access using grid technology to combine files distributed across multiple institutions and heterogeneous storage systems into a virtual local collection. Many of the Centre’s joint projects will require large scale data analysis and compute power available through QFAB’s established expertise in the fields of bioinformatics, statistics and computer science. CASE STUDY – INNOVATIVE WOUND MANAGEMENT Professor Zee Upton is leading the Tissue Repair & Regeneration Program within the Institute of Health and Biomedical Innovation at the Queensland University of Technology. With participants from all States in Australia, a new Collaborative Research Centre is being proposed to improve wound healing, quality of life and cost-effectiveness of wound care in Australia. The goals are to advance current knowledge of the key aspects of chronic wound care and wound healing, and to translate this knowledge to transform wound healing and wound management through the development of innovative products and practices, delivering benefits to both communities and industry. A unique strength of the initiative is the integration of the diverse elements contributing to wound management into a cohesive program of research which reflects the combination of the key biological, materials, medical, nursing, epidemiology, economics, health service delivery and industry expertise of the participants. The outputs of the research program will lead to markedly improved, evidence-based wound management, a better quality of life for patients and a reduced burden on health services. Advanced genetic, biochemical and metabolite-based biotechnologies will be used to analyse an extensive library of sequential samples collected from patients with chronic wounds. The data generated will be correlated with matched clinical data, leading to a revolutionary advance in fundamental knowledge of wounds and healing. State of the art bioinformatics tools will be used to integrate and analyse this data, and novel techniques developed to support data mining and association studies. Exploration and visualisation tools from the Microsoft QUT eResearch Centre [10] will be specialised to the wounds domain, and integrated with the QFAB facilities. Dedicated local systems and the high performance clusters of the Australian National Computational Infrastructure are available to the Program. This will support the JCS 67 development of new diagnostic and prognostic tests to inform and guide decision-making by clinicians, new wound therapies and appropriate delivery strategies, and the development of improved wound care practices and strategies for prevention. Perspectives The future understanding of human health and disease resides in a systems level approach to biology [11]. Systems biology focuses on biological systems as a whole, combining the facets of an organism into a collective view rather than looking at individual genes, proteins, or parts. Systems biology underpins the development of translational research and it is this integrated view of biology which will provide the answers to many of the questions about the mechanism of diseases. This methodology requires a multidisciplinary approach to deriving models of systems which can then be tested experimentally. Multidisciplinary science requires the biologically meaningful integration of data recovered from heterogeneous platforms in, amongst others, the genomic, proteomic and metabolomic domains. Deriving computational models in-silico will accelerate the discovery process, but they are just that, models, and without interactive testing will continue to be useful as signposts only [12]. Validation of the models through wet lab and clinical testing will ultimately lead to discovery. Data integration and privacy present enormous challenges to the biologist, the clinician, the biostatistician and the computational scientist. The marriage of these disciplines to enable the collective understanding of the nature of disease and, importantly, the specificity of the clinical intervention required will one day deliver tailored medical solutions. The fulfilment of this promise is still some way off although there is a considerable global research focus in this area. Significant funding is being directed to this endeavour [2] and specifically into centres such as Informatics for Integrating Biology and the Bedside, i2b2 [13], Dana Faber Cancer Institute [14, 15], Scottish Universities Research Alliance [16], or in Australia, the Translational Research Institute which is a joint project between the Queensland Government, UQ and its Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Mater Medical Research Institute (MMRI), Princess Alexandra Hospital and Queensland University of Technology [17]. QFAB is not itself a translational research institute, but it does help scientists with access to the bioinformatics tools and computational capability to carry out this type of research. Building on its strengths in understanding and translating the needs of the researcher into the language of the bioinformatician and IT professional, QFAB will continue to develop its platform and skills. Continuing to grow from the experiences gained through its role in the case studies outlined above it has a goal of expanding its functional capability to include a chemical biology interface which will integrate tightly into its bioinformatics platform. This collective bioinformatics platform will then be available to the researcher and, when combined with the linkages to clinical and population studies, should provide the nucleus for accelerating translational research in Australia. I References: 1. Beaulah, S.A., et al., Addressing informatics challenges in Translational Research with workflow technology. Drug Discov Today, 2008. 13(17-18): p. 771-7. 2. NIH Roadmap. Available from: http://nihroadmap.nih.gov. 3. McConnell, P., et al., The cancer translational research informatics platform. BMC Med Inform Decis Mak, 2008. 8: p. 60. 