Pharma Focus Asia - Issue 12 by Ochre Media Pvt. Ltd.

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Moving to Pharmacodiligence Risk minimisation in ensuring drug safety

Clinical Trials in Asia Overcoming regulatory and IP roadblocks

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Pharma Industry In times of the downturn

Foreword

Translational Medicine

Strengthening presence in Asia Pacific Translational Medicine points to a paradigm shift in the way drugs are manufactured.

ranslational Medicine (TM) has redefined Pharma R&D. It has broken down the silos that existed between research, drug development and clinical medicine, and, as a result, presented a great promise. At a time when the industry is struggling to keep up with rising costs, thinning pipe lines and a high failure rate for drugs during trials, a process like TM points to a paradigm shift in the way drugs are manufactured. Rising research costs and low returns on the investment coupled with patent expiries call for a relook at the current drug development process. In such a scenario, a process that encompasses key participants across the continuum of a drug’s life cycle, has a better chance of creating a successful drug. The growth of TM has been aided by developments in Evidence-based medicine and personalised medicine. TM fills the requirement of the Pharma industry for better R&D which would result in superior products that ultimately benefit the patient. Translating the research from Evidence-based medicine to TM is an emerging concept. The research done here, in the form of three phases, is the process of converting knowledge into effective treatments / therapies for better clinical and public health results. TM is considered transformative, integrative and conceptually communicative. Though TM has been taken up in a big way in many regions, it is still taking roots in Asia Pacific. Countries like Singapore have shown a keen interest in moving towards TM and collaborations are on the rise. It can

be said that the region is getting ready to incorporate TM to both healthcare innovation and continued economic success. The cover story in this issue by Andrew Wilson and Christopher-Paul Milne at Tufts University talks about current progress and future directions of translational medicine movement in the Asia Pacific region. This issue also presents insightful articles from key industry leaders such as ‘Moving towards Pharmacodiligence - Risk minimisation in ensuring drug safety’ by Rashmi Hegde at Global Solvay Pharmaceuticals; ‘Clinical Trials in Asia - Overcoming regulatory and IP roadblocks’ by Alan Adcock and Clemence Gautier at Tilleke & Gibbins International Ltd.; ‘The movement towards information transparency - A gateway to opportunity in clinical trials’ by Alan S Louie at IDC Health Insights. Also, Chris Lee from Bayer Schering Pharma presents his views on how the industry in coping with the downturn. I hope you enjoy reading this issue. Please feel free to get back to me with your feedback.

Prasanthi Potluri Editor

Contents

The Translational Medicine Movement in the Asia Pacific Region Current progress and future directions Andrew Wilson and Christopher-Paul Milne Tufts Center for the Study of Drug Development, Tufts University, USA

Strategy

Clinical trials

04 Moving to Pharmacodiligence Risk minimisation in ensuring drug safety

38 Collaborative Clinical Trials A solution for comprehensive cancer care

Rashmi Hegde, Global Solvay Pharmaceuticals, India

Mark Byrne and Kathryn D Stadler Pennsylvania Cancer Control Consortium (PAC3), USA

11 Clinical Trials in Asia Overcoming regulatory and IP roadblocks Alan Adcock and Clemence Gautier Tilleke & Gibbins International Ltd., Thailand

16 Contract Manufacturing of Biologicals What is in store for India? Dhananjay B Patankar, Intas Biopharmaceuticals Limited, India

42 The Movement Towards Information Transparency A gateway to opportunity in clinical trials Alan S Louie, IDC Health Insights, USA

46 Pharma Industry In times of the downturn Chris Lee, Bayer Schering Pharma, Singapore

Research & Development 20 Genotoxic Impurity Issues in Drug Development Bernard A Olsen, Aptuit Consulting, USA

24 Clinical Development Strategy for Biosimilars Partha Ghosh and Cecil Nick PAREXEL, USA

Manufacturing 34 Sustainability Practical applications to biopharmaceutical plant design Andy Rayner, PM Group, Singapore

Information technology 48 Clinical Data and the e-Clinical Landscape A need for integration Norbert Fritz, F. Hoffmann-La Roche Ltd, Basel, Switzerland

Advisory Board

Alan S Louie Research Director, Health Industry Insights an IDC Company, USA

Christopher-Paul Milne Associate Director, Tufts Center for the Study of Drug Development, Tufts University, USA

Editors Prasanthi Potluri Akhil Tandulwadikar Art Director M A Hannan Visualiser Ayodhya Pendem Sales Manager Rajkiran Boda

Douglas Meyer Senior Director, Aptuit Informatics Inc., USA

Frank A Jaeger Director, New Business Development Solvay Pharmaceuticals, Inc., USA

Sales Associates Kunal Ahuja Murali Manohar John Milton Khaja Ameeruddin Jeff Kenney Assistant Manager â&#x20AC;&#x201C; Compliance P Bhavani Prasad CRM Yahiya Sultan

Georg C Terstappen Chief Scientific Officer, Siena Biotech S.p.A., Italy

Kenneth I Kaitin Director and Professor of Medicine, Tufts Center for the Study of Drug Development, Tufts University, USA

Subscriptions incharge Vijay Gaddam IT Team Ifthakhar Mohammed Azeemuddin Mohammed Sankar Kodali Thirupathi Botla Chief Executive Officer Vijay Chintamaneni Managing Director Ashok Nair

Laurence Flint Associate Director, Clinical Research Schering-Plough Research Institute, USA

Neil J Campbell CEO, Mosaigen Inc. and Partner Endeavour Capital Asia Ltd., USA

Pharma Focus Asia is published by

A member of

Confederation of Indian Industry

Phil Kaminsky Founder, Center for Biopharmaceutical Operations University of California, Berkeley, USA

Rustom Mody Director, Quality and Strategic Research Intas Biopharmaceuticals Limited, India

Sanjoy Ray Director, Technology Innovation Merck Research Laboratories, USA

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Sasikant Mishra Business, Policy and Network Strategist Pharmaceutical Industry, India www.pharmafocusasia.com

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Moving to Pharmacodiligence Risk minimisation in ensuring drug safety

Product safety is the continuum through the lifecycle of the product that begins in the development phase and continues during the life of the product in the marketplace. Risk management and Risk minimisation are two mutual activities which play a leading role in securing drug safety for patients as well as products. Rashmi Hegde, Director, Pharmacovigilance, Global Solvay Pharmaceuticals, India

ew Drug Development is big and inherently uncertain business, as recent years have shown. In the modern era, we hear time and again, of aborted clinical trial programmes, drug withdrawals, expensive litigations and negative publicity to the pharmaceutical industry. If we look at the Balance sheet, new products enter the markets after a mindboggling expenditure of billions of dollars spent over decades of investment in the R&D of a single compound. Not only in terms of currency, but also in terms of human effort and loss of viable therapies, the expenditure is mammoth.

not necessarily certify product safety. In the past, pharmaceutical compounds were viewed in two dimensional or black versus white terms. We presumably had good products, which were safe, efficient, effective and once they had crossed the regulatory hurdle, we could ubiquitously and securely use them. Or else, there were bad products, which caused side effects and did not deserve regulatory

approval and elevation to â&#x20AC;&#x2DC;Marketed productâ&#x20AC;&#x2122; status. The real truth lies somewhere in between. All goodness and badness is contextual. One product may be good in certain circumstances, for certain diseases, in a certain subgroup of patients and equally the same product, may be contraindicated for use in other conditions. One of the ways to standardise this

Contemporary approach to risk

See in colour !!!!

History

In the recent years, the pharmaceutical industry, the regulators and the patientpublic have been increasingly awakened to the fact that marketing approval does

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Figure 1

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by a proactive approach, as well as by a network of ramifications within the Drug Safety departments.

Drug safety in product life cycle 1

Adr. frequent

Adr. rare

Walking by the river’s edge

Data availability

Efficacy

Discovery

Precunical development

IND

Clinical

‘Good’ and ‘Bad’ product is via calibration of the Benefit-Risk Ratio. I have attempted to explain this new paradigm via the picture in Figure 1. Given the current therapeutic environment, there is urgency and an importance to identify very early in the drug development process, therapies and compounds which have a high Benefit-Risk ratio. As we see in Figure 2, most rare adverse events are uncovered only after the product enters the market and is used in a larger cross section of patients. What’s more, the frequency and the significance of most serious adverse events becomes apparent only after the drug is on the market and prescribed to the larger numbers of real-life patients. The emphasis is therefore on early identification of these adverse events. In other words, efficiency in drug development—in terms of expenditure, human currency and also in preservation of vital viable therapies will be the focus of the coming years. One of the efforts in this direction is the assembly of detailed risk management plans; the guidance for which has been the focus of recent regulations in developed markets. The purpose of risk management activities is to have a continuous oversight on the risks of products during the development and marketing phase, so as to be able to detect, evaluate, and minimise risks, keeping in mind both

NDA

Market Figure 2

the regulatory requirements as well as patient and product safety. The process of Risk management and Risk minimisation applies to both marketed as well as investigational products. Figure 3 shows the umbrella under which elements of product risk, both in the pre-marketed and post-marketed phase, is defined. In fact, Risk management has entered so much into the core of drug safety departments, that Risk management processes are designated as such within these departments. The plural Risk management activities are now grouped under a common umbrella with well defined roles and complex intertwining. These processes are characterised

Drug Safety is now characterised by multiple stakeholders with a common relevance. We see pharmaceutical companies, academicians, regulators, physicians and patients collaborating with a common end in mind—namely Patient and Product Safety. The common goal is ‘Safe Medicines, with No Surprises!’ How much of this is achievable, and how much necessary, will only be evident to us in the coming years and decades. While Benefit-Risk is an easy term to proclaim, in reality, it involves walking by the river’s edge on several fronts. First is the difficulty in collating evidence and pronouncing a judgment either in favour of or against a particular course of action? This is also linked with challenges in communicating the favoured course of action to the lay public as well as to the professional bodies. What is an acceptable risk for one is quite often an unacceptable risk for a comparable group of people. This is a grey area defined by emotions, and differing critical valuation of factors which makes for multiple plural judgments. In all reality however, the pharmaceutical industry accepts very well that early

Elements of product risk Preclinical

Pipeline

Postmarket

CCSI PSUR Signalling Risk MAPs

IB, DCSI, ASR, DSUR DRMP

Product Risk Figure 3

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Conflicting concerns in assessing benefit risk of compound

Safety actions Publicity

Regulatory

ADR Seriousness ADR Frequency ADR Preventability Premature action

Indications for use of drug

Delayed action

Benefit risk of comparator drug Population of use Completeness of information on ADR Destroy product Loss of lives Loss of valuable treatment

Strength of signal

Destroy product Loss of lives Loss of valuable treatment

Chronic / short term use Seriousness of disease Table 1

reconnaissance of the real-life product characteristics and risks is a preferable alternative compared to hasty product withdrawal following negative media publicity or regulatory action. Both premature action and delayed action on product risks equally harm the patient and the product (Table 1). Ironically, products are oftentimes so sacrificed in contrast to a comparator product which may have no Benefit- Risk advantage other than that of escaping such negative attention. Currently there is a multiplicity of data, also a wealth of evidence concerning drug side effects. Assembly of data or evidence is one aspect of the game; the other of which is appropriate analysis and suitable action on the data elements thereafter. Most companies and

regulators distillate the processes, therefore compliance on aspects such as reporting timelines, or PSUR production activities—that is activities relating to the production of data are assiduously carried out—but to what avail! More beneficial aspects such as appropriate analysis and critical judgment often stand ignored in favour of empty processes. One of the ways to overcome this hiatus is to refer to collations from Independent bodies; as an example referencing the WHO Model Lists of Essential Drugs which offer Evidence-based advice on treatment modalities for different diseases and patient groups. Are drug withdrawals warranted or is there any other action which could ensure patient safety as well as appropriate use of the drug?

