Pharma Focus Asia - Issue 34

ISSUE 34 2019

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BLOCKCHAIN IN PHARMA PATIENT SAFETY AND BEYOND

The Virtual World of Digital Clinical Trials Is it becoming a reality?

IoT and AI Create ‘Smart’ Digital Assistants Opening new possibilities for drug development www.pharmafocusasia.com

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Foreword Blockchain in Pharma Patient safety and beyond In the digital age where, technology is leading the way, blockchain has emerged as a disruptor in several industries from financial services to energy and life sciences.

Blockchain allows visibility and data integrity along with security against data hacking through decentralised blocks linked by the cryptography technique.

The pharma industry has for long been crippled with privacy and transparency issues impacting areas such as clinical trials, supply chain, counterfeit drugs. To address these challenges, the industry and players alike have been turning to latest technologies such as blockchain.

When it comes to clinical trial management, there have been concerns around data accuracy and privacy.

Patient studies results in huge amount of data sets that can be tampered with. Blockchain makes it easy to manage complex data in secure decentralised ledgers, thus providing patients with real-time insight into the clinical trial outcomes and increasing their confidence to be open in sharing their medical information. This also leads to shorter cycles for drug discovery and development.

Integration of blockchain technology thus allows drug companies to ensure regulatory compliance, product integrity, and consumer trust.

the world to be counterfeit and these drugs lead to estimated 1 million deaths every year. In the hope of slowing the fake meds, governments around the world are tightening their supply chain integrity requirements.

In the European Union, the Falsified Medicines Directive stipulates that pharma companies and others in the drug supply chain will need to serialise their products for track-and-trace by February 2019. The US introduced the Drug Supply Chain Security Act in 2013, giving the industry until 2023 to institute full, unit-level track-andtrace systems for products as they move through the supply chain. Blockchain enables verifiable transactions through digital records at every point of change thus curbing the prospect of fake drugs becoming part of the supply chain.

Blockchain has the potential to provide a platform for the protection and facilitation of intellectual property, including the facilitation of royalties, payments, and incentivisation models that could encourage participants to provide input into the research and development process.

Blockchain can provide anonymity and trust to verify and audit any activity and hence many companies have begun to realise the specific utility of blockchain technology.

The pharmaceutical industry’s supply chain is vast and complex, and products undergo multiple transfers along the chain. This leads to a logistical nightmare for manufacturers as they do not have visibility into the process of sale to the end consumer. Blockchain technology helps manufacturers with real-time access and visibility into the supply chain beginning with supplier product codes through the drug dispensing to patients.

Blockchain technology also helps manufacturers bring down dependencies on third parties resulting in data authenticity and cost savings.

The cover story of this issue delves into the various use cases of blockchain for the pharma industry.

Pharma companies face another serious challenge in counterfeit drugs — the World Health Organization (WHO) indicates around 10 per cent of drugs across

Prasanthi Sadhu Editor

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CONTENTS

COVER STORY

STRATEGY

BLOCKCHAIN TECHNOLOGY

06 Reduction of Health Costs

Swiss government chooses the wrong medicine with reference price system for drugs

Axel Müller, Managing Director, Intergenerika

Use Cases in the Pharmaceutical Industry

11 Medical Marketing Superheroes

Imagine you could genetically engineer your medical marketing team. You can

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Brian D Smith, Principal Advisor, PragMedic

22 Ethical Business Stimulates Best Value in Health Economy Thomas Cueni, Director General, International Federation of

Pharmaceutical Manufacturers and Associations (IFPMA)

CLINICAL TRIALS 28 The Virtual World of Digital Clinical Trials

Is it becoming a reality?

Manuela Maria Schöner Financial Economist and Data Analyst

Nimita Limaye, Practice Lead, Life Sciences Applied Technology Solns, Inc.

Michaela Kazmaier Digital Strategist Philipp Sandner Head, Frankfurt School Blockchain Center

MANUFACTURING RESEARCH & DEVELOPMENT 34 Academic Ventures and Professional Service Companies

Partnering issues in early stage drug development

Roberto Parente, LISA Lab, Department of Management DISA University of Salerno

Rosangela Feola, Technology Transfer Office University of Salerno

Valentina Cucino, PhD Student, Scuola Superiore Sant’Anna

38 Microneedle Array Patches

The way forward for the management of diabetes

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Ashish Wadhwani, Head, Department of Pharmaceutical Biotechnology, JSS Academy of Higher Education & Research College of Pharmacy

Baishali A Jana, Senior Research Fellow, Indian Council of Medical Research (ICMR)

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43 Systematic Framework for Implementation of RTD-based Control System into Continuous Pharmaceutical Manufacturing Pilot-plant

Ravendra Singh, C-SOPS, Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey

INFORMATION TECHNOLOGY 50 Customer Centricity on Social Media

Are there lessons for pharma from other industries?

Awani Saraogi, Analytics Consultant

54 IoT and AI Create ‘Smart’ Digital Assistants

Opening new possibilities for drug development Isabelle de Zegher, Vice President, Integrated Solutions PAREXEL Informatics

62 Books

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Advisory Board

Alan S Louie Research Director, Life Sciences IDC Health Insights, USA

EDITOR Prasanthi Sadhu EDITORIAL TEAM Debi Jones Grace Jones

Christopher-Paul Milne Director, Research and Research Associate Professor Tufts Center for the Study of Drug Development, US

ART DIRECTOR M Abdul Hannan Douglas Meyer Associate Director, Clinical Drug Supply Biogen, USA

PRODUCT MANAGER Jeff Kenney SENIOR PRODUCT ASSOCIATES David Nelson Peter Thomas Sussane Vincent

Frank Jaeger Regional Sales Manager, AbbVie, US Georg C Terstappen Head, Platform Technologies & Science China and PTS Neurosciences TA Portfolio Leader GSK's R&D Centre, Shanghai, China

PRODUCT ASSOCIATES Austin Paul John Milton CIRCULATION TEAM Naveen M Sam Smith

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

SUBSCRIPTIONS IN-CHARGE Vijay Kumar Gaddam HEAD-OPERATIONS S V Nageswara Rao

Laurence Flint Pediatrician and Independent Consultant Greater New York City

Neil J Campbell Chairman, CEO and Founder Celios Corporation, USA Phil Kaminsky Professor, Executive Associate Dean, College of Engineering, Ph.D. Northwestern University, Industrial Engineering and the Management Sciences, USA

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

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Sanjoy Ray Director, Scientific Data & Strategy and Chief Scientific Officer, Computer Sciences Merck Sharp & Dohme, US

Stella Stergiopoulos Research Fellow Tufts University School of Medicine, USA 4

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STRATEGY

REDUCTION OF HEALTH COSTS Swiss government chooses the wrong medicine with reference price system for drugs

Since autumn 2018, the first package of cost-cutting measures in Switzerland’s health care system is being reviewed. One of the measures is the socalled reference price system for pharmaceuticals whose patents have expired. Under the leadership of the industry association Intergenerika an alliance of doctors, pharmacists and patient organisations fiercely opposes the Federal Council's plans.