4. Athey, B.D., Keeping up with Bioinformatics and Computational Biology - Where have we been? Where are we going? First Annual ORNL Biomedical Science and Engineering Conference 2009 March 18-19; Available from: http://portal.ncibi.org/gateway/pdf/ AtheyORNLTalk.pdf. 5. Inforsense. Available from: http://www.inforsense.com. 6. IO Informatics. Available from: http://www.io-informatics.com. 7. The Koala research portal. Available from: http://koala.imb.uq.edu.au. 8. Swaby, R.F., Sharma, C.G., and Jordan, V.C., SERMs for the treatment and prevention of breast cancer. Rev Endocr Metab Disord, 2007. 8(3): p. 229-39. 9. ARC Centre of Excellence in Bioinformatics. Available from: http://www.bioinformatics.org.au/. 10. Microsoft QUT eResearch Centre Available from: http://www.mquter.qut.edu.au. 11. Systems Biology Available from: http://www.systemsbiology.org. 12. Russel, J. and Davies, K., Eric Schadt’s Integrative Approach to Predictive Biology, in Bio-ItWorld.com. 2009. 13. i2b2, Informatics for Integrating Biology and the Bedside. Available from: https://www.i2b2.org/. 14. Kahvejian, A., Quackenbush, J., and Thompson, J.F., What would you do if you could sequence everything? Nat Biotechnol, 2008. 26(10): p. 1125-33. 15. Poh, A., Integrating clinical and Genomics Data, in Bio-IT World Magazine. 2009: Digital Issue March/April. 16. Scottish Universities Research Alliance Available from: http://www.sulsa.ac.uk. 17. Translational Research Institute Available from: http://www.investbrisbane.com.au/News/News.aspx?ID=264. 18. Shannon, P., et al., Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res, 2003. 13(11): p. 2498-504. Jeremy Barker, MSc, MBA, GDCSP, Founding CEO of QFAB, Brisbane, Australia, with over 20 years experience building life science enterprises including director of four biotechnology companies. Dr Dominique Gorse is Technical Manager at QFAB with over 18 years experience in information management and mining in the biotechnology and drug discovery sectors. QUEENSLAND BIOTECHNOLOGY – RIPE FOR THE PICKING There are many regions around the world jockeying to become local biotechnology powerhouses. Few, however, possess Queensland’s unique environment for biotechnology growth. Queensland is Australia’s second-largest state, encompassing tropical, sub-tropical, temperate and desert climates. Located in the nation’s northeast, it is actively positioning itself as a modern, dynamic and progressive 21st Century economy. Queensland’s biotechnology strategy The Queensland Government understands that building a strong knowledge economy is essential to future prosperity. This philosophy lies at the very heart of its Smart State strategy. Developing a thriving biotechnology industry is an integral part of Queensland’s Smart State strategy. That’s why, in 2005, the Government launched a 10-year strategic plan. Developed in consultation with industry through the Queensland Biotechnology Advisory Council, the plan sets out a vision and action plan to accelerate growth and develop Queensland into a regional hub for biotechnology. The state is well on track to meeting its industry targets of 16,000 employees and $4 billion in annual revenues by 2025. From a standing start a decade ago, Queensland’s biotechnology industry now has around two dozen drugs from local biotechnology companies in clinical trials. In 10 years the number of publicly listed biotechnology firms in Queensland has risen from two to 12, and both revenues and employee numbers have jumped by a factor of six. The overall market value of the state’s biotechnology industry is projected to be $20 billion by 2025. That outstanding growth is underpinned by the government’s efforts to build a critical mass of world-class scientists and infrastructure across Queensland. World-class infrastructure Over the past decade the Queensland Government has invested an unprecedented $297 million in R&D infrastructure, leveraging a further $580 million through its Smart State Innovation Fund. That’s money well spent. Thirty-six new research institutes have been established, providing researchers with enviable facilities that place Queensland firmly on the map as a hub of globally-competitive research and innovation. Further infrastructure commitments in facilities like the Boggo Road Ecosciences Precinct and the Translational Research Institute will create more platforms for growth in the breadth and depth of the state’s research capacity. There is a real opportunity in Queensland to focus on our investment in translational research and development, using our outstanding research base as the engine to generate more effective healthcare services and a stronger life sciences industry. In fact, that’s already happening. The University of Queensland's 70 JCS Centre for Clinical Research (UQCCR) is a new $66 million facility designed to bridge the gap between exponentially-expanding biomedical science and the increasing complexity of modern patient care. UQCCR offers a unique and exciting opportunity for new and established investigators to pursue cutting-edge, clinically-relevant research in a world-class facility on one of Australia's largest health campuses. When it’s built, the Translational Research Institute, located in the capital of Brisbane, will be a one-stop-shop for discovery, production, clinical testing and manufacturing of new biopharmaceuticals. Critical mass of scientists The Smart State strategy is already paying dividends, attracting some of the world’s top minds to Queensland. Perhaps the most internationally renowned is Professor Ian Frazer, who discovered and developed the world’s first cancer vaccine. Professor Frazer isn’t the only Queensland researcher at the top of their game. Professor Mark Kendall from The University of Queensland has developed a nanopatch that could soon replace needles as the preferred method of delivering vaccines, includes those for malaria. Professor Kendall’s work has won him the 2008 Amgen Medical Research Award as well