Risk-Benefit Assessments and Risk Management Strategies now form an integral part of the regulatory requirement prior to product approval. The CIOMS documents, the ICH and the EU, MHRA and US FDA guidelines all define this requirement. While the essential content remains the same, there are minor differences in terms of application. In comparison terms, the EU Risk Management Plan (RMP) is equivalent to the ICH E2E pharmacovigilance Planning document. The RMP document is a product specific safety discussion and consists of 3 parts that is the safety specification, the pharmacovigilance plan and the Risk Minimisation Action Plan (Risk MAP). The US FDA’s Risk MAP guidance is comparable to

US FDA guidance on risk MAP document

Elements of risk MAP submission to FDA

Role of risk MAP

Background

Tool for achieving risk MAP objective

Goals & Objectives

Risk MAP evalution

Strategy & Tools

Risk MAP communication to FDA

Evaluation Plan

Elements of risk MAP submission to FDA Table 3

Table 2

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Table 4

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the EU Risk MAP, which makes up a part of the EU pharmacovigilance risk management plan. The complete process of Risk Management consists of all 3 components: Risk Assessment, Risk MAP, based on Risks uncovered during the Assessment, and Risk Evaluation and, periodically, Re-evaluation. Benefit-Risk assessment seems simple in theory, although in truth, decisions based on Benefit-Risk of the pharmaceutical compound are difficult to formulate given the conflicting concerns governing such decisions. Some of these concerns are listed in Table 2. In an attempt to achieve standardisation, the US FDA guidance issued in March 2005, defines the elements of Risk MAP submission to the agency and provides guidance on the Risk MAP document as detailed in Tables 3 and 4. Risk Assessment

Different elements are used to assess risk arising from a compound, such as signals, use of concomitant drugs, dose effects and the science of pharmacoepidemiology. The Risk is also quantified for different Subgroups of patients, and from chronic use during Long term followup of patients. Additionally factors like Time-to-Event are calibrated in cases of certain Serious Sideeffects. Tailored Strategies are expected to be provided for chronic use, Titration of doses and special group use such as paediatric use. The most important part of risk is assessment of the effect of the product on vital systems such as heart, kidneys, bone marrow and liver as well the causality assessment. One of the routine measures used in Risk Minimisation is to update the label of the product so as to reflect the new safety information. This could then be communicated to targeted healthcare professionals, who prescribe the medication or to consumers of the medicine. Such measures would involve CME programmes, notification of changes

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Post approval safety assessment

Dosage range and changes assessment of Indications

– Restriction

– Population, Dosage

– Extension

– Therapy areas

Safety profile

– Long term safety

– Chronic use safety

– New ADR

– New drug

– Drug interaction

– New drug

– Food interaction

– New population subgroup

– Rare side effects Table 5

in safety information both to doctors and patients, advertising and training to doctors and patients on use of the product. The tools or measures used to achieve minimisation of risk differ with different products, and is based on the safety information as well as the patient and product group and characteristics of these. More stringent measures such as data collection systems, limiting prescription of the new drug to a select group of specialist healthcare professionals, special product packaging, or documentation of continued safety of the product via clinical data and laboratory tests are advocated in the more serious types of risks. One other modality to document and minimise risk is via the large simple safety study, which is a post-approval study, documenting data pertaining to any lingering safety concerns; such a study helps to calibrate the expected safety signals. Regulatory actions related to risks

In case the regulatory authorities deem it necessary, they may in addition to the above actions, issue product recalls, warnings to the company or provide safety alerts to the health-

care professionals. In several countries, the regulators are now also authorised to provide regulations, guidance documents which deal with risk management and to judicially enforce these regulations. Evaluation of risk minimisation actions

It is imperative not only to assess risks, calibrate them, undertake measures to reduce these risks, and assess them but also to periodically evaluate the Risk minimisation measures and the tools used. It is suggested to use at least two different, complementary, quantitative and minimally biased evaluation methods. The Risk evaluation should cover the number, percentage, rate of the particular event, and also assess the efficacy of tools used in Risk minimisation. Ideally, the criteria for success needs to be defined as also the review period of the Risk MAP; prior to institution of these actions.

Risk minimisation action plan Risk Minimisation Action Plan (Risk MAP) is a strategic safety program designed to meet specific goals and objectives in minimising known risks of the product while preserving its benefits.

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to be referenced to the Developmental Safety Update Report for pre-marketed products and to the Periodic Safety Update Report in case of products in the marketing phase.

Post approval safety assessments

Conclusion

Non clinical assessment for PK & PD Assessment of safety in terms of Taratogeneicity, Carcinogenicity, Organ effects Comparative assessment of Benefit Risk vis-a-vis comparator product Quality of life assessment

In cases where a Risk minimisation plan has been put into action, the progress will need to be mapped in similar terms and conclusions on future actions will have to be drawn. The Risk MAP Progress report will require to be periodically submitted to the regulatory authorities. All such documents will need

Author

Table 6

In the end, Risk minimisation is an iterative process that transpires throughout the product lifecycleâ&#x20AC;&#x201D;its different sequential componentsâ&#x20AC;&#x201D;Risk assessment, Risk minimisation and Risk evaluation continue through the product lifecycle and ideally should be assessed even thereafter to gauge any long-term product risks to humans. The ultimate aim of these exercises and processes is to move from pharmacovigilance to pharmacodiligence and to ensure patient safety along with enrichment of the therapy basket for the eventual and enduring benefit of the patient community.

Rashmi Hegde is a paediatrician by training and has vast experience with the medical departments of pharmaceuticals companies. She has now been associated with the pharmaceutical Industry for over 15 years in several global companies such as Novartis. Hegde takes a keen interest in pharmacovigilance training, pharmaceutical laws, and safety regulations (EU, US FDA & Asia Pacific) and safety reporting within licensing agreements.

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Clinical Trials in Asia Overcoming regulatory and IP

roadblocks As Asia continues to attract an increasing number of clinical trials, project sponsors need to take into consideration the specific laws and regulations of each country where the trials take place. This article will highlight the different processes in place in China, Thailand and Vietnam, as well as the importance of the agreements signed between the parties from the perspective of intellectual property law and drug importation. Alan Adcock, Deputy Director Clemence Gautier, Consultant Intellectual Property Department, Tilleke & Gibbins International Ltd., Thailand

s Asia the new place to be for clinical trials? It has only been twenty years since commentators ceased describing all Asian countries as “developing nations.” At present, it is recognised that most of the world’s products are manufactured in Asia, and more specifically in the People’s Republic of China (PRC), India, Taiwan, Thailand, and Vietnam. But these countries do not limit their activities only to manufacturing. Due to infrastructural improvement and an increasingly educated workforce, Asian countries now attract numerous clinical trials from phases 1 to 4 which previously had been primarily conducted in the United States or

in Western Europe. A few reasons are usually invoked by the industry as well as governments for Asia’s rise: (1) a large population ensuring availability/diversity of patients, (2) a broad range of developed and developing markets, (3) expanding markets, (4) infrastructure at standards almost identical to Western countries, (5) competitive pricing, and (6) increasing experience in conducting multinational trials.

Due to population growth and the rise of traditional and new diseases, Asia is seen as an expanding pharmaceutical market and is expected to observe a continued rise in consumption and market share with the PRC taking third place by 2013, below the US and Japan but ahead of France and Germany, according to the IMS Health study Changing Faces of Top 20 Global Pharmaceutical Markets Through 2013.

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Regulatory process in Thailand

In Thailand, the process by which the Thai Food and Drug Administration (TFDA) reviews a new drug application takes up to two years. However, the time frame for obtaining marketing approval for generic drugs is usually shorter—six months to one year only. This discrepancy can also be observed in other countries. Very often, the reasons for a lengthy approval process include a lack of staff competent to review the applications, as well as the increasing list of documents required for submitting not only new drug applications but clinical studies as well. However, in a desire to harmonise with the most efficient regulatory practices worldwide and thus accelerate the approval process, ASEAN countries have implemented the ASEAN Common Technical Requirements and Dossier (ACTD) on Quality, Safety and Efficacy, which provides guidelines on analytical and process validation, stability studies, and bioavailability / bioequivalence.

Moreover, the diseases present in Asia are not confined to infectious diseases typical of developing countries but also include diseases usually found in the richer countries, including cancer or heart diseases. Asia is also attractive due to the competitive pricing offered to both patients and pharmaceutical companies for services offered. Singapore and Thailand are head-to-head in both promoting and attracting medical tourism. ClinicalTrials.gov, a U.S. registry of federally and privately supported clinical trials conducted worldwide, states that since 2000 at least 1,286 clinical trials have been or will be conducted in Southeast Asia, with 571 in Singapore and 572 in Thailand. In comparison, in the PRC more than 1,200 clinical trials have been listed. However, despite Asia’s appeal as a place to conduct clinical trials, there are still regulatory and intellectual property roadblocks to overcome. In order to highlight this contrast, we have targeted

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three countries which in our view represent three different pictures of the clinical trial industry in Asia: the PRC, recognised as a large market commonly targeted by pharmaceutical companies; Thailand, which offers infrastructure on par with Western countries; and Vietnam, which is starting to attract more companies since its WTO accession in 2007. Regulatory process Drug registration process

Drug registration in Asian countries is generally slow compared to the process in European countries or in the US. The length of time required for the process may be attributed to the insufficient number of regulators. Drug registration regulations in the PRC were the subject of important changes after the 2007 recall of Chinese products such as toys, medicine, and food exported to the US. Subsequently, the PRC’s New Measures for the Administration of the Registration

of Pharmaceuticals have significantly curtailed individual regulator authority over drug registration and approval, clinical trials, generic pharmaceutical approval, and manufacturing. While data protection safeguards remain in place in terms of new drug application dossiers, most of the State Food and Drug Administration’s (SFDA) internal procedures and requirements which before were arbitrarily and sometimes inequitably disseminated and practiced are now publicly available, the majority of them online. Nevertheless, the drug registration process has not changed and in most cases still takes a minimum of 7.5 months. With its accession to the WTO, Vietnam has in recent years implemented new laws regulating the registration of drugs. Vietnam’s registration process is deemed slower than the PRC’s but faster than Thailand’s. Nevertheless, even though it is a member of ASEAN, Vietnam has not yet implemented the ACTD guidelines and has been granted an extension until mid 2010. Its implementation should facilitate the registration process for foreign companies, largely due to how it harmonises the documents required. Clinical trial approval process

Even though similarities exist in the clinical trial approval process, especially due to the fact that countries in practice follow the international guidelines such as International Conference on Harmonization of Technical Requirements for registration of pharmaceutical products for medical use (ICH) on Good Clinical Practice (GCP) guidelines and the Declaration of Helsinki, some particularities exist in each country. Although the number of clinical trials in the PRC has been greatly increasing in recent years, companies still face difficulties in commencing them. Indeed, the clinical trial application approval process can take up to nine months, since no less than four entities have to review the application, includ-

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ing multiple reviews by certain entities. The SFDA is the first agency to review the application and also reconsiders it for final approval at the conclusion of the process after being reviewed by the Center for Drug Evaluation, the Coast Institute for the Pharmaceutical & Biological Products Control, and the National Institute for the Control of Pharmaceutical & Biological Products. Since 2000, more than 1,200 clinical studies have been conducted or are planned to be conducted in China, particularly for oncology. Thailand is seen as a more attractive location for clinical trials than the PRC due to the lack of stipulated regulations. While a bill governing human clinical trials is still under consideration, the TFDA currently recommends following the ICH GCP guidelines. Contrary to other countries, the duty of review is not centralised with the TFDA, which

only reviews and approves the license to import clinical samples. The lack of regulations may explain the numerous clinical trials conducted in Thailand, estimated at 572 clinical studies since 2000. Most clinical trials in phases 1 and 2 have involved HIV and other infectious-disease-related drugs, and in phases 3 and 4, cancer and heart disease drugs appear heavily. Further to its WTO accession, Vietnamâ&#x20AC;&#x2122;s objective is to attract as many companies as possible in order to become a medical hub like Thailand or Singapore. The Pharmaceutical Law of June 2005 and the Regulations on Clinical Trials of 2007 have centralised the duties to review and control clinical trials in the hands of the Department of Science & Training of the Ministry of Health. Compared to PRC, the process is quite straightforward and should take at minimum two months after receipt

of the application. But it must be noted that clinical trials in Vietnam are still in their early days, with an estimated number of 49 trials since 2000. IP roadblocks

When conducting a clinical trial, not only does the study have to be approved by the relevant authorities, but the agreements between the parties involved have to be clearly described as well. Key issues in such agreements are those relating to intellectual property rights, such as ownership rights, control of such rights, limitations on publication, and the level of confidentiality. These issues are usually addressed in an Investigator Agreement. Publication rights

As in other jurisdictions, investigators or their teams normally request the rights to publish information about the study they are conducting in academic

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Data protection

Data protection or data exclusivity is normally established in many jurisdictions or in bilateral trade agreements as a period of five years for pharmaceutical products and three years for new clinical information. This protection is referred to as â&#x20AC;&#x153;TRIPS-plus,â&#x20AC;? since it is not mandatory for the signatories of TRIPS to implement this protection. Data exclusivity is aimed at safeguarding with the FDAs the registration files for pharmaceutical products that are deemed to contain trade secrets. These data, especially clinical studies, are important for generic companies because when filing an FDA application, these companies will claim bioequivalence to the original drug, arguing that their pharmaceutical products are clinically interchangeable in terms of efficacy and safety and that they meet the requirements regarding quality standards. By implementing a data protection system, the FDAs cannot

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Confidentiality Confidentiality constitutes a request to use the information solely for the agreed purpose and not to disclose the information to any person other than as permitted. The essential element is the definition of confidential information. By including a confidentiality provision, the parties will clearly define what has to be kept secret, that is to say not disclosed to any third parties or competitors. Moreover, such provision will avoid any disclosure of relevant information prior to filing a patent application, which could defeat the novelty criteria.

rely on data that is TRIPS-plus protected when registering a generic product. Due to this protection, generic companies have two options: either conduct clinical trials or wait until the expiration of the data protection. In Asia, data exclusivity is not always guaranteed, as the guidelines across the region are often unclear. However, almost every ASEAN country has set up a data protection/exclusivity system. Some particularities in these systems are apparent. In China, protection of undisclosed data is provided for a period of six years, but anecdotal evidence suggests that domestic generics can still indirectly get access to these data through regulatory loopholes. In Thailand, although data protection lasts for five years from the date of recordation, the protection available is limited to physical protection. In Vietnam, data protection is not automatic and has to be requested to be enjoyed. Interestingly, data protection does not apply to new chemical entities in Vietnam.

Authors

journals. However, the investigator must be made to understand that a publication can defeat the required novelty criteria of a patent application for the tested drug. Thus, in practice, the sponsor will request no publication or publication under their supervision in order to avoid any obstacles to their patent application. Another important point regarding publication is the timeline for filing a patent application, which usually occurs at the beginning of phase 3. Nevertheless, in case of a more indepth publication which is not controlled by the sponsor, many laws (such as those in Thailand or Vietnam) authorise a six-month period during which the applicant, usually the sponsor, can file the application. It is also notable that if the publication occurs in the US, for example, it can still defeat novelty for a patent application in Thailand. Thus, when deciding whether to file a patent, the sponsor should consider the information disclosed in the publication as well as the expected timeline for filing patents, which could differ from one country to another.

