Pharma Focus Asia - Issue 25

Issue 25 2016

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Pushing the Limits of Temperature Control Transforming packaging perceptions Nils Markmann

Vice President Global Operations, World Courier, Germany

Electronic FDA Submissions Is APAC prepared for the 2017 mandate?

Drug Development A question-based process

Foreword Electronic Document Management Mandate from May 2017 Pharmaceutical regulators are becoming more cautious about approving innovative medicines for consumers’ safety. The US Food and Drug Administration (FDA) has established many regulations that govern the development, testing and production processes of drugs. As part of streamlining these processes and addressing the cost trends, FDASIA (FDA Safety and Innovation Act) has redirected generics and biosimilars companies to file submissions electronically from May 5, 2017 and pay user fees to the FDA. In the absence of electronic document management, quality management and submission management systems, pharmaceutical companies will find it tough to do business with FDA and also with their own governments as it was done earlier. Electronic Common Technical Document (eCTD) is an interface through which pharma companies can transfer regulatory information to agencies like the FDA. This interface is supported and enabled by enterprise Document Management Systems (eDMS).

Section 745A(a) of the Federal Food, Drug, and Cosmetic (FD&C) Act states content should be submitted in electronic format in new drug applications (NDAs), abbreviated new drug applications (ANDAs), certain biologics license applications (BLAs), and investigational new drug applications (INDs) to the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER). Submissions in other formats, barring the ones under section 561, will not be considered for filing.

These mandates will have considerable impact on pharmaceutical companies that are still using paper-based documentation and allows the transition to an industry standard eDMS and eCTD. Also impacted by this would be generic drug and biosimilar manufacturers currently not meeting the industry standards giving them an opportunity to improve their businesses by being a part of more unified global industry. With benefits like reducing automation and storage costs by having all data in a centralized electronic environment, regulators and pharma companies will enjoy streamlined workflows in development, regulatory and marketing departments with increased collaboration between teams.

Now is the time for management of pharmaceutical companies to come forward and comply with stringent FDA mandates.

In this issue, the article ‘The Electronic FDA Submissions - Is APAC Prepared for the 2017 Mandate?’ by Warren Perry, of Dassault Systèmes BIOVIA, USA, explains how generic drug companies have to align their businesses with policies and how FDA is directing companies towards making electronic submissions.

Prasanthi Potluri Editor

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COVER STORY

Contents

EXPERT TALK

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40 Pushing the Limits of Temperature Control Transforming packaging perceptions Nils Markmann Vice President Global Operations World Courier, Germany

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STRATEGY

58

06 Four Switches of Success

Brian D Smith, Principal Advisor, PragMedic, UK 12 The Future of Pharma Regulations

YogiRaj, Associate Vice President, Freyr Solutions, India 18 Rigour or Rigmarole

Brian D Smith, Principal Advisor, PragMedic, UK

RESEARCH & DEVELOPMENT 24 Drug Development

A question-based process

Rajendra Talele, Head of Clinical Development Services, Accutest Research Laboratories Pvt Ltd, India

MANUFACTURING 32 Immunogenicity of Protein Biotherapeutics and Methods for Assessment of Immunogenicity

Mallikarjun Narayan Dixit, Vice President Director and Test Facility Management Accutest Biologics Private Limited, India

46 Biologics’ Drug Delivery Systems

Peter Soelkner, Managing Director Vetter Pharma International GmbH, Germany

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INFORMATION TECHNOLOGY 52 Cost effective Data Operations

The need for an E2E data standards

ecosystem

Isabelle de Zegher, Vice President, Integrated Solutions at PAREXEL INFORMATICS, Belgium

Michael Goedde, Vice President, Global Data Operations PAREXEL, US

Benedikt Egersdörfer, Vice President, Global Data Operations PAREXEL, US

58 Electronic FDA Submissions

Is APAC prepared for the 2017 mandate?

Warren Perry, GRCP Compliance Consultant Dassault Systèmes BIOVIA, USA

62 Books

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Advisory Board

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

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

Douglas Meyer Senior Director, Aptuit Informatics Inc., USA

Frank Jaeger Regional Sales Manager, Metabolics, AbbVie, USA

Georg C Terstappen Director and Head of Biology, Neuroscience Discovery AbbVie Deutschland GmbH und Co. KG, Germany

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

Laurence Flint Head Clinical Research Cough, Cold & Respiratory Disease Novartis Consumer Health, Inc., USA

Neil J Campbell President & CEO, Helomics Corporation HealthCare Royalty Partners University of Liverpool, UK

Editorial Team Grace Jones Art Director M A Hannan Product Managers Jeff Kenney Senior Product Associate David Nelson Product Associates Ben Johnson Tina Williams Peter Thomas Circulation Team Naveen M Nash Jones Sam Smith Subscriptions In-charge Vijay Kumar Gaddam IT Team Jareena K Ranganayakulu.V Sitaram Y Uday V Head-Operations S V Nageswara Rao

Pharma Focus Asia is published by

In Association with

A member of

Phil Kaminsky Chair, Department of Industrial Engineering and Operations Research University of California, Berkeley, USA

Rustom Mody Senior Vice President and R&D Head Lupin Ltd., (Biotech Division), India

Sanjoy Ray Director, Strategic Alliances & Health Innovation Merck, US

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STRATEGY

Four Switches of Success

Very similar firms often achieve very different results.

This is explained by their genetic switches.

Brian D Smith, Principal Advisor, PragMedic, UK

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ife science firms exist to meet the needs of patients whilst simultaneously creating value for their shareholders or owners. That much is obvious. It is also apparent that firms vary greatly in their ability to do these two things; the different longevities of companies tell us that. What is much less

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clear is why firms differ so much in their ability to thrive in the market environment. Even harder to understand is why very similar firms, with benchmarked processes, produce very different results, as we observe in the recent very different performances of the big, research-based Pharma and Medtech companies. Of

course, luck pays some part in this and “culture� is often used as an overreaching, ill defined explanation. However, neither of these are very useful rationalisations.

My research into the evolution of the life sciences industry suggests a more tangible cause: the intriguing idea that firms have the equivalent of regulatory DNA.

STRATEGY

To understand these ideas, we need first to understand what research has revealed about the nature of organisational capabilities, their origins, and how they differ from each other.

A capability is nothing more than a process that enables something to happen. In that respect, processes are

analogous to the proteins that do the bulk of the work in biological systems.

And just as proteins are expressed by genes, so capabilities are expressed by ‘organisational routines’ — small, stable and reproducible patterns of activity that every company uses to store information about how to do things. Your body has a genome of thousands of genes that expresses a proteome of up to a million proteins, from testosterone to haemoglobin. Your organisation has a routineome of thousands of routines that express a capabileome of tens of thousands of capabilities, from raising an invoice to screening a drug candidate.

But the biology-industry analogy can be taken one step further. Whilst some of your genes express functional proteins that perform some kind of metabolic function, other genes express regulatory proteins whose function it is to bind to specific DNA sequences, so turning on or off other, functional genes. In the same way, my work is uncovering that an organisation’s routineome expresses three kinds of different capabilities, two of which are analogous to functional proteins and one of which is better understood as analogous to regulatory proteins. See box 1.

Both hygiene and differentiating capabilities are very visible to customers and competitors. We can see if a firm lacks them (for example, in the case of Theranos lacking hygiene capabilities for compliance) and when a firm has them (for example, Illumina’s strong differentiating capabilities in product development).

Three kinds of capabilities Hygiene capabilities are necessary to operate in a market but are similar in all companies and so contribute little to competitive advantage. The capability to produce annual accounts is an example of a hygiene capability.

Differentiating capabilities vary between business models and infer competitive advantage. The ability to design value propositions is an example of a differentiating capability.

Dynamic capabilities are those that allow a firm to create new or reshape its existing capabilities.

The ability to work cross-functionally is an example of a dynamic capability.

Because they are visible to competitors, hygiene and differentiating capabilities are the most likely to be imitated by rivals. Consequently, they are less valuable as explanations of long-term, sustained organisational effectiveness. That leaves us with dynamic capabilities, the organisation’s equivalent of regulatory proteins, which create and shape other capabilities. We know that, in biology, creatures with www.pharmafocusasia.com

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capability that switches other, differentiating capabilities on and off.

The capability to create insight is often confused with the capability to gather, process and analyse data.

In fact, whilst such organisational routines for data processing are often a necessary prerequisite to creating insight, they are rarely sufficient. On its own, data processing may lead to new knowledge but generally of the generic type that is easily available to all firms in the sector and which does not enable differentiating capabilities. The creation of true market insight almost always requires routines for inductive or deductive learning processes (or a combination of both) in addition to data processing.

Transformational leadership

almost identical functional genes can differ greatly because of small but crucial differences in regulatory genes and proteins. The finches of the Galapagos Islands that inspired Darwin are good examples of this, although Darwin knew nothing of DNA regulation, of course.

Such biological analogues hint that even small differences in a firm’s dynamic capabilities, which are analogous to its regulatory proteins, may be the explanation for substantive differences in effectiveness between firms that look superficially very similar.

The challenge for management scientists then is to identify those capabilities that act as regulatory switches, enabling and disabling other parts of the firm’s routineome and so leading to differences in organisational effectiveness. Every organisation, like every organism, probably has a large number of dynamic capabilities that act in a complex manner in different parts of the company. However, my research has uncovered four dynamic capabilities that have fundamental, systemic influence on an organisation’s effectiveness. In that sense, they are analogous to master regulatory genes and proteins, influencing a cascade of subsidiary capabilities and so directing the overall development and 8

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effectiveness of the firm. These four master dynamic capabilities are described in the following paragraphs.

Insight creation capability

This is the capability to create knowledge that has the characteristics of an organisational strength. In other words, knowledge that is valuable, rare, hard to copy and upon which the organisation can act.

Although insight creation is often conflated with customer insight, it can equally be knowledge relating to any part of the value chain. Insight creation enables other capabilities by reshaping and improving knowledge assets, which is necessary for differentiating capabilities such as proposition development. For example, insight into how payers vary according to their risk attitudes enables a firm’s differentiating capability to understand market heterogeneity and to develop and target extended value propositions. Similarly, insight into causes of cost variation in the supply chain enables firms to develop an industry-leading cost base, whilst insight into disease mechanisms can inform drug discovery. In all cases, the ability to create some new piece of valuable, rare, inimitable and organisationally useful knowledge is a dynamic

This is the capability to envision a desired future situation, the broad path towards that situation, and to communicate that vision effectively throughout the organisation. (Note that although this term is often used loosely, my use of it is influenced by Bass’s important work on the topic.)

Transformational leadership enables other capabilities by allowing firms to prioritise the differentiating capabilities they need to develop, thereby allowing resources to be allocated accordingly.

For example, a clear vision of the future development of a given technology can enable the differentiating capability of selecting from alternative new product possibilities on the basis of commercial viability. Similarly, the clear communication of a vision of operational excellence can enable the disciplined maintenance of a low cost base supply chain.

Transformational leadership is often confused with either detailed management or charismatic leadership. In fact, attention to detail and charisma may contribute to transformational leadership, but they do not appear to be sufficient on their own.

Rather, clarity of vision and consistency in using that vision to guide action seems to be central to the way in which

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transformational leadership enables differentiating capabilities.

Cross-functional working

Critical and metadisciplined thinking

This is the capability to process complex information effectively. It combines two elements: the ability to combine knowledge from multiple disciplines and the ability to use that information in a rational, considered manner.

Critical, metadisciplined thinking enables other capabilities by enabling better choices between options and overriding irrational, habitual decision 10

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A capability is nothing more than a process that enables something to happen.

making behaviour. For example, critical, metadisciplined thinking may avoid the allocation of resources between countries on traditional, population-based lines and instead lead to resource allocation based on the existence of targeted, global segments. This dynamic capability may also significantly change the assessment and comparison of market opportunities, so altering choices about which market to attack and thus shaping resource allocations.

Critical, metadisciplined thinking is often confused with evidence-based decision making. Whilst the use of data to support decisions is often a component of critical thinking, life science firms often mistakenly assume that the only good kind of data is quantitative and so restrict their evidence base. Critical, metadisciplined thinking is characterised by using multiple types of data and combining methods from both natural and social sciences.

To summarise then, superficially similar life science companies often

A u t h o r BIO

This is the capability to perform tasks across functional boundaries. My use of the term here is based on another of my research streams and covers two aspects of cross-functional working: alignment of individual behaviours and managing intra-organisational conflict.

Cross-functional working enables other capabilities by minimising negative behaviours, such as politicking, and maximising positive behaviours, such as information sharing. For example, pooling of information about patent loss, customer needs and technological possibilities enables the differentiating capability to identify opportunities for profitable imitation. Similarly, positive interaction between headquarters and operating affiliates enables, in global companies, the effective localisation of global competitive strategies.

The capability to work crossfunctionally is often confused with collaborative teamwork and structural devices such as brand teams and other matrix structure working groups. In fact, whilst such commonplace management techniques often contribute to cross-functional working, they may also hinder it by blurring task ownership and encouraging compromise instead of consensus. Effective cross-functional working involves the alignment of goals and removal of sources of conflict, such as shared resources and asymmetries of status.

differ greatly in their performance and effectiveness, even when many of their major processes are very similar.

This is an important and puzzling paradox. Although luck and culture may partly explain this phenomenon, if we are to learn from the most effective companies, we need a better understanding of what makes them different. Clearly, the answer lies in superior capabilities, expressed by distinctive organisational routines. However, neither hygiene capabilities nor differentiating capabilities seem to provide a sustainable explanation of firm effectiveness.

Instead, dynamic capabilities seem to be the answer. Just as significant differences between genetically similar organisms can be explained by small differences in regulatory proteins, significant differences between superficially similar life science companies can be understood in terms of small differences in their dynamic capabilities, which enable and disable the other abilities throughout the value chain. And, just as all regulatory proteins are not equally important, there appear to be four dynamic capabilities that are dominant influences on firm effectiveness.

The practical implications for this are clear. The leadership and management of life science companies need to concern themselves with their firm’s entire complement of necessary capabilities – its capabileome – but they need to pay particular attention to the organisational routines that express the four master dynamic capabilities. Without these four switches of success, every other process in the organisation’s metabolism will be at best hindered and at worst incapacitated.

Brian D Smith is the world’s leading authority on the evolution of the life sciences industry. Working at Bocconi University, Italy and University of Hertfordshire, UK, his most recent book is “Darwin’s Medicine: How Life Science Business Models are Evolving”. He welcomes questions and comments at brian.smith@pragmedicic. com

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The Future of Pharma Regulations The future of pharma regulations is challenging with diverse and complex regulations globally. It will be challenging for industry to adapt to regulated and semi-regulated markets alike while attempting to develop a harmonised strategy with ever-growing cost pressure on off-patent products for both small molecules and biologics. Differentiating new and legacy products with established safety profile and evolving a new compliance paradigm that shifts from traditional methods to a new, global, intelligence-driven regulatory compliance structure along with a judicial mix of centralised and localised regulatory teams is the key to reducing the cost burden and achieve global compliance in a timely manner.