as a US$100,000 Grand Challenges Explorations grant from the Bill & Melinda Gates Foundation. Professor Michael Good heads the Queensland Institute of Medical Research, the largest medical research institute in the Southern Hemisphere. In 2008 Professor Good was made an Officer of the Order of Australia for his invaluable work developing a vaccine for malaria, a disease that kills as many as three million people every year. But there’s more to Queensland than smart people and smart facilities. Low-hanging fruit Smart investors and big pharma are constantly scouring the biotechnology world for low-hanging fruit. They need look no further than Queensland, where the supply is abundant - and mostly unpicked. Queensland’s biotechnology research intensity is on par with the world’s most research-intensive nations, based on the number of refereed biotechnology-related publications per million of population. That indicates a rich supply of fruit. The amount of fruit already picked within a given biotechnology industry depends of investment intensity – how much business expenditure on R&D is happening relative to non-business expenditure on R&D. Queensland’s investment intensity is quite low compared to other biotechnology hubs, leaving plenty of opportunity for international companies and investors to commercialise Queensland discoveries. The state is not just rich in research – its biodiversity is almost unrivalled. And how much better is it to pluck a chemically novel lead acting at a biologically unexplored target than to be content with another me-too? Queensland biotechnology offers more than twice as many investment opportunities per capita compared to, say, the USA. More importantly, www.jforcs.com many of those opportunities are unique, offering the chance for investors to back first movers in emerging fields. The combination of its R&D strength, relatively low costs, competitive environment and superb quality of life make Queensland an obvious target for biotechnology investors. Queensland’s tropical focus Queensland’s unique location is an obvious advantage for biotechnology companies and researchers focused on tropical discoveries. The state is one of the few first-world economies with both a significant tropical footprint and the capacity to undertake substantial tropical R&D. The Australian Institute of Marine Science, near Townsville in the state’s north, boasts the highest concentration of tropical marine scientists in the world. James Cook University is also at the forefront of tropical science research. Other world-class facilities based in Queensland’s tropics include: the Marine and Tropical Sciences Research Facility; the National Climate Change Adaptation Research Facility; and the Australian Tropical Forest Institute. The Queensland Government recognises the enormous opportunity that tropical science represents for the state. That’s why it developed the Q-Tropics: Queensland Tropical Expertise Strategy 2008-2012, aimed at stimulating jobs growth by building tropical knowledge industries. It has also committed $19.5 million to a new Queensland Tropical Health Alliance (QTHA), which will focus on reducing the burden of tropical diseases in Queensland and surrounding regions. The alliance is a joint venture between James Cook University, the Queensland Institute of Medical Research, Griffith University and the Queensland University of Technology. The QTHA will interface through ongoing partnerships and linkages that its members have with the Tropical Population Health Unit, the Australian Biosecurity Cooperative Research Centre, the Australian Centre for International and Tropical Health, the Australian Army Malaria Institute and Queensland’s clinical health industry. The proposed QTHA will undertake tropical health and medical research and development in three key areas: drug and vaccine discovery and development; diagnostics; and disease surveillance and control. This is a substantial investment in Queensland’s tropical capabilities, and will be leveraged by $33 million in cash and in-kind contributions from the partnering institutions. What the QTHA learns about dealing with biosecurity threats, improving detection, diagnosis and treatment of tropical diseases, and managing health risks associated with tropical disasters will vastly improve health outcomes for people living in Queensland as well as those living in tropical areas around the globe. Industrial and agricultural opportunities Queensland is also positioning itself as a formidable industrial and agricultural biotechnology hub. In response to spiralling greenhouse gas emissions and periodic crises in the supply and price of fossil fuels, biofuels have emerged as an attractive renewable energy alternative to conventional petroleum-based fuels. With established feedstocks and significant expertise in metabolic 72 JCS engineering, Queensland is well placed to be a world leader in the development of biofuels and bio-based speciality chemicals. The Queensland Government has made significant investments in second generation biofuel research and development. While much of this research is based on ethanol production, biodiesel and a range of other fuels including hydrogen have also received significant research funding support. Recognising the potential of algae in the context of a biofuel strategy and the need for Queensland’s heavy industries to reduce their carbon footprint, the Queensland Government is supporting research and development that aims to improve efficiencies and reduce the cost per litre of algae biofuels. In addition to world-class research expertise, Queensland has a number of competitive natural advantages for algae biofuels production including: prolific sunlight; abundant saline and brackish water; considerable tracts of non-arable land; and a readily available source of CO2 from power stations. Queensland is a major centre for agricultural biotechnology in the Asia Pacific, with particular expertise in tropical