Conclusion

Pharmaceutical companies should remember that directly contacting regulatory agencies when an issue arises may facilitate the acceptance of the application. In the meantime, using the language of the regulatory agency, such as Thai in Thailand, also permits better understanding and cooperation by the examiners. When a foreign company decides to conduct a clinical trial for the first time in Asia, they sometimes forget a basic rule, which is to conduct due diligence on their partners regarding issues such as their experience in clinical trials and the quality of the infrastructure, especially if a GMPqualified site is required. Finally, a sponsor should always keep in mind that while an agreement can limit any breach of confidentiality or intellectual property and provides grounds in case of litigation, it does not prevent such risks. Thus, information should be provided only when required and sometimes only sparingly.

Alan Adcock is deputy director of the Intellectual Property Department and a member of the Regulatory Affairs Department in the Tilleke & Gibbins Bangkok office. With more than 10 years of registration, enforcement/litigation and commercial IP experience in China and Hong Kong, Alan has particular strengths in the commercialization/registration and clinical trial side of the pharmaceutical and medical device sector. Alan speaks and writes regularly on IP aspects of the Asian medical landscape. Clemence Gautier is a consultant in the Intellectual Property and the Regulatory Affairs Departments of Tilleke & Gibbins. Among various matters she handles, Clemence works closely with pharmaceutical companies on issues including trademark and patent registration in ASEAN countries, infringement, and industry-specific issues such as data protection, product liability, clinical trials, and labeling.

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Contract Manufacturing of Biologicals What is in store for India? An increasing number of global biopharmaceutical companies are outsourcing bio manufacturing (bio outsourcing) to bring their products to market in a costeffective and timely fashion. This article explores the pros and cons of bio outsourcing and provides some insight into the prospects for future growth of this newly emerging industry both globally and from an Indian perspective. Dhananjay B Patankar, Chief Operating Officer, Intas Biopharmaceuticals Limited, India

uring the past 25 years, the biopharmaceutical industry has transformed itself from a research and development enterprise into a robust, product-driven sector of the global economy, with worldwide sales of biopharmaceutical products topping US$ 80 billion, an estimated 174 approved products, and 800+ products in various stages of clinical development. Historically, biopharmaceutical companies have chosen to bring bio manufacturing â&#x20AC;&#x2DC;in-houseâ&#x20AC;&#x2122; to retain control over personnel, production schedules, intellectual property (IP), and regulatory and quality concerns. However, many smaller companies do not possess the internal expertise or the financial resources to manufacture their own products and turn to contract manufacturing organisations (CMOs) for clinical or commercial production of

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their products. This also helps them in that they are not saddled with expensive facilities that they cannot even use, if their product fails in clinical trials, a part of normal life in this industry. Outsourcing of bio manufacturing globally grew at annual rate of 20 per cent for the last decade, and is expected to cross US$ 4 billion by 2011 from US$ 2.8 billion in 2008. What is getting outsourced?

Two distinct philosophies have been seen to be at work. One trend has seen large companies outsource their clinical manufacturing, which requires flexible manufacturing facilities, uncertain quantities, and less focus of cost of goods, while they retained commercial manufacturing, where they could maintain control over cost of goods, consistent quality and reliability of supply. The growth of large, specialised CMOs has also seen a

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reverse trend, where the product companies retain their clinical manufacturing, which is tied in to their core business of research and development, and outsource the routine job of commercial manufacturing, which they no longer see as their core competence. Biologics CRAMS in India

India, with more than 80 US FDAapproved manufacturing facilities and efficient, low-cost production models resulting from the highly competi-

tive domestic generic pharmaceuticals market, is one of the most preferred locations for outsourcing manufacturing by global pharmaceutical companies. The Indian pharmaceutical contract manufacturing market stood at US$ 1.21 billion in 2007, and is estimated to reach US$ 3.16 billion by 2010. Last year, India’s Biotechnology Industry grossed revenues of US$ 2 billion and is amongst the top countries in the Asia Pacific region. Some of the active players in the Biologics

development and manufacturing space are Syngene, Biocon, Intas Biopharmaceuticals Ltd, Avesthagen. Other product companies such as Reliance Biopharma, Shantha Biotech, Panacea Biotech, Wockhardt and Dr. Reddy’s are also eyeing Contract Manufacturing as the scales of operation become bigger and facility utilisation and operational cost control becomes critical. As an industry, we in India are moving from the “hundreds of litres”

Outsourcing strategies

2% 36%

Early Clinical in-house, Commercial Outsourced

Early Clinical Outsourced, Commercial in-house

12% Almost all in-house 27% Almost all Outsourced 24%

“Only 12% of the companies do everything in-house in the Biotech Industry” - demonstrating the available scope and opportunity

Case-by-case deal done

Based on a global survey of 41 companies that outsource and 27 that provide Biopharma service

Facility of Intas Biopharmaceuticals Limited www.pharmafocusasia.com

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US $ Billion

Outsourcing of bio manufacturing 4.5 4.5 4.0 3.0 2.5 2.0 1.5 1.0 0.5 0

2006

2008

2011

Based on a global survey of 41 companies that outsource and 27 that provide Biopharma service

Examples of discovery research deals: Transition from generics to new molecules (collaborative and–or contract) • Syngene & BMS – to establish a dedicates contract research facility to house more than 400 scientists • Wyeth & GVK bio – dedicated facility and terms • Jubilant & Eli Lilly – started with CRAMS and is now a JV operation with risk charing and milestones • Suven & Eli Lilly - risk sharing model adopted • Ranbaxy & GSK - risk sharing model • NPIL & Eli Lilly - risk sharing model • Astra Zeneca India – full fledged R&D center and adopting partnership / risk sharing models • Dishman & Solvay – long term fill finish supply agreement Source – from News clippings and published data

scale most facilities had until recently to the “thousand-litre” scale on the mammalian side and these scales become a good entry point for such Bio manufacturing opportunity. With the increasing titres of today’s expression systems, scales of a 1000 litres are likely to be adequate for a great proportion of clinical as well as commercial requirements of future products. The size of the overall biologicals market in India will remain small due to the high cost of therapy as well as the changes in the IPR landscape with introduction of the product patent regime. As a result, unlike the traditional pharmaceutical sector, the contract manufacturing business in biologicals may not piggyback only on the generic manufacturing capacity, but may develop as an independent business segment. The Biosimilars (Biogenerics) sector still has an important role to play, as it will demonstrate that high quality biologics can be manufactured in India, and go a long way towards establishing a critical mass of scientific, technical and engineering talent. Intas Biopharmaceuticals in the CMO business

Intas Biopharmaceuticals Ltd. (IBPL) is bullish on the opportunity for contract development and manufacturing in India and has a dedicated business segment for pursuing this business. IBPL is

Sustaining the competitive edge The Indian cost advantage extends well beyond low labour costs and ensures that the cost reduction process is a continuous process. The factors that derive India’s cost advantage include: Capital efficiency: Indian companies are able to reduce the upfront capital cost of setting up a project by as much as 25-50 per cent due to access to locally fabricated equipment and highquality local technology or engineering skills. Indian companies have been able to establish USFDA standard plants at approximately 50 percent lower capital costs as compared to US or Europe based manufacturing units. Lower filling costs: Generic fillings require complex technical and

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legal documentation, which takes about eight quarters. The cost of filling DMFs and ANDAs is at least 50-60 per cent lower for Indian companies as compared to their US or European counterparts. Process engineering: The highly competitive local market and lack of pricing power force Indian companies to continuously work on the molecule even after a product is launched. This often results in gains in the form of improved yields and more cost-effective manufacturing processes. The customer and supplier generally share such benefits in a pre-determined ratio, thus providing the benefit of continuous cost reduction.

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cell culture capacity for monoclonal antibody production. Products manufactured at the facilities in IBPL have been supplied for clinical trials in Europe and the company is currently executing contract research projects from clients from the USA. We see a sound understanding of regulatory requirements in product development and manufacturing as a key strength. Contract manufacturing in India: beating the slowdown

Manufacturing Facility of IBPL Inc., which is fulfilling the requirements of its clients in North America and Europe. A new facility under construction, meeting both US FDA and EMEA GMP requirements, will add 5000L of

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India’s first and only biotechnology manufacturing facility EU-GMP certified by a European regulatory authority. It has the capability to meet requirements of small to medium scale GMP production microbial- as well as mammalian-derived products, including fill-finish of liquid and lyophilised products in syringes and vials. The company has expanded its Contract Research and Manufacturing Services (CRAMS) business with acquisition of US-based biotechnology company Biologics Process Development

There are ‘Push’ and ‘Pull’ factors that make outsourcing a prudent option. The ‘Push’ factors are pressure on the company to reduce cost, time-tomarket and the ‘Pull’ factors are proven track record of the CRAMS company to handle product development and comply with GMP as per international requirements. These are challenging times where the global financial crisis has affected many smaller Biotech’s who may be forced to license out earlier than they would have liked to, while larger companies will be constrained in their ability to pursue the entire pipeline. These ‘push’ factors combined with the ‘pull’ factor of companies such as Intas Biopharmaceuticals Ltd. with demonstrated capabilities and the required scale could create significant opportunity to bring such development and manufacturing business to India. References 1 JAMA. 2008;300(16):1887-1896. by Thijs J Geizen et al. 2 E.S. Langer, Genet. Engin. News (2), 20–25 (2004).

Dhananjay B Patankar is the Chief Operating Officer at Intas Biopharmaceuticals Ltd, Ahmedabad, India, where he leads the development and manufacture of recombinant protein drugs and is responsible for expansion and establishment of manufacturing facilities for its new products. Patankar is a Chemical Engineer and did his B.Tech from Indian Institute of Technology, Mumbai (India), and MS and PhD from the University of Utah, (USA), followed by a postdoctoral fellowship at Rutgers University (USA) for 2 years.

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Research & Development

Genotoxic Impurity Issues in Drug Development Although the FDA has outlined expectations for assessment and control of genotoxic impurities, there are many questions that require interpretation and decision-making that will be a function of the compounds involved and the stage of clinical development. Bernard A Olsen, Managing Director, Aptuit Consulting, USA

enotoxic impurity control in drug substances and products has become a topic of increased regulatory concern as indicated by the EMEA guidance and a draft guidance issued by FDA. Although these documents outline expectations for assessment and control of genotoxic impurities, there are many questions that require interpretation and decision-making that will be a function of the compounds involved and the stage of clinical development. Dealing effectively with these questions is necessary to address safety concerns and avoid delays during drug development. Regulatory expectations

Evaluation of drug genotoxicity is a standard regulatory expectation; however, impurities from the drug manufacturing process or degradation may also have genotoxic potential and are receiving increased regulatory scrutiny. Acceptable limits for such impurities are given in regulatory guidance from Europe and draft guidance from FDA as shown in the table below. These limits are based on a Threshold of Toxicological Concern (TTC) approach previously developed for evaluating cancer risks. The limits are staged corresponding to duration of

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exposure with 1.5 μg / day as the limit for long term use and product registration. Other factors that can impact impurity limits include available toxicity data for impurities, the treatment group or indication for the medication, and exposure to the impurity from other sources such as food. For example, higher impurity limits may be justified for a life-saving therapy or for use with geriatric vs. paediatric patients. Impurity assessment for genotoxicity

Decisions must be made regarding which of the many potential impurities arising from a synthetic route or via degradation needs to be evaluated for genotoxic potential. Some reagents used in the synthesis of the drug are known carcinogens or mutagens. Extensive toxicological data are not usually available for starting

materials, intermediates and by-products, but they can be examined for socalled alerting structures i.e. structural elements that have been shown to give rise to genotoxicity in other compounds. Some alerting structure examples are alkyl halides, benzyl halides, sulfonate esters, hydrazines, nitro groups, and epoxides. Compounds with alerting structures are often assessed further using in silico tools for predicting genotoxicity. If the evaluation of genotoxic potential using software such as MCASE and DEREK is negative, no further investigation of genotoxicity is necessary and the impurity can be treated according to thresholds described in ICH impurity guidelines Q3A(R2) and Q3B(R2). Further steps are necessary when a genotoxic impurity is identified through a structural alert or in silico assessment. The genotoxicity of the impurity may be

Staged thresholds of toxicological concern Genotoxic impurity limits, μg / day Single Dose

<14 days

≤ 1 mo.

≤ 3 mo.

≤ 6 mo.

≤ 12 mo.

> 12 mo.

EMEA

120

1.5

FDA

120

1.5 Table 1

Research & Development

checked in a bacterial reverse mutation assay i.e. Ames test. In most cases, a negative result would remove concern about genotoxicity of the impurity. It is preferable to perform the test using a sample of the neat impurity but the test can also be done with the drug containing the impurity at a sufficient level. The latter approach may be needed if the impurity is difficult to isolate or synthesise. It is clear that impurities identified in the drug substance or product need to be assessed for structural alerts. The expectations are less clear regarding other compounds identified during the course of development. Synthetic reaction and drug degradation studies are often performed under stress conditions far from typical reaction or storage conditions. These conditions may produce by-products or degradation products that are structurally identified but will not be relevant to impurity formation under normal conditions. To focus assessment efforts

effectively, risk-based judgment must be used to determine the compounds that can reasonably be expected to be present in the drug substance or product. When the genotoxic impurities of concern are identified, several options are available to address their control as described below. Synthetic route redesign

The most effective way of dealing with genotoxic impurities in a synthetic route is to redesign the route to avoid the use of genotoxic reagents or intermediates that contain structural alerts. Factors such as environmental impact, prohibitive expense, technical issues, or other quality issues may limit the feasibility of alternate routes. Even the design of the drug itself can be a factor. For example, with drug substances that are sulfonate salts, the risk for sulfonate ester impurities may be outweighed by desirable pharmaceutical properties of the salt. Different

considerations will also apply for early development routes compared to routes intended for commercial production. Process capability rationale

If a genotoxic impurity is introduced early in a synthetic route, the probability of the impurity carrying through multiple subsequent reaction and purification steps to the final drug substance is greatly reduced. By their nature, many genotoxic impurities are chemically reactive and would not be expected to survive beyond the reactions where they are introduced, much less through multiple downstream purification steps. A risk assessment based on process capability involves chemical judgment on a case-by-case basis. There is not a formal regulatory opinion about use of process capability rationale for justifying lack of concern for an impurity; however, such an assessment can help focus priority on impurities with the greatest probability of appearing in the

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drug substance. Regulatory acceptance of process capability rationale may also be a function of phase of development.