YogiRaj, Associate Vice President, Freyr Solutions, India

T

he Pharma industry at large is faced with challenges due to fast changing global regulations and many countries moving towards adopting a tighter control over drugs. The patent cliff has pushed the industry to maximise their revenue from the existing portfolio in the past few years and thus resulted in expanding their market in emerging markets. This thought process, however, is not limited to off-patent or soon to

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be off-patent drugs, but companies with the product under development are also adopting a global strategy for trials either to address niche therapeutic indications or maximise their drug’s commercial potential. Both the scenarios pose a common challenge of understanding, assessing and implementing a global regulatory strategy in a timely manner. While global ICH guidelines and countries moving towards CTD/eCTD format offer a way of harmo-

nised regulatory strategy to these markets, regional regulatory complexities largely continue to pose a challenge and despite certain commonalities, each country is handled individually impacting the subsequent timelines and cost of compliance significantly. The region-specific challenges span across the local GMP requirements(as not all the countries follow a lead country model), semi-regulated, unstandardised documentation, multi-agency interactions,

STRATEGY

requirement of intensive health authority interactions, language nuances, export and import licenses, need for local applicants or representation, regulations on biological samples, and ICF requirements, to name a few.

Adopting a centralised regulatory strategy

It will be ideal if global markets could adapt to harmonised regulatory stand-

ards and procedures; however, it is unlikely to happen anytime sooner, due to socioeconomic and political factors that play a key role in countries’ applied regulatory frameworks. Nevertheless, the industry is diligently identifying areas across the regulatory value chain that can potentially be centralised and harmonised to achieve compliance faster using cost-effective methodologies.

Pharma companies are increasingly

investing in global regulatory strategies using a two-pronged approach, including comparative assessment of global regulations and formulating template-based strategies to address the regulatory gaps across markets while also integrating technology-enabled intelligence frameworks to tap on potential changes in regulations in these markets that can impact existing procedures and thus the regulatory strategies at large.

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Figure 1

The ever-increasing pressure with R&D costs will lead to the evolution of new business models where traditional ways of regulatory aspect of global clinical trials will shift from localised/nationalised to a combination of a centralised and localised model. The model already exists for regulatory operational functions such as publishing, labeling, and artwork. However, this approach will expand to regulatory affairs functions such as dossier preparation and chemistry, manufacturing and control (CMC) functions that are traditionally supported locally.

Regulatory information management transformation

The way forward for pharma industry will be to bring efficiency and boost productivity through comprehensive global regulatory information management and achieve compliance in a timely manner by reducing costs.

Over the past few years industry has been seeking transformation in regulatory information strategies and solutions across the value chain i.e., regulatory data management as per the HA

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standards (XEVMPD, IDMP and UDI), submissions planning, dossier management, product registrations, label management, submissions management, HA interactions and product lifecycle management among others. It will take another few years for companies to have implemented validated systems for end-to-end regulatory information management; however, this strategy is the key for centralisation of key regulatory activities focusing on core portfolio to enable better control and ensure key challenges are addressed. The challenges include Compliance Monitoring and Business Risk Management, Inconsistency across markets impacting brand image, Non-traceability of information, Slower response to changes in regulations, Ineffective approval process, Non-uniform versions of documents, Undefined turnaround time, quality metrics and focus on reusability of documents.

Integrated regulatory intelligence

Existing regulatory frameworks within the Pharma companies are often fragmented, except few centralised func-

tions, with diverse products and markets and respective product and market representatives. Cross-functional teams located in different regions often slow down the information exchange process and further change assessment and implementation. Hence, the industry is realising the potential of agile solutions and strategies that can enable faster change assessment and implementation.

Current processes and vendor landscape allow less flexibility to innovate, thus offering greater opportunities for aggressive processes, frameworks, and technology solutions to evolve. As these challenges become part of major discussions, industry will look towards solutions that change the current landscape. Effectively integrated intelligence-driven regulatory frameworks will be one of the key elements possibly to drive the change with desired flexibility complimented by flexible and scalable technology solutions. An integrated regulatory intelligence system will not only provide access to global regulations, but such systems can also provide a real-time notification of changes in global regulations that can potentially impact organisations’

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regulatory strategies, regulatory processes, and even operational frameworks.

Collaborative models where the systemenabled teams can assess the impact and implement the change efficiently can save huge cost for organisations while ensuring compliance.

Current processes and vendor landscape allow less flexibility to innovate, thus offering greater opportunities for aggressive processes, frameworks, and technology solutions to evolve.

Identify and focus on growth functions

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models for R&D programs to reduce the cost of development programs across regions.

Cross-functional, cross-market excellence

The supply chain of pharma continues to grow globally, posing greater challenges to track compliance. While leading agencies such as the Food and Drug Administration (FDA) is working with regional authorities to distribute the sheer number of registrations assessments and audits, pharma companies will have to soon align with comprehensive data management and traceability of drug products to ensure they manage their global registrations in a timely manner. Guidelines such as UDI for devices and IDMP for drugs in the USA and Europe respectively designed to ensure medicinal products and devices can be traced and can be held accountable for any adverse event.

This also aims at addressing the chal-

A u t h o r BIO

Increasing cost pressure, reducing margins, and growing competition including that from counterfeit products, pose significant operational challenges for regulatory teams. While regulatory professionals in different regions spend about 60-70 per cent of their time in life cycle maintenance activities against 40-30 per cent on growth activities (where growth activities include those supporting innovation, R&D, new product roll outs, market expansion etc.), the organisation focus is diluted leading to reduced growth rate and shareholders value. It will be imperative for organisations to identify and clearly differentiate these activities and implement alternative models that can centralise the non-growth operational activities (often routine and scripted) for legacy products versus growth activities driven by innovation.

Centralisation of such operations not only bring efficiency, and consistency across documents and document types, but also reduce the costs significantly if combined with low-cost operations and delivery centers. During the past couple of years, organisations have invested increasingly on assessing their regulatory organisation landscape for assessing the opportunities that can impact their bottom-line and realign their focus towards boosting the topline through innovation. This trend will continue and will potentially give rise to a combination of models, integrating global, centralised, uniform, process driven, and fast-paced low-cost models to address the margin gap. The industry is also trying to implement those

lenges from counterfeit products that are increasingly gaining market share in the multi-billion dollar industry worldwide.

This requires smarter tracking systems and cross-functional, cross-market integrated applications to ensure uniformity across the board and the global compliance monitoring. Global registrations management traditionally has been handled in silos. The entire ecosystem including the pharma companies and vendors are evolving towards an end-toend submissions management structure where there is a visibility across the board on the current status of documents and document components, submission timelines, deviations across countries and proactive measures driven by real-time intelligence. This means cross-functional stakeholders will have to work using centralised systems as well as work closely with stakeholders and regional market representatives to maintain the uniformity.

To summarise, it is unlikely in near future to have harmonised global regulations on medicinal products and devices alike. The country-specific socioeconomic and political situations might pose challenges in managing different documentation standards for a product across markets, managing submissions timelines, quality and compliance and further gaining visibility of overall status. An all-round regulatory affairs and operations management strategy, driven by regulatory intelligence, coupled with significant transformational technology intervention for information management is a way forward to address the regulatory needs of the pharma industry.

Yogi Raj is a seasoned competitive, clinical, market and regulatory intelligence professional with over ten years of multi-disciplinary experience within the life sciences industry. A science driven, entrepreneurial and resourceful professional with hands on experience in building processes, systems and solutions ground up solving critical industry needs.

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STRATEGY

Rigour or Rigmarole

All companies plan to succeed but only a few succeed in planning. The differences between them lie in how they answer seven fundamental questions.

Brian D Smith, Principal Advisor, PragMedic, UK

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ife sciences companies vary enormously in their size, structure and processes but almost every firm shares the annual ritual of the strategic plan. Whatever the business, the intended outcome of this near-universal process is an agreed view on how the firm intends to win in the market place.

As such, it ought to be seen as the most important and fundamental of the firm’s many processes, one that guides all other activities. But catch executives in an unguarded moment and that is not what they describe. They paint a picture of a time consuming task that adds little real value. They talk of the explicit cost of time spent in meetings and crunching data but they also rue the opportunity cost of what could have been achieved in that time but wasn’t. This dissatisfaction is not limited to a few companies nor to those in which executives have not been taught strategic planning techniques. In fact, the inefficiency and ineffectiveness of the strategic planning process is rife across the industry and, if anything, is often worse in companies filled with MBAs. To quote one of my research respondents ‘What we want is rigour, what we get is rigmarole.’ Why is this and how can life science companies make 18

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their strategic planning more effective?

This question is part of my research into the evolution of the life science industry and the answers are as surprising as they are simple.

The first step in understanding this issue is to see the wood for the trees, as we English say. On the surface, companies use a bewildering array of planning methods and the obvious assumption is that better planning methods lead to better strategic plans. But, as is often the case in management science, the obvious answer is not the right one. Dig beneath the surface and the same basic planning approach is used by almost everyone, albeit with different jargon and acronyms. Stripped of that jargon, almost all planning methodologies are intended to address the same handful of questions. A minority of effective planning firms manage to get good answers to these questions but most don’t, so the answer must lie not in what planStrategic Planning Question

ning method is used but in the skill with which it is applied. My research into these skill differences reveals that the practice of effective ‘rigour’ firms and their less effective ‘rigmarole’ peers differs fundamentally, as I’ll describe in the following paragraphs. In essence, the differences lie in how firms think about seven fundamental questions.

1. What market are we in?

All strategic planning begins with this question. In rigmarole companies, the answer is typically assumed, implicit and expressed in terms of the product category. ‘We’re in the statins market’ or the ‘immunoassay market’. By contrast, ‘rigour‘ companies define the market explicitly as the customer need to be met: ‘People who need to manage hyperlipidaemia’ or ‘People who need to measure blood protein levels’. This seemingly trivial and pedantic difference is in fact crucially important. This

Rigmarole Firms

rigorous approach to market definition widens and improves answers to the other six questions, whilst the rigmarole approach narrows and constrains market understanding. Why don’t all firms define their market in this way?

This behaviour seems to be culturally embedded. Rigmarole firms are culturally product-oriented, rigour firms are customer-oriented.

2. Where is the market going?

Strategic plans concern tomorrow’s market, not yesterday’s, so anticipating the market is essential. In ‘rigmarole’ companies, the emphasis of the anticipation process is on forecasting by extrapolation from historical data: ‘We anticipate the market will continue to grow at 5 per cent p.a.’ for example.

Sometimes, an important market trend is considered: ‘Changes in payment systems will increase price pressure’ for example. Rigorous companies recognise that

Rigour Firms

What is our market?

Our market is those people who buy products like ours

Our market is those people whose needs we can meet

Where is the market going?

The market is going where the past extrapolates to

The market is being shaped in a complex way by its social and technological environment

Who are the competition?

Those companies who want to take our market share

Anyone who wants to take our profit

How is the market segmented?

Into data-defined categories such as speciality, current usage or clinical need

Into homogeneous groups who respond in the same way to the same offer

Who shall we target?

Wherever the largest opportunity is

Wherever offers the best risk adjusted rate of return

What shall we offer?

A combination of product, price, promotion and place

Clinical, economic, systemic and emotional value as perceived by the targeted segment

What shall we measure?

What we spend and what we get for that spend

The outcomes of our effort, the things that predict those outcomes and the things that test our planning assumptions

Box1 What differentiates effective and ineffective strategic planners? www.pharmafocusasia.com

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markets are too complex to extrapolate in this simple way. Instead, they gather disparate information about a very wide range of factors in both the technological and social environments. They draw out the implications of these for their market and then, critically, synthesise those numerous implications into a small number of market-shaping factors. The result is a much deeper understanding of what forces are shaping the market and where the market is going. However, most firms stick with simple extrapolation because they feel comfortable with trusted, hard data and simple data manipulation. Equally, they feel uncomfortable with weaving together diverse information from qualitative and quantitative sources and the inductive thinking needed to make sense of it all.

3. Who is the competition?

Competitive advantage is, by definition, relative to competitors. In rigmarole companies, competitors are defined as those companies selling similar products. In other words, they are the people trying to erode our market share. Rigorous companies look at the competitive environment in a different way. They see competitors as people trying to erode our profit. This means they consider suppliers and channels, customers, new entrants and substitutes in addition to direct competitors. This gives rigorous firms a much fuller view of the competitive arena. The reason most firms don’t do this seems to be semantics and tradition. Conditioned to defining competitors as product rivals, they blind side themselves to indirect but often more important challenges.

4. How is the market segmented?

Understanding the differences between customers is fundamental to strategy. In rigmarole companies, segmentation is synonymous with data categorisation.

Customers are grouped according to data on things like their current usage, size of the account or perhaps disease stage. In rigorous firms, by comparison, segmen-

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5. Who shall we target?

Effective strategies focus resources onto those parts of the market where risk adjusted return on investment is optimal. In rigmarole companies, targeting is driven by opportunity size. Firms focus on customers not yet using our products and on large, untapped markets or segments. In rigorous companies, opportunity size is only half of the picture. They also consider the difficulty of seizing that opportunity and target according to both criteria at once. This methodology enables a much more sophisticated kind of targeting that treats the market as a portfolio of customer segments.

Like market definition, the failure to target effectively seems to be a cultural issue: organisations with strong sales cultures have no difficulty deciding where to attack but find it much harder to choose where not to focus their efforts.

tation is synonymous with homogeneity of needs. Data is understood to be nothing more than a proxy for customer needs. It is used to aggregate and divide customers into groups who respond the same way to a given value proposition.

This needs-based segmentation enables rigorous firms to target more effectively and design more compelling offers. That most firms don’t segment effectively has been understood for years. It seems to be explained by a fundamental confusion about how segmentation works and, again, the comfort blanket of existing, quantitative data.

6. What is our offer?

The most visible part of any strategy is the offer made to the customer. In rigmarole companies, this offer is based on the classic 4Ps of product, price, place and promotion. However, these components are driven by different departments and as a result are often disjointed and driven primarily by internal considerations. In rigorous companies, the offer begins with the needs of the targeted segment and different kinds of value – clinical, economic, systemic, emotional–are built on those needs. The result is more coherent and

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STRATEGY

My research reveals that the practice of effective ‘rigour’ firms and their less effective ‘rigmarole‘ peers differs fundamentally, as I’ll describe in the following paragraphs. In essence, the differences lie in how firms think about seven fundamental questions.

• What market are we in?

• Where is the market going?

• Who is the competition?

• How is the market segmented?

• Who shall we target?

• What is our offer?

• What shall we measure?

7. What shall we measure?

In most companies, metrics have an almost sacred status. What gets measured gets done is a common mantra. In rigmarole companies, the metrics component of strategic plans is focused on what will be spent and what will be earned. Budgets and targets are often the largest, most argued-over section of a plan. Rigorous companies look at metrics in a different way. Budgets and targets are used, of course, but they are only part of a more thoughtful approach to metrics.