and subtropical agricultural biotechnology. The state’s natural advantages enable tropical, sub-tropical, and temperate crops to be grown. Queensland has extensive field trial sites, laboratories and research institutes, an international clean and green reputation, and a supportive regulatory and governmental framework for biotechnology. International alliances Queensland’s biotechnology potential is staggering, but it can achieve only so much with its relatively small population of 4.2 million. That’s why the state is actively building strong strategic alliances of value to Queensland bioindustries. Although small compared to major international players such as the United States, Queensland’s research is second to none. But the state does have to work twice as hard to attract overseas markets when world markets view Australia as too far away or too small. It’s for that reason that we have developed strategic international alliances with Washington State, South Carolina, British Columbia and New Zealand, all of which are now helping to build Queensland’s global biotechnology reputation. Queensland researchers have 25 collaborations in development with Washington State alone. I Professor Peter Andrews is an eminent Queensland scientist and bio-entrepreneur whose role as Queensland Chief Scientist involves advising government on policy and economic development issues associated with science, research and innovation. Author of more than 100 publications and inventor of two patents, he has led multifunctional scientific teams at research institutions in Victoria and Queensland. Peter has been at the forefront of initiatives to develop the Australian biotechnology industry and is an active participant in the commercialisation of Australian science and research. Since 1985, he has founded, co-founded or been a director of more than 10 scientific companies. He currently serves as a director of two Australian biotechnology companies. Email: [email protected] Website: www.chiefscientist.qld.gov.au Phone: +61 7 3224 7630 or Facsimile: +61 7 3404 6975 www.jforcs.com ENABLING A NETWORKED AND COLLABORATIVE R&D ENVIRONMENT Recent reports by PriceWaterhouseCoopers (1), Deloitte (2) and in the Harvard Business Review (3,4) address challenges that the biopharmaceutical industry is facing regarding patent expiration on existing products and the failure of their current R&D business models to efficiently bring innovative drugs to the market. The R&D challenges can be summarised as follows: • • • • • • • Elucidate underlying disease mechanisms Identify markers to distinguish between patients with similar symptoms but distinct biological conditions Identify targets that are amenable to therapeutic intervention Identify clinical biomarkers: different treatments for different patient subpopulations Reduce both number and size of trials required to prove efficacy Test the hypotheses underpinning the new molecules in man as early as possible Reduce R&D costs its service offering, yet being responsible for managing the sub-contractors. In both the one-vendor and preferred vendor model, the biopharma company deals with one party which has advantages in terms of robust sourcing governance, i.e. managing the business relationship between the biopharma company and vendor. If the outsourced R&D process is quite predictable and operationally focused, the two models can work well as in the case of phase III/IV trials However, there is now ample evidence in the industry that the onevendor model in which one organisation provides end-to-end services to a biopharma company across several years, usually packaged as a strategic alliance, does not always provide the expected cost efficiencies, time savings or quality benefits. Biopharma companies need to stay in control of their product development processes, avoid being locked into a longterm contract and accept that there are transaction or coordination costs associated with selecting, and overseeing the performance of contractors. Category Leaders One trend is for companies to restrict the expenditure on R&D and Marketing and Sales (M&S) by focusing the company’s efforts on a limited number of therapeutic areas and diseases. Consequently, the aim of the company is to become a (Global) Category Leader. Nonetheless, while this strategy provides focus to the research and development efforts of a company, it only emphasises the need to establish collaborative networks with specialist academic and commercial researchers outside the company. Collaborative R&D Networks In view of the breakdown of the current R&D paradigm and one-vendor model, the trend is that companies are looking outside their company and geographic borders to identify the appropriate capabilities and expertise at academic institutions and commercial contract research services providers having specialised know-how and technical capabilities. In other words, they are looking for research institutes and CROs that are most suited for a particular R&D process, task or activity or who can execute functions that are highly specific or strategic. This is called the “best-ofbreed” or “multisourcing” model. It provides greater control to the biopharma company and delivers higher performance than “single” sourcing. However, it also requires multiple vendor negotiations and, although risks can be shared across multiple vendors, the biopharma company bears the coordination risk. It is here that coordinating entities like QCTN Inc. and new technologies such as collaborative electronic work environments and portals can play a role in reducing the biopharma’s coordination risk and reaping the benefits of accessing high-end, specialised groups. Outsourcing Models Over the last two decades, many biopharmaceutical companies introduced outsourcing of preclinical and clinical studies and scale-up manufacturing to CROs and CMOs as a way to create economy of scale and shorter time to market. As CROs grew and became multinational companies in their