Axel Müller, Managing Director, Intergenerika

S

ince autumn 2018, the first package of cost-cutting measures in Switzerland’s healthcare system is being reviewed. One of the measures is the so-called reference price system for pharmaceutical whose patents have expired. The Government Health Department has given two models to the consultation.

We, i.e. Intergenerika in alliance with healthcare system’s key players, reject both for the following reasons: They

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severely limit the freedom of choice for physicians, patients and service providers, a consequence that Swiss insured persons are unlikely to accept in view of the clear verdict in earlier referendums with similar aims. In addition, they only lead to marginal premium reductions, which are barely noticed by the insured. Sick people will also have to make additional payments that are not counted towards their franchise. In short: Above all, the patients would be the big losers in this

system with its thoroughly antisocial consequences. Both models jeopardise the security of supply because falling prices lead to lower yields for manufacturers.

These will in turn have to respond with reduced services and smaller warehouses, which will lead to increased delivery difficulties. With the models presented, low-cost generics and biosimilars will be increasingly withdrawn from the market after the renewed, disproportionately high price reduction. Delivery bottlenecks in primary care Swiss patients are becoming more frequent in the remaining products. This will weaken the generics industry as a whole and reduce the share of generic and biosimilars, a consequence that runs counter to the will of politicians and consumers. Both want to promote generic and biosimilars. Security of supply - despite alleged countermeasures - is also endangered because manufacturers must focus on fewer products in view of the sharp drop in prices and can no longer offer additional services.

In addition, the choice of drugs will be smaller.

Last but not least: the intended changes in the Health Insurance Act leave many questions open and lead to legal uncertainty. The corresponding regulations will lack democratic legitimacy.

Plea for Preservation of the Existing System

We completely reject both models and demand the preservation of the generic pricing system, which has only recently been adapted and significantly tightened. This system has already resulted in increased savings in the short time.

The price reductions in 2017 alone led to savings of CHF 146.5 million in the patent expired area (generics CHF 60.1 million, originals CHF 86.4 million). It is precipitous in our view, if this effective system is already rejected shortly after its successful introduction, before it could unfold its effect sustainably.

STRATEGY

The existing system in addition to a defined price difference to the original preparation and dynamic differentiated deductible has proven itself. It is accepted and appreciated by the participants for the following reasons: • It guarantees patients freedom of choice and gives them reassurance that they will receive a consistent medication without constant change • Uninterrupted medication increases adherence and success, reducing costly hospitalisations • It increases the security of supply of drugs in various dosage forms and pack sizes, even in niche indications • It allows a predictable and socially acceptable burden for the patient with deductible and franchise without additional payment in the pharmacy • There is planning and legal certainty for manufacturers and their distributed medicines • It allows for competition among manufacturers and leads to regular significant savings in patent expired areas.

With the two proposed reference price models, these benefits will not only disappear, the universal service in Switzerland with low-cost generics will also be damaged.

Opinion on the Models

The criticisms of the two models are identical with the exception of a few points. The models do not lead to the promotion of generics and biosimilars as intended by the Federal Council, but will destroy or at least greatly reduce the Swiss generics and biosimilars market in the medium term.

Impact on the Patient and Premium Payer

In terms of treatment, patients and premium payers will suffer losses.

The freedom of choice of patients is limited. Depending on the choice of drug, they risk having to make a co-payment because insurers only have to reimburse certain drugs at the reference price. Long-term patients will be confronted with frequent drug changes if drug prices are reviewed and adjusted on a short-term basis insurers will only reimburse the cheapest It is well-known that such frequent drug changes have a negative impact on adherence to therapy (compliance), especially in

long-term therapy. In the long term, this will result in higher costs for the Compulsory Health Insurance, because the diseases worsen in the absence of compliance or inadequate treatment.

The choice of added-value medicines (special galenics, different dose strengths and pack sizes, divisible tab-lets, etc.) will be smaller, as manufacturers will have fewer resources at the proposed discounts. Also, because of uncertainty as to whether their product will ever be remunerated by health insurance, there will no longer be any incentive to develop such special, valued forms by patients. These will include those patients who may need to be treated with a drug that is not optimal for them.

The potential financial savings are also barely noticed by the patient. On the contrary, they even have a negative effect on the patient in the form of additional payments in the pharmacy. In addition, co-payments are not counted towards his

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STRATEGY

franchise. His deductible - if he accepts a generic at a reference price level - will be imperceptibly a few centimes cheaper than is the case in today's system. If the doctor prescribes a certain, more expensive drug for medical reasons, the patient has to make additional payments.

According to calculations by market research firms, these add up to CHF 41.7 million per annum. The same applies if, due to supply bottlenecks with generics, only the original is available. If all savings in the patent expired area of approximately CHF 423 million were completely passed on by the health insurance companies to approximately 8 million insured persons, this would lead to a one-time reduction in the monthly patient premium of approximately four to five francs. This saving is smaller than the annual premium increase, that is, the effect would not be noticed by the patient. In addition, a representative study carried out by Gfs Zurich in 2017 showed that three out of four patients would not be willing to switch to a model offering only the cheapest generic, even if the premium would decrease by five Swiss francs per month.

As a result, healthy insured persons would be marginally relieved of the health insurance premiums, but patients would have to pay more, in addition to their franchise and deductible, they would already have high ‘out-of-pocket’ payments compared to other countries.

In these countries, Switzerland is in the lead compared to others. They account for 28 percent of total health expenditure, compared with only 20 percent in the OECD. The models also mean that the prices between patented original preparations and generic drugs are aligned to a large extent. Thus, the price advantage of generics in comparison to the current model is largely eliminated, and patients have no incentive to use more generics.

In addition, the principle of the differentiated deductible, which in today's system ensures fair price competition and companies, is eliminated in the reference price model.

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With the new model, the prices of patented originals would probably be between 20 per cent and 70 per cent, and for imported products 10-35 per cent below the EU average (nine reference countries), since Foreign Price comparison’s reference price is the benchmark and to a certain tee comes.

At the same time, the patient's deductible difference between the original and the generic decreases compared to today's system. That's why the patient will be in the future have fewer incentives than today to replace an original with a generic one. The negative consequences for the generics market and security of supply are shown below.

Impact on The Market

The newer generics are already at the planned, so-called "maximum price" (Foreign Price Comparison minus defined price gap). Further price reductions, depending on the number of suppliers, would therefore come about primarily as a result of the price reduction to be set by the Federal Council on this maximum price. The size of this price difference is not defined in the law, but can be determined by the Federal Council in the ordinance. This means that the Federal Council can determine the amount of the discount freely. Since the regulations on the Health Insurance Act are only so-called enforcement orders, such a competence goes too far. This would

have to be specified in the higher-level law. Otherwise, the democratic legitimacy for the amount of such deduction is missing. Without binding information on the price intervals, which can be changed arbitrarily by the Federal Council according to time and amount, the manufacturers are not able to plan ahead and reliably budget. For older, very cheap generics, a price reduction on the "reference price" defined under new rules would lead to price levels, which in many cases would no longer allow further marketing for economic reasons.