More effective companies define three categories of things that have to be measured: • Lag metrics that record what has happened (Sales and profit targets are part of these) 22

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• Lead metrics that predict what will happen (Spending budgets are a component of these) • Learning metrics that test working assumptions (Budgets and targets contribute little to these).

Used as a synergistic set, these three types of metrics measure outcomes but also allow mid-course corrections to strategy and, via organisational learning, provide better inputs for the next planning cycle. The reason most companies don’t do it this way seems to be the political dominance of finance departments, whose narrow obsession with results distorts the use of metrics, and reward systems, which are usually based on outcomes.

So the differences between effective firms, whose planning is rigorous, and

A u t h o r BIO

compelling offer in which the 4Ps are components but not drivers. The failure of most companies to take this customer-centric and holistic value approach derives from the siloed way in which most life science companies are structured and their difficulties in working cross-functionally.

ineffective firms, whose process is a wasteful rigmarole, is surprising but simple. It is not in the questions their strategic planning process addresses, but in how they try to answer the same seven questions everybody else asks.

There is an important, counterintuitive and very practical lesson to be learned here, one that senior executives should apply to their strategic planning processes.

Before this research, and based on my twenty years of experience as an executive in the industry, I thought that rigour was synonymous with lots of data, analysis, spreadsheets and charts. In other words, I thought effectiveness in strategic planning is derived from the precision and meticulousness with which the seven questions were answered. But now, having built on my industry experience with almost two decades of academic research into the life sciences industry, I can see that rigour is synonymous with holism, the viewing of the business and market as a whole, integrated system. In other words, meticulous data gathering and precise analysis is necessary but insufficient to an effective strategic planning process. Equally important and more fundamental is the way that firms think about the seven questions.

And that way of thinking has less to do with tools and techniques and more to do with the firm’s way of looking at the market, which is often culturally embedded. The important differences between the perspectives of effective ‘rigour’ and ineffective ‘rigmarole’ firms are summarised in box 1. These, my research concludes, are the most important differences between those firms where strategic planning is a rigorous, value-adding process and those where it is a value destroying rigmarole.

Brian D Smith is the world’s leading authority on the evolution of the life sciences industry. Working at Bocconi University, Italy and University of Hertfordshire, UK, his most recent book is “Darwin’s Medicine: How Life Science Business Models are Evolving”. He welcomes questions and comments at brian.smith@pragmedicic. com

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Drug Development A question-based process Drug development is a complex, time consuming and expensive process involving numerous stakeholders, activities and regulatory authorities. Broadly it can be classified in six steps, starting from identification of lead molecule till submission of reports for marketing authorisation. This process evolved and technology has changed over development in last two decades.

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1. With over two decades of experience within the realm of Drug Development behind you, what are the milestones of your career journey that you would like to share with us?

Last two decades was really wonderful and exciting journey working in drug development industry. Though I cannot claim, but have experienced almost entire process of drug development together in my professional career and college days. My experience goes from the first step of identification of lead and synthesis of a drug till the last stage of submission of documents to regulatory authorities for marketing approval of a drug in the drug development process.

The drug development is a complicated process involving various

activities. On a broader level we can categorise these activities in six steps: (1) identification of a lead and target for new chemical entity (NCE), (2) synthesis of the identified NCE, (3) developing a suitable formulation, (4) conducting pre-clinical and toxicology studies of developed formulation, (5) clinical study and last one is (6) submitting data to regulatory authorities for approval to market the drug in prescribed format.

I studied Pharmacy, specialised in Pharmaceutical Chemistry; hence in my post-graduation dissertation I experienced first two steps of drug development. I synthesised a non-opoid analgesic compound based on fentanyl, requiring 14 steps synthesis. That was my first experience of drug development process. Being a Pharmacy student I theoretically studied all six

RESEARCH & DEVELOPMENT

steps of drug development, but was not sure whether will get a chance to experience them. Luckily, after completion of post graduation, and at the start of my professional career, I got an opportunity to work in Formulation and Development (F&D). After F&D I joined Clinical Research and since two decades I am conducting trials, compiling data, and submitting to Regulatory Authorities for marketing approval. So all in all after completing more than two decades, I experienced all the six steps of drug development.

In F&D department, which I joined immediately after completion of my post graduates I experienced third step of drug development, i.e. how to develop a formulation. I was handling solid dosage forms, where I learned Physio-chemical characteristic, compatibility studies of drug powder with other ingredients, the stability studies of developed formulation. It was fun and exciting working with powders and making a stable solid oral dosage forms. After 4 years of experience in F&D, I moved to emerging stream and jumped into Clinical Research. It was in 1996 when I took a decision to move to clinical research when this industry was nascent in India.

In those days we did not have many

options as only handful of companies was doing clinical research. I remember my classmates questioning and giggling at my decision and were laughing at me. However, I was determined. The clinical trial experience helped me to understand remaining steps in drug development. I understood different pre-clinical studies, their importance and also testing methodology and how drug acts on your body, as well as how body reacts to the drug. This experience covered the next two steps, i.e. steps four and five of drug development. The last step of documentation any way was part of my clinical trial activities; where last step of trial is usually compilation of the documents in prescribed forms by regulators and then submission. In clinical research I monitored, managed and handled number of clinical studies for New Chemical Entities (NCEs); New Biological Entities (NBEs), or for modified Generic compounds. Therefore, as said earlier, I effectively experienced all the steps of drug development, and thoroughly enjoyed every steps of drug development.

In last two decades, I witnessed number of technological and regulatory changes in this process. Every change in this industry was a milestone in itself.

In this period the research has moved from person dependent to process dependent; from manual methods to the technological driven and from local to global. Technology literally changed the entire drug development industry, such as introduction of Computer Aided Drug Designing (CADD) systems for identification of lead molecules; new method and new technique for formulation, sophisticated instruments for analysis, use of high speed internet, highly developed communication system from manual printed reports or letters to electronic submissions. These changes brought a sense of confidence and transparency in the entire drug development process.

These are all milestones in this process which I witnessed in last two decade.

On the other hand Regulators also changed their way of working, across the globe they become more vigilant, stricter in scrutinising the clinical trial reports and became more technology savvy. Regulators also adopted new methods and new technique to evaluate the result of clinical studies.

All these changes are made the drug research more attractive and accurate, but on the other side these changes also increased overall cost for development to many folds.

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Rajendra Talele Head of Clinical Development Services Accutest Research Laboratories Pvt Ltd, India

2. Being an integral part of a Contract Research Organisation like Accutest, in your opinion, how much of an impact does research make on the functional output of a medication?

Research has great impact on functional output of the medication, research provides answers to the question whether medication is a safe and efficacious for use or not. Research has both positive and negative impact in the drug development process. Many times due to poor efficacy or safety the development of new discovery has to stop in between and developing Pharmaceutical company suffers a big loss; but on the other side you

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may get some wonderful discoveries or accidental discoveries during research that may result in block buster!

Ancient civilisations relied on medical observation to identify herbs, drugs and therapies that worked, but beginning in the early twentieth century, therapeutic reformers in various countries including United States began to develop the concept of the "well-controlled" therapeutic drug trial, which was through research such as laboratory analysis and clinical studies.

In general, medication is a foreign material for the body, and whenever any foreign material enters in the body, it reacts to that material and tries to defend itself by different means. Excess

consumption of any foreign material is also harmful; hence it is important to know safety level for consumption of such material. Research helps in understanding safety level of medication and gives us an idea about the maximum tolerated dose or level of any particular medication.

Medication should not only be safe, but should be effective, and effectiveness of any medication is evidenced through different experiments. A worldwide drug disaster in 1961 resulted in the enactment of the 1962 Drug Amendments of US FDA, which explicitly stated that the US FDA would rely on scientific testing and that new drug approvals would be based not only upon proof of safety, but also on "substantial evidence" of a drug's efficacy, i.e. the impact of a drug in a clinical trial setting. To know the efficacy of the medication, various experiments are carried out to find the therapeutic window of the medication based on their efficacy. Hence, research is only the way we prove medication is the safe and efficacious.

Moreover, as an impact of research many newly synthesised / discovered molecules are dropped in the process of development. It is a known fact that when 10,000 molecules are synthesised in the lab to test for the hypothesis, only few of them make it to clinical trials and couple could complete entire process till submission to regulatory authority for marketing approval. The rest thousands may get dropped due to either poor safety or efficacy during the preclinical or clinical trial stages. I remember in 1997, when we were part of one of the global Phase III oncology studies, our study was called off midway due to poor response of the drug. It was a Phase III study enrolling breast cancer patients; and, in interim analysis it was observed that the newly developed entity was not showing any significant benefit to the patients when compared with placebo.

The product was failing in efficacy, and hence, sponsor decided to call off the study. This was identified or noticed

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only because of research. Every year number of studies are failing because of poor safety or efficacy, which can be identified only through research.

Research also gives accidental discoveries turning new entity into a blockbuster. The classical example of this is Sildenafil (Viagra (R)) . Initially, Pfizer started life of this drug as UK92480, a new treatment for angina,. Pfizer was looking for a new medication that would relax these blood vessels; however its trial results in people were disappointing. Pfizer was about to abandon further trials when few volunteers of the trial started coming back and reporting an unusual side effect: which was penile erections. This gave new direction to Pfizer scientists and they started experimenting use of sildenafil on relaxation of penile blood vessels. In these experiments scientists found restoration of the erectile response, which they confirmed in clinical trials. Before the launch of Viagra, which was in 1998 there was no oral treatment for erectile dysfunction; and available options were either injections or a fairly gruesome prosthetic implant, but Viagra provided oral option.

And, now, Viagra is one of the most prescribed drugs in the world, thanks to a failed angina treatment. This is a positive impact of research.

3. Kindly take us through the formative stages of a new medication, for instance, at the onset of a clinical study conducted by you.

What course of action is taken once the concept of an introduced drug is proven?

Once the concept of the drug is proven in Phase I or Phase II astudies, that means the drug has shown expected response in pre-clinical, toxicological and early phases of the studies, indicating the drug is now ready to take bigger leap in clinical studies. Often Proof-of-Concept (PoC) studies give idea on pharmacokinetic and pharmacodynamic pattern / behaviour of the drug molecule; it also answers the question

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of selection of dose for higher clinical studies. Therefore, the subsequent step after completing PoC is Phase II b, if required, and then a big Phase III trial involving investigational sites from various countries.

The planning of Phase II b or Phase III study is initiated well in advance.

The documentation part, conducting feasibility, and decision on selection of the countries are all kept ready before getting results of a Phase II study are in.

During this period, the pharmaceutical company also collects information from different CROs on their capabilities, with regard to experience, resources, and global reach. This is the Request for Information (RFI) stage. List of eligible CROs are identified well in advance for further phase(s) of the trial. This helps to reduce overall timeline for Phase III study and then submission to authorities. On receipt of favorable results of Phase II a study, the pharmaceutical company sends a Request for Proposal (RFP) to already identified CRO. At the RFP stage, the pharmaceutical company tries to select BEST FIT solution for their study. This selection process and decision depends on various factors and differs from company to company. The final decision on selected CRO is intimated through the Letter of Authorisation issued in the name of the CRO. The association with this newly identified partnered CRO starts with a kick -off meeting, where project teams from both side meet face-to-face and discuss operational points as well as timelines and expectations. The kick-off meeting is crucial, as the entire road map for execution of the project is defined in this meeting. After getting a clear understanding of what is expected and when it is expected, the CRO plans the study, and then exchange of relevant documents starts between both the sides.

The start up phase / activities for the project initiated with the first step, i.e. development of study protocol or protocol synopsis (if not available),

The drug development is a complicated process involving six steps: (1) identification of a lead and target for new chemical entity (NCE), (2) synthesis of the identified NCE, (3) developing a suitable formulation, (4) conducting pre-clinical and toxicology studies of developed formulation, (5) clinical study and last one is (6) submitting data to regulatory authorities for approval to market the drug in prescribed format.

followed by identification of investigational sites in the countries, followed by . detailed feasibility of the project, performed Site Selection visits and record the observations and come to the realistic execution plan. All of this information is shared with the sponsor Pharmaceutical Company as per contractual obligation in defined frequency and methods. The selected sites are conveyed about their selection in the study, and then collection of Essential document process initiated. As a parallel process to be of collection of essential documents, a separate team at CRO starts preparing applications for Regulatory Authority (RA) and Institutional Review Board (IRB) or Institutional Ethics Committee (IEC). After collection of required essential documents and application, and depending on requirements for that country, the CRO or sponsor Pharmaceutical Company or the Principal Investigator apply to obtain approval from respective RA and IRB/ IEC for conducting the planned study in that country. In many countries this

RESEARCH & DEVELOPMENT

application process to RA and IRB/IEC is parallel; whereas in some of the cases it is sequential. In some countries RA demands an approval from IRB before considering the application for processing and in some other countries IRB / IEC demands an approval from RA to give their opinion. After receipt of the respective approvals, the drugs get imported and sites are initiated.

Meanwhile, depending on the complexity of the study and requirement of the study, the Investigators’ meeting may take place. This completes the start up activities of the project. This process is followed by Active Phase of the trials.

Active Phase of the project starts from enrolling the eligible patients.

Once the sites are initiated, investigators are allowed to screen and enroll suitable and eligible patients in the study after taking valid written consent from each patient. A protocol process is followed for screening and enrolment of the patients in the study. During the process of enrolment and treatment of patients as per the protocol, CRO monitors (CRAs) either visit the hospital, or do remote monitoring or perform riskbased monitoring activities, as specified in the contract to check quality and compliance of the investigational sites. Often the sponsor pharmaceutical company also carries out the audit of these sites making sure that the study is conducted according to protocol and regulatory requirements. During this entire process of Active Phase data collection process takes place, which is either through electronic data capture technique, or through a manual paper recording system. The collected data is transferred to the Data Management team of the CRO or sponsored pharmaceutical company or third party agency.

The data from patients is compiled and collated in the already developed database using various software; queries, if any, are fired to correct the data. Once entire study is over, i.e. all patients get enrolled and treated as per the protocol,

and data for all patients getsstored in the database, the data base is called as locked. Once the database is locked, the monitors start closing the investigational sites. This ends the Active phase of the trial. Now the trial enters the last phase i.e. close out phase.

In this phase, the locked data base is transferred for statistical analysis or extracting various tables, listings and graphs. On completion of the statistical analysis, the data is then moved to medical writers for writing the final clinical study report. After completion of this report, the sponsor pharmaceutical company files the report to the regulatory authority.

During this entire process the sponsor pharmaceutical company is involved at various stages and interacts with the CRO as and when required.

4. Considering the dynamism in federal and government policies as well as regulations, how challenging is it to procure permissions in a compliant manner?