own right, the larger pharma companies entered into long-term, crossborder arrangements with such CROs in order to achieve the aforementioned benefits and to try to reduce R&D costs. Typical outsourcing models are the one-vendor model, the preferred vendor model and the best-of-breed model. In the one-vendor model, a CRO provides end-to-end R&D services across (parts of) the R&D pipeline to a biopharma company. In this model, the biopharma company deals with one CRO only. Very few CROs can claim (and demonstrate) that they have available in-house, all services and all required (medical) expertise. In the preferred vendor model, the contracted CRO can provide many services but uses sub-contractors to complement Translational Research and Bioinformatics in Queensland Managers and scientists in medical research institutes, universities, pharmaceutical and biotechnology companies, laboratory equipment manufacturers and relevant software companies have witnessed an explosive development in the application of high-end computing, laboratory automation, computational biology, medical research and molecular sciences. The convergence of these disciplines brings about a fundamental paradigm shift in the way medical research, drug research and, ultimately, patient care is undertaken. Hence translational medicine is the continuum by which the biomedical community aims to move research discoveries from the laboratory into clinical practice to diagnose and treat patients. Examples in this context are the emergence of disease-centered visualisation of biological pathways, genetic profiling enabling personalised medicine, and the ability to identify auto-antibody “signatures”, i.e. profiles of potentially hundreds of biomarkers which are In addition, new exciting R&D capabilities have emerged as a result of the convergence of genetic research, bioinformatics and IT. As a result of these developments, biopharmaceutical companies are reassessing their R&D strategies as well as their R&D business models, i.e. the way they have organised their R&D processes. www.jforcs.com JCS 73 indicative for a particular disease. According to a very recent report, Australia could realise a net economic benefit of more than $12 billion over five years by wider adoption of pharmacogenomics (PGx) which has the clear potential to improve patient safety and quality of care by reducing adverse drug events and improving the effectiveness of the pharmaceuticals by prescribing the right dose the first time (5). These promising directions depend heavily on the strategic use of genomics, proteomics and metabolomics (“-omics”), but these techniques produce a tremendous amount of data that has to be managed, analysed and interpreted in a relevant biological and medical context. Clearly, bioinformatics has become a critical capability. Bioinformatics is the application of information technology, statistics and mathematics to biological and medical problems involving large volumes of data with complex interrelationships. It provides the foundation for much of modern medicine and biotechnology and is evolving rapidly into a complex multidisciplinary field encompassing nearly all areas of biological, translational and clinical research. Examples of how this is manifested can be found in the article (elsewhere in this journal) by Baker and Gorse of the Queensland Facility for Advanced Bioinformatics (QFAB). The early recognition of the abovementioned developments by State and Federal Governments and R&D service providers in Australia, and the corresponding response in investment in infrastructure and attracting world-class researchers, has made Australian institutions and service providers future-ready in terms of their translational research and bioinformatics capabilities. A recent example is the investment by the Queensland and Australian Governments of AUD $300 million in a new Translational Research Institute in Brisbane. Another example is Professor Ian Frazer of the University of Queensland who discovered Gardasil. These developments provide huge opportunities for international sponsors to establish new collaborations with cutting-edge research facilities across all areas of human disease research, drug and diagnostic discovery and development, and bioinformatics in Australia. In this context, QCTN facilitates international bio-pharmaceutical companies to visit Australia and to explore the numerous opportunities for R&D and commercial collaborations on offer. QCTN will hold its first Translational Research Excellence symposium, called TRX09, in Brisbane, Australia, in October 2009. This showcase will provide an excellent opportunity for the global biopharma industry to see what the Queensland-based translational research institutes and commercial service providers have to offer. Immediately after TRX09, the international biotechnology conference AusBiotech 2009 will be held in Melbourne, 27-30 October 2009. Clearly, QCTN’s mediated service provision now extends beyond the traditional preclinical and clinical services to provide the biopharmaceutical industry a very modern offering in terms of translational research capabilities and a best-of-breed network of service providers (figure 1). Figure 1: QCTN: Network of Specialised R&D Service Providers QCTN is a not-for-profit peak industry association (cluster) initially established with funding from the Queensland Government and representing national and international businesses (QCTN members) that have a presence in Queensland, Australia – and which represent every component in the therapeutic product development pipeline. QCTN members are life sciences research organisations and commercial R&D service providers and related entities serving the pharmaceutical, biotechnology, complementary medicines and medical devices industries. It is important to realise that QCTN is a coordinating body and does not itself undertake any research activities. McKinsey has partnered with the World Economic Forum