As a result, especially these low-priced generics in the universal service would disappear from the market, resulting in higher costs of the Compulsory Health Insurance and thus runs counter to the objectives of the Health Insurance Act. We expect drastic consequences: • Manufacturers will reduce their stocks.

This will lead to increased supply bottlenecks and a reduction in security of supply, followed by an increase in the number of necessary drug changes in the patient • Generics with additional benefits such as confusion-proof packaging, special galenics, additional dose levels, etc. will disappear from the market, as the more expensive manufacturing and development costs can no longer be met • Manufacturers will try to focus on high-volume packs and less frequently take prescribed packs off the market. This, in turn, has implications for the security of supply and patient choice • Declining revenues and earnings as a result of price reductions will lead to a reduction in generic drugs and, as a consequence, elimination of smaller generics companies. Over time, it is likely to form a monopoly or duopoly in Switzerland • The idea that the reference pricing system will lead to more competition in the market is inappropriate. In addition, security of supply is jeopardised if the market is dependent on a few companies.

A loss of production at one supplier has a much greater impact in such cases because no other supplier can fill the gap

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STRATEGY

Aggravating Supply Shortages

We fear that the new models will increasingly lead to supply bottlenecks.

• It is envisaged that the reference pricing system will only be effective if at least three medicinal products with the same composition of active ingredients are listed in the Specialties List (SL) • But nowhere is it defined what kind of vendor it must be. It is also unknown if the rule also applies if, for example, there are two big providers and one very small provider or even just one big and two small ones. The security of supply in such a constellation is by no means guaranteed, even if the number of providers meets the legal requirements • Companies could refrain from marketing their products if there are already three suppliers in the market, as they would have to start with lower prices • It is envisaged that the Federal Council can take measures if security of supply is jeo-pardised. This is hardly effective in practice to implement, because often not even the manufacturer knows when a supply bottleneck occurs • It is acknowledged that security of supply in the Swiss generics market is currently high, especially when compared to other countries.

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This high level of security has two main reasons: • The comparatively higher prices in Switzerland automatically direct international drug flows first to ‘'stock-out’ situations in Switzerland, and any inventories are also preferred to Switzerland.

This mechanism would be compromised.

• Due to the high service expectations of the customers, the ability to deliver is an important competitive factor. Generic companies in Switzerland therefore keep above-average stocks in order to compensate for external supply fluctuations as much as possible. For economic reasons, such warehouses will no longer be possible in the future, which will lead to increased supply bottlenecks. Due to these circumstances, the reference price system will inevitably lead to increased supply bottlenecks as the balanced system that exists today will no longer be possible. The countermeasures can not in any way capture or neutralise the expected consequences of the new system. On the contrary, supply insecurity will worsen because of the mechanisms outlined.

With the new model, the prices of patented originals would probably be between 20 per cent and 70 per cent, and

AUTHOR BIO

• By aligning the prices of generic and patented original products, generic products be-come less attractive to patients and healthcare providers compared to today's systems. Generic penetration of the market will decrease in comparison to today, and there will be a decrease in generic generics. This in turn has far-reaching consequences for manufacturers • Quantity reduction will increase manufacturing costs. Switzerland already has very small quantities by international standards, which aggravates the problem of more ex-pensive production • By simultaneously reducing the prices, the contribution margins and, as a result, the investment opportunities for generic companies will decrease in percentage and absolute terms. This, in turn, affects supply and supply security.

for imported products 10-35 per cent below the EU average (nine reference countries), since Foreign Price comparison’s reference price is the benchmark and to a certain tee comes. For the pharmaceutical country Switzerland, with the highest wage level in Europe, this is an absurd situation.

The consequences are foreseeable: Some original manufacturers will take their originals from the market, since their sales no longer pay off due to the fixed costs with the massively reduced yield. Others will reduce the price to the highest price and thus be close to the price level of the generics or the reference price. This increases the pressure on generics and their prescription would collapse. Many patients and doctors would prefer the original if it is as expensive as a generic. With a greatly reduced prescription, many generics no longer pay off for the manufacturers, with the result that they are taken off the market. The market would then be largely dependent on the original preparations. As shown above, with declining revenues, the original manufacturers will examine which medicines can still be marketed profitably and which are to be withdrawn from the market. However, the market will hardly contain any generic drugs because they had to be taken off the market for economic reasons. The result is that while the proposed reference price system will result in a short-term price reduction, in the longer term it threatens the security of supply and the selection of medicines to a considerable and probably irreversible extent.

With over 30 years of experience in leading companies in general management, development, regulatory, manufacturing and marketing, Axel Müller knows the pharmaceutical and generic industries in all aspects across the entire value chain. The study of pharmacy and PhD in pharmacology were followed by specialised training at international educational institutions such as Columbia University, New York.

STRATEGY

MEDICAL MARKETING SUPERHEROES

Imagine you could genetically engineer your medical marketing team. You can One of the big differences between the life science industry and other sectors is the way that the marketing process happens not only in the marketing department but also in sales, medical affairs, market access and many other departments. This ‘distributed competency’ means that excellent marketing flows not only from superior capabilities in each department but also from effective and efficient cross-functional capabilities. But where do these come from? What distinguishes companies that are great at it from other companies for fail to coordinate well? In this article, Professor Brian D Smith will describe his research findings in this area and how they guide firms to become better at creating value across functional boundaries.

Brian D Smith, Principal Advisor, PragMedic

A

llow yourself a moment to dream. Imagine that you could give your medical marketing team superpowers. What would they be?

Being invisible would allow your marketers to watch competitors as they work. Being able to read the minds of key opinion leaders would make your medical affairs team incredibly insightful. Time travelling market access teams could observe the future and use that knowledge to shape reimbursement. A team of medical marketing X-men would be unbeatable.

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STRATEGY

It’s a dream of course. The fictional superheroes owe their powers to the mutated X-gene and we can’t genetically modify our medical marketers.

Or can we? There is a very real and practical sense in which we can. This idea emerges from my research into the evolution of the industry and, if you stay with me whilst I make a diversion into that science, I’ll explain how your firm might transform the abilities of its medical marketing teams in the real world.

A process for understanding the market situation

The traits of any living creature — a giraffe’s neck, an eagle’s eyesight, your intelligence – are the result of physiological processes. Those processes are enabled by proteins, the workhorses of the body. And as any high school biologist knows, those proteins are expressed by sequences of DNA that we call genes. The triumph of modern biology is the way we understand observable traits as the result of sequences of base pairs, shaped over millennia by evolution.

But this idea — the neo-Darwinian synthesis — has spread far beyond biology. Since the 1980s, management scientists have been using the same idea to explain the evolution and performance of organisations. And my research group at the UK’s University of Hertfordshire is the only one in the world applying it specifically to the pharma and medtech sector.