Federal and government policies are in favour of drug research if it is conducted in ethical and regulatory complained manner. All governments in the world seek new, effective and safe medicines for their country, and as a result several

governments proactively came up with various initiatives to facilitate this drug development process. Almost all the governments in the world have a certain timeframe in approving application for the various processes involved in drug development. However, sometimes these set timelines may get altered due to different reasons. Some of them are: incomplete application, inadequate documentation, or some time unavailability of competent staff at government offices. Overall the process is not a complicated process and the permission is obtained easily from federal and government agencies.

5. While developing a drug, what is of a more critical importance: the compound’s favourable effect in terms of the disease or its clinical pathophysiology?

It is difficult to answer and differentiate the critical importance of drug development. Whether a drug should show excellent results, i.e. show great efficacy, or should have results in clinical pathophysiology depends on targeted disease. If the drug is developed as an anti-infective or anti-tuberculosis or anti-malarial, then the critical factor is to show greater efficacy. However, if the drug is developed to treat cancer

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6. Are there any pre-emptive measures taken to mitigate the possibility of a poor drug response which may find fault with the clinical analysis?

If it would have, then drug development would have been a smooth ride and less expensive, but this is not the case. Drug development remains complex and becoming more and more expensive. But a number of different ways were tried to reduce unnecessary drug exposure of patients and also reducing overall cost of development. One of the ideas is conducting smaller studies that expose fewer patients to understand the behaviour of a new drug early in development.

However, it is not necessary that the behaviour observed in one set of patients will repeat when same drug and conditions are exposed to larger group. Therefore, it is difficult to suggest any pre-emptive measures to mitigate the risk. There are concept of ‘adaptive trial design’ or Phase Zero trials, pilot studies or pivotal studies well in discussion and in use, but again at a larger level the results may be different.

There are numerous examples indicating a promising drug candidate failing when exposed to the larger patient population. Scientists are working on pre-emptive measures to mitigate the possibilities of poor drug response, but I have not heard of any major break through in this direction. or to treat neurological disorders such as Parkinson’s or Alzheimer’s disease, then having significant changes in pathophysiology would be the critical. No patient suffering from an infection would like changing only pathophysiology and not getting cured from infection. At the same time it is really difficult or nearly impossible to

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cure diseases such as cancer if detected at last stage; and patients suffering from such diseases will be happy to change their pathophysiological conditions.

7. Would you say that the clinical evaluation of drugs is a questionbased process?

Yes indeed. The entire clinical evaluation process is developed to satisfy specific objectives — either single or multiple — for the newly developed molecule. And these objectives are based on certain hypothesises that are either identified in early development or targeted.

Hypotheses are questions, and you have to prove the set hypothesis right or wrong through experiments. Clinical evaluation is one type of experiment; and in this experiment the researchers try to satisfy their hypothesis. In other words the clinical evaluation process is nothing but to find answer or answers for pre-defined question or questions.

8. What are the challenges faced in ensuring utmost safety and confidentiality when it comes to documentation and recording clinical research procedures? Is every piece of information chronicled on a study stored for potential reference?

Not really. Safety and confidentiality of documents are important in clinical trials, but at the end of the study when results are out the drug developers provide all this information to the authorities.

Often developers publish articles on their discovery and during this publication certain confidential information about the study is shared which then comes into public domain. Moreover, the molecule under development is anyway under patent protection which means a large amount of information is already in public domain. Therefore, the confidentiality is protected in one or other way. The most confidential part of the clinical trial process is the information relating to the enrolled patients. By ICH GCP guidelines, we are not allowed to discuss patient information openly and

therefore in clinical research very minimal information is collected from participating patients beside the study-relevant details. The challenges to protect this patient confidentiality are numerous, but researchers do take precautions, such as patient names do not get reflected anywhere on any document; the records of participating patients are revealed to only the study personnels. If an outsider wants to review patient data then the confidential part is required to black out.

According to the international guidelines, no one except an investigator can see participating patient details.

9. Finally, as the Head of Clinical Department at Accutest Global, what would you advise pharmaceutical companies who are swathed in controversial conferences about drug toxicology and counterfeiting?

Drug toxicology and counterfeiting are really two major issues facing the pharmaceutical industry. Toxicology is nothing but the safety of the drug. Often, the toxic effects of a drug are observed after repetitive use of medicine for a longer period. Clinical trials are certainly used to identify any untoward effects of a drug on the body; however, these trials have limitations, such as, either they are for shorter time or they expose limited number of patients in the study to satisfy a statistically significant result.

Therefore, to understand the prolong side effects of the drug one approach is to keep exposing animals for longer period while clinical trials are on-going.

Some of the companies are doing this, but if such practices is made mandatory in toxicological studies, then it will help minimise issues arising afterword due to toxicity. Counterfeiting is a vast and burning issue; however, general public education, creating awareness among the people regarding safe use of drugs, its side effects, its importance towards our health, harm caused by counterfeit medicines, etc. are the only remedies I can suggest here to control counterfeit.

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MANUFACTURING

Immunogenicity of Protein Biotherapeutics and Methods for Assessment of Immunogenicity All protein biotherapeutics are potentially immunogenic and hence could elicit immunogenicity response. These responses could be of different types such as binding antibodies or neutralising antibodies.

Immunogenicity of protein biotherapeutics is a major concern especially when the biological function of the drug and the endogenous counterpart are neutralised by Anti-Drug Antibodies (ADA). Hence the regulatory agencies insist that the immunogenicity response should be assessed by validated sensitive assay formats during the different stages of drug development and the antibody response be characterised.

Mallikarjun Narayan Dixit, Vice President, Director and Test Facility Management Accutest Biologics Private Limited, India

T

he development of recombinant DNA technology has dramatically increased the use of protein biotherapeutics such as antibodies, hormones, and enzymes. These are useful in the treatment of a wide range of diseases, including cancerous conditions, infections, diabetes, and rheumatoid arthritis. The relative success of these new drugs has stimulated the development of new candidates that are evaluated in clinical studies for desired and adverse effects in patient groups. While all protein biotherapeutics are potentially immunogenic in nature, recombinant human biotherapeutics, however, are not expected to evoke an immune response in humans

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given their similarity to endogenous proteins. Recombinant human proteins do display reduced immunogenicity compared with non-human sequences (Wadhwa & Thorpe,20071), yet formation of Anti-Drug Antibodies (ADA) was noted after patient treatment with such therapeutics (Sauerborn et al.,20102; Schernthaner,19933). Therefore, ADAs pose a challenge in the biotherapeutics industry and in clinical medicine due 1 http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4002659/#b108 2 http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4002659/#b84 3 http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4002659/#b87

to possibility of neutralisation of endogenous protein thus reducing the efficacy of a biotherapeutics. Immunogenicity is therefore a key limitation for the clinical use of biotherapeutics and the drug development process requires a number of analytical methods to support efficient product development with high safety or low risk potential.

Protein biotherapeutics

Recombinant DNA technology is not only an important tool in scientific research, but is also responsible in enormous progress in the diagnosis, treatment and production of protein derived biotherapeutics of high purity,

MANUFACTURING

high specific activity, steady supply and batch-to-batch consistency. These protein biotherapeutics are inherently highly specific for the target with minimum risk for non-mechanism based toxicity and safety issues. Protein biotherapeutics augment normal growth factors, hormones, enzymes and are able to modulate protein/protein interactions.

Protein biotherapeutics are aapplicable in multiple therapeutic areas and for a variety of antigen targets Unlike the generic small molecule drug products, protein biotherapeutics are large molecules (higher molecular weight) such as peptides, proteins, hormones and therapeutic monoclonal antibodies with molecular weight ranging from 3000-150000 Da. These protein drug products are the human gene sequences expressed in suitable host and purified for the specific drug product of interest.

Table 1 summaries some of differences in small and large molecule therapeutics.

The production of recombinant protein biotherapeutics and successful launch involves multiple critical steps such as selecting the target protein, determining the amino acid sequence for expression, optimisation of codons and synthesis of DNA. Other critical steps include, buildingtheconstruct with

various expression vectors, screening the best expression route, production and purification of proteins, characterisation of protein, locking the API, performing the preclinical studies and Clinical studies.

Immunogenicity of therapeutic proteins

Immunogenicity is the ability of a substance to trigger immune response. All protein biotherapeutics have the ability to induce immunogenicity. Immunogenicity triggered by Biopharmaceuticals is mainly linked to production of anti drug antibodies and unwanted immunogenicity.

However, in case of vaccine candidates it is wanted immunogenicity.

A well-documented example of biotherapeutics immunogenicity is the neutralising antibody responses that developed in patients receiving treatment with human erythropoietin. This was associated with the development of Pure Red Cell Aplasia (PRCA) among patients with chronic renal failure (Casadevall et al.,20024). Erythropoietin is a hormone that is required for Red Blood Cell (RBC) development, and PRCA manifests as 4 http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4002659/#b18

Small Molecule

Large Molecule

Size is <600 Da

Size is ~150,000 Da

Organic or metallic compounds which bind with proteins in the body, thereby function in disease

LM Therapeutics treat diseases using biological matter, e.g., proteins, mAbs, peptides, cells, vaccines etc

Synthesised utilizing chemistry synthesis

Typically grown and extracted from living cells

Function intra-cellular

Work extra-cellular

Less specificity • Can inhibit multiple targets in family • Non-specific off-target toxicities

High specificity Limited off-target effects / toxicities

Easier to deliver (often oral)

Difficult to deliver (usually injected) Difficult to affect targets inside the cell

Generally cheap to manufacture, and easy to replicate after patent expiration

Generally expensive to manufacture Requires sophisticated technology

Table 1 Differences in small and large molecule therapeutics.

severe sudden-onset of anaemia that is characterised by the absence of red cell precursors in the bone marrow (Boven et al.,2005b5). In PRCA which is a very rare serious adverse drug reaction seen in the patients treated erythropoietin for renal anaemia, the neutralising antibodies blocked exogenous and endogenous EPO functions. The patient became severely anaemic and required regular blood transfusion. Several deaths were also reported. When EPO therapy was ceased, antibody levels declined and the condition was reversed. Therefore, risk based immunogenicity assessment of the protein biotherapeutics has been recommended in the regulatory guidance to confirm that the drug product does not elicit immune response which potentiates the neutralisation of administered /endogenous protein biotherapeutics compromising the efficacy of the drug product.

Immunogenicity of protein biotherapeutics

A non-self recognition and interaction of protein therapeutic by immune cells initiates the immunogenicity process. There are essentially two ways in which a protein therapeutic may elicit immune responses in the subjects administered with the drug product under investigation. The first is an adaptive immune response if the therapeutic agent is recognised as Non-Self or ‘foreign’ protein which subsequently leads to production of specific anti-drug antibody response. Foreign antigens trigger a ‘classical’ immune reaction that is dependent upon T-cell activation. This mechanism requires interaction of antigen with APC that, in turn, prime naïve T-cells. Primed T-cells may then interact with B-cells displaying the antigen within a Major Histo-compatability Complex (MHC) molecule. Interaction with co-stimulatory molecules further activates T-cells and stimulates cytokine secretion, leading to the proliferation of B-cells and antibody production. Depending on the 5 http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4002659/#b14

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nature of drug product, its purity (with the contaminant protein, DNA), the antibody response can be as follows: • Antibodies which bind and neutralise protein • Antibodies which bind, but do notneutralise protein • Antibodies against non-product related proteins e.g. host cellderived proteins (expression system related proteins) • Antibodies against product and nonproduct related proteins • No antibodies.

Thus the nature of antibody response has to be evaluated with the help of sensitive validated bioanalytical methods to know whether the immune response has effect on neutralisation of the protein drug in the subjects which could be detrimental.

Regulatory considerations and immunogenicity testing

Regulatory agencies have recognised the importance of screening for protein biotherapeutics arising from concerns over its safety and efficacy. In order to demonstrate clinical safety and efficacy, immunogenicity testing is now a key component of biotherapeutics drug development. Immunogenicity testing is required under ICH, US-FDA and EMA guidance documents to characterise the ADA response.

The formation of neutralising antibodies can affect safety and efficacy, but non-neutralising antibodies can also be a concern due to effects on half-life and bio distribution of the product (Shankar et al., 20066). Neutralising antibodies can deplete both endogenous and exogenous protein. Hence risk based immunogenicity assessment is recommended. Wherever the endogenous counter parts are available, appearance of neutralising antibody in subject samples to the treatment regime will be viewed as serious concern and regulatory acceptance of such products becomes questionable (e.g. Insulin). The regulatory guidance recommends use of

of the confirmed positives for antibody titer and for assessing neutralising abilities with class of antibody response.

Besides increasing the quality of drug development processes, it is also important to develop and validate bioanalytical methods to detect very low levels ADA responses in presence of high quantity of circulating drug concentration.

Factors influencing the immunogenicity and ADA

There are multiple factors causing immunogenicity of the protein drugs administered to clinical subjects. Some of the factors triggering the immunogenicity are presented in Fig 1 below.

These factors can be classified under major groups such as, product, patient, assay, process and administration related, which are to be suitably addressed at an early stage when product and processes are finalised. The variation in human gene sequence can lead to the drug to be recognised as a foreign or non-self particle provoking an immune response. Protein aggregation can increase the immunogenicity of biotherapeutics which can be a key

multi-tiered strategy for immunogenicity testing using validated bioanalytical approaches for various assay steps such as, screening, confirmatory, characterisation

Human gene Sequence Vareiation Other factors Unknown

Glycosylation

Assay Sensivity

Contaminants and Impurities

Factors influencing Immugencity of protein Biotharapeutics Treatment Duration

Aggregates

Route of Administration

Patient Characteristics Dose

6 http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4002659/#b91 Fig 1 Factors influencing the immunogenicity of protein biotherapeutics 34

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factor in causing adverse events associated with immunogenicity in the clinic (Rosenberg,2006). The level of contaminant proteins and DNA components from the expression systems or from the host cell is considered to be another major concern for immunogenicity. The levels of such contaminants are to be assessed by highly sensitive methods to ensure that the levels are at or below the acceptable limits as per regulatory norms. Immunogenicity assessment may become necessary for the host cell related protein in certain drug product depending on its expression system and on the nature of the drug product under investigation. The route of administration, dose and frequency of administration can also account for immune responses.

Subcutaneous route of administration is more likely to induce immunogenicity than the intravenous route due to slow absorption and possibility of recognition by antigen presenting cells. Post translational modifications and glycosylation pattern are likely to induce confrormational changes in the structure of the drug product which may lead to immunogenicity. PRCA was observed in patients treated with the epoetin-Îą formulation that contained polysorbate 80 (Villalobos et al.,2005).

The elicitation of ADA against biotherapeutics can have detrimental effects on drug safety, efficacy, and pharmacokinetics. The immunogenicity of biotherapeutics is, therefore, an important issue. The bioanalytical methods developed to evaluate the pharmacokinetics profile and immunogenicity should be of adequate sensitivity and these are to be validated as per regulatory requirements (USFDA and EMA guidance). The immunogenicity method developed and validated should be able to detect low levels and low affinity anti-drug antibodies in presence of high circulating concentration of drugs.