to create an “Innovation Heat Map,” by identifying factors that are common to successful innovation hubs. As part of this effort, they have examined the evolution of hundreds of such clusters around the world and analysed over 700 variables, including those driving innovation, and classified innovation clusters into four categories. One category is called “Hot springs” which are small, fast-growing innovation hubs on track to become world players. QCTN is based in Brisbane and the McKinsey analysis identified Brisbane as one of the few innovation “Hot Springs” (6). QCTN has a business model which allows sponsors to outsource elements of their preclinical research and clinical research to QCTN’s bestof-breed network of service providers, which gives sponsors more flexibility and access to high-quality, customer-focused research and service delivery (figure 2). Figure 2: To further support the local CRO industry and biopharma industry’s legitimate desire to reduce “time-to-data”, QCTN has established an independent Institutional Biosafety Committee (IBC) and an independent Human Research Ethics Committee (HREC), the Australian equivalent of an IRB, making use of Australia’s favourable regulatory regime for undertaking preclinical and clinical research as explained elsewhere in this journal. Working both of these committees in tandem further assists sponsors in undertaking time- and cost-efficient clinical research in Australia. In this internet age, our collaborative and networked best-of-breed model clearly has caught the attention of the international biopharma industry, with American and Japanese companies leading the pack. Network of Networks Recognising that no single entity, regardless of their size and reach, can now bring a new product to market, QCTN has established strategic 74 JCS www.jforcs.com partnerships with the Korea Health Industry Development Institute (KHIDI) and the Gangwon Technopark (GWTP), both in South Korea, the Kansai Bio Promotion Council (KBPC) of Japan, and BIOCOM, the peak industry association representing the Southern Californian life sciences industry. These partnerships entail among other things the undertaking of collaborative projects and programmes, introducing sponsors and service providers and organising conferences and seminars. For sponsors this means that the QCTN and its network of networks of academic and commercial R&D service providers extends beyond the borders of Australia and ensures that sponsors have the opportunity to work with global leaders regardless of where they are located. Conclusion Biopharmaceutical companies are looking at new R&D business models by compartmentalising, outsourcing and networking their R&D activities with a multitude of research organisations. Given the explosive development in the application of high-end computing, laboratory automation and molecular science, QCTN has pulled together a cluster of Australian R&D service providers with excellent and mutually complementary capabilities in the fields of translational and clinical research, supported by a robust bioinformatics and biostatistics www.jforcs.com infrastructure. QCTN’s role is to coordinate and facilitate between national and international sponsors and its Members - Australian R&D service providers. Australia can serve as a safe stepping-stone to the Western Markets, since data generated in clinical trials in Australia is generally well received by the American and European regulators – in fact most of the early phase trials done in Australia are for US and EU companies – to repatriate the data for use in their regulatory jurisdictions. Several Japanese pharmaceutical companies are also now undertaking preclinical and clinical research activities in Australia, not only accessing specialised expertise but also realising cost efficiencies and time benefits. As Australia’s peak service industry representative organisation, QCTN invites biopharmaceutical companies to discuss their product development requirements in light of the state-of-the-art translational medical research and bioinformatics capabilities and expertise amongst its member organisations and associated networks. I Otto Damsma. Prior to joining QCTN as business development manager, Otto Damsma held the positions of director of clinical data management and biostatistics and director of information management for a major international pharmaceutical company. Email: [email protected] JCS 75 FACILITATING GENOMICS AND TRANSLATIONAL RESEARCH As a result of the mapping of the human genome, along with recent significant advances in technologies used to study genomes, genomic research is now yielding increased amounts of information and understanding about the role and function of genes in human disease. Consequently, this increased understanding and level of information relating to the human genome is now enabling scientists to translate this information in such a way that this will lead to new diagnostic tests and therapeutics. The impact of genomic research will likely lead to a shift in the clinical management of human disease from treatment based on symptoms to treatment based on each person's unique genetic make-up. From the laboratory bench to the patient’s bedside, discoveries in genomic science will increasingly lead to the translation of basic scientific discoveries that will lead to clinical applications such as new genomic technologybased diagnostics and treatments. In the context of the human genome, translational research is where the data and tools necessary to identify genes are utilised so that there is a better understanding of how genes play a role in diseases and the genetic changes which contribute to disease progression and response to therapy. The Australian Genome Research Facility Ltd (AGRF). Now in its twelfth year of operation, the AGRF operating model has continued to evolve as genomics research has evolved. Landmark projects such as the Human Genome Project have directly influenced the