When an impurity has the potential to be present in the drug substance or product, it is likely that a specification control for it will need to be established.

Analytical testing

Process capability data

Impurity rejection studies can be performed to demonstrate the ability of the synthetic process to remove impurities. These studies involve spiking reactions with relatively high levels of the impurity and then analysing downstream samples to check for the level of impurity carry through. Showing that an impurity is completely removed even if present initially at much higher than typical levels can be used to justify lack of routine testing for the impurity. The upfront expense of laboratory spiking studies and analytical method development can be offset later by avoiding unnecessary specifications and testing. Laboratory studies are usually supplemented by analytical data from scale up samples from the synthetic process, drug substance batches and drug product batches. Similar approaches can be used to evaluate future process changes to show that the impurity rejection efficiency is maintained. Of course, process capabil-

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ity studies may also show that critical process controls and / or specifications need to be applied to ensure adequate impurity control. Specifications

When an impurity has the potential to be present in the drug substance or product, it is likely that a specification control for it will need to be established. The specification might be on a starting material or intermediate at a level known to ensure conformance to the staged TTC level in the drug substance or product. In these cases, it is important to leverage process knowledge to set appropriate impurity limits depending on point of control in the synthetic process. For example, process capability data may show that a limit of 0.1 per cent for a genotoxic impurity in an intermediate will result in a level below the TTC in the drug substance. This may allow the use of a less sensitive, but more rugged analytical method that is better suited for a quality control environment. In the unfortunate case of a genotoxic degradation impurity in the drug substance or product, there is no opportu-

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Sensitive analytical methods for genotoxic impurities using techniques such as HPLC-MS can be developed and used to analyse the drug substance, drug product or samples from various points in the synthetic route. Results may show that impurities are controlled well below levels of concern as given by the staged TTC. The sensitivity requirements for the method will increase as the duration of exposure and / or dose of the drug increase. Other decisions about the methods such as extent of validation are important. Validation will be a function of how the method is used (e.g. development information vs. quality control or quantitative test vs. limit test). Regulatory expectations for impurity data from analytical testing are likely to increase as a product moves toward registration.

nity for purification. Formulation design and appropriate packaging and storage conditions would be needed to prevent the impurity from exceeding the TTC limit during product shelf life. A sensitive method would be necessary to check for the impurity at the TTC limit at time of manufacture and during stability studies. Regulatory overkill?

Significant debate continues within the industry as to whether undue regulatory attention is being focused on genotoxic impurities in pharmaceuticals. The discussion includes challenges to some of the data and basic assumptions used in arriving at the TTC as well as positioning the cancer risks posed by impurities in pharmaceutical products compared to other sources of risk such as the environment and foods. Some assert that the need to perform some type of genotoxicity assessment on a large number of potential impurities identified during development will constitute a significant disincentive to identify any impurities that do not exceed the ICH identification threshold. This could cause some firms to pursue a less rigorous understanding of process chemistry and drug degradation, contrary to Quality-by-Design goals. While it is important that the regulatory debate continues, drug development firms will need to address the issues as outlined above in order to meet regulatory expectations and avoid costly delays. Good judgment based on risk assessment can help achieve an appropriate balance such that patient safety in terms of exposure to harmful impurities is ensured without resorting to measures that add little benefit in that regard.

Bernard A Olsen is a managing director at Aptuit Consulting where he provides expertise to clients for drug development programs as well as leading a group that provides expert support for patent litigation and other intellectual property matters. He has over 29 years of drug development experience at Eli Lilly and Company where he was a Senior Research Fellow in the Product Research and Development component of Lilly Research Laboratories.

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Clinical Development Strategy for Biosimilars Addressing clinical development challenges for biosimilar products through development pathway planning, and integration of clinical and regulatory demands. Partha Ghosh, Director Cecil Nick, Vice President, Biotechnology PAREXEL, USA

t is now generally accepted that biological products cannot be regarded in the same way as standard small molecule generics. Minor differences in heterogeneity, post-translational modifications, folding and / or impurities will arise from differences in the production process. Such differences could impact safety and efficacy profiles through possible changes in pharmacokinetic, pharmacodynamics, off-target effects and immunogenicity. In the European Union, the European Medicines Agency (EMEA) has developed a number of guidelines which outline the basis for development of biosimilars for quality, non-clinical and clinical requirements. In addition, following the provision of Scientific Advice on a number of biosimilars, the EMEA has produced ProductSpecific Guidelines covering biosimilar soluble insulins, erythropoetins, somatotrophins, Granulocyte Colony Stimulating Factor (GCSF), alphainterferon and low molecular weight heparins. Development guidelines for more complex molecules such as monoclonal antibodies are being considered, while currently blood products, such

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as recombinant factor VIII, are being thought of as too complex to consider as biosimilars. Furthermore, it is not intended that the guidelines be followed slavishly although very clearly, sponsors need to be cognizant of them. Nevertheless, as knowledge and experience of biosimilar development is accumulating, regulatory views are constantly evolving. Sponsors need to maintain a flexible approach to Biosimilar development and be prepared to introduce innovative approaches during scientific advice procedures. Each product raises its own specific challenges, which need to be addressed on a case-by-case basis. A key principle of ‘biosimilarity’ is that it is based on consideration of the totality of the data, including physicochemical properties, biological effects, toxicology, relevant pharmacokinetic and pharmacodynamic data and clinical efficacy and safety. Where differences are observed, the relevance of these to clinical efficacy and safety will need to be considered. So called ‘similar’ products may turn out to be sufficiently different to necessitate a stand-alone development path, particularly where differences

in physicochemical and/or biological effects, translate into differences in pharmacokinetic, pharmacodynamics, efficacy or safety. This will be the case even if these differences are viewed as beneficial e.g. enhanced efficacy over the reference product. In such situations, a stand-alone programme demonstrating superior efficacy, enhanced safety or an improved dosage regimen may provide competitive advantage over the innovator product but this will generally require a more extensive and costly development programme. Clinical studies

Often pharmacodynamic endpoints alone are not considered sufficient to provide robust evidence of therapeutic equivalence. In these circumstances, the efficacy of a biosimilar product has to be demonstrated in the clinical setting. Efficacy will need to be justified or, if necessary, demonstrated separately, for each claimed indication. For extrapolation to other indications, it is important to conduct studies in a population with the highest probability of showing any potential differences in therapeutic effect.

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Pharmacokinetics / Pharmacodynamics Even for small molecules, formulation and manufacturing differences can impact pharmacokinetics, so bioequivalence trials in healthy volunteers are generally required. The need for comparative pharmacokinetic data is even more pressing in the development of biosimilars since the pharmacokinetics of proteins may be impacted not just by formulation but also by structural differences such as glycosylation e.g. Kanda et.al. demonstrated that for an IgG1, the presence of high mannose at the Asparagine 297 glycosylation site on the heavy chain, significantly increased clearance (Kanda Y et. al. Glycobiology 2007 17(1):104-118; doi:10.1093/glycob/cwl057) The normal primary endpoints for bioequivalence of maximum plasma concentration, Cmax; and area under the concentration-time curve, AUC, are also relevant for biosimilars. In addition clearance parameters such as plasma half-life should be monitored as secondary end points. While the normal equivalence margin for AUC and Cmax applied in standard bioequivalence trials, namely 80 – 125 per cent may be accepted, this will need to be justified and in certain circumstances a tighter margin might be appropriate. There will be considerable reluctance to accept a broader margin. In circumstances where several doses are used therapeutically, e.g. for different indications, there may be the need to study pharmacokinetics for each of these doses. Working with biologicals may present further challenges. Studies in healthy volunteers may not be feasible due to toxicity or profound pharmacodynamic effects such as the total B-cell depletion seen with rituximab. It may not be possible to restrict patients to a single dose e.g. in oncology where patients need to receive a full treatment course. In these circumstances, steady state pharmacokinetics need to be compared, which will need to be defined, requiring the need to treat for at least six half-lives.

Generally, therapeutic equivalence clinical trials are required: if these are not feasible, other designs will need to be explored with the competent authorities. Overall, equivalent therapeutic efficacy should be demonstrated with therapeutic equivalence margins being pre-specified and justified, primarily on clinical grounds, although this is not always possible. Evidence to justify the therapeutic equivalence margin can be derived from information based on accepted precedents e.g. European Public Assessment Reports (EPARs). The expected standard deviation for the selected primary endpoint will

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Thus, the long half lives, typically 21 days, for IgG1 would mean six months to reach steady state and for IgG1, a single dose crossover trial would need a three month washout period. High variability and low plasma concentrations may further confound attempts to demonstrate pharmacokinetic equivalence with an 80 - 125% equivalence margin. Furthermore, there is the need to be aware that protein content may vary between batches of reference product by as much as ± 10 per cent or more, further impacting the ability to meet the equivalence criteria. Pharmacodynamic endpoints are important and where possible should be incorporated into the comparative pharmacokinetic study program: often qualitative comparisons may suffice. Pharamcodynamic measures are only of value if determined along the steep part of the dose-response curve, otherwise differences in potency or activity will not become apparent. Batch differences in potency may vary even more than protein content e.g. the epoetin Ph Eur monograph permits an 80 – 125 per cent margin and this could impact on meeting the pharmacodynamic equivalence criteria. Pharmacodynamic markers may be acceptable as a surrogate for clinical efficacy. However the marker should be both clinically relevant and have a predictable correlation with the therapeutic dose response. Notably, for filgrastim and insulin, pharamcodynamic endpoints may be used as a surrogate for clinical efficacy, but for interferon beta, no suitable surrogate pharamcodynamic is known. In other situations, such as some monoclonals, there may be no pharmacodynamic marker at all. Where pharmacodynamic markers are used as a surrogate for efficacy, an equivalence margin will need to be set apriori and this must be justifiable and clinically relevant, based on a quantitative relationship between the marker and the clinical endpoint.

need to be established for estimation of sample size. This can often be obtained from the published literature, otherwise a pilot study may be required or an adaptive design discussed with the competent authorities. An uneven randomisation can be considered as a way of reducing the amount of comparator drug required to reduce costs or to increase the test drug’s safety database; however, there is a penalty in requiring a slight increase in patient numbers over a study with an even randomisation. Poorly designed or conducted equivalence trails are prone to indicate equiva-

lence falsely e.g. a lack of efficacy in both arms because of poor compliance may be interpreted as equivalence. Any study will require adequate assay sensitivity to demonstrate a difference, if a difference were to exist. This is generally achieved by replicating a design that has been used to demonstrate superiority over placebo for the reference product and to compare results with the earlier originator study to confirm that the expected therapeutic effect is achieved. A trial may also not display assay sensitivity if the study is conducted in the flat part of the dose response curve. This situation may be

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Immunogenicity can be a major safety issue, particularly where there is potential for neutralising antibodies to cross-react and knock out a critical endogenous protein. Regulators pay special attention to immunogenicity, which needs to be monitored throughout clinical development, and requires a testing plan and a validated assay in line with current guidelines and precedents. If serious immunogenic events are rare, then potentially a very large exposure will be required to detect the event reliably; the classic example is the 30,000 patients needed to detect a 1:10, 000 incidence of Pure Red Cell Aplasia (PRCA) that occurred following reformulation of an epoetin product. It is not feasible to conduct studies of this size and, therefore, post marketing monitoring represents the only feasible option. Looking ahead

Methodology is becoming more sophisticated, enabling far better characterization of complex proteins. This even applies to the potential development of biosimilar monoclonal antibodies, which only a few years ago were regarded as unique and unlikely to be amenable to biosimilar development. The EMEA has proved to be open to new ideas in the development of biosimilars and the Scientific Advice procedure should be regarded as high points in a

Authors

more common than generally recognised because biological medicines often have a high safety margin and originator product doses may be higher than actually needed. Thus pharmacodynamic studies in healthy subjects using lower doses may actually prove a more sensitive model for detecting differences than comparing products in the normal therapeutic setting, although regulators will require some convincing. Generally efficacy studies should use a double-blind design to avoid investigator and patient bias, however sometimes this will not be feasible e.g. where the innovator product uses proprietary closure/containers that can not be replicated. In these circumstances, every effort is required to limit the impact of bias. The duration of clinical comparability studies will be driven by a number of factors but key is the need to demonstrate meaningful therapeutic equivalence. These include whether there is an accepted early marker; the time required to achieve a response; a need to demonstrate duration of response and the number of events needed to fulfil the equivalence criteria. Safety relevant differences need to be detected: a study should not necessarily seek to establish a major safety database for the test biosimilar but to allow evaluation of differences in the rate of occurrence of major safety issues, which may affect the benefit—risk evaluation. Similarly, the size of the study population should also detect differences in safety and not solely be based on considerations of clinical efficacy. Further, safety monitoring on an ongoing basis will require a significant post-marketing pharmacovigilance commitment. Particular attention needs to be given to possible differences in the clinical presentation (duration, magnitude, reversibility, response to rechallenge and / or treatment) of major adverse events as this will influence the benefit—risk evaluation, the pharmacovigilance risk management plan and post-marketing safety commitments.

relationship rather than a one-off transaction. Advice is not legally binding but applicants are generally expected to adhere to advice or justify the deviation. Sponsors should be aware that the advice received will be based on the robustness of the arguments and data presented to support the company position: it is vital that a sponsor presents a credible, efficient and achievable programme with strong scientific justification. Across the world, different attitudes and regulations are evolving, which makes global development of biosimilars particularly complex. These include differences in viewpoints and regulatory constraints, the impact of population ethnicity, the acceptance of a single reference product internationally and changes or uncertainty in the regulatory environment, especially in the US. In Japan the Ministry of Health, Labor & Welfare is about to give its formal approval for the first therapeutic biosimilar. While great advances have been made in establishing a pathway for the development of biosimilars in many countries, there is still a long way to go to enable global development of similar biological medicinal products. These are not new entities and they are not generics; their development requires new paradigms and innovative thinking. It is an entirely new area where the innovative and the daring are likely to triumph.