Strategy for immunogenicity testing

The immunogenicity should be assessed in the pre-clinical and clinical subject

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Screening Assays Confirmatory Titre Confirmatory Assays Neutralizing Ab Isotyping

Fig 2 Strategy for immunogenicity testing in preclinical and clinical study samples

samples using validated bioanalytical approaches. The method developed should be able to detect the false positive samples and should be performed preferably using the drug specific critical reagents including positive control antibodies and appropriate cut-point criteria. The immunogenicity methods are quasi quantitative as surrogate positive controls are used as assay system suitability. However, the positivity is declared based on the statistically derived screening assay cut point during validation using the experimental values for minimum of 200-300 drug free naĂŻve matrix data points (preferably using disease state matrix, for clinical 50-100 individual matrix samples to be used). The method should also be robust to detect ADA in presence of high circulating drug. The method should have adequate sensitivity for detecting the ADA in neat matrix (250ng/mL for clinical and up to 500-1000ng/mL for Non-Clinical samples). All the study samples are to be tested first for screening assay, screened positives to be taken for confirmatory assay and the confirmed positives samples for further characterisationantibody titer assessment. The confirmed positives also need to be tested for presence of neutralising antibodies using functional assay preferably cell based

assays. The strategy for immunogenicity assessment is summarised in Fig 2.

Method of immunogenicity testing

To study the immunogenicity of protein therapeutics, ADA detection and characterisation methods are required. Such methods should be adequately sensitive to recognise and detect low affinity and low titer ADA in both clinical and non clinical samples. A range of techniques exist which are useful for investigating the presence of antigen-specific antibody.

These methods include immunoassays that can identify ADA (capable of binding to antigen) and bioassays that can distinguish between neutralising and non-neutralising antibodies (Wadhwa & Thorpe,2007). Some of the sensitive immunoassay formats used in Accutest Biologics are ELISA (bridging, acid dissociation), Electro chemiluminescence (Meso Scale Discovery), GYRO Lab, cell based assays (neutralizing Abs); In vitro immunogenicity and LCMS/MS based assaysas indicated in Fig 3 below.

Following section discusses each assay platforms: 1. ELISA (Enzyme Linked Immunoadsobant Assay)

Species independent bridging acid dissociation ELISAs are commonly adopted to detect ADA in presence of

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nogenicity. Generally, assay duration is short (2-3 hours) due to homogenous assay format. The method is similar to ELISA however all reaction take place on an electrode surface hence background values are observed.

3. SPR (Surface Plasmon Resonance)

SPR also offers a good platform for label-free interaction of antigen and antibody on a gold coated sensor chip which measures the binding response based on mass deposited on the chip surface. The SPR offers online acid dissociation benefits and ability to handle multiple samples with 6 concentrations simultaneously. Antibody titration becomes much more easier on SPR assay format.

Fig3 immunogenicity testing assay formats available at accutest biologics, mumbai, India

4. Cell based assays

Drugâ&#x20AC;&#x201C;Antibody Complex. This can be done by coating the drug on an ELISA plate and detecting the captured ADA with the help of biotin labeled drug using SA-HRP and TMB substrate. The samples with absorbance values above plate specific cut-point are treated as positive for ADA. These are taken for confirmatory assay and the confirmed positives are tested for antibody titer

assessment. Depending on the quality of critical reagents ELISAs can assay sensitivity below 50ng/mL 2. Electro chemiluminescence using MSD (ECL- MSD)

This method offers higher sensitivities and higher assay ranges as compared to traditional ELISA. The method is highly suitable for evaluating PK and immu-

These are generally employed for detecting the neutralising antibodies in the pre-clinical or clinical samples. The assays generally include proliferation assays, MTT assays, ADCC assay, CDC assay, intracellular messenger levels, multiplexing assays, receptor up/ down regulation studies, uptake assay and gene expression assays. These methods are to be developed and validated as per the assay design using the specific cell models.

Table 2 A standard curve run with different concentrations of IgGs in a GYRO Lab immuno assay system www.pharmafocusasia.com

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Table 3 The recovery of quality control sampels in GYRO Lab immuno assay format

5. LCMS/MS

Besides the characterisation services LCMS/MS based method is also used for ADA detection and quantification in the biological matrix. This method does not require use of the labeled critical reagents.

6. In vitro immunogenicity

This method is mainly used for assessing the T-Cell activities and also to assess the cytokine production on a multiplex assay format using cell based assays. The cells are given a trigger of the test item to evaluate level of proliferation and the cytokine secretion in the cell culture supernatants.

The levels of cytokines are measured with the help of MSD or LUMINEX assay format. The T-cell proliferation is measured by analysis of cell surface markers using Flow Cytometer.

GYROS immunoassay format

GYRO LAB Immunoassay system is a highly sensitive assay format which offers advantage of high sensitivity,

Fig 4 Standard curve constructed from 7 concentration of IgG

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high throughput, broad range and requirement of ultra low sample and critical reagent volume. The GYROS system uses 200nL of reaction mixture in micro column on a CD which can analyse multiple samples at a time. The partially automated system involves one step of reagent preparation followed by automated sample processing.

The following case study describes detection and quantification of intact human IgG on Gyrolabâ&#x201E;˘ immunoassay platforms. In this immunoassay format, a biotinylated reagent was introduced into a microstructure in the CD to saturate a capture column packed with porous beads coupled with streptavidin. The samples containing intact human IgG were then introduced into the microstructures where intact IgG is captured in the capture column. Finally, a detecting reagent labeled with a suitable fluorophore is added. The integrated signal in the capture column represents the total response from the sample. The positive control samples were loaded at 7 differ-

ent concentrations in duplicate and the data was evaluated in Gyrolab Evaluator version 3.3. The results of the experimental runs are presented below Results

The results indicated that all the 7 different concentrations of positive controls exhibited a high percentage recovery in the matrix with very low %CV for standard points (<8%). The background values were found negligible. The experiment demonstrated that the observed concentration is similar to the expected concentration indicating the assay format is precise and accurate.

Summary

The development of recombinant technology has helped in large scale production of protein biotherapeutics useful for many indications and in diseased conditions. These protein biotherapeutics may elicit unwanted immunogenicity and may pose significant clinical, scientific, and manufacturing challenges. The

observation of immunogenicity is thus a major concern for industry, regulatory agencies and for the efficacy of the drug product. Besides increasing the quality of drug development processes, it is also important to develop and validate bioanalytical methods to detect very low levels ADA responses in presence of high quantity of circulating drug concentration. Accutest Biologics has made available multiple immunogenicity testing assay formats for assessment of ADA responses in preclinical and clinical study samples for submission to the regulatory agencies. Besides the commonly used assay format like ELISA and MSD, Accutest is also equipped with GYRO Lab. The data from GYROS immuno assay format demonstrated that the assay is sensitive, precise and accurate for detecting the very low levels of ADA response in matrix.

References are available at www.pharmafocusasia.com

A u t h o r BIO

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Dixit (graduate from University of Illinois) is a scholastic personality with several patents and publications to his credit and with more than 25 years of rich experience in pharmaceuticals, biopharmaceutical and CRO industries in the area of drug discovery and bio-analytical services. He has extensively worked on method development and validation of various assay platforms such as LC-MS, ELISA, MSD, SPR, RIA/RIPA and Cell based assays for Immunogenicity and pharmacokinetics evaluation of non-clinical and clinical study samples under GLP and GCLP compliant practices for regulatory submission studies.

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Cover Story

EXPERT TALK

Pushing the Limits of Temperature Control Transforming packaging perceptions 1.What is the current state of temperature-controlled transport?

Today’s pharmaceutical environment has become increasingly complex, with more specialty products like biologics, injectable and clinical trial drugs, being shipped than ever – which in turn raises the stakes, and the costs, of mishandling. There is a greater need for more sophisticated and personalized temperature control solutions, and one solution will not fit all distribution models. The big takeaway for pharmaceutical logistic providers is that better temperature control and the right packaging is essential to keeping product integrity intact.

The current logistics environment grows more complex as demand for time- and temperature-sensitive transport increases. Pharmaceutical products in particular, are generally high value with very specific temperature requirements, particularly at the clinical phase, thus increasing the importance of state-of-the-art temperature control solutions in the supply chain. All pharmaceutical products must meet exacting specifications with some needing extreme temperature ranges like -35°C to -25°C, with variances of 5°C or less. The industry standard for commercial packaging is 120 hours, or five days, which in our experience is no longer always adequate, particularly when it comes to delivering to remote or more challenging locations with extreme temperatures,or those with extended clearance times, South East Asia or Latin America as examples.

We also see increasing demands from the regulatorybodies and agencies, which can often lead to extended transit times. In the past only the pharmaceutical industry was on the radar of the regulative bodies and somehow responsible for validating and qualifying their partners. Now, the authorities are aiming more and more for the suppliers and the vendors themselves—the freight forwarders, the packaging suppliers, the airlines—anyone participating in the supply chain.

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In spite of all of the challenges ahead, I believe there is equally great potential for pharmaceutical logistics and cold chain management. According to Pharmaceutical Commerce’s annual Cold Chain Sourcebook, the overall cold chain market is growing at double the rate of conventional pharma products, and will reach $288 billion (out of a $1.3-trillion) global biopharma market in 2017. These are tremendous figures pointing to a robust area of opportunity.

2. How has pharmaceutical packaging evolved over the years? What are the biggest trends in packaging solutions?

As I said before,120 hours validation time for shipping systems has become the new industry standard, and anything less is no longer really cutting it. As most clinical trials migrate to the emerging markets and patients that are untouched by clinical trials, it has become necessary to lengthen the transport time. Reaching a very remote destination, with a high-value pharmaceutical shipment involves extended transport time because of the potentially limited infrastructure.

Our priority now is to raise the industry bar on quality and achieve the same level of temperature control precision to a remote location in an emerging market that we would be using for sending it to New York, or Germany.

The future predicts that we’ll become increasingly reliant on passive shipping solutions, as the old active container systems don’t always offer these longer validation times, and ease of handling into remote locations.

With passive-temperature controlled systems, capacity is not restricted, and the shipment size determines the solution used, whether it be single small doses or multiple pallets. The ease of handling is greater because passive systems can be passed through whole journeys with little or no special handling. When passive shipments are stored in the right temperature, the containers can be recharged without further intervention by trained agents at airports,

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Today’s pharmaceutical environment has become increasingly complex, with more specialty products like biologics, injectable and clinical trial drugs, being shipped than ever. The industry standard for commercial packaging is 120 hours, which is no longer always adequate. Better temperature control and the right packaging are essential to keeping product integrity intact.

Nils Markmann Vice President, Global Operations, World Courier, Germany Nils Markmann is responsible for the daily management of the company’s global operation, for network-wide implementation and adherence to global standards and for ensuring consistent operational excellence throughout the company’s 140 offices. Formerly General Manager (Operations) for World Courier Germany, Nils has been with the company since 1995.

and without accessing the contents, solving the new challenges of extended transit times that we often encounter with pharmaceutical products.

For biologics in particular, there is recognition for better temperature requirements which go beyond the traditional cold chain range of 2–8°C. Many demand tighter ranges from 4-6°C or 4-8°C. ‘Temperature control’ may be a more accurate term compared to ‘coldchain’ as temperatures control requirements range from at “body temperature”, close to 37°C, to controlled room temperature at 20-25°C, ultra-frozen products which can go as low as -80°C, and at its most extreme Cryo-frozen at -196°C. To keep up with evolving packaging trends, World Courier has recently launched a series of new packaging innovation solutions. This includes CORE Climate Optimisation Research & Engineering labs in Cologne Germany-our companyowned solutions and centre of research and excellence, and also Cocoon, our state-of-the-art passive temperature control shipping container catered at bulk shipments of highly temperature-sensitive materials and the reliable transport of API and commercial drugs. Together, CORE and Cocoon deliver on maximum reliability, combined with a network of temperature control experts that can help manage shipments from point A to B and everything in between.

3. In 2014 World Courier launched a new Centre of Excellence for Packaging, CORE Climate Optimisation Research & Engineering labs in Cologne, what brought about this launch?

CORE Climate Optimisation Research & Engineering is World Courier’s scienceled and data-driven solutions center driven to support clients to make the best and most informed packaging decisions. The origins of CORE labs came about in Rommerskirchen just outside of

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EXPERT TALK

Cologne Germany, after one of our pharmaceutical customers approached World Courier with a specific packaging question. It became apparent that an off-the-rack solution wouldn’t work, and that we needed to develop a new type of container. From there, it just made sense that, if we developed our own container, we needed to do it internally.

CORE was launched in December 2014 and is our “secretweapon” to pilot product innovation. CORE labs allows World Courier to partner with shippers to evaluate, validate and where necessary create the right climate-controlled packaging even for the most delicate products that must remain perfectly within specification. All qualifications and learning and development can be done through CORE in-house, and it is this level of precision that we are very extremely proud of.

CORE labs is currently comprised of three distinct areas: a 200m2 packaging production facility, a 200m2 testing and qualification lab, complete with our own temperature testing chamber, and a 600m2 storage warehouse. It is much more than simply a centre of excellence for packaging. We now have the capability to gather end-to-end insights to test, all in-house, how different packaging solutions perform in identical situations, allowing us to refine improvements and develop the most advanced packaging technologies in the business.

CORE’s commercial grade climate chamber is used to test packaging across hundreds of transport lanes before actually putting anything on-ground and into service in order to select the most appropriate option.

Shippers can now make more informed decisions across their entire specialty logistics portfolio and ultimately, translate that into more cost-efficient decisions with a best-in-industry turnkey solution from a trusted service partner.

4. What are the key challenges in the market today that World Courier is looking to solve by creating Cocoon?

Cocoon is the first innovation to come out of World Courier’s CORE Labs, and we’re all very excited and proud to unveil it to the world. Cocoon is World Courier’s new proprietary bestin-class passive packaging system for pallet-sized shipments, in multiple temperature ranges. Compared to the industry standard, Cocoon delivers better thermal performance, while weighing 30% less than comparable boxes which offers superior reliability and lower shipping costs.

The key challenges Cocoon addresses are improved reliability for temperature-controlled shipments and lowered shipping costs. Cocoon is made with a new polypropylenebased glass-reinforced honeycomb composite that offers thermal protection and stability well beyond any conventional passive packaging currently on the market. It is perfectly suited for larger-sized, highly temperature and high-value shipments, with lengthy transit times. We know from experience that Cocoon surpasses the industry standard of 120 hours, in one instance, a Cocoon travelled from Austria to

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Baghdad in Iraq. The container maintained internal temperature for a full 13.5 days, including 10 days of storage during customs clearance, in significantly out-of-spec warehouse temperatures.

As Cocoon units weigh 30% less, and require no external power source during transit as a passive system, it is the most cost-effective solutions on the market. In our view, Cocoon is the best passive container solution in existence anywhere in the world today.

5. What is the outlook / opportunity for innovation in pharmaceutical packaging solutions in Asia?

It was recently reported that Asia Pacific will emerge as the fastest growing market for temperature-controlled packaging1. Asia is an attractive market on many levels - its large population and emerging markets, increasing government initiatives, and growing contract manufacturing activities, are all contributing factors pointing towards its positive outlook2.