remarkable advances in the efficiency, automation and throughput of technology platforms for genomic research. The latest technology platforms for genomic research are offered by AGRF via an integrated and scalable genomic service pipeline (refer to Chart 1 below). As a consequence, AGRF’s role as a genomics service provider is www.jforcs.com characterised by a core focus on enabling genomic research via access to a suite of technology platforms, as well as collaborative rather than transactional relationships with customers. Typically, this means AGRF works with its customers from project planning, to data production, to bioinformatics analysis. The role of AGRF in supporting translational research Access to a fully integrated service pipeline means that for genomic researchers, the application of many of the rapidly evolving technologies to real-life applications is now possible. An example of how current genome research technologies are used is in the area of genome-wide association studies (GWAS). Such studies enable the researcher to find and understand the genetic contributors in diseases such as cancer (eg breast and colon cancers). The use of state of the art technologies along with computerised databases means that GWAS of clinical samples for genetic variations and their potential impact on disease is now rapid and accurate. As such, the use of GWAS in a translational research setting has the potential to impact on downstream patient care and disease management. In cancer research, information generated by GWAS could lead to improved outcomes for patients via a better understanding of the role of genetics in factors such as disease predisposition, progression and response to therapy. I Tony Feneziani is Sales and Marketing Manager at AGRF (Australian Genome Research Facility Ltd ) with responsibility for sales, promotion and positioning of AGRF's new and existing services to local and regional genomics markets in academia and industry. Tony has a Science degree with honours in Biochemistry and prior to joining AGRF he worked for 17 years in the life sciences and diagnostics markets with Boehringer Mannheim and Roche Diagnostics. JCS 77 FLEXIBLE FRAMEWORK FOR DATA MANAGEMENT AND BIOSTATISTICS FUNCTIONS Current Scenario Several models such as Functional Outsourcing and Full Time Equivalent (FTE) have evolved in Clinical Data Management and Biostatistics function and been implemented by biotech and pharmaceutical companies. Each of the models have their own advantages and shortcomings. These models have been received well with large pharmaceutical companies who have the resources / budgets to customize the service offerings provided by large CROs. Mid and small sized pharmaceutical companies do not find it comfortable working with large CROs on these models due to a variety of reasons which include • • • • • Very high costs for Data Management activities Lack of transparency in pricing structure Need to re-negotiate prices with study changes High Project Management costs Quality issues with offshore teams CDM and Biostatistics services for small / mid sized companies should focus on accountability, cost-effectiveness as well as flexibility without compromising on quality of deliverables. LAXAI’s Unique Solution To address the unique requirements, LAXAI provides its customers a framework to carry out Clinical Data Management and Biostatistics services. This framework is based on a global delivery model from US and India and a competitive unit pricing model for CDM services. The key benefits of this model include • • • • • • • • • • Risk sharing Unit based pricing model (Pay only for units consumed) Knowledge Sharing Cost competitive Transparent pricing model Combination of offsite (NJ,USA) and offshore model (India) Contingency staffing plan for quick ramp up / down No infrastructure investments to make LAXAI SOPs available for DM , Biostatistics, IT Support and CDISC compliance Open lines of communication with the client The Unit Pricing model provides the customer with a clear understanding of what to expect from LAXAI based on the itemized costing structure. The Unit Pricing model has 2 parts, the first one is activity or task based billing and the other one is milestone based billing. www.jforcs.com Tasks which fit under milestone billing include where the cost is fixed for the deliverable and this does not change: • Data Management Plan • Statistical Analysis Plan • Database setup and Validation Tasks which fit under activity / unit based and are driven by the units consumed for a particular billing period. Some of the activities which can be classified under this category include: • • • • • • • Edit Checks Number of pages data entered Number of queries raised to site Number of AE Terms coded / Number of Conmed terms coded Number of SAS datasets created Number of Tables, Listings and Figures Number of Status meetings attended by the team LAXAI uses a blended outsourcing model where critical functions are executed from its NJ, USA solution center and non-critical functions are executed from its Hyderabad, India solution center. Program Management, Project Management and Lead Data Manager/ Biostatisticians are from the US. Technical activities such as Database Build, Edit Check Programming, SAS Programming, double data entry are carried out from India. This model ensures that the key management team is in constant communication with the client and are accountable. Activities are shared between offsite and offshore teams. LAXAI Program Management team works closely with the client to identify performance metrics for the partnership and ensure that they are collected, reported and reviewed. Setting up a metrics program for the partnership between CRO and the sponsor provides transparency, identifying areas of improvement, taking corrective corrections as needed and provides a quantitative measure of the performance of the partnership. The metrics program emphasizes on reliability, predictability