The Darwinian evolution of industries is directly analogous to biology. The traits of a firm – its innovativeness, its operational efficiency,

its marketing prowess – are the results of business processes. These processes are enabled by capabilities, the ability of the firm to do certain things well.

And just as proteins are expressed by genes, capabilities are the expression of organisational routines. These are the thousands of little sub-processes that every organisation has for doing everything from ordering stationery to making sense of the market.

Routines are just like genes. They store information about how to do something, they can be copied and they can mutate.

And just as genes are sequences of DNA, organisational routines are aggregates of micro-foundations, a term I’ll explain later in the article.

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A process for understanding the market situation

A process for making & executing a strong strategy

Figure 2: The Capabilities for Understanding the Market Situation

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A process for making & executing a strong strategy

A process for working cross functionally

Figure 1: The Processes of Effective Medical Marketing

The Genetics of Teams

The capability for understanding the external social and technological environment

An effective medical marketing team

The Engineering of Excellence

This scientific analogy between biology and business is not just a figure of speech. It is a direct parallel with important consequences. If we want to give a living creature a particular trait — a child without cystic fibrosis, for example — we would need to modify its genes by changing its base pair sequence.

We would regard as insane anyone who thought they could train the child not to have that genetic condition.

The same logic applies to pharma and medtech companies. If we want a certain trait to be strong — insightful market understanding perhaps or compelling value propositions — we would need to change its capabilities.

To do that, we must modify the organisation’s routines, which would mean changing the micro foundations of those routines. Training is not enough; many firms find that training fails to deliver the traits it wants. That is explained by seeing training as superficial, like training a wolf to be a

A process for understanding the market situation

A process for making & executing a strong strategy

STRATEGY

The capability for identifying critical alignment issues between internal and external environments

A routine for identifying genuine strengths

A routine for identifying genuine weaknesses

A routine for identifying genuine opportunities

A routine for identifying genuine threats

A routine for identifying SWOT alignment

Figure 3: The Routines for Identifying Critical Alignment Issues

family pet. Most of us would not trust our children to a wolf. But many of us trust our children to the family dog.

The difference is not training alone, it is genetic modification. In other words, improving the performance of your firm, or a part of it like the medical marketing team, is a matter

ATTRIBUTES

of engineering its microfoundations, to change its routines, to express stronger capabilities, to improve its process and so transform its traits. To repeat, this is not a metaphor; it is a direct analogy.

Gene Therapy for Marketers

Enough of the science. How does this

CONFLICT

OF THE INDIVIDUALS

MANAGEMENT METHODS

TEAM

GROUP

STRUCTURES

PROCESSES

new perspective help us to create a medical marketing team of X-men and women? It’s not enough to grasp the principle, we need to understand the practice. And the best way of explaining that is by example.

An effective medical marketing team understands the market situation, it creates and executes a strategy that fits that situation and it does these three things by pooling its crossfunctional expertise. As figure 1 shows, effectiveness is the result of these three processes.

Each of these processes is made possible by a set of capabilities. Figure 2 shows a simplified picture of the capabilities than enable the process for understanding the market situation.

Each of these five essential capabilities is the combined expression of a set of organisational routines. For example, figure 3 shows the routines that enable the identification of critical alignment issues between the market’s opportunities and threats and the company’s strengths and weaknesses.

And each of these five routines is the result of a set of microfoundations, which are aspects of the medical market team that make routines possible and effective. These routines fall into four categories, which usefully share the same initial letters of their biological analogues- ACTG – as shown in figure 4.

Figure 4: The Four Classes of Microfoundations www.pharmafocusasia.com

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STRATEGY

It is the detail of these microfoundations that are the devil of creating a medical marketing team with superpowers. The microfoundations of a routine are specific to that routine, just as the base-pair sequence that characterises a gene is specific to that gene. But my work has uncovered many of the microfoundations that lead to effective routines and so enable strong capabilities. An example of these, the microfoundations involved in understanding the market situation, is shown in figure 5.

e.g. Skilled at applying RBTbased reality filters to outputs of internal and external analysis

e.g. Interdependencies built into performance assessment

TEAM STRUCTURES

GROUP PROCESSES

e.g. Cross-functional mission teams with line management connectivity

e.g. Distributed environmental scanning roles

Figure 5: The Microfoundations of Understanding the Market Situation

What process improvement would lead to this improvement?

What medical marketing traits do you most need improve?

CONFLICT MANAGEMENT METHODS

ATTRIBUTES OF THE INDIVIDUAL

What capabilities does the improved process require?

What routines would be needed to express those capabilities?

What microfoundations do you need to build?

Figure 6: Five Steps to Transforming A Medical Marketing Team

From Theory to Practice

In the above paragraphs, I’ve outlined some concepts that might seem theoretical but, like their genetic engineering analogue, have very important practical implications.

They mean that it is possible to engineer a medical marketing team that is much superior to the present and to your competitors. But training alone is not the answer.

In practice, transforming the capabilities of the medical marketing team involves answering a sequence of five essential questions. These are summarised in figure 6.

As figure 6 reveals, creating a medical marketing team of X-men and women demands more thought and effort than the routine, bottoms-on-seats training that most pharma and medtech companies often use. The lesson is that superpowers don’t come easily. But nor does anything worth having.

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AUTHOR BIO

Brian D Smith works at the University of Hertfordshire in the UK and Bocconi University in Milan, Italy. This article is based on his latest book “Brand Therapy: 15 Techniques for Creating Brand Strategy in Pharma and Medtech."

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COVER STORY

STRATEGY

BLOCKCHAIN Use Cases in the Pharmaceutical TECHNOLOGY Industry

This paper examines the Blockchain technology applied to the pharmaceutical sector. The article is threefold and provides an overview on (1) the Blockchain technology, (2) the pharmaceutical industry and its unique complexities and (3) the potential of Blockchain technology to reduce some of those complexities.

In the paper, we discuss two use cases for the Blockchain technology: (a) The pharmaceutical supply chain, (b) pharmaceutical development with focus on clinical trials and (c) the pharmaceutical research & development (R&D) process.

Manuela Maria Schรถner, Financial Economist and Data Analyst Michaela Kazmaier, Digital Strategist Philipp Sandner, Head, Frankfurt School Blockchain Center

W

hat is Blockchain? A Blockchain is a global distributed ledger or database running on millions of devices and open to anyone, where information and particularly anything of value 16

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can be moved and stored securely and privately (Tapscott et al., 2016). On the Blockchain, trust and integrity amongst strangers is established, not by intermediaries, but through mass collaboration and clever coding (Tapscott et al., 2016).

Key benefits of the Blockchain technology include trust, transparency, disintermediation, immutability and consensus. These characteristics ensure that the Blockchain technology is considered to be the digital disrupter to exchange anything of value

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Stage

Testing ground Purpose Years in phase

Discovery/ Pre-clinical Research and animal tests Patent protection 3-6 yrs

Phase I Healthy individuals (~50) Safety 0.5-1.5 yrs

Phase II

Phase III

Approval

Volunteer patients (~500)

Volunteer Patients (~1000)

Approval with regulatory authorities

Safety/efficacy

Satistical validity

1.5-2yrs

3-3.5 yrs

1.5-3yrs

Figure 1: The drug development process (Himmelmann, 2009)

(e.g. transactions where we have doublespend problems); just as the internet is considered to be the digital disrupter to exchange information. This has big implications for private businesses, corporations and the public sector.