Partha Ghosh is a director for PAREXEL consulting and leads the consultancy’s European Early Stage Development practice. Prior to joining PAREXEL, Ghosh served for ten years as a clinician in the NHS specialising in ophthalmology with sub-specialty experience in medical retina, corneal disease and glaucoma. Ghosh’s professional degrees include an MBBS Medicine from Guy’s Hospital Medical School, London, an FCRS from the Royal College of Physicians & Surgeons, and an MBA. Cecil Nick is the principal consultant for PAREXEL consulting. He provides expert consulting services to clients particularly on the clinical and regulatory development of biotech and biological products. He has been involved in the development and regulatory approval of a number of innovative and biosimilar medicinal products in Europe. He also has extensive experience in the development and EU registration of biotechnology and blood products, devices, new chemical entities, CMC, orphan drugs, health economics, and scientific advice.

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The Translational Medicine Movement in the Asia Pacific Region Current progress and future directions Translational medicine is still developing in the Asia Pacific region, but it is clear that countries see it as integral to domestic biopharmaceutical innovation.

Andrew Wilson Research Associate

Christopher-Paul Milne Associate Director

Tufts Center for the Study of Drug Development, Tufts University, USA

he Translational Medicine (TM) movement has generated much attention over the last few years as a series of public sector programmes and small private endeavours within companies and universities, incorporating a variety of its tenets, are underway in the US and EU. Much of the discussion has focussed on the efforts of ‘big science’, such as those described in the NIH Roadmap, and the endeavours of ‘big pharma’ public-private partnerships such as the Critical Path Initiative (CPI) and the Innovation Medicines Initiative (IMI). These efforts, however, are taking shape predominantly within the context of biomedical R&D as it exists in North America and Europe. Less is known about the breadth and direction of the TM movement outside of those regions. One area of particular interest is the Asia Pacific region. Recent decades have seen it rapidly emerge as an important

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player in the global economy. Economic success has also clearly led to an emerging importance in biopharmaceutical innovation as the region has made great strides in scientific and technological expertise. In terms of pure capability, measures of innovativeness suggest the Asia Pacific region as a whole is rising fast. For example, Asian countries accounted for a third of US patent applications, a common gauge of innovation, in 2007. Remarkably, this was a more than 800 per cent increase over 1980 totals. A few member countries, such as Korea, even outpaced practically all of Europe. As further evidence of the region’s emergence, several big pharma firms, such as Novartis and AstraZeneca, have recently taken advantage of its growing capacity by opening multi-million dollar advanced research centres in China, India and Singapore. In light of these trends, it is important to consider how TM is currently being harnessed in the

region to further biopharmaceutical innovation. What do we mean by Translational Medicine?

The modern definition of TM recognises the need for a more dynamic and complete R&D process—a bench-tobedside feedback loop. Basic science researchers take what is known about a disease from various disciplines together with what they are told by clinicians in the field, and in turn, inform clinicians about what they have learned in order to develop safer and more effective medicines and better clinical practices. Conceptually, TM is transformative, integrative and communicative. It is transformative because it turns basic discoveries into clinical applications to improve patient health. TM is also integrative because it requires integration among the various phases and disciplines involved in medicines’ R&D, as well as

among stakeholders from scientific, social, political and economic walks of life. It is communicative because it provides a series of feedback loops through professional training and academic certification curricula as well as in-house programmes that connect those downstream with those upstream in the R&D continuum. Translational medicine is synonymous with the role of translational research in addressing three ‘translational blocks’: T1 involves the transfer of the understanding of disease mechanisms from the lab to first-in-human testing; T2 adapts results from clinical studies to inform clinical practice and healthcare decision-making; and T3 uses practice-based research to facilitate the implementation of distilled knowledge from systematic reviews and guidelines into practice. Operationally, the movement has incorporated a set of technologies being utilised to smooth bumps along the development pathway. These include biomarkers and imaging technologies to better predict safety and efficacy, bioinformatics for data standardisation and centralisation, and pharmacogenomics for more individualised therapies according to stratification by disease subtype and / or patient sub-population characteristics. There are also tools to improve adoption and diffusion post-approval including comparative and / or costeffectiveness research and implementation research. Practically-speaking, TM requires a functional research infrastructure. Without this foundation, overcoming each hurdle along the development pathway is exponentially more difficult. Ideally, a solid foundation should include: a capable education system and supply of quality researchers; competent regulatory agencies to properly evaluate safety, efficacy and quality; a competitive private sector; efficient healthcare delivery systems with ability to diffuse new technologies into clinical practice; and sustainable financial resources available to both the public and private sectors.

Forces influencing the diverse character of TM in Asia Perhaps one of the stronger forces influencing the diverse character of TM in the region is the stratification in R&D capacity. With each country possessing its own strengths and weaknesses, efforts to improve efficiency, through TM or otherwise, will reflect domestic conditions. Countries at the top rung of the ladder—Japan, Korea, Australia—with more advanced relative R&D capacity, must address TM barriers with less of an emphasis on basic infrastructure development. In Australia, for example, the Cooperative Research Centre for Biomarker Translation is a publicprivate-partnership meant to integrate TM concepts and techniques into a system already strong in basic R&D and early-stage clinical development. Here, the main challenges come down to matters of research efficiency since most of the basic pieces are already in place. Current Translational Medicine trends in Asia Pacific

Translational medicine is still developing in the Asia Pacific region, but it is clear that countries see it as integral to domestic biopharmaceutical innovation. On the whole, activity appears to be largely fragmented with little communication between early translational activities (e.g. basic research and biomarker development) and those at later stages (e.g. clinical trials). In other words, present initiatives make up more of a patchwork rather than any coordinated effort, even where it would seem to be otherwise. For example, the Ministry of Education, Science, Culture, and Sports in Japan oversees five university-centred translational research centres, each with its own research activities in a variety of different areas. Despite this, attempts to better coordinate activity among centres have been slow and linkage with the country’s biopharmaceutical industry is scarce. Some coordinated efforts are emerging; however, they remain small in number. One of these is a joint initiative between the Agency for Science, Technology, and Research of Singapore (A*STAR) and the Health Research Council of New Zealand (HRC). The more than US$ 2.4 million fund, which will be equally financed by both agencies, will provide grants for research in metabolic diseases and cancer. In addition, projects are also required to be collaboration between at least one researcher from

each country. With both A*STAR and HRC identifying genomics and translational research as high priority research areas, it can be expected that proposals will include the application of pharmacogenomic approaches to TM. Still, other members of the region must shore up more basic deficiencies in R&D infrastructure. One common approach among virtually all Asia Pacific has been national strategies to stimulate domestic biotechnology. These are typically large, systematic programmes that include provisions to increase R&D capacity, industrial development, education, regulatory environments and publicprivate synergy. Most importantly, they tend to be individually tailored to address each country’s own unique challenges. To illustrate, two criticisms have been put forth as hindrances to further growth in the biotech sector in India. One is that Indian universities do a poor job of providing life science graduates with the skills required by biotech companies. As a result, only 2 per cent of graduates are able to find employment. The other is an absence of linkage between the public and private sectors. In its 2007 National Biotechnology Strategy, India responded to these problems by mandating that 30 per cent of all programmes from the Department of Biotechnology have a private partner. Provisions were also included to mandate improvements in university programmes and create new funding mechanisms for graduate and post-graduate research programmes.

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Despite the challenges of these more basic needs, the adoption of TM tools is already becoming a significant feature of the emerging R&D landscape in the region, and initiatives are being implemented that will develop domestic capacity and improve innovation efficiency at the same time. In fact, examples abound. While India continues to address the challenges discussed above, the country has also leveraged its strengths in IT to make large advancements in bioinformatics. In Taiwan, the Critical Path Initiative is being used to develop the domestic biopharmaceutical industry along with a complementary regulatory capacity. By using certain ‘index cases’ as lessons learned, the goal is to incorporate new tools such as biomarkers and adaptive clinical trials into the development process and use the experience to modernize regulatory review. In these cases, the fruits of TM efforts will be realised once basic infrastructure needs are adequately addressed. What needs to happen next to move TM forward?

Although the TM movement in Asia Pacific is still in its infancy, there is little doubt that it will be an important driver of the growth of the region’s biopharmaceutical R&D capacity. Given this, challenges remain and there are some key strategies that could potentially help countries to take better advantage of what TM has to offer. First, better coordination of efforts is needed. One possible approach is through leadership emanating from the public sector. Initiatives in the US such as the Critical Path Initiative or NIH Roadmap have helped to provide a common vision around agreed objectives and priorities among different stakeholders. For example, the CPI’s focus on certain precompetitive aspects of TM such as safety biomarkers has been able to bring otherwise divergent groups together. Publicly funded bioscience parks can offer an attractive and practical ‘bricks and mortar’ approach for domestic coor-

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While India continues to address the challenges, the country has also leveraged its strengths in IT to make large advancements in bioinformatics.

dination. In Singapore, for example, the Biopolis complex houses a mix of public and private entities across a range of research areas. Collaboration through regional organisations, such as the Association of Southeast Asian Nations, can be an effective vehicle for rallying around common objectives and for more efficient utilisation of individual country strengths. Regulatory harmonisation and cooperative research in region-specific therapeutic areas have been suggested as potential opportunities for regional collaboration. Second, the region should also expand the scope of TM implementation. As discussed, the goal of TM goes beyond just getting new discoveries into pre-clinical and clinical development. It even goes beyond improving R&D and industrial development. Its ultimate purpose must be to make better medicines while making the best use of healthcare resources, i.e., maximising both innovation and efficiency. This will mean taking post-approval issues into account beyond the establishment of cost-effectiveness criteria for reimbursement , which is being implemented in the region to varying degrees, and focusing on needs relevant to domestic healthcare delivery and financing as well as patient outcomes. One way to do this may be to more closely align domestic health conditions with research and funding priorities. Such a strategy would encourage more integration and communication among domestic stakeholders at all levels of medicine development and utilisation,

establishing a feedback loop critical to advancing TM goals. Third, Asia Pacific must find ways of incorporating TM into broader development efforts. In the US and EU, TM is being billed as part of the solution to remodel an inefficient and ineffective research enterprise that is over a halfcentury old. It for this reason that the CPI, IMI, and NIH Roadmap talk of modernising and ‘re-engineering’ the research enterprise. For the majority of Asia Pacific, however, progress in building a stable, but growing, research economy are still variable, and a certain degree of infrastructure must precede TM. This could provide an opportunity to make TM a structural component of the research foundation itself. Governments could start this process by including TM as a national priority for broader scientific and economic development efforts. As a possible strategy, countries may find inspiration in Taiwan’s CPI or Singapore’s Biomedical Science Initiative in which the stated goal of phase two of the programme is “strengthening capabilities in translational and clinical research”, following an initial phase of infrastructure development. Finally, countries should take advantage of globalisation trends such as the increasing outsourcing of basic and clinical research by biopharmaceutical MNCs to the Asia-Pacific region. As companies improve their own experiences with the tools of modern TM, outsourcing will bring with it a high potential of spillover effects through knowledge sharing and technology transfer. Policies designed to facilitate these effects through collaboration and cooperation with foreign partners could hasten the accrual of these benefits. There is great promise for TM in the Asia Pacific region as it will contribute to both healthcare innovation and continued economic success. The key will be to incorporate TM in a way that is consistent with the unique needs and indigenous capacity of the countries that comprise Asia Pacific.

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Manufacturing

Sustainability Practical applications to biopharmaceutical plant design

Across all sectors of business and industry, companies are receiving direction from their boards of directors, shareholders and customers that their operations should become more sustainable. It is seen as a socially responsible approach to business in a time where more and more people are becoming concerned for the long term outlook for the environment.Pharmaceutical and biopharmaceutical companies are responding to these requirements when undertaking new build projects or retrofitting existing buildings used in manufacturing, research, quality and administration. Andy Rayner, Group Director of Technology, PM Group, Singapore

he first step in successfully implementing sustainable design into a project is to decide on the criteria upon which the sustainable design concepts will be selected. If identified upfront in the design, some sustainable design concepts will not require more capital investment, or time to implement. Some add initial capital cost, but provide payback in terms of savings in operating cost over a number of years. Others donâ&#x20AC;&#x2122;t provide

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payback in their own right but could, when assisted by capital grants from local government agencies, become attractive. Some sustainable design solutions have no payback at all, but appear to be the socially responsible solution. Each company will have its own view on these criteria. Successful implementation occurs within a project where the specific criteria are well known to the design team from an early stage in the design.