and cost reduction for Data Management and Biostatistics functions. Conclusion The model suggested above requires the commitment from both the client as well as the CRO to make it a success. Both the parties should foster a long term relationship of trust and knowledge sharing. Return on Investment should not be calculated in the short term and should look at medium to long term considering both the tangible and intangible benefits associated with the framework. JCS 79 JOURNAL FOR U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets Classified Specialist in pharmacokinetics and proof of concept in target population which serve as pharmacological models. Phase I & IIa in patients is the core business in private hospital settings. www.ipr-ee.com Midsize CRO, broad range of personalized services, international capabilities, regulatory, nonclinical, CMC, clinical, client satisfaction, quality service, people, data , proven track record. www.cato.com OR email: [email protected] Dr. Oestreich + Partner GmbH was founded in 1991 as full-service CRO, with its headquarters in Cologne, Germany, one of the most densely populated regions of western Europe. We are engaged in implementing; running and statistically evaluating clinical trials phase II to IV and PASS projects over the last 18 years. www.OandP-CRO.com OR email: [email protected] Thomson Reuters is the leading source of intelligent information for professionals around the world. Our customers are knowledge workers in key sectors of the global economy. www.thomsonreuters.com PDP is a Global Premium courier dedicated to the Clinical Trials and Life Science industry. When you need to ship your time and temperature sensitive diagnostic specimens, Investigational materials, medical supplies and dangerous goods Trust PDP. www.pdpcouriers.com QCTN is a primary point of contact for domestic and international organisations seeking to undertake preclinical and clinical research in Australia, helping them to identify and connect with appropriate research institutes, hospitals, CROs and other life science service providers. www.qctn.com.au Synergy Research Group is a Russian CRO, successfully operating in Russia since 2002. SynRG™ offers services for conducting clinical trials– from study approval to pharmaco-economic survey. Represented in Moscow, SaintPetersburg, Novosibirsk, Yekaterinburg, Perm and Almaty (Kazakhstan). [email protected] Medical translations for clinical research, registration, pharmacovigilance and use of medicines. All European and many non-european languages. www.medilingua.com Founded by Professor Keith Wesnes in 1986, CDR has offices worldwide and is the world’s leading provider of automated cognitive function assessment in clinical trials. www.cdr.eu.com OR email: [email protected] Conres is a Contract Research Organisation covering Slovenia, Croatia, Serbia and Bosnia & Herzegovina. We maintain local offices and are working with local staff familiar with local habits, language and culture. www.conres.si ACM Global Central Laboratory specializes in delivering high quality central laboratory services. Flexible in Our Approach. Precise in Our Delivery. www.acmgloballab.com InCROM CHINA has established a vast affiliated network consisting of over 30% of all SFDA approved clinical trial facilities. www.incrom.com Medidata Solutions (www.mdsol.com) is committed to providing life science organisations the most advanced tools for planning and managing clinical trials. 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[email protected] Marken is a specialist logistics and support services company supporting the global pharmaceutical industry, offering courier solutions in all phases of research and drug development. www.marken.com www.jforcs.com JCS 81 U CLINICAL STUDIES Advertisers index 35 49 41 33 IFC 17 39 27 79 37 IBC 23 3 15 45 13 5 19 80 29 43 7 48 OBC 21 11 25 47 9 ACM Global Central Laboratory Australasia Subsection Analytical Biochemical laboratory BV Beardsworth Consulting Group CATO Research Chiltern International Cognitive Drug Research Ltd Conres d.o.o Cliniminds CMED Group Ltd Congenix LLC DIA - Drug Information Association Dr. Oestreich + Partner GmbH Gleneagles CRC IBC Lifesciences - CLinical Partnerships Asia 2009 InCROM Group INNOPHAR GmbH INTERLAB Central Lab Service - Worldwide LAXAI Marken Medilingua BV Medidata Solutions Worldwide Oxford Global – 10th Annual Drug Discovery Leaders Summit Parexel International Corporation PDP Couriers QCTN - Queensland Clinical Trials Network Synergy Research Group Temmler Pharma Thomson Reuters JOURNAL FOR Your Resource for Multisite Studies & Emerging Markets JOURNAL FOR U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets Subscribe today at www.jforcs.com or email at [email protected] 82 JCS Journal for Clinical Studies – Your Resource for Multisite Studies & Emerging Markets (JCS) is also available from Center Watch Today. Please visit: www.clinicaltrialstoday.com www.jforcs.com Congenix Helping Shape Your Future Our strength is in well-established relationships with the local regulatory authorities and investigational sites within our geographic area. Congenix is a contract research organisation, operating within the Commonwealth of Independent States (CIS) including Russia, Ukraine, Byelorussia, and Kazakhstan, as well as the CEE. Congenix offers an integrated package of customised services for both American or European pharmaceutical and biotech companies in Phase I-IV clinical trials: 14, Kolomensky Pr., Moscow 115446, Russia Tel: +7 495 775 0263 Fax: +7 495 775 0264 www.congenix.com • Protocol and subject recruitment feasibility assessment • Investigator selection and investigational sites’ qualification • Regulatory affairs (regarding the countries of CIS and CEE) • Project management and clinical monitoring • Site management and grant/contract administration • Quality assurance and quality control • Medical writing • Data management biostatistics • Investigator training