The Pharmaceutical Value Chain

The pharmaceutical value chain is a complex procedure which on average takes about fifteen years from drug discovery to regulatory approval (Ding, 2014). It is structured into different phases, from the initial start, where the company decides to invest into research of certain therapeutic areas, to identifying and developing the most promising molecules, to several pre-clinical and clinical test phases and a final stage where market access is granted.

After successful market approval, pharmaceutical firms negotiate pricing with other stakeholders such as payers.

In many countries (such as the United States) value-based pricing plays an increasingly critical role in the price negotiations of drugs. After approval and pricing discussions, the drug is up-scaled for manufacturing and distribution. Quality and patient safety are priority issues when we speak about manufacturing and distribution.

Use Cases along the Pharmaceutical Value Chain

The Blockchain technology offers several fields for application along the pharmaceutical value chain.

Use Case 1: Pharmaceutical Supply Chain

Pharmaceutical supply chain involves the process by which the drug is supplied in an affordable manner and in sufficient quantities from manufacturer to pharmacies, hospitals and patients. The supply chain in the pharmaceutical industry is complex, with drugs changing ownership from manufacturers to distributors, repackagers and wholesalers before reaching the customer. There is little to no visibility for manufacturers throughout the supply chain to track authenticity.

Two major concerns within the pharmaceutical supply chain context include the counterfeit drug problem and pharmaceutical arbitrage

Roughly 19 per cent of all business spending on R&D worldwide is held by pharmaceutical R&D (Ding, 2014). Top pharmaceutical firms invest up to 20 per cent to 30 per cent of their topline into R&D each year.

opportunities. Counterfeit drugs are pharmaceutical products that are sold with the intent to deceptively represent its origin. Counterfeit drugs may contain inappropriate quantities of active ingredients, ingredients which are not labelled and/or no active ingredient at all. The burden of counterfeit is enormous and can result in treatment failure, health damage, toxicity, death, economic loss as well as in loss of trust in the healthcare system. The World Health Organization (WHO, 2010) estimates worldwide sales of counterfeit medicines to $75 billion in 2010, a 90% rise in five years. According to the WHO, in more than 50% of cases, medicines purchased over the Internet from illegal sites concealing their physical address are counterfeit drugs.

Even lifesaving prescription medicines for cancer and serious cardiovascular diseases are being sold to consumers (WHO, 2010). Counterfeit drugs are motivated by potentially huge profits and especially developing countries are targets, because the cost of legitimate drugs is often beyond the reach of much of the population (WHO, 2010).

The overall death toll attributable to counterfeit medicines, like the scale of the business, is unknown but the costs to public health are huge, since apart from death counterfeits can cause resistance to medicines (WHO, 2010)1.

1 https://www.experfy.com/blog/blockchain-technology-inthe-pharmaceutical-industry

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Figure 2: The pharmaceutical supply chain (adapted from the U.S. Food and Drug Administration, 2016)

Pharmaceutical arbitrage defines the problem, when for example governments grant subsidies for expensive but lifesaving drugs to be sold on a lower price in order to increase access of medicines to patients. Arbitrage opportunities are exploited when drugs are purchased on a low price with the intention to sell to patients on a high price. Pharmaceutical arbitrage erodes affordable prices and undermines access to medicines and health and causes financial losses for the government.

The Blockchain could be an opportunity platform to increase trust and transparency, with customers being able to track pharmaceutical products throughout the supply chain.

The packaging of a drug could be scanned by a bar code any time, the drug changes ownership. Only trusted parties are granted access to write on the Blockchain. The record is delivered on the Blockchain in real time.

Manufacturers and end customer can scan the bar code and see the history.

Optimally, the platform ensures drug identification, tracing, verification and notification in case an illegitimate drug 18

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is found. The intelligent Blockchainbased control system ensures end-to-end tracking. It will eliminate the opportunity for illegible drug modification, in particular at interfaces and where-ever there is manual intervention.

Use Case 2: Pharmaceutical Clinical Trials

Clinical trials provide challenges to the pharma industry: lack of trust between the parties, multiple parties and intermediaries, complexity, compliance to regulatory standards and controls, patient recruiting, data security and privacy issues.

Trust and transparency amongst different parties Throughout the clinical trial, multiple parties are involved which adds costs and creates complexity: patients, pharma companies, Contract Research Organisations (CROs), hospitals, doctors, regulators. The various parties involved may not trust each other, especially with regard to data collection and data integrity.

Blockchain may present a solution and act as an audit trail for pharma companies and auditors. The data is uploaded in real-time on the Blockchain

which increases the transparency. The data cannot be manipulated which establishes trust. Instead of third parties auditing the data, the Blockchain solution works with a consensus mechanism which does not need external auditors to validate the transaction. Instead, code auditors are required. At the end, the data owner and the legible data user could exchange data peer-to-peer. The Blockchain solution inherently provides data quality and drives a new governance model that is compulsory to be followed by all participants due to the Blockchain solution features.

Patient recruitment, control and trackability of data Successful clinical trials require patient groups that fulfil specific requirements.

Patient data is sensitive and for this reason not freely and easily accessible.

Data security and privacy is a sensitive topic, in particular with patient health data, and multiple parties involved.

As soon as the patient is on boarded, patient retention and satisfaction become increasingly important for a successful completion of a milestone of the clinical trial. Multiple locations

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of data origin in manual and electronic form and centralised data storages make it difficult to track back data or to recall who accessed or changed information at a specific time.

A Blockchain platform provides the opportunity to act as distributed ledger system where patients may use the platform to enter their data once on the central distributed data base and share it with interested third parties such as CROs. The patients keep full control of their data. Via a public ledger the data purchaser may see the data available without being able to identify a patient. The patient is in control of what they share via a public and permissioned Blockchain. They could at any time eliminate the data if otherwise not agreed on via a smart contract which is a “piece of code implementing arbitrary rules� (Buterin, 2014).

If the patient intents to allow a data purchaser to have access to more information on the private Blockchain, access can be granted any time by the owner.

Throughout the clinical trial the data is save and immutable on the Blockchain due to the shared data record that acts as a single source of truth. Due to the time stamped data collection and data flow on the Blockchain, defined access rights and verified identities may enter the system. There is full reliability and trackability of any change at any time.

Precision medicine and advanced analytics could lead to major milestones in clinical trials as soon as an electronic data base and security

The Blockchain could be an opportunity platform to increase trust and transparency, with customers being able to track pharmaceutical products throughout the supply chain

is established within the ecosystem of stakeholders with a Blockchain solution. Collaboration in form of industry consortia including legislators are required to make this happen. As a result, time savings in the length of clinical trials and long-term cost savings could potentially be achieved via a Blockchain solution.