Secondly, companies should decide early on if they wish their buildings to ultimately have some external recognition for the sustainable design features that are implemented. There are a number of accreditation schemes, that offer guidelines for sustainable design, and accredit points for solutions implemented, leading to a recognised award on completion of the building. Internationally recognised schemes include LEED (Leadership in Energy and Environmental Design)

Centocor’s BioCork facility in Ireland; Sustainability Category Winner in the ISPE/ Interphex Facility of the Year Awards 2009.

and BREEAM (Building Research Establishment Environmental Assessment Method), whilst country specific schemes include Green Mark (Singapore), GRIHA (India), Green Building Rating System (Ministry of Construction in China), CASBEE (Japan) and Green Star (Australia). Each of these accreditation schemes provides awards based upon the degree to which sustainable design principles have been implemented. So, for example, the LEED scheme accredits buildings as being Certified, Silver, Gold or Platinum—whilst the BREEAM scheme accredits buildings as being Pass, Good, Very Good, Excellent or Outstanding. These schemes can be applied equally to new buildings or to retrofits and upgrades. The schemes have variants within them to suit the type of project being implemented. Even if you decide that you don’t ultimately want to accredit the building using one of these schemes, they provide a framework and checklist in the design process to allow a development to be internally assessed for its sustainable performance as the project progresses. In addition, deciding on a possible sustainable design accreditation scheme, consideration should be given to setting a

carbon footprint standard for the project. International Standard ISO-140641 provides a methodology for setting guidance on carbon footprint at organisational level, whilst the Greenhouse Gas Protocol Initiative provides guidance on carbon footprint measurement at both corporate and project level. Some projects will set objectives that buildings must be zero carbon developments (with zero net carbon emissions from a site), low carbon, or carbon neutral. Once design development criteria are established, the design can progress. The first step in design of a new facility is often selection of a site location. A sites potential for sustainable performance should be one of the criteria used in site selection. Important factors include whether the site is a Greenfield or a Brownfield redevelopment, whether public transport is available to access the site, the developments potential impact on the local resources and community, and what development density is permitted. New buildings bring new power usage requirements, and usually, when sustainable design is mentioned in a project, the first thought of most people is that this means the project will utilise renewable energy sources such as wind or solar power. However, large pharmaceutical

manufacturing buildings often have a power draw of greater than 1Mega Watt, and the number of wind turbines or solar panels required to supply such demand would be just too large for most projects. Additionally the cost of these items remains too high to justify a realistic payback period, unless local Government grants can be obtained for the provision of such renewable energy solutions. Typically, a more realistic solution is to choose a building with a low power draw (such as an administration building supporting a manufacturing plant) and to provide solar or wind power just for that building. Within local communities, concerns also exist relating to noise emitted from wind turbines. This could be a deterrent to their implementation as part of a major project, as public concerns could cause objections to planning applications. An alternative available in some countries is to consider purchasing green power (generated from renewable sources) from the power grid. Less known, but sometimes more realistic sources of renewable energy, include geothermal heating systems (where heat is drawn from underground geothermal systems—this only works in certain locations), biomass boilers

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Manufacturing

(where a source of biomass is available) and solar collector water heating. When it comes to energy conservation, one of the first decisions on the project can have a significant impact on the thermal performance of the building. Significant solar gain issues can be eliminated by careful consideration of the buildings orientation. This in turn can reduce cooling load within a building. Energy efficiency is the area where sustainable design principles can be most effectively applied to a pharmaceutical or biopharma facility. With little or no capital investment, key decisions in the design can have dramatic impacts on operating costs. One of the biggest energy users in any facility is Heating, Ventilation and Air Conditioning (HVAC). In particular, cleanroom designs utilise norms for air change rates established over the years to cover all instances of operations that could occur within the room, whilst still

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guaranteeing maximum particle counts. However, modern equipment designs have resulted in more closed operations, and modern automation systems have reduced the number of operators in production areas. As a result, air change rates applied on projects are often too conservative. Reducing the air change rates to agreed acceptable minimum level for a given operation can significantly reduce building heating and cooling loads, and reduce capital investment costs. Furthermore, consideration to widening humidity control bands, reducing specific fan powers, and installing primary/secondary air handling units can all contribute to reducing capital investment costs and operating costs. Energy conservation can be achieved through use of technologies such as concrete thermal slabs, and within offices chilled beams can reduce the need for cooling.

Lighting energy can be a major power user, and simple low cost solutions such as occupancy sensors, or the use of light pipes to bring natural light to areas that wouldnâ&#x20AC;&#x2122;t normally see natural light, can all reduce operating costs. The internal environmental quality of the space is also important to personnel within the facility. In particular, the provision of daylight into workspaces dramatically improves the quality of a workspace, whilst at the same time reducing the need for internal lighting, and often contributing towards increased productivity. Laboratories are another key energy user in a pharmaceutical facility. The Labs 21 organisation, a joint EPA / DOE programme to improve the environmental performance of US Laboratories, has published a Design Guide for Energy Efficient Research Laboratories. Some of the key principles

Manufacturing

Author

embodied in this guide include optimizing the air change rates, reducing the number of fume hoods, limiting the extent to which fume sashes can open, using occupied and unoccupied ventilation rates, using high performance hoods, right sizing the utilities, avoiding reheat batteries and dropping the flow rate in ducting. Clean utilities are also one of the largest energy users, particularly hot WFI systems, where both the mode of operation and the operating temperature should come under scrutiny. Also, in biopharmaceutical operations, any heat treatment of waste is a significant energy user. Water efficiency throughout the facility can be optimised through systems such as rainwater harvesting, storm water management, high efficiency purified water generation systems, and high efficiency water treatment and water recovery systems. The use of reclaimed (grey) water for non product contact water use functions within the facility should be considered. Consideration should be given in design to the choice of materials used in the construction of the facility. Whilst options within cleanrooms are limited, in remaining areas of the plant a wide choice of materials can be used, and wherever possible, consideration should be given to utilising regional materials from the locality, rather than importing materials from across the world. In particular, the use of rapidly renewable materials should be considered. Attention should be paid to the recycling philosophy for the facility. Recycling means segregation at source and the ability to segregate inevitably leads to provision of extra space to

facilitate segregation, so early consideration of the recycling strategy ensures that physical segregation areas are of sufficient size. In conclusion, many aspects of sustainable design are simpler to implement than may initially be considered, and the combination of many small sustainable design techniques into a large project can pay significant dividends in both operating costs and the quality of the working environment. These techniques are now starting to find their way into everyday good engineering practice, but to achieve the optimum results the approach to sustainable design should be carefully planned from the start of the project, and systems put in place to ensure the techniques are co-ordinated across the many disciplines involved. When properly implemented, this approach can bring exciting results, and even the occasional accolade. In our own experience, one of our clients, Centocor was recently named Sustainability Category Winner in the ISPE ‘Facility of the Year’ Awards for a new cell culture facility in Cork, Ireland. More importantly, Centocor were able to achieve 40 per cent greater energy efficiency and a 97 per cent smaller carbon footprint than in their equivalent existing facilities around the world. The challenge of improving the sustainability of designs to meet the expectations of the global community is increasing every day. As designers, there is an onus on us to raise our game in what we do. This article has hopefully given you food for thought for your own projects, and will hopefully guide you towards implementing a better facility design.

Andy Rayner is Group Director of Technology for PM Group, a role which includes responsibility for sustainable design practices on projects. Andy, a chemical engineer, has 25 years experience designing large biopharmaceutical projects, including many large scale cell culture & fill finish projects for many major biopharmaceutical companies.

BOOK Shelf

Sustainable Facilities: Green design, construction, and operations Author: Keith Moskow Year of Publication: 2008 Pages: 208 Published by: McGraw-Hill Professional Description: Sustainable Facilities offers building professionals everywhere a compelling, in-depth look at 20 facilities that were designed for environmental organizations and were constructed and now operate using green building methods and materials. Written by award-winning architect Keith Moskow, together with a team of leading architects in green building, the book focuses on the unique challenges of each building—from planning through operations—covering new construction, energy-efficient design, operational cost savings, historic preservation, renovation and expansion, land conservation, and LEED ratings. Sustainable Facilities also explores the advantages and an obstacle building team’s face on green projects, and explains how to weigh up-front costs against operating costs for facilities. For more books, visit Knowledge Bank section of www.pharmafocusasia.com

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Clinical Trials

Collaborative Clinical Trials

A solution for comprehensive cancer care Harnessing the collective power of various public, private and volunteer organisations from across Pennsylvania, PAC3 began the PAC3 Pennsylvania Cancer Clinical Trials Network, or CTN, in 2006 to address the need to increase patient accruals to clinical trials. Mark Byrne, Operations Coordinator, Pennsylvania Cancer Control Consortium (PAC3), USA Kathryn D Stadler, Executive Director, Pennsylvania Cancer Control Consortium (PAC3), USA

he Pennsylvania Cancer Control Consortium (PAC3) is a 501(c)(3) non-profit organisation that was built on the foundation of collaboration. It is one of approximately 69 US state, tribal, and territorial comprehensive cancer control coalitions tasked with identifying key cancer needs in their regions and developing a plan to address those needs. Founding members of PAC3 joined together in 2001 to develop Pennsylvaniaâ&#x20AC;&#x2122;s first comprehensive cancer control plan. After the completion of that plan in 2003, the group realised the value and potential of what they had begun. Development of the Pennsylvania Comprehensive Cancer

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Control Plan led to the formation of PAC3 as a consortium of organisations, with the vision of joining knowledge, expertise and resources from all sectors to have a significant impact on cancer care. Harnessing the collective power of various public, private and volunteer organisations from across Pennsylvania, PAC3 began the PAC3 Pennsylvania Cancer Clinical Trials Network, or CTN, in 2006 to address the need to increase patient accruals to clinical trials. The organisationâ&#x20AC;&#x2122;s goal with the CTN was to facilitate increased awareness of and access to the many research studies across the state and move those studies forward

through a collaborative clinical trials process. It was believed that this approach to clinical research could dramatically impact the time and money required to move through the stages of clinical research and increase overall accrual rates to innovative, investigator-initiated, phase II and III clinical trials. The CTN was funded by a grant from C-Change, a national organisation cochaired by former President George H W Bush and former First Lady Barbara Bush, which seeks to leverage the leadership and expertise of all sectors of society to eliminate cancer as a major public health problem. Similar to C-Change, the CTN was formed from a diverse

Clinical Trials

pool of academic and community cancer centres from across Pennsylvania, led by an experienced and renowned group of cancer care professionals. The PAC3 Coordinating Office served as the central administrative hub for activities, coordinating communications, advertising the web-based CTN, seeking new partnerships between institutions, and promoting collaboration among the professionals involved in the network and those conducting the research. Clinical trials posted on the CTN website were from CTN-participating institutions and were open to accrual throughout Pennsylvania at any CTN site, enabling patients to join trials that may have otherwise been virtually unavailable to them due to barriers of geography, cost or access to the trials. With the assistance of a state-wide network, the CTN’s intent was to help researchers accrue patients to trials faster, expediting the transfer of new therapeutic approaches to the bedside as standard care. In short, if research is done collaboratively, it can theoretically be expedited; while if it is not, the collective progress of all involved is slowed. Challenges to collaboration

Overall, the CTN yielded a comprehensive website that provided the opportunity for increased access to information on clinical research in Pennsylvania and nationwide. Additionally, the website created a centralised repository of website links to institutions conducting research studies and cancer clinical trials available through the CTN and elsewhere. Unfortunately, one of the main objectives of the CTN—to foster collaborative participation in clinical trials among participating institutions—was not realised since there was no increase in accrual rates to those clinical trials posted through the CTN. The project, however, yielded important information relative to the challenges and barriers to be overcome in sharing clinical trials. The challenges became evident once the CTN website was

developed and opened to participation. First, investigators at the CTN institutions were very limited in the amount of time and funding they could contribute to this voluntary collaborative network. Assuming joint responsibility for additional research studies appeared to be more difficult than anticipated, and with the constant need for researchers to apply for funding to continue their work, the collaborative CTN was secondary to individual research studies or institutional priorities. According to sources at institutions that decided not to participate, funding from the grant to support CTN participation was ‘less than optimal.’ This is particularly noteworthy since the trends in research point to a greater amount of time being spent on trying to secure funds to continue research, subsequently resulting in less time devoted to conducting the research. Time and funding constraints of researchers proved to be tremendous impediments to improving patient accrual rates through the CTN. Institutional Review Boards, or IRBs, also played a key role in the lack of patient accruals to CTN protocols. The extensive review process required for clinical trials at each individual institution, despite the trial’s initial approval by the host institution, constructed a significant barrier to opening a trial at multiple institutions. It impeded the speed with which a trial could be approved, posted, and thus opened to patient accrual across the CTN. This time-consuming review process, albeit one that must be legally implemented for patient protection, proved to be so cumbersome that researchers chose not to post or open CTN trials. Related to this, there were also contractual questions that arose from trial sponsors regarding which institutions and researchers were actually performing the research, as well as how the results of the research were to be reported back to the trial’s originating institution. Finally, perceptual issues played a significant role in the challenges faced by the CTN. PAC3, as an organisation,

was not widely recognised in Pennsylvania when the CTN began. This raised some question of the organisation’s capacity and credibility in leading this effort. Additionally, there was perceived competition between the CTN trials and those at a researcher’s institution of employment. Inter-institutional competition in a collaborative cross-institutional network can quell the spirit of collaboration and negatively impact the outcomes for either institution or the larger network. Overcoming the barriers for future collaborative efforts

Communication among collaborative partners is critical in transitioning collaborative clinical research from a somewhat abstract principle to a proven practice. Despite the fact the CTN did not realise its goal of increasing accruals, PAC3 coordinated the information from participating institutions and made it accessible in one central location. Centralised monitoring of research puts a structure in place that can be useful for researchers and institutions to share information and develop collaborative approaches. Centralised information and coordination of efforts can enable a planned and proactive approach to collaborative research that can increase the likelihood of success from these efforts. In addition to the coordination of efforts among research institutions, a coordinating centre can work jointly with pharmaceutical companies and researchers—at trial inception—to ensure that protocols include provisions that allow for and promote cross-institutional collaboration. The coordinating centre can also assist in alerting physicians about information on clinical trials and how to assist their patients in joining those trials. A central administrative entity has the potential to take on the role of a central IRB, providing an overall review of trials, with local IRBs conducting a streamlined review. This could all but eliminate limitations on accruals due to the extensive review processes and contractual