Demand from Asia is more global than ever, which means diverse traffic routing and variations of external temperature are bigger considerations when deciding on what type of pharma packaging solution to use. This presents new challenges and problem solving compared to when looking at intra-regional solutions.

Certain emerging markets in Asia coming to the fore may have to deal with fragile or lack of infrastructure.

Stakeholders like airlines, ground handlers and airports are major considerations when any company considers innovation in this region. Not all facilities have the capability to support all types of packaging, which is why we see innovations like Cocoon meeting a real need for extended temperature-control beyond the 120 hour mark.

Lastly, the demand for quality and compliance is growing at a faster rate than innovation. Logistics providers that can find ways to implement the most robust system while keeping costs down will have great success in this region.

To get to the point of where World Courier is today, being viewed as the most trusted specialty logistics company in the world, it takes an extensive global network (in Asia alone we operate in 11 company-owned offices), and a constant eye on innovation. There’s a quote from Grace Hopper, a computer scientist who said that “The most dangerous phrase in the language is “we’ve always done it this way”. I love this saying, and I think innovations like CORE and Cocoon prove that there are better, lighter, and more cost-effective ways of doing things that have the potential to take the industry by storm.

1 Temperature Controlled Packaging Solutions Market: Global Industry Analysis and Opportunity Assessment 2015-2025. October 2016. http://www.futuremarketinsights.com/ reports/temperature-controlled-packaging-solutions-market 2 Strong Growth Ahead for Contract Manufacturing.Market’s robust in 2015, but for how much longer? January 2016. http://www.pharmamanufacturing.com/articles/2016/stronggrowth-ahead-for-contract-manufacturing/?show=all

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CORE (Climate Optimisation Research & Engineering) Labs

CORE Climate Optimisation Research & Engineering Labs is World Courier’s new data-driven solutions center supporting client packaging decisions and product innovation.

Using proven data to help customers make the best possible packaging decisions has now become a reality since the opening of World Courier’s cutting-edge CORE Labs. Science-led and data-driven, this new companyowned solutions center focuses exclusively on helping pharmaceutical manufacturers evaluate, validate and

select the right climate-controlled packaging for their specific needs.

The facility is currently comprised of three distinct areas: • a 200m2 packaging production facility • a 200m2 testing and qualification lab, complete with temperature testing chamber • a 600m2 storage warehouse

Cocoon Cocoon is the first packaging innovation from CORE labs. With transparent qualification tested through CORE Labs, Cocoon reduces total shipment costs while ensuring shipment security for large-scale, temperature sensitive materials.

Cocoon drives significant performance enhancement by maintaining temperature 40% longer than primary competitors, while weighing up to 30% less. The passive “light” system uses a “Honeycomb” vacuum insulated panel system that requires no external power source during transit, making Cocoon not only cost-effective but ecologically friendly compared to active systems.

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From clinical development to commercial production

Your strategic partner in aseptic filling Vetter is a leading contract development and manufacturing organization (CDMO) that specializes in the aseptic filling of syringes, cartridges and vials.

Vetter holds numerous patents and has extensive experience with biologics and other complex compounds, including monoclonal antibodies, peptides, interferons and vaccines. More than 70% of Vetter’s active projects are biologics, and Vetter currently manufactures five of the world’s top 10.

Collaborating with the top 10 (bio-)pharmaceutical companies worldwide, Vetter supports products from preclinical development through global market supply. Through its U.S. and European facilities, Vetter Development Service provides state-of-the-art support for early-stage products, with seamless transfer at Phase III to Vetter Commercial Manufacturing for large-scale production. The company offers state-of-the-art technology and innovative processes to promote product quality and maximize API yield.

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Contact us: Asia Pacific inquiries: infoAsiaPacific@vetter-pharma.com • Japan inquiries: infoJapan@vetter-pharma.com • P h a rm a F oOther: c u s A sinfo@vetter-pharma.com i a ISSUE - 25 2016

Vetter at a glance Q Q Q Q Q Q

Q

Headquarters in Ravensburg, Germany Additional clinical development facility in Chicago, US A Representative office for Asia Pacific in Singapore and a subsidiary in Japan Approximately 3,900 employees Worldwide specialist in the aseptic production of prefilled drug delivery systems Global experience and expertise with regulatory authorities including FDA, EMA, PMDA (Japan), and RP (Germany) Approx. 50 customer products with FDA approval

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EXPERT TALK

Biologics’ Drug Delivery Systems In this interview, Peter Soelkner of Vetter discusses drug delivery trends for biologics and, in particular, prefilled syringes. He offers insight into the advantages and challenges of this system for biologics, important issues to consider upfront, and talks about two differing manufacturing technologies for prefilled syringes.

To begin, what trends do you see in drug delivery systems for biologic drugs?

There are several trends that we see in drug delivery systems in general, and more specifically, in the fast and continuously growing biologic drug sector: • The first trend is the need for drug delivery systems that are patient friendly.

This means the development of drugs that are of a very high compatibility with the human body, and that can be made available in more convenient delivery

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forms, especially ones where patients can self-administer.

• This trend corresponds with the expanding home healthcare market which is itself, a direct result of a rapidly aging world population including in the Asian countries.In order to control costs, healthcare authorities are putting pressure on the industry to develop medicines which enable patients to undertake more procedures in a private setting and avoid more cost-intensive therapies that would

occur in either a hospital or a doctor’s office.

• Another trend is the rapid increase in therapies focused on conditions with small patient populations, or Orphan Drugs, which by definition are drugs developed for treating condition affecting fewer than 200,000 persons.

• Finally, we are seeing one negative trend that unfortunately is costing the industry a significant amount of moneyand even more importantly, putting patient’s lives at risk. This negative

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trend is, of course, drug counterfeiting.

A very important step the industry and the government are taking together to fight this growing problem is the clear identification of products through a process known as ‘serialisation’. This process has already been implemented in China, South Korea and other countries and within the next few years will be enacted in still more countries in Asia and worldwide.

In this context do you see an increasing demand for prefilled syringes? What are the factors driving this demand?

Let me answer that question by taking a look at the drug development sector since projects that are in early and latestage development phases are a good indicator for determining demand.

Factors which include a higher complexity of new compounds in development, have led to a drug development model that is far more intricate than some years ago.To succeed in today’s market and well into the future means companies must make innovation central to their drug development business approach. That means looking outside traditional methods of drug delivery in the clinical phases.

The reasons that support the taking of an innovative approach include: • Several syringe market reports which indicate that the global prefilled syringe market is expected to show continued positive growth due to rapidly increasing development of biologic drugs and other suitable compounds.

• The rising demand for greater ‘friendly’ patient and caregiver administration, starting in the clinical phase and continuing in the commercialisation of a drug.

With more biologics competing in the same therapeutic space, launching directly in a syringe can help set a drug product apart from the competition and offer an advantage that other companies may not be able to beat.

In summation, we see increased interest and demand in prefilled syringes. For many indications, prefilled

Peter Soelkner has been a Managing Director of Vetter Pharma-Fertigung GmbH & Co. KG since June 2008. In 2009, he was also appointed Managing Director of Vetter Pharma International GmbH, the company’s marketing and sales organization. Soelkner graduated from the University of Dortmund, Germany, in 1992 with a degree in chemical engineering and earned an MBA from Columbia University, New York, in 2001. Before joining Vetter, he held positions in Germany and North America at Sartorius AG and Sartorius North America Inc., in R&D, marketing, key account management and general management roles. At Vetter, from 2003 to 2007, Soelkner managed the company’s key account program and global end-to-end supply chain. He left the company for a year to serve as Vice President of global key account management at Sartorius Stedim Biotech (USA), before returning to Vetter in 2008.

Peter Soelkner

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EXPERT TALK

syringes seem to be the way of the future. Being part of this future via earlyin-the-process clinical syringe development provides an innovative approach for innovative companies to gain an early market advantage.

What are the advantages of prefilled syringes for delivering biologic formulations compared to other injection technologies?

As already discussed, the key to the rapidly changing healthcare market is offering solutions for the need of patient friendly systems. Prefilled syringes are such a system. Instead of undertaking several preparation steps prior to administration, the prefilled syringe, also called an “all in one system”, provides a number of advantages in the clinical stage as well as in the day-to-day operations of a product already launched.

These include: • Improved trial appeal, making it easier to recruit medical clinics for clinical trials that use prefilled syringes instead of traditional vials • Greater patient compliance and consistency resulting from the ‘userfriendly’ nature of prefilled syringes • Precision single-unit dosing which better meets the requirements of today’s more complex compounds • The avoidance of overfilling which reduces loss and thus, saves valuable API as compared to vials • The possibility of a higher drug reimbursement from payers • An increase in the value of a drug product early in its life-cycle given its competitive edge • An increased attractiveness to outlicensing partners What are the challenges in the manufacture of this drug delivery device?

It is our experience that creating easyto-apply systems often means a more complicated production process at the outset. After all, a syringe system is a sophisticated and complicated instrument, consisting of a number of

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Syringes, in their role as an advanced drug delivery system, can offer significant potential for biotech companies, particularly in their use with innovative drugs.

individual components. The correct interaction between the components that comprise each module is critical to its successful operation.

To illustrate, let us look at the administration of a drug using a syringe system. The system itself requires a plunger rod that operates in concert with the other components, particularly the glass barrel itself. To achieve a smooth operation, a small coat of silicone is applied at the inner surface of the glass barrel. It is a significant challenge to determine the correct amount of silicone required to achieve the correct movement of the plunger rod while avoiding any interaction between the silicone and the drug substance coming into contact with each other.

And, because the glass barrel of a syringe is more complex than the glass of a vial, consisting of a finely shaped area within the barrel, there is a higher risk for mistakes or damage to the barrel such as glass scratches, or even glass breakage. This is why all partners involved in the supply chain are focused individually and collectively on this issue. Glass manufacturers, along with manufacturers of the prefilled syringes; which can be either the biopharmaceutical company or their assigned contract development and manufacturing organization (CDMO) and, if applicable, the processors,strive to achieve optimal results for the benefit of the patient.

If a manufacturer is considering prefilled syringes as part of its drug-delivery option for a drug, what would be the most important issues they would need to take into account before proceeding?

This is an excellent question since its answer helps to better illustrate the thinking that must be done prior to committing to prefilled syringes. The first consideration is the issue of dosing.

For example, before making the decision to use prefilled syringes, a biotech company must first answer the question “what different drug concentration presentations do we want to bring to market?” The answer to this question will have different actions associated with it depending upon whether the product is to be offered in just one, or in multiple syringes.

Other critical issues that must be considered include silicon oil reactivity, the use of non-fluro tech or flurotech stoppers, glide and release forces, and the time that the drug will be held in storage. Additionally, issues such as plunger rod and finger flange design, secondary packaging issues like blistering, and other manufacturing issues must be carefully verified, discussed, and decided upon prior to making the overall decision to use prefilled syringes.

Thinking about the two prominent manufacturing technologies for prefilled syringes, presterilized or bulk process,what influences the choice of the correct technology for each individual product?

Overall, the choice of selected technology is often driven by the characteristics of the drug substance itself. This is particularly true for sensitive biologics or complex compounds that have diverse product specifications. The choice of the right syringe platform technology is a decisive factor for the successful development and commercialization process.

The two prefilled syringe platforms available in the market; presterilized and bulk syringes have their differences. Presterilized syringes are tub-

MANUFACTURING

based, ready-to-use systems that are well-suited for a broad range of drug products. The washing, siliconization, nesting, and sterilization takes place at the supplier for the primary packaging, while filling occurs at the filling site.

When working with sensitive biologics, the possibility for customization is often a ‘must have’ option. That is why bulk syringes are often a good choice for complex compounds such as monoclonal antibodies, peptides, interferons, vaccines or opthalmics. With bulk syringes, as opposed to presterilized syringes, the pre-treatment steps of washing, siliconization and sterilization take place at the filling site in an integrated, customizable inline-process.

Also, the tighter specifications of the bulk process often help to reduce particle levels, adjust silicone levels to meet exact specific product requirements, offer different methods of sterilization, and increase dosing and fill-volume accuracy for small volumes.

A full range of readily available bulk syringe formats also allows for numerous customizable options. Obviously, the advantages of using this format are maximum possible control of the process and flexible primary packaging material combinations.

In summation, both prefilled syringes platforms offer biotechnological companies innovative delivery options and value in drug development programs for sensitive biologics. But, it is the nature of the compound itself that most often drives choice. Therefore, knowing how the two platforms differ will be essential in choosing the right syringe system for the individual drug product.

By design, a significant amount of research into areas such as patient requirements and device design are necessary when intending to market a new parenteral drug. However, profit margins are also essential. Can the two coexist?

Increasingly, healthcare authorities expect the industry to develop medicines

that allow patients to take more control over their own health care. That means the potential for self-administration in the home. The primary purpose behind this request is an attempt to control costs through the avoidance of cost-intensive therapies in either a hospital setting or a doctor’s office. When we consider the ever-increasing complexity of drug products, this is a difficult, but not an impossible task to balance. Certainly, it creates challenges for all parties involved in the drug manufacturing industry that must develop new packaging and delivery formats that meet or exceed the required standards of these drugs, all while controlling costs.

At the end of the day, however, we must never forget the human element of our business, always keeping in mind the fact that patients rely on our industry to help make their lives easier and safer when managing their disease, and helping to improve their quality of life.

Is there anything further you want would like to add or any closing thoughts for our readers?

I would like to emphasize that syringes, in their role as an advanced drug delivery system, can offer significant potential for biotech companies, particularly in their use with innovative drugs. Undertaking a drug development program with a clear goal in mind from the very start can often make the difference between success and failure. That is why the involvement of an experienced service partner early in the process can help maximize the value of a complete drug package which consists of the compound itself, the drug delivery system, as well as the experience and trust the CDMO partner brings to the development and manufacturing project and process.

Therefore, when choosing a partner, customers should consider the total project including decisive aspects of quality, experience, flexibility, financial stability and a shared vision. We see these as central to a due diligence approach in the partner selection process.

Company profile:

Vetter is a global leader in the fill and finish of aseptically prefilled syringe systems, cartridges and vials. Headquartered in Ravensburg, Germany, with production facilities in Germany and the United States, the contract development and manufacturing organisation (CDMO) is an innovative solution provider serving the top 10 (bio-) pharmaceutical companies, as well as small and midsize companies. Its portfolio spans state-of-the-art manufacturing from early clinical development through commercial filling and final packaging of parenteral drugs. Known for quality, the company of approximately 3,900 employees offers a foundation of experience spanning more than 35 years, including dozens of customer product approvals for novel (bio-) pharmaceutical compounds. More than 70% of Vetter’s active projects are biologics, and Vetter currently manufactures five of the world’ top 10. The CDMO is also committed to patient safety and compliance with user friendly solutions such as Vetter-Ject®, as well as its dual-chamber syringe Vetter Lyo-Ject® and cartridge system V-LK®. Vetter’s branch office in Singapore and its subsidiary in Tokyo, Japan, increase the presence of the company and the awareness of its service portfolio in the Asian healthcare market.