Use Case 3: Pharmaceutical R&D Process

The pharmaceutical R&D process is a complex procedure: high upfront investments, long lead times to market and high failure rates: High upfront investments Pharmaceutical companies invest a large portion of their resources on R&D. Roughly 19 per cent of all business spending on R&D worldwide is held by pharmaceutical R&D (Ding, 2014).

Top pharmaceutical firms invest up to 20 per cent to 30 per cent of their topline into R&D each year. The average cost of developing a new drug is estimated to be about 800 million US Dollars (Grabowski et al., 2002; DiMasi et al., 2003).

Long Time-to-Market Pharmaceutical R&D is a complex development process that is structured into different phases, from discovery and pre-clinical and clinical testing to a final stage where market access is granted. All in all, from initial discovery to a stage where market access has been granted, the process can take up to 15 years (Himmelmann, 2009). During this time, pharmaceutical firms face cash-outflows for investments without having any cash-inflows yet.

High Failure Rates The drug development process is characterised by high uncertainty. After identifying a promising substance, it remains unclear whether it will make it through the different development stages. Based on the 2008 report of the Pharmaceutical Research and Manufacturers of America (PhRMA), only one candidate out of about 5,000 to 10,000 evaluated chemical entities will be granted market access approval (Himmelmann, 2009).

The complexity of the pharmaceutical R&D process and the high risk associated with may serve as a potential explanation for above average expected returns by capital markets. Pharmaceutical firms only have few possibilities to diversify their risks. Especially young firms face a high degree of non-diversifiable risk, which is expressed in high systematic risk and consequently high expected returns by capital markets leading to high cost of capital for such firms (Goncharov et al., 2014).

Especially in the early research phase, funding is critical for successful drug development. High cost of capital may adversely affect funding opportunities. One potential opportunity to increase information access to investors in the early research phase, while at the same time keeping track of ownership of proprietary information, could be the management of an open innovation process via the Blockchain. Trust and integrity between several stakeholders, such as research organisations and investors, is established through active collaboration and clever coding (Tapscott et al., 2016). The Blockchain ensures information exchange and flow across different processes of the innovation stage, while at the same time keeping track of ownership rights. In real time, information is visible to the regulator and funding parties, reducing information asymmetry and potentially reducing cost of capital2.

2 https://www.experfy.com/blog/blockchain-technology-inthe-pharmaceutical-industry

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Conclusion Manuela Maria SchĂśner is a financial economist and data analyst focusing on pharmaceutical markets. She holds a triple degree in Finance allied with 8 years of professional experience in top management consulting & corporate finance. Her expertise in Blockchain concentrates on use case analyses in the pharmaceutical industry, in particular within pharmaceutical supply chain and clinical trials.

AUTHOR BIO

The Blockchain technology is a disruptive digital technology which is capable of supporting existing processes and disrupting existing business models.

Blockchain-enabled solutions help building trust, transparency and traceability. In this paper, we give a short introduction to the Blockchain technology and describe how it can be applied in the pharmaceutical industry. We provide insights into three different use case scenarios: (1) Blockchain in the pharmaceutical supply chain, (2) Blockchain in clinical trials and (3) Blockchain in pharmaceutical R&D.   References are available at www.pharmafocusasia.com

Michaela Kazmaier is a Digital Strategist with 10 years of professional experience in Financial Services, Information Technology and Corporate Finance Advisory. Her expertise in the field of Blockchain is concentrated on digital advisory and transformation of start-ups and corporates, Blockchain funding structures, Initial Coin Offerings (ICOs), use case and concept creation in multiple verticals.

Philipp Sandner is head of the Frankfurt School Blockchain Center at the Frankfurt School of Finance & Management. The expertise of Prof. Sandner in particular includes blockchain technology, crypto assets, initial coin offerings (ICOs), digital transformation and entrepreneurship.

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ETHICAL BUSINESS STIMULATES BEST VALUE IN HEALTH ECONOMY Pharmaceutical business performance is widely perceived to be about robust sales, successful launches, financial results, profit margins, and the like. However, a very crucial measure of success relates to ‘how’ the industry conducts its business and achieves its mission. Ethics and building patients’ trust are at the core of how the R&D-based biopharmaceutical industry regulates itself today. In this opinion piece, Thomas Cueni, Director General of IFPMA, explains why the R&D-based biopharmaceutical industry has adopted the New Code of Practice and why it makes good business sense to win and retain the trust patients place in healthcare professionals, medicines and vaccines produced by the R&D-based biopharmaceutical industry.

Thomas Cueni, Director General, International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)

S

eventy years ago, average life expectancy globally was 47; today it is 72.

Seventy years ago, 50 million people worldwide were infected with smallpox; today none. The disease is eradicated.

Thanks to initiatives such as Gavi (the Vaccine Alliance), more than 80 per cent of children now get early immunisation.

The world’s state of health is better than ever, even though headlines often focus on the negative: Zika, outbreaks of Ebola and the lack of a cure for Alzheimer’s.

Successful biomedical research has, along with modern sanitation and global political will, contributed significantly to this phenomenal global health progress.

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Yet, the pharmaceutical industry is often criticised in the public debate for the values that guide its behaviour. One wonders why is the pharma industry so exposed in the public debate? Perhaps the answer lies in the core nature of our business. Unlike any other industry that sells consumer goods, our innovations can save lives. This leads to raised expectations within society for the industry to meet the highest standards of safety and effectiveness in medicines as well as to ensure ethical business conduct.

Companies that are virtually as one in putting “patients first” in their mission statements should not be surprised if

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the criticism is harsh when something goes wrong.

Return on Ethics

While it’s easy to prove the impact of bad commercial decision-making, ethics however, also impacts the bottom line.

An analysis by Ethisphere1, an institute defining and advancing the standards of ethical business practices, has shown that there could be a 6.4 per cent “ethics premium” on the stock-market. Ethics and financial value are tied together.

According to the World Bank and the European Bank for Reconstruction and Development (EBRD), more than 70 per cent of small and medium-sized enterprises (SMEs) in transition economies perceive corruption as an impediment to their business and one-third of SMEs see corruption as a major business obstacle. 2 The consequences include higher consumer distrust, unfair business conditions and/ or inaccessible market opportunities, stifled innovation and investment, burdensome regulations, and differing standards across borders leading to elevated business cost and legal risks.

There is, therefore, a strong business and economic case for ethical conduct, since companies generally, and SMEs in particular, are the engine of economic growth but need to operate and innovate within ethical corporate environments.

In the “ethics business”, our industry has been and remains ahead of the curve. I’m proud to be associated with the world’s largest public-private partnership to strengthen ethical business practices in 1 https://ethisphere.com/ 2 The Business Environment and Enterprise Performance Survey (BEEPS)

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BUSINESS ETHICS FOR APEC SMES INITIATIVE - IMPACT Largest Public-Private Partnership in the World to Strengthen Ethical Business Practices for SMES.