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Clinical Trials

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Conclusion

Clinical research requires the willingness from those involved to consider alterations to their hypotheses based on the scientific findings of the research. It can be difficult to change the direction of oneâ&#x20AC;&#x2122;s research when a strong hypothesis is not supported by the data. Should he or she choose not to change course, not only will the hypotheses fail to be supported, research as a principle will fail. Methods must change and hypotheses must be modified. Unless this is done, the research will not move forward and progress will be obstructed. According to the World Health Organization, cancer is the leading cause of death, globally, and will increase by 45 per cent over the next 20 years. In the United States, there are 5,598 cancer clinical trials currently open, yet no more than 5 per cent of eligible patients are participating in those trials. Low accrual rates to clinical trials impede progress since the collective scientific community cannot practically apply potentially effective interventions to treat patients across the broad spectrum of comprehensive cancer care. Patient accruals must be improved, but how is this done? The status quo simply is not working. The only answer is that the scientific community must alter its current methods of conducting clinical research

Authors

deliberations present in conventional IRBs and rapidly move the approval process forward, affording researchers more time to devote to conducting and completing critical research. Diligent planning and clearly defined expectations for developing a collaborative endeavour, such as the CTN, are crucial. By establishing a clear understanding of the existing internal and external relationships and policies, as well as the expectations of participants from the beginning, the effort can yield a commitment to devoting the necessary time and resources needed to achieve the purpose of the collaborative partnership. With a clear purpose, the value of the collaborative experience comes into focus, and with value, support and engagement from others is easier to secure. Bringing new partners into the research one finds value in and convincing financial supporters that the project offers potential value or profit can be difficult. The value of collaboration is recognised but requires time, testing, and persistence in order to yield the outcomes that can more quickly advance research and subsequently, improve the lives of many people. Collaboration takes time to build trust and reach a maturity that engenders participation and risk-taking to achieve greater rewards. The collaborative networks that are built can lead to additional cooperative studies and collaborations. By clearly establishing procedures to address proprietary issues and promote a sense of inclusivity and mutual ownership of the project, trust is built. Perceived competition can lead to a lack of trust that trickles down from organisation, to researcher, to physician, to patient. It is yet another barrier to cause patients to be even more sceptical of clinical research, as evidenced by the currently anaemic participation rates in clinical trials. Building trust among organisations, researchers, physicians, and patients can and will move clinical research forward.

and adapt a new way of thinking about clinical trials by creatively discovering new ways of performing clinical research in a collaborative manner. Such a bold step could lead to increased accessibility and awareness of available clinical trials and further, an increase in the number of lives saved as a result of treatments, heretofore unknown, becoming available to patients. It is incumbent upon us to do so if we are to move research and cutting-edge treatments forward to meet our goals of eradicating cancer and other chronic diseases. The systemic lack of communication and collaboration among institutions, physicians, and patients in conducting clinical trials must be abandoned if we hope to see greater strides in moving research to care. The current system is failing, both patients and the concept of progressive research. A faster, more efficient clinical trials process by means of a collaborative, cross-institutional approach can improve clinical trial accrual rates and thrust scientific progress forward. Collaboration, in clinical settings and beyond, is an opportunity for scientific progression. As a culture, we must be bold enough to display the scientific bravery to work together and achieve more for patients and for science. Full references are available at www.pharmafocusasia.com/magazine/

Mark Byrne, in addition to his responsibilities as Operations Coordinator for the Pennsylvania Cancer Control Consortium, coordinates the Pennsylvania Cancer Resource Database, an online database of cancer-related programs and services, and was the Project Coordinator for the PAC3 Pennsylvania Cancer Clinical Trials Network. Additionally, Byrne is the author of the recently released On Human Survival By Means of Reason and Common Sense (iUniverse, 2008) which is available through iUniverse.com or Amazon.com. Kathryn Stadler is currently the Executive Director of the Pennsylvania Cancer Control Consortium (PAC3), where she directs the operations and activities of this statewide volunteer organization. She earned a degree in Business Administration, with a minor in Political Science, from Geneva College in Beaver Falls, Pennsylvania. Before commencing her employment with PAC3, Ms. Stadler served as the general manager of operations and administration for a commercial printing corporation. She is a native Pennsylvanian and resides with her husband and two children in Pittsburgh

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Clinical Trials

The Movement Towards Information Transparency A gateway to opportunity in clinical trials Information transparency in clinical trials is delivering improved efficiencies to the clinical development process and promises to flatten the world as well as create new opportunities for greater participation from around the globe. Alan S Louie, Research Director, IDC Health Insights, USA

he move towards information transparency in clinical trials is intended to create a powerful information management foundation that should streamline the clinical development of new treatments and cures for diseases. This foundation is becoming increasingly more comprehensive, geography independent, web-accessible and regulatory compliant in its design. From automated data entry through to regulatory submissions reporting, the approach promises to empower drug development on a worldwide basis. This foundation opens up new commercial opportunities around the world as the greater global brain trust becomes more empowered and introduce new ideas and solutions to address new and current unmet health care needs. Information transparency enables a flatter world, levels the playing field for those who couldnâ&#x20AC;&#x2122;t previously compete, and jumpstarts new opportunities for companies with previously inaccessible capabilities. For Asia in particular, this opportunity should not go unnoticed.

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The clinical trials information ecosystem

Clinical trials are the key element in the transformation of a medically interesting compound into an approved drug, able to then provide a new option to treat (or hopefully cure) disease. The clinical trial process is highly rigorous, as expected, and is growing increasingly complex as the amount of data needed continues to grow at a geometric pace. In addition, the management of clinical trials is also becoming more difficult as trials grow larger (in both size and geography) and increasingly more complex. With regards to information management, the eClinical software vendor community is rising to the challenge to enable better interoperability and increased transparency in the collection, management, and analysis of clinical data, leaving trial sponsors to focus primarily on the scientific details needed to advance compounds into new approved drugs. As shown in Figure 1, the IDC view of the eClinical information ecosystem is comprised of a number of component

Clinical Trials

elements that, taken together, comprehensively support clinical trial information management. In the beginning, these components replaced their paper-based counterparts and worked independently to support their respective parts of the clinical trials process. For example, Electronic Data Capture (EDC) and clinical data management systems (CDMS) served to facilitate the collection and management of clinical data respectively. As these and other eClinical solutions have advanced, there has been the clear recognition and aspiration that these functions should work together and that synergistically, considerable process efficiencies could be extracted as a result of the interoperability. In parallel, general advances in technical innovation (e.g. the Internet, wireless communication, computing platforms etc.) have also been harnessed by clinical trial processes to further improve development efforts. We are now at the cusp of full information transparency in clinical trials, an advance that should be highly beneficial to accelerating the development and commercialization of medical innovations for the benefit of mankind. The growing clinical trial dilemma Clinical trials continue to grow larger and more complex in response to increased needs to more thoroughly validate both drug safety and efficacy during clinical development. The amount and types of patient data collected as well as the logistics necessary to effectively manage overall trial efforts is also growing at a rapid pace, making it increasingly difficult to manage from a trial sponsor perspective. In addition, as the need to identify and enrol greater numbers of ideally treatment naĂŻve patients has grown, trials have become increasingly distributed geographically. It is not uncommon for a large scale, late stage, cardiovascular clinical trial to be conducted at multiple sites, in several countries, on multiple continents simultaneously in order to obtain sufficient numbers of patients to collect the data needed to effectively demonstrate drug performance. In the

absence of effective clinical information management, the logistics alone for a trial of this kind become impossibly unwieldy and unmanageable. Both clinical researchers and eClinical software vendors recognized these trends early in the process and identified potential paths forward, leading to the diversity of process solutions available today. In addition, the varied needs of the clinical development ecosystem has produced a number of niche eClinical point solutions that can also be expected to be gradually incorporated into comprehensive eClinical suites. A key advantage offered by comprehensive eClinical suites is the ability of individual eClinical components to transparently share data, reducing the potential for data errors and enabling earlier analysis of available data. These abilities produce tangible improvements to the overall process, including significant time and resource savings, greatly improved process efficiencies, more effective patient safety controls, and reduced PI dissatisfaction.

Organisations including CDISC (Clinical Data Interchange Standards Consortium) and HL7 (Health Level 7) are driving efforts to establish standards to enable data interoperability across the clinical development spectrum. Through the participation of most of the major industry stakeholders, these community-based organisations are working together to ensure that data collected from different trials, different sites, and from different patients can be brought together in common data repositories and compared to extract scientifically sound insights. While generally of mutual benefit to all stakeholders, progress in advancing common standards in the clinical development space has been slowed somewhat by the presence of proprietary legacy solutions that previously empowered specific organizations (both life science companies and vendors) with some commercial market advantages. While slowly diminishing over time, the move towards standards-based clinical trial information management is continuing and is directly supporting both collaboration and competition in the commercial marketplace. The second approach to the development of a comprehensive eClinical information management solution comes from the commercial vendor side of the equation. Several major commercial IT vendors have recognized the opportunity to provide a complete eClinical product solution for their clientele.

The path to transparency

Information transparency is actually more of an outcome than an end-goal in the clinical trials process. The path to information transparency has been driven from two primary directions, namely the development of industrywide data standards and the development of comprehensive commercial eClinical product solutions.

The IDC Health Insights view of the eClinical Ecosystem Trial Sponsor

Trial Admin. Mgmt TM

IXR

CTMS

PI Clinical Trial Design EDC

CRAs

CDR

CDMS

FDA Submission

CRO Patien ts

ePRO

Drug Safety

CRO Mgmt

Source: IDC Health Insights, 2009

Figure 1

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Clinical Trials

Market convergence In an increasingly mature commercial eClinical IT ecosystem, it makes no sense anymore for eClinical vendors build companion applications de novo to add to their existing eClinical solution offerings. As vendors assess the weaknesses in their current eClinical product portfolios, they have regularly looked at competitive offerings as opportunities to rapidly fill gaps and move forward. Mergers and acquisitions (with a particular focus on acquisitions) has been a primary approach to growing both capabilities and market share across the eClinical ecosystem. While questions regularly arise regarding the ability to integrate external product solutions into existing vendor product suites, these concerns have not prevented acquisitions from occurring, possibly in part due to the concurrent move towards standards-based interoperability. Several examples of recent acquisitions are highlighted below: • (2008) PAREXEL’s purchase of ClinPhone • (2008) Clinsys Clinical Research’s purchase of TrialStat Clinical Analytics • (2008) BioImaging’s acquisition of Phoenix Data Systems (rebranded jointly as BioClinica) • (2009) Merge Healthcare’s planned acquisition of eTrials • (2009) Oracle’s acquisition of Relsys International • (2009) OmniComm’s acquisition of eResearch Technologies EDC business • (2009) Phase Forward acquisition of Maaguzi • (2009) OmniComm’s acquisition of Logos Technologies EDC business • (2009) Phase Forward acquisition of Covance’s IVRS business

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ISSUE - 12 2009

logistical issues associated with multi-site clinical trials, enabling diverse geographies to regularly participate in large trials. Recognizing this opportunity, most, if not all, eClinical software solutions are designed to accommodate language and other country-specific requirements. Webbased solutions have effectively eliminated the need to maintain different versions of trial software at different trial sites, greatly simplifying infrastructure management requirements. Next steps

Even in the absence of information transparency innovations, life science efforts have been expanding globally for a number of years now. Initial efforts

Author

Designed with interconnectivity in mind, a comprehensive single vendor eClinical solution fulfills the same interoperability that standards-based solutions aspire to deliver, while reducing the trial sponsors burden of managing multiple vendors from the equation. In some cases, it becomes possible to upsell companion eClinical solutions to trial sponsors, based on an individual, foundational best-ofbreed eClinical solution that a vendor has developed and is already in place at the sponsor. Despite the competitive advantage afforded by proprietary eClinical platforms, companies have also recognized the inevitable industry trend towards standards-based interoperability and are moving in this direction concurrently. eClinical information transparency could not be attained if not for broad advances in information connectivity on a global basis. Ubiquitous real-time access to the Internet, combined with advances in web-based clinical trial software solutions, has largely eliminated most of the

nucleated around lower cost API manufacturing, with subsequent expansion to multi-site, globalisation of late stage clinical trials. More recently, efforts have expanded in the area of discovery research, both for supplementation of existing capabilities as well as research directed at emerging markets. The development of a ubiquitous approach to eClinical information management is opening both end-user and vendor access to clinical development processes on a more global basis. Once the primary purview of big pharma, opportunities in the broader life science industry have expanded with geography no longer a boundary. In the near term, expect small to mid-tier companies (especially biotechnology and biopharmaceutical companies), regardless of geographical location, to directly conduct their own efforts, supported by contract research organizations (CROs) and other outsourcing service vendors, both existing and emerging. From a broader perspective, information transparency in clinical development is enabling entrepreneurs worldwide to more easily participate in global efforts and reach global markets with their resources and services. This may include populations of treatment naïve patient populations that could participate in clinical trials, lower cost or market specific analytic services supporting clinical trials, or IT infrastructure supporting regional information connectivity. Emergence of new biotechnology companies also becomes possible, leveraging global access and infrastructure to build on local research discoveries. Information transparency is a key element in moving beyond process details to empower higher value pursuits, along with its more lucrative outcomes.

Alan Louie is Research Director at IDC Health Insights. He is spearheading IDC research covering innovation and best practices in pharmaceutical R&D and personalized medicine. Dr. Louie is a recognized thought leader in both the health and life sciences industries and has written and spoken extensively in these areas.

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Chris Lee

Regional Head Asia Pacific Bayer Schering Pharma Singapore

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Pharma Industry In times of the downturn Do you believe that the pharma industry has been adversely affected by the downturn? Generally speaking, the current global economic crisis, triggered by financial events in the US has had less impact on the Asia Pacific region, compared to the 1998 Asian Economic crisis. There are a few signs of economic recovery—decreasing rates of unemployment, more interest in the housing market, increased spending by small businesses and increased consumption demands. Moreover, inflation has declined sharply and the banking system is now stable and better regulated. If we look at the individual locations in the region, China is one of the fastest countries to recover from the global financial crisis. India’s recovery will be faster as it is backed by strong fundamentals and untapped growth potential. The rest of South East Asia will follow this trend.

markets, and the most attractive areas for growth are in emerging markets.

The recession has come at a time when the pharma industry was already struggling with various problems like drying pipelines, what sort of a challenge do you think this presents to the industry? In addition to the recession, global pharma growth declining for the past 5 years, particularly in the USA, top 5 Europe / Japan. Lower GDP growth and tax revenues will impact healthcare budgets / promote more aggressive cost containment. Biotechnology, a big growth area affected by lack of investment funds and new product launches are not replacing revenues lost to generic competition, especially in primary care. Traditional markets are not delivering significant levels of growth, growth now relies on smaller

Is Asian Pharma better placed in the recession than the rest of the world? Over the next 5 years, Asia Pacific region will remain 13-16 per cent growth rate which is highest among other regions according to IMS outlook 2010. IMS forecasts China will achieve US$ 67 billion due to massive expansion in wealth and healthcare spending continues to drive market growth. Till 2013, China will move up to one of top 3 biggest pharmaceutical markets globally. China and India growth continue to lead the pharmaceutical emerging markets. Bayer Schering Pharma employed a combination of continued engagement in the emerging markets, increased R & D and a product portfolio that addresses

Big Pharma is best prepared to survive the recession given its financial strength, but would they also be the most affected? The current financial crisis started with the collapse of several of the world’s largest financial institutions, and has since turned into a global economic crisis. The financial sector could be the most affected. And it began in North America, UK and other European countries; Asia Pacific would see less impact than Western regions. All sectors may feel the impact, but big Pharma may not be the most affected. Not all of the smaller biotech companies will survive intact, especially struggling baby pharma companies which will wash out as the current economically induced corrective era plays out and redefines the near-term therapeutics R&D and financing market landscape.

medical needs such as cardiovascular, diabetes and other chronic illnesses. As an inventor company, has always been focussing on innovative product pipeline, Bayer Schering Pharma will continue to invest some 15-17 per cent of its sales to further expand its R&D activities despite the current financial and economic crisis. For example, our company has recently decided to invest some 100 million Euro over the next five years to establish global R& D centre in Beijing China which is the third country besides Germany and the US to host a Global R&D Center for Bayer Schering Pharma. Scientific teams will work towards systematically including Asian patients earlier in global drug development, breaking the tradition of including US and EU patients first. This is also a chance to seize the opportunity to develop Asian talents and partner with top local universities like Tsinghua University to pursue research collaborations and innovation for new disease-related targets in oncology, women’s health, diagnostic imaging, and cardiology. What challenges / opportunities do this present to Indian Pharma? India holds great potential due to their large populations, changing lifestyles, unmet medical needs and increasingly evolving healthcare systems. According to IMS date, India has been listed as one of emerging countries with great opportunity of Pharma market expansion. Possibly, India will move up to the top ten pharma market worldwide over the next decade. We do foresee the potential development in Indian Market.

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INFORMATION TECHNOLOGY

Clinical Data and the e-Clinical Landscape A need for integration The increasing needs for Data Integration have to be met by any state-of-the-art e-Clinical Landscape. Norbert Fritz, Head, Clinical Architecture & Information, Pharma Operations F. Hoffmann-La Roche Ltd, Basel, Switzerland

he development of new medicines requires extensive generation and usage of medical information. In this context, Data Integration represents the methodology by which data generated in heterogeneous data sources is aligned, moved into a common environment and finally made sharable for different ways of data usage. Therefore, the increasing needs for Data Integration have to be met by any state-of-the-art e-Clinical Landscape. Data Integration

The purpose of Data Integration is determined by different ways of data usage required to support the business processes of Pharma Development. Therefore, the following programmatic statement about Data Integration holds true for the world of Pharma. Data Integration enables easy access to: • comprehensive, up-to-date and qualified information • originating from different internal and external sources

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• created under Sponsor control • or created outside of Sponsor control • as required for the benefit risk analysis of new medicines. A multitude of different intermediate tasks have to be completed before the final stage of ‘the benefit risk analysis of new medicines’ is reached. Each of those tasks adds specific value to the overall Pharma Development process requires specific sets of integrated data and is enabled by a specific information flow. A few of these Value Chains are selected for further characterisation since they have a specific impact on the e-Clinical Landscape. The Value Chain to Analysis and Submission

The purpose of this Value Chain is to provide Clinical Data and Safety Data for analysis in order to assess benefits and risks of new medicines, to support managerial decisions about the future development and to submit data to Authorities for approval. The frequency of data processing in this Value Chain is typically low; e.g. it is typically carried out at major study milestones—such

as for interim analysis or for a final study report. The Data Integration challenge is caused by heterogeneity of data sources providing data in diverse data structures not following unified standards and semantics. Different organisations involved in a submission as for inlicensed compounds, co-development with external partners or the evolution of standards during the development period of a Clinical Project contribute to this challenge. Mitigation of this challenge typically relies on reformatting or transforming Clinical Data prior to pooling data across different trials. The Value Chain for Study Conduct

The Value Chain for Study Conduct has two main purposes: To merge and reconcile data from different data sources and to enable near-realtime reporting of merged data. Thus, Clinical Data can already be continuously monitored at a pre-analysis stage with regard to data quality and medical data content. This is typically accomplished by importing data from different sources onto one central platform and by

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INFORMATION TECHNOLOGY

post-processing the imported data prior to further usage. Integration challenges originate from the fact that imported data can be temporarily unclean, that reconciliation of data retrieved from different sources can reveal inconsistencies and that amendment may need to be initiated. Resolution of these data issues has to be accomplished by querying across multiple data sources which requires bidirectional pathways between the data sources and the central data platform. The biggest challenge, however, is related to scale and performance. This problem arises when all data from all ongoing Studies are frequently refreshed, e.g. on a daily basis, and when data is always imported and processed in a cumulative mode. A superior solution would use an incremental approach and only import and process those data which have been added, updated or deleted since the last refresh; such a solution, however, would require a supporting system with considerable sophistication. Value Chains for operational purposes

These Value Chains which integrate Clinical and administrative data have manifold purposes supporting the management of Study Conduct. Some out of many examples: Manage relationships with Investigators and investigational staff, ensure regulatory compliant Clinical Trial monitoring, enable the computation of Operational Metrics which monitor the performance of Study Conduct. The Data Integration challenge of Clinical Trial Management is based on the fact that data originates from many sources (e.g. IVRS, Clinical Data on recorded Patient visits transmitted from EDC systems) and is quite often redundantly stored in variety of systems. Since similar data is often represented in different systems in a slightly different way, the well-known problem of disparate systems arises. Similarly, the

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definition of proper algorithms for operational Metrics is complicated by the heterogeneity of data sources. Integration of Clinical Data—Common implications

One thing common to all Value Chains is that they use data from different data sources and, typically, a single data source feeds into multiple Value Chains. Thereby, some processing steps can be shared between different Value Chains, such as Lab unit conversion, Thesaurus validation of verbatim terms etc. In general, data flow and data processing follow a typical ‘Data Warehouse-like’ schema with data import via an ETL (extraction-transformation-loading) process, central staging in a repository, restructuring / transforming of data during extraction for analysis and reporting or publication via specific tools such as dashboards. These common features point to a central data hub as a preferred option to cover the needs of all Value Chains by a single approach. However, as pointed out before, there are some requirements for a central data hub which are specific for Pharma Development, but are different to a typical ‘Data Warehouse-like’ design and also different to an environment designed for clinical data analysis:

1. Storing and reporting of data which is temporarily or permanently unclean 2. Management of data quality across several levels of the information flow 3. Frequent data refreshing e.g. on a daily basis 4. Bidirectional connections between involved systems 5. Managing multiple standards of data sources 6. Support evolving standards for data models Solution Design Drivers

The Design of a suitable solution has to incorporate the implications for Data Integration as fundamental requirements. In addition, depending on the Sponsor’s environment and needs, other interrelated key factors such as the nature and number of the trials conducted and the expected volume of data to be processed in various Value Chains have to be taken into account for the design of the e-Clinical Landscape. Transactional vs. analytical environment

Data Integration implications 1—3 (daily refresh of temporarily unclean data including updates and deletions) raise the need for a transactional environment

CDMS EDC Lab

Conversion

ECG

Conversion

Medical Data Review

Diaries Upstream date flow Downstream queries / discrepancies Across-source cleaning / reconcilication Figure 1. Typical Study Conduct scenario. Different data sources – EDC (electronic data capture), CRF (data capture on paper), Laboratory data, ECG and Diary data (all electronically loaded data) – feed into a central platform e.g. into a CDMS (Clinical Data Management System). Queries are generated during medical review and within the CDMS and are sent back to the appropriate data sources. Figure 1

INFORMATION TECHNOLOGY

with the capability of incremental data processing. Transactional environments are typically required when the total volume of data is slowly increasing while, in comparison, the daily data additions or changes remain small. According to our experience, less than 0.2 per cent of the total data volume in all ongoing studies is added or changed per day; this condition precisely matches the definition of ‘slowly changing dimensions type 2;’ Kimball & Ross 2002). In contrast to this, typical analytical environments work with intermediate or final snapshots of Clinical Data as of a given time point in the history of the Study Database. If an analytical environment is intended to be used for processing all data (in a non-incremental fashion), short-comings in performance have to be expected. Depending on the volume of data to be processed, different ways of mitigation might be

indicated when analytical environments are used for transactional processing: Give up the requirement of frequent data refreshes or furnish the environment with adequate—perhaps gigantic—horse power. Nature of trials

The nature and number of expected trials determines the necessary scale and performance of a suitable solution. Since the conditions are specific for each Sponsor, an extrapolation can be gained from historical data such as: Metrics on the number and Phase of Trials conducted, the number of data points collected per Trial and the average number of data points in all active Trials. Additional parameters indicating utilisation of computational resources can help to clarify the specific Sponsor needs. It is important to take into consideration that different types of Trials generate different amounts of data and put different loads

on the systems processing Clinical Data. Thus, Phase III and IV Trials generate by far most data and utilise by far most computational resources than Trials of the early development phases. CDMS as repository for Data Integration?

A view on Clinical Data Management Systems (CDMS) as hubs for Data Integration reveals that mature systems are established on the market, which have the necessary transactional capability to collect and reconcile data from different sources near-real-time. However, this approach—shown in Figure 1—implies that all data is collected in data structures which are supported / limited by the options for data representation of the specific CDMS in use. As a consequence, the data reconciliation programmes have also to cope with system-specific constraints and the conversion to system-independent data standards can

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INFORMATION TECHNOLOGY

only happen during or after extraction from the CDMS. Furthermore, Data Integration of the Study Database with other data sources is impeded if the Study database is located outside of the Sponsor environment such as in cases of outsourcing, co-developments or in-licensing. Before Drawing the Map – Considerations for the Solution Design

Increasing scope and complexity of Data Integration raises the need for a supporting architecture of the system landscape. Whereas Data Integration for analytical purposes is an established concept and is supported by offthe-shelf products, Data Integration in the context of Study Conduct is less well-recognised as a business need. Thus, many Sponsors attempt to use either their CDMS or their analytical environment or a combination of both as central facility for Data Integration—also within the Study Conduct context—and accept the inherent limitations. The decision to opt for a transactional environment for Data Integration has to face two challenges: 1) The Business needs and benefits of such an environment have to be clearly demonstrated to obtain management support. 2) It is difficult to find off-the-shelf solutions for Data Integration environments supporting Study Conduct and in all likelihood available systems might need strong customisation or even a co-development together with the Vendor.

Conclusion

It was the intent of this paper to clarify some dependencies between mechanisms and needs for Data Integration and the design of an e-Clinical Landscape. Moreover, it was rather attempted to highlight the need for a solution than to suggest a specific one. In conclusion, the concept of Data Integration has to be widened in order to cover Clinical Data which is in constant flow and to guarantee the final quality of Clinical Data which is temporarily not validated. Furthermore, the challenges for Data Integration get even more predominant due to the increasing quantity and variety of Clinical Data generated and new ways of using Clinical Data. This will finally influence the way how processes and systems will develop and how Pharma Development organisations will shape their e-Clinical environments in future. Acknowledgements

This paper includes concepts which have discussed with many colleagues at F. Hoffmann-La Roche Ltd in the context of various initiatives. Nevertheless, the content of this paper represents solely the opinion of the author. Part of the material and thoughts published here have also been presented at the ‘Oracle Life Sciences: European Pharmaceutical & Biotechnology Industry Forum Apr 2007, Mainz’ and at the ‘e-Clinical Trials conference, ViB, May 2009, London.’

Author

Reference: Ralph Kimball, Mary Ross: The Data Warehouse Toolkit. The Complete Guide to Dimensional Modeling. 2. Ed. John Wiley & Sons, New York u. A. 2002, ISBN 0471-20024-7. Norbert Fritz is Head Clinical Architecture & Information in Roche Pharma Development Operations where he has previously held positions such as Global Head Clinical Programming and Site Head Data Management. Prior to Pharma Development, he was working in the field of Neuroscience at the University of Munich and at Roche.

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