Visit www.vetter-pharma.com.

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MEDICAL FAIR THAILAND 2017

The Regionâ&#x20AC;&#x2122;s Most Complete Medical & Healthcare Exhibition Returns!

6 - 8 Sep 2017, QSNCC, Bangkok, Thailand.

The 8th installment of the international exhibition on Hospital, Diagnostic, Pharmaceutical, Medical & Rehabilitation Equipment & Supplies continues its proud tradition of show-on-show growth, with an expected international participation of 700 exhibitors, 17 national pavilions and country groups as well as an anticipated attendance of 8,500 qualified trade buyers and decision makers from across Asia.

Creating an international marketplace that allows global companies to access a targeted audience is MEDICAL FAIR THAILANDâ&#x20AC;&#x2122;s strongest suits that have contributed to making it one of the most influential shows on the region's medical and healthcare trade 50

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calendar. In 2017, MEDICAL FAIR THAILAND will take place at the Queen Sirikit National Convention Centre in Bangkok, from 6 - 8 September.

What to Expect in 2017?

In the spotlight at MEDICAL FAIR THAILAND 2017 are two special platforms in the areas of Rehabilitative Care and Connected Healthcare. Complementing these dedicated showcases will be a suite of co-located conferences, technical seminars and themed workshops presented by key thought leaders and industry experts in their respective fields, involving delegates, visitors and exhibitors in

“Gain access to Southeast Asia’s dynamic medical and healthcare market. Bookings for exhibitor spaces are now open! For more information visit www.medicalfair-thailand.com”

About the Organiser

meaningful discussion on the future of health care.

Among them is ARTeC 2017, returning for the 3rd edition, the Advance Rehab Technology Conference, will emphasise innovative and effective technological solutions that could decrease mobility-related disability, reduce related complications and improve quality of life.

Connecting Healthcare Innovations with Medical Professionals An unparalleled opportunity to showcase your latest products and build invaluable relationships with key industry players from around the globe. Be part of MEDICAL FAIR THAILAND 2017 and tap into the region’s burgeoning growth potential.

Organised by Messe Düsseldorf Asia, MEDICAL FAIR THAILAND is the region’s number 1 event for the medical and healthcare industry, bringing together all facets of the industry for networking, sharing of best industry practices, as well as products, services and solutions development. Part of MEDICA – World Forum for Medicine, a global series of medical events, MEDICAL FAIR THAILAND’s contribution and growing relevance to the region and its associated industries is further underlined by the endorsement and continued support it receives from hospitals and medical associations all across Asia as well as from the Ministry of Public Health Thailand and the Thailand Convention and Exhibition Bureau.

For more information, please visit mda.messe-dusseldorf.com Advertorial www.pharmafocusasia.com

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Cost effective Data Operations The need for an E2E data standards ecosystem Successful organisations need to modify reactive operating model and develop an E2E data standards ecosystem with a different organisational structure.

Isabelle de Zegher, Vice President, Integrated Solutions at PAREXEL INFORMATICS, Belgium Michael Goedde, Vice President Global Data Operations, PAREXEL, US Benedikt Egersdรถrfer, Vice President Global Data Operations, PAREXEL, US

T

he main focus of Data Operations groups within biopharmaceutical companies is to ensure the highest possible quality of data for clinical studies. With the combined challenges of compliance to Data Standards, increasing diversity of data collection tools, nearreal time visualisation of safety data, and the opportunity of in-silico studies, Data Operations must now produce high qual-

ity data throughout the entire execution of a study, not just at the end. There active operating model in place in many companies and focusing on data standardisation at submission time is unsustainable.

Successful organisations will manage the burden of data standardisation proactively to solve these emerging challenges in a cost effective way, through the establishment of an End-to-End (E2E) Data Standards

ecosystem, from protocol to clinical study report and beyond.

Data Operations is Faced with a Combination of Challenges

Over the last five years, the number of challenges has grown for Data Operations.

The FDA has mandated CDISC SDTM and ADaM standards1 for regula-

1, CDISC is the Clinical Data Interchange Standard Consortium, who produced several standards including CDASH (Clinical Data Acquisition Standard Harmonization) for collected data, SDTM (Study Data Tabulation Model) for submission of raw data and ADaM (Analysis Data Model) for submission of derived data.

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tory submission as of December 2016 [1]. Japanese authorities will require SDTM as of October2016, with a transition period of 3.5 years [2]. In addition, regulatory agencies expect full traceability of data, from source data to analytic data sets.

Personalised medicine and adaptive trial design increase the diversity of data points to be collected. New data collection modalities, and specifically patient mobile apps and wearables, are

being introduced. They have all different implementation formats, yet they need to be integrated for analysis and reporting in the same way as classical Electronic Data Capture (EDC) systems.

Data surveillance and near-real time visualisation of safety profiles throughout execution of a clinical study have become regular practice. This requires periodic delivery of standardised data sets, integrated across all data collection tools, during the conduct of the study.

In-silico clinical studies are increasingly accepted as supporting evidence toward market authorisation anddecrease the need for costly in-vivo studies. However, the predictive value of the models underpinning in-silico clinical studies is directly related to the quality of data used to generate and test these models. While Electronic Health Recorddatais predominantly used, availability of standardised clinical study data, comparable across studies, would

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contribute to higher quality predictive models.

In the reactive operating model in place in many organisations, clinical study data isstandardised at submission time. Contextual information on the study is frequently absent and implicit data is not collected. As a result, post data collection standardisation of study data is difficult, workload intensive, and the quality of transformed data is questionable, while traceability from data sources to analysis results issuboptimal.

The new data standards paradigm requires not only organisational adaptations but also technology upgrades in the MDR and SCE space.

To be cost effective, data operations need to implement data standardisation prospectively within an E2E data standards ecosystem

Going forward, data gathered for a single clinical study should be collected with the end in mind, for example continuous delivery of data during study execution, integrated across several data collection tools, and re-use of data beyond the clinical study report should all be considered. The current, reactive operating model must be replaced by a proactive approach: E2EData Standards, starting at data collection.

Data Operations most often consists of the following groups (Figure 1 -left).

• Data Management coordinates data collection and monitors data quality.

This group is usually responsible for Data Collection Standards – such as CDISC CDASH – and management of electronic Case Record Form (eCRF) libraries for EDC • Clinical Programming transforms collected data into the CDISC SDTM format required for submission 1; they maintain the SDTM Standards and related mapping programs • Statistical Programming and Biostatistics is responsible for analysis & reporting, and delivers submis1 The transformation of collected data, from CDASH into SDTM, is needed because of SAS technology constraints.

sion ready material to the Medical Writing group. They typically maintain the Analysis Data Standards, CDISC ADaM, synchronised with a set of re-usable statistical programs managed within a “macro library”.

In this environment, Data Standards are maintained through siloed, disjointed governance processes and tools. Generation of submission data is done sequentially: data collection standards are defined first as part of study set-up; when this is approved SDTM mapping is specified; and finally ADaM is defined after SDTM mapping has been validated. This is inefficient, certainly in case of changes or error tracking, and results in workload intensive mapping exercises.

Successful organisations need to modify this operating model and develop an E2EData Standards ecosystem with a different organisational structure (Figure 1 – right).

• A central Data Standards group coordinates integrated Data Standards, from data collection to reporting: there is one single set of Data Standards across the organisation, with different “views” for data collection, submission and analytics, maintained within a central Metadata Repository (MDR).

• Clinical Programming focuses on the implementation of EDC specific eCRF libraries, synchronised with the

Figure 1 Successful data operations will move away from the current operating model, toward an e2e data standards ecosystem

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INFORMATION TECHNOLOGY

standards defined within the MDR. This enables maintenance of different EDC specific eCRF libraries from the same central data specifications and allows for flexibility when selecting EDC systems across trials. In addition, as other data collection tools are being added (central laboratory, eCOA, wearables, mobile apps, etc.), it is possible to implement “eCRF library” equivalents for these other tools in synchronisation with the MDR. • Finally, Statistical Programming generates SDTM and ADaM through re-usable programmes, managed within an integrated Statistical Computing Environment (SCE) and synchronised with the standards definitions contained in the MDR. The E2E data standards ecosystem requires new technologies: MDR and SCE

The new Data Standards paradigm requires organisational adaptations but also technology upgrades in the MDR and SCE space.

AnE2E ClinicalMDRmust go beyond management of standard variables. It needs to support concepts, where each concept is a group of variables that must be managed together to ensure proper meaning [4].A concept is defined through a semantic group – or “hub” – and has different context-specific views– or “spokes”: the data collection spoke include CDASH and supports the definition of the eCRF forms synchronised with the EDC eCRF library, the SDTM spoke supports SDTM mapping and the ADaM spoke provides the template for ADaM derivation.

When the clinical programmer selects the data collection forms for a study, the Clinical MDR automatically identifies the related SDTM and ADaM spokes, and generates the SDTM and ADaM specifications, eliminating the need for sequential work and automatic traceability [5]. A Clinical MDR should also support structured entry of study design information such as arms and epochs,

visit schedule, phase, indication, patient population2 and make this information available in a standardised format, ready for re-use across all applications of the eClinical landscape enabling the“Enter once, use everywhere” principle.

The SCE[5], supported by a set of macro libraries, is another technology that must go beyond the currently fragmented statistical programming tools. A common SCE should be used for SDTM mapping and ADaM generation and should support the maintenance of macro libraries synchronised with the definition of the standards contained in the MDR. Whenever there is a change in SDTM or ADaM, the changes need to be propagated to the SCE where updates of the relevant macros are controlled through workflow.

AnSCE should also support recurrent execution of macros for a specific study with version control and full traceability of the different runs required during study execution. Ultimately, an SCE should generate output that supports automation of the Clinical Study Report and electronic Common Technical Document (eCTD) publishing.

2 SDTM has a subcomponent called Trial Design Model, including more than 50 parameters describing the clinical study and needed across most eClinical applications.

E2E data standards: impact on Sponsor / CRO partnership

The new E2E Data Standards approach impacts the way contract research organisations (CROs) collaborate with clinical trial sponsors.

Be it in a complete or partial outsourced model, sponsors must ensure central management of Data Standards, as “single source of truth” across the different stakeholders; this can be outsourced to a CRO with pre-existing Data Standards. Each partner CRO needs to ensure synchronisation with the “single source of truth” of the Sponsor Data Standards, and when delivering data back to the sponsor, CROs should issue a compliance report checking conformance of the data to the standards.

E2EData Standards require linkages across all standards. Many sponsors still maintain their Data Standards separately in EDC-specific eCRF library and SAS based tools. CROs will have to work with sponsors to enable “Hub & Spoke” definition of Sponsor Data Standards toward the E2Eecosystem.

The choice of EDC – or any data collection tool - for a CRO becomes irrelevant; what is important is conformance of the EDC/data collection tool output to the Sponsor

Figure 2 Hub & spoke definition of data standards. www.pharmafocusasia.com

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Data Standards, independently of the technology used.

Successful organisations must transform the burden of data standardisation into an opportunity to address emerging challenges most effectively.

The introduction of the E2E Data Standards ecosystem is a challenge in itself, but is required to meet wider industry challenges in a cost effective and high quality manner.

• Compliance to Data Standards for regulatory submission - with traceability from data collection onwards – is the primary target and must start at data collection, in conformance with a central MDR. Additionally, conformance reports must be produced to measure compliance to FDA standards as well as conformance to sponsorspecific Data Standards.

• Generation of integrated SDTM data sets across a diverse set of data collection tools must be facilitated

A u t h o r BIO

Isabelle de Zegher is Vice President, Integrated Solutions at PAREXEL INFORMATICS. She has 12 years of experience in pharma through PAREXEL, Novartis, UCB and Cap Gemini, and 10 years in Health Care IT. She served on the CDISC Board of Directors for three years.

Michael Goedde is Vice President Global Data Operations, PAREXEL, since 2014. He has more than 25 year of experience in the Pharma and CRO industry, working in all areas of Clinical Data Management and Programming. Michael is a Certified Clinical Data Manager and holds a BS in Computer Sciences .

Benedikt Egersdoerfer is Vice President Global Data Operations at PAREXEL. He has 25+ years industry experience in the Pharma and CRO sector and developed/led data related functions from safety data processing through clinical DM, Medical Coding, DB Programming, Statistical Biostatics, Medical Writing to Data Science.

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by implementing tool specific “eCRF libraries” conforming with the enterprise Data Standards managed within the MDR. • Specification of SDTM must be automatically generated at study set-up, together with data collection, in order to enable near-real time data visualisation from first patient, first visit onwards.

• And finally, each clinical study must come with a rich layer of metadata.

Clinical studies data should be stored in the format they have been generated, with the metadata layer enabling just in time transformation for modelling and simulation and in-silico studies or for other secondary data use.

The implementation and utilisation of an E2E Data Standards ecosystem is the most cost-effective and efficient way for Data Operations groups to remain competitive while providing the highest possible quality of data within each clinical study.

Reference [1].“Providing Regulatory Submissions in Electronic Format — Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act”.

Guidance for Industry. December 17, 2014.

[2].http://www.cdisc.org/Japan-PMDATechnical-Conformance [3]. Cantrell, Kusserow, James, Copeland, Patro, de Zegher. “Paper CD12. Pattern based Metadata Repository: toward high quality data standards”. PhUse Annual Conference, Barcelona 2016.

[4]. de Zegher, Gray, Sullivan, Goedde.

“Paper DH01. Effective use of a Metadata Repository across data operations: the need for a machine readable form of (part of ) the protocol”. PhUse Annual Conference, Barcelona 2016.

[5]. Hopkins, Duke, Dubman, “Statistical Computing Environments and the Practice of Statistics in the Biopharmaceutical Industry”, Drug Information Journal, Vol. 44, 2010.

Role of Thermal Covers/Blankets in Air Transportation of Pharma CRT Products As a common saying goes â&#x20AC;&#x153;A chain is as strong as its weakest linkâ&#x20AC;?. In air transportation of temperature sensitive pharma products, the weakest link and the most vulnerable area is the TARMAC. Why is it the weakest link? This is the point where the cargo is left at the mercy of ground handlers and the harsh environment. Typically any time and temperature sensitive pharma shipment must not take more than 60 minutes for ramp transfer and loading/unloading, but this does not happen in most cases. There are delays due to : 1. Lack of training 2. Absence/non compliance of protocols 3.Uncontrollable/black swan circumstances.

With an understanding that the delays are inevitable, how do we then ensure that there are no temperature excursions on the Tarmac? Here are some of the common precautions that are adopted A) An active containers - one that have a cooling unit operated by battery/plug-ins/charged with dry-ice B) Validated Passive Shippers with gel-packs/phase change materials C) Passive thermal pallet covers that are based on resistive properties of heat transfer.