Source: http://www.mcprinciples.org/CMFiles/Events/2017%20Ethics%20Forum/DraftStrategicAssessment.pdf Table 1 Business Ethics for APEC SMEs Initiative

the medical device and biopharmaceutical sectors: The Business Ethics for APEC SMEs Initiative.

As the premier forum for facilitating economic growth, cooperation, trade and investment in the region, APEC (AsiaPacific Economic Cooperation) has shown great leadership. The potential rewards of increasing business ethics are considerable since APEC countries account for approximately 60 per cent of world GDP (US$19.254 trillion) and about 47 per cent of the world trade. Not only does the APEC Business Ethics initiative addresses a major challenge facing SMEs in target sectors and developing economies (e.g., in the identification and cost-effective implementation of the highest standard of ethical business practice), but it sets out a collaborative vision for the APEC region as a whole. This vision showcases how ethical business can support innovation, as well as strengthen economic growth, increase competitiveness, foster cross-border trade, reduce public waste and mitigate regulatory burdens. And critically, it can strengthen health systems 24

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and improve patient outcomes, build public confidence and trust in healthcare systems, promote access to life-saving and enhancing products, and boost innovation capabilities.

The results are incredible. In five years, the initiative has achieved nearuniversal adoption of codes of ethics by medical technology and biopharmaceutical industry associations within APEC economies, more than doubling the total number of codes from 37 to 77, including within ten economies where they previously did not exist (Chile, China, Indonesia, Malaysia, Peru, Philippines, Singapore, Chinese Taipei, Thailand, Vietnam). High-standards of business ethics are now part of normal business in 18,000+ companies, making real progress in raising the ethics bar and laying a solid foundation for trust in the healthcare sector. The speed of this achievement is better understood when recognising that the region’s initial 37 codes in these sectors took over three decades to develop. These efforts will continue to take shape and will be given a further

impulse at the 2019 APEC Business Ethics for SMEs Forum, Santiago de Chile, in September 2019. As industry co-chair, I look forward to taking part in these discussions and bringing to the table IFPMA’s contribution.

While the core of the innovative biopharmaceutical industry’s work is the discovery of new medicines and vaccines, it also needs to develop, promote, sell and distribute these in an ethical manner and in accordance with the rules and regulations for medicines and healthcare.

It’s not just what pharmaceutical innovation achieves that matters, but how the industry goes about achieving it.

Ethical Collaboration

An efficient healthcare system depends on mutual trust between patients, healthcare professionals, regulators and pharmaceutical companies. Today, global organisations representing doctors, nurses and hospital workers all bestow a great deal of importance on the culture of ethics.

And crucially, patient-centred care has emerged in recent decades as the solution

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Figure 1 IFPMA Ethos diagram www.pharmafocusasia.com

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ago may well be no longer acceptable, the IFPMA has reviewed and relaunched on January 1, 2019, its global Code of Practice as well as its ethical framework.

More Than a Code

But improving ethical conduct and increasing its undoubted benefits for the economy does not mean business and innovation should stop at codes and consensus frameworks. To be credible and in-step with societal expectation, we need to do more to reach all patients, regardless of their economic circumstances. Investment in health infrastructure, pathways to delivering services and prevention must be part of the dialogue.

Today, more than half the world’s population have to pay for their medicines out of pocket, potentially putting a huge strain on a patient’s family finances.

Progress will be hampered as long as Universal Health Coverage (UHC) is not in place.

But this requires a political rewiring.

Since far too often, governments worry more about the cost of treatment and prevention – but rarely do they tally the cost of inaction.

To do better, go further and faster, we’ll need partnerships, of all kinds.

Partnerships are crucial to improving patient access through strengthening health systems: 90 per cent of ‘essential’ medicines are generics, and yet

not all reach patients. Without access to prevention support and quality health services, global progress will be uneven. Achieving UHC means ensuring all people receive essential healthcare without risking financial hardship. There is also an important upside to this. As put so eloquently by Tedros Adhanom Ghebreyesus, Director General, at the World Health Organization (WHO): “If countries invest in making progress towards universal health coverage, they lay the foundation for progress towards ending poverty, improving gender equality, decent work and economic growth, and more.”

Achieving UHC is one of the health targets under the Sustainable Development Goals (SDGs), and will be the focus of the United Nations High Level Meeting (UNHLM) in September this year. Partnerships contribute to this by training healthcare workers, building infrastructure such as testing facilities, and delivering education to schools and community organizations to promote prevention. For instance, UHC2030 (a global platform for promoting UHC) brings together diverse stakeholders to advocate for political commitment, strengthen dialogue and facilitate knowledge sharing in order to strengthen health systems. These close partnerships could hardly have been imagined in previous decades and will only thrive with mutual trust.

AUTHOR BIO

for an improved healthcare systems. It represents a shift from “doctor knows best” to a new pact between patients and healthcare professionals, where the patients are actively involved at every stage of decision making regarding the effect of medicine on their well-being.

However, to empower patients, the right environment is needed — one based on trust. Trust has proven to be a critical factor influencing a treatment decision.

This includes whether a patient accepts a treatment and agrees to follow the prescription of medicines.

For this reason, in addition to ensuring a level playing field in terms of implementing codes of ethics, it is also essential to create consensus-based, multi-stakeholder ethical frameworks across health systems. In 2016, the world’s first economy-wide consensus framework agreements were concluded in Canada, Chile, Peru, and the Philippines, bringing together industry, healthcare professional associations, patients' organisations and governments. It is heartening to see that over the last summer, framework was also finalised in Australia, China, Mexico, Thailand, Japan and Viet Nam. At a global level, in Geneva, the R&D biopharmaceutical industry has instigated in 2014 a consensus framework for ethical collaboration supported by patients (International Associations of Patient Organizations - IAPO), nurses (International Council of Nurses ICN), pharmacists (the Federation of International Pharmacists - FIB), physicians (the World Medical Association WMA) and our industry. All partners are united in a mutual interest in ensuring that the relationship between patients, healthcare professionals, the pharmaceutical sector and their representative organisations is based on ethical and responsible decision making.

These partners are part of an ethical healthcare ecosystem, with patients at the centre: because patients need to be able to trust the interactions between pharma, healthcare professionals and medical representatives. Given that what was acceptable and normal practice a few years

Thomas Cueni is Director General of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), based in Geneva, Switzerland, and Industry Co-Chair of the APEC Biopharmaceutical Working Group on Ethics (http://www.mcprinciples.org/CM Files/Resources per cent202015/ TermsofReference.pdf ). He was previously Secretary General of Interpharma, the association of pharmaceutical research companies in Switzerland.

www.pharmafocusasia.com

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CLINICAL TRIALS

The Virtual World of Digital Clinical Trials

Is it becoming a reality?

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CLINICAL TRIALS

Increased access, rapid recruitment, remote monitoring of patients, enhanced patient engagement, reduced costs, and faster approvals are some of the major advantages associated with digital clinical trials. Even as digital transformation is gradually picking up speed, multiple challenges related to data privacy and security, compliance with evolving regulations, and logistical challenges still need to be addressed. While hybrid trials are increasingly being deployed, ‘patient-centricity’ should remain the priority.

Nimita Limaye, Practice Lead, Life Sciences, Applied Technology Solns, Inc.

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merging technologies have the potential to fundamentally alter how patients engage with and participate in clinical trials. Creating a digital strategy for drug development has become a critical focus area for pharmaceutical companies. Virtual / digital clinical trials minimise the burden on clinical sites, typically retaining a central coordinating site for the study. Patient enrolment is usually done remotely using social media and e-consenting tools, drugs and assessment tools such as sensors, are home delivered and conduct most trial procedures can be performed at home.

With leading pharma companies such as Novartis rebranding themselves as a ‘Medicine and Data Sciences’ companies (Narasimhan, V, 2018), it is time to sit up and think. Vas Narasimhan, the CEO of Novartis, believed that digital technology could save up to 10 to 25 per cent of the cost of clinical trials (Neville and Atkins, 2017). There are currently 294,244 research studies ongoing in 50 states and in 207 countries (clinical.trials. gov, as of 12th Jan, 2019). A very small percentage of these are virtual clinical trials. While hybrid clinical trials (using at least some components of digital technology) are the accepted norm today, Anthony Costello, VP, Mobile Health, Medidata has predicted that one-fourth

of clinical trials in the US could be completely ‘virtualised’ (Baum, 2018).

Spiralling drug development costs and an increased focus on ‘patient centricity’ are driving change in the conventional model of clinical trials.

To put it simply, as Dr. Eric Topol’s book states ‘The Patient Will See You Now’ and dwells upon how the technology is enabling the ‘democratisation of medicine and empowering the patient (Parish, 2015). The pharma industry is increasingly trying to minimise the need of the subject to visit the site. Technology cycles are shorter than pharma product lifecycles, thus driving the need for agility and speed of adoption, in what is per se, a highly regulated industry, where a culture of risk taking has not been the norm.

The Virtual Clinical Trial Revolution

This decade rang in the digital clinical trial initiative, with the first ‘virtual’ trial being approved by the FDA in 2012.

This was Pfizer’s Research On Electronic Monitoring of Overactive Bladder Treatment Experience (REMOTE) trial. It used e-consenting, web and smartphone-based recruitment, the study drug was delivered to patient’s and patient data and patient safety were monitored remotely by physicians throughout the trial. The objective was www.pharmafocusasia.com

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to enrol 600 patients from about 10 states across the USA. However, the trial failed, primarily as recruitment targets were not met, owing to the fact that technology proved to be challenging for an elderly patient population (Applied Clinical Trials Editors, 2011).

Sanofi, in 2015, ran an entirely remote online Phase IV clinical trial for diabetes. This was Europe’s first remote clinical study to use only e-consenting.

It used eClinical Health’s online clinical trial platform and tested Mendor’s 3G-enabled wireless blood glucose meter.

60 patients were recruited through Facebook and the conversion ratio was 81 per cent. There were no site visits and study materials were delivered directly to patients. The patients and the site could review the glucose measurements real-time review. Interestingly the average age of patients was 56, with several over 70: thus, the technology barrier related to age that had been reported to be the cause of failure of the REMOTE trial was overruled. Even more significant were the high patient satisfaction scores of 4.52 out of 5, with a drop-out rate of 9 per cent, which was the same as a comparator study. Notably, the site spent 66 per cent less time in study coordination (Adams, 2016). Thus, one drug trial (REMOTE) in the US and one device trial (VERKKO) in the EU setting the stage for virtual clinical trials, many more organisations are following suit.

Science 37 is a Los Angeles-based company which uses a blend of a proprietary cloud-based mobile platform called the Network Oriented Research Assistant (NORA), telemedicine technology, wireless devices, decentralized physician networks, and in-house experienced clinical study staff to conduct virtual clinical trials. It is running virtual trials in partnership with Novartis (with plans to launch up to 10 virtual trials in the next three years) and has also partnered with UCB for the same (Adams, 2018; Tyer, 2018). It also partnered with AOBiome Therapeutics to conduct a phase 2b clinical trial on an experimental 30

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With the cost of managing a study site ranging from $1,500 and $2,500 per month, the potential benefits of moving to a ‘siteless’ virtual clinical trials are significant (Petersen, M, 2018).

acne drug and the study was completed much faster than planned. Eleven physicians across 10 states, enrolled patients through Facebook and Google. More than 8,000 subjects were screened; finally, 372 participants received the drug or a placebo via mail. Companyissued iPhones were used to take selfies of their acne and photos were sent to the investigators via a phone app for evaluation, and video conferencing was used to communicate with study staff.

No CROs were involved (Muoio, 2017).

Novartis’ ‘Trials of the Future’ initiative attempts to digitally connect and aggregate medical device data during clinical trials. It follows a twopronged strategy — “around the pill” and “beyond the pill” (Alsumidaie, 2017). The “around the pill applications” support or enable the efficacy of drugs, by using adherence tools and applications (such as mobile patient engagement apps), intelligent drug delivery systems, remote monitoring tools and precision diagnostic tools.

The “beyond the pill” involves things such as digital therapeutics. While many have still not even heard of ‘a chip in a pill’, Proteus has used Ingestible Event Marker (IEM) technology which was approved by the FDA in 2012 to develop it. The IEM is a tiny IC on which an anode and a cathode are placed and serves as a sensor. The gastric juices in

the stomach activate the sensor and the electric signal that is generated creates unique signatures which are detected by a wearable patch applied to the skin of the patient. communicate information After about seven minutes, the sensors which have transmitted information about the body become inactive and are eliminated in the faeces or are absorbed in the body (Limaye, 2018). The first ‘chip in a pill’ to receive FDA approval in 2017, was Otsuka’s ‘Abilify’ used for the treatment of schizophrenia and bipolar disorder (FDA, 2017). Earlier on in 2015, Aprecia’s Spritam for the treatment of seizures became the first 3-D printed prescription drug to receive FDA approval (Scott, 2016). With 3D – printing reaction ware that can actually custom-print drugs in the making, one may not only be able to increase the access to drugs in remote settings, but distributed chemical manufacturing may also help curtail the counterfeiting of drugs (Service, 2018). Janssen partnered with Scripps Translational Science Institute, Aetna, and iRhythm Technologies to run a home-based trial on 2,659 subjects, called mSToPS (short for mHealth Screening To Prevent Strokes). It assesses a wearable ECG patch as a new way to remotely detect a trial fibrillation. Results showed earlier diagnosis as compared to routine medical care. Since untreated a trial fibrillation is associated with a fivefold increased risk for stroke this could be of considerable value and a similar approach is now being tested for rheumatoid arthritis using real-world data to identify subjects, including data from Aetna’s Healthagen insurance databases. Janssen is running this as a part of part of an umbrella project called Global Trial Community, which aims to keep patients engaged, by sharing some patient data during the trial