Each of the above solutions comes with its limitations.

While active containers are considered most secure their limitations are 1) They have very high rental cost 2) Availability at all stations is a question mark? But even with these limitations they are considered an ideal choice for high value products.

Next is the Validated Passive Shippers.These are generally validated for 48/72/96 hours but are very high in volumetric storage but low in product storage. These are considered very good option for small shipments and clinical trials.

Finally comes, Thermal Covers/Blankets, these are most popular due to 1) Low cost, 2) Easy operation, 3) Low storage space and 4) Easy availability.The limitation of these blankets is that they are considered unreliable for extended period of extreme temperature.

Thermal covers/blankets make an ideal choice for logistics and quality assurance people for short durations of exposure on the Tarmac. A low cost thermal pallet cover can start at US$ 10 and can go as high as US$ 250. The huge difference in cost is due to the quality of the thermal cover/blanket. The principle on which these thermal covers work is their ability to reflect the heat by almost 99%. Some companies claim that the white fabric has better efficiency which is, not true.

The use of highly reflective aluminum layer/s is the core of all efficient thermal covers.

The future of thermal pallet covers/blankets is far greater than its current status. The key to fully explore the true benefits of this product lies in their customization. One shoe does not fit all!

At Weather Shield, we are constantly working closely with Pharma, Logistic & Aviation industry to produce some of the best and most cost effective solutions for the industry.

Pharmaceutical companies are slowly but steadily graduating and becoming more GDP compliant than ever. The term room temperature is replaced by Controlled Room Temperature (CRT), more specifically +150C to +250C. Those companies who were earlier using no protection for the tarmac have started using a basic thermal cover. And some of them have replaced active containers and validated shippers with top of the line thermal blankets, resulting in a lot of saving.

The next role of thermal blankets will be seen in bulk air transportation of +20C to +80C product, thereby creating a more robust, space-saving and cost effective supply chain for pharma industry.

Kapil Gupta is director at Weather ShieldÂŽ brand of thermal pallet covers and blankets.

He has a keen insight and experience in CRT pharma air logistics. Kapil is responsible for the development of customized thermal cover and blankets for global pharma giants and air cargo carriers.

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Electronic FDA Submissions Is APAC prepared for the 2017 mandate?

“If your time to you is worth savin’, then you better start swimmin’ or you’ll sink like a stone, for the times they are a changin’” – Bob Dylan Warren Perry GRCP Compliance Consultant Dassault Systèmes BIOVIA, USA

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T

wo pieces of US legislation impact the future of the life sciences industry: the Food and Drug Administration Safety and Innovation Act (FDASIA) and the Affordable Care Act (also known as Obamacare). FDASIA establishes user fee acts, brings generic drugs under a stronger set of guidelines and sets into motion a countdown to May 2017 when all submissions to the US Food and Drug Administration (USFDA) must be made electronically. The main purpose of the Affordable Care Act is to drive down the cost of health care. To that end the act encourages the use of less expensive generic drugs.

The generic drug industry is based primarily in Asia, Africa and South America where generic drug companies have typically not been subject

to the same level of scrutiny, industry standards and best practices that the new FDA regulations now require.

They will need to comply with more stringent FDA mandates by deploying new electronic document management, quality management and submission management systems, and they will not be able to do business with the FDA in the same way they have done business with their own governments in the past.

Generic drug companies need to understand that compliance risk equals brand risk. The FDA can and does place import bans on non-compliant foreign companies. If a company is out of compliance, there is a very real possibility that it will soon be out of business.

INFORMATION TECHNOLOGY

An industry divided

The global pharmaceutical industry can be divided into aligned vs. non-aligned countries. In aligned countries such as Japan, US, Canada and most European Union countries, most companies rigorously follow industry best practices and established standards and maintain a genuine commitment to quality.

In aligned countries, when people are trained in the correct processes for doing their jobs, they usually adhere to those practices. But in non-aligned countries, there might be a tendency for people to try to find ways to shortcut the process (“I don’t need to fill out all those forms or follow those procedures. I can get this done quicker.”) They might believe these shortcuts benefit their company because they can create more of a product faster if they skip a few steps. But those steps are built into the process to ensure safety, control quality and enforce traceability that supports defensibility for auditors and inspectors.

New mandates established in FDASIA will have a substantial impact on pharmaceutical companies in non-aligned countries, and this has implications for US markets. The vast majority of the generic drugs consumed in the US come from pharmaceutical companies in the Asia-Pacific (APAC) region and other non-aligned countries. The US market can or soon will represent as much as 80 percent of their profits. A significant number of pharmaceutical companies in non-aligned countries will go out of business if they can’t sell their products in the United States.

Half of the drugs consumed in the US are used by people over the age of 65 and are paid for by Medicare. The largest integrated healthcare system in North America is the US Veterans Administration (VA). With more than 1,700 hospitals, clinics, community living centres, and other facilities, the VA writes the most prescriptions and dispenses a large percentage of drugs in the US. A major objective of the Affordable Care Act is to lower the cost of health services that the US Government directly

FDASIA dictates that generics and biosimilars companies must now pay user fees to the FDA, and by May 5, 2017 all submissions to the FDA must be made electronically.

funds – including Medicare and the VA–and this initiative is compelling a move toward generics and biosimilars that are often not manufactured in the US. So if Obamacare is to lower the cost of national healthcare in the US, that must be done by a move toward less expensive generic drugs that come from Asia and other non-aligned regions.

FDASIA dictates that generics and biosimilars companies must now pay user fees to the FDA, and by May 5, 2017 all submissions to the FDA must be made electronically. The purpose of these policies is to create a more efficient industry and safer products for consumers by streamlining the submission and approval process for new drugs and by generating funds for the FDA to inspect pharmaceutical factories in foreign countries more frequently.

Senior management and decision makers in pharmaceutical companies based in non-aligned countries must understand how serious this is. It’s not realistic for them to expect that they can comply with these mandates without investing in their business or changing the way they operate.

Data quality and data integrity drive best practices

The Electronic Common Technical Document (eCTD) is an interface used by the pharmaceutical industry to transfer regulatory information to agencies like the FDA. This interface is supported

and enabled by enterprise Document Management Systems (eDMS). Why is it better for companies to have eDMS systems? Some years ago that was the conversation within the industry. We talked about improving return on investment by making processes more efficient and enforcing unified information and standardisation. But today the conversation has changed. Soon companies will not be able to communicate with the FDA without eDMS. They will not be able to make regulatory submissions to the FDA without eCTD publishing software.

There are countless business advantages compelling pharmaceutical companies to invest in integrated systems, unified data, end-to-end information flow and standard ways of identifying records across all systems and departments. However, it can be difficult to sell that story into Asia and other nonaligned regions today. Because labor is cheap there, company decision makers often solve problems not with automation, standardised processes and best practices—but with people.

In some non-aligned countries, companies don’t care if they need to re-run an experiment or process to restore data that was lost due to poorly integrated or non-existent information systems. They simply dedicate plentiful and inexpensive human resources to solving the problem. Unfortunately, this tactict ends to compromise data quality and data integrity, which can lead to violations in current Good Manufacturing Practices (cGMP). In April 2016 the FDA issued new guidance for the pharmaceutical industry to clarify the role of data integrity in cGMP for drugs. The regulator drafted the guidance because its inspections were increasingly revealing cGMP violations due to poor data integrity.

Throwing more manpower at issues like process duplication, siloed information and other common challenges doesn’t truly solve problems. Companies that do this may have found a shortcut, loophole or a quick way around an issue. But that doesn’t help the industry move toward www.pharmafocusasia.com

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Fig 1 Generic drug companies that believe they will be exempt from new mandates must understand that their business may be at risk.

An industry united

As US policy makers push to lower the cost of healthcare, eliminate millions of pieces of paper from FDA processes and enforce safety guidelines, many companies in APAC and other non-aligned countries will no longer be able to continue doing business the way they previously did.

The US is not trying to compel these companies into compliance just because it is easier for its regulatory bodies and safer for consumers. In the long run, 60

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improved compliance will shorten manufacturing cycles, accelerate processes, and improve productivity. Deploying bestpractice systems and processes will make companies more capable, responsive and proactive.

Some industry watchers in APAC and non-aligned countries imagine there will be a massive failure of the supply chain if the FDA enforces the new mandates. They think regulators will be forced to make exceptions to the rules and companies wonâ&#x20AC;&#x2122;t need to invest in new systems or enforce best practices.

Because so many generics come from non-aligned regions and the US wants lower-cost healthcare, some executives might think they will have negotiating power in this dispute.

A u t h o r BIO

an optimal outcome. We want safer products on the market. That can only be accomplished when every company makes regulatory submittals using the same standardised forms and with data that can be trusted.

Itâ&#x20AC;&#x2122;s a tall order to ask large established companies in non-aligned countries to change their culture, systems and processes. But the message from the FDA is clear. If companies want a piece of the lucrative US generic drug market, they can only get it through compliance with regulations in a way that is defensible to FDA auditors and inspectors.

But over the centuries, people have united to establish rules that minimise threats to human populations. FDA regulators bring the full weight of that momentum to bear as they implement new guidelines for the global life sciences industry. Companies that have previously been out of compliance have an opportunity to be on the right side of history.

The short-term ramification of compliance means large investments but the benefits include a strong competitive advantage. Having the right document management systems in place meets demands from more sophisticated sponsors who want controlled, audited environments to exchange information across their supply chainsâ&#x20AC;&#x201D;from research phases through commercialisation. The generic drug company that can quickly deliver CFR21 Part 11 compliant data for audits and inspections stands to gain more business. CFR21 Part 11 of the Code of Federal Regulations establishes the USFDA regulations on electronic records and electronic signatures (ERES).

Understanding these regulations is essential for a successful deployment of any system that is subject to FDA inspection.

Companies that postpone this initiative until the regulations go into effect will find it much more difficult and expensive to achieve compliance. There might not be enough technology vendors with the time and bandwidth to get complex information systems installed and validated by the deadline. Now is the time for generic drug companies to align with policies and practices that support a stronger, safer, more unified and compliant global pharmaceutical industry.

Warren Perry has held various positions during his twelve years with BIOVIA including Product Marketing Manager, Marketing Manager, and Project Lead. He applies his understanding ofgovernance, risk management, and compliance (GRC), regulatory publishing,and eDMS systems in global markets with clients such as Takeda, Samsung Biologics, Roche, BoehringerIngelheim, GlaxoSmithKline, Fidelity Investments, Bank of America, Logica CMG, and Aspen Pharmaceuticals.

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Books

Developments in Statistical Evaluation of Clinical Trials

Translating Clinical Trial Outcomes Measures: An overview

Author: Kees van Montfort, Johan Oud, Wendimagegn Ghidey

Author: Sergiy Tyupa, Diane Wild

Author: Robert A Parker, Nancy G Berman

Year of Publishing: 2016

Year of Publishing: 2016

Year of Publishing: 2016

No. of Pages: 71

No. of Pages: 543

No. of Pages: 361

Description: The purpose of this book is to provide a general overview of the translation and cultural adaptation process of clinical research survey instruments with a focus on the linguistic aspects of the process. Survey instruments here refer to any text, printed or electronic, prepared in order to collect information in a clinical research setting. This broad definition covers patient-reported, clinicianreported, and caregiver-reported outcomes measures, as well as patient diaries, indexes, scales, symptom checklists, etc. The first part of the book offers a brief introduction to selected linguistic aspects of translation in order to provide definitions of key linguistic concepts and to set a tentative theoretical framework for the translation and cultural adaptation process.

The second part describes the main steps used in the translation process

Description: Planning a clinical study is much more than determining the basic study design. Who will you be studying?

How do you plan to recruit your study subjects? How do you plan to retain them in the study? What data do you plan to collect? How will you obtain this data?

How will you minimize bias? All these decisions must be consistent with the ethical considerations of studying people.

This book teaches how to choose the best design for your question. Drawing on their many years working in clinical research, Nancy G. Berman and Robert A. Parker guide readers through the essential elements of study planning to help get them started.

Description: Over the past few decades the role of statistics in the evaluation and interpretation of clinical data has become of paramount importance. As a result the standards of clinical study design, conduct and interpretation have undergone substantial improvement. The book includes 18 carefully reviewed chapters on recent developments in clinical trials and their statistical evaluation, with each chapter providing one or more examples involving typical data sets, enabling readers to apply the proposed procedures. The chapters employ a uniform style to enhance comparability between the approaches.

62

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ISSUE - 25 2016

Planning Clinical Research

Management of Data in Clinical Trials: Medicine, Medicine

Cancer Clinical Trials: Proactive Strategies (Cancer Treatment and Research)

Essentials of Clinical Research

Author: Cram101 Textbook Reviews

Author: Stanley P L Leong

Author: Stephen P Glasser

Year of Publishing: 2016

Year of Publishing: 2016

Year of Publishing: 2016

No. of Pages: 56

No. of Pages: 340

No. of Pages: 461

Description: Facts101 is your complete guide to Management of Data in Clinical Trials. In this book, you will learn topics such as as those in your book plus much more. With key features such as key terms, people and places, Facts101 gives you all the information you need to prepare for your next exam. Our practice tests are specific to the textbook and we have designed tools to make the most of your limited study time.

Description: The ever-changing regulations for clinical trials and the ethical dilemma of treating cancer patients as subjects have made it ever so difficult for the principal investigators to conduct clinical research, especially when they are often ill-informed of the complex nature of the regulations and over-worked.

Therefore, cancer clinical trials are at a critical junction. The objective of this book is to bring the issues of cancer clinical trials into focus so that proactive strategies may be developed to make such trials more user-friendly. Ultimately, the cancer patients will be benefited.

Description: All chapters have been updated with new information and many new tables have been added to elucidate key points. The book now offers discussion on how to handle missing data when analyzing results, and coverage of Adaptive Designs and Effectiveness Designs and new sections on Comparative Effectiveness Research and Pragmatic Trials. Chapter 6 includes new material on Phase 0 Trials, expanded coverage of Futility Trials, a discussion of Medical Device approval, Off Label Drug use and the role of the FDA in regulating advertising. Additional new information includes the role of pill color and shape in association with the placebo effect and an examination of issues surrounding minority recruitment. The final chapter offers a new section on manuscript preparation along with a discussion of various guidelines being adopted by journals: CONSORT, STROBE, PRISMA, MOOSE and others; and coverage of Conflicts of Interest, Authorship, Coercive Citation, and Disclosures in IndustryRelated Associations.

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Company.........................................................Page No.

Analytica Vietnam...................................................23 www.analyticavietnam.com

Lufthansa Cargo AG............................................ IBC www.lufthansa-cargo.com

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Etihad Cargo......................................................... IFC www.etihadcargo.com

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INDEX Conferences & Exhibitions..........................27 www.index.ae

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ITALVACUUM Srl.....................................................17 www.italvacuum.com

Weather Shield India..........................................35,57 www.uvws.co World Courier.............................................. 09, 40-43 www.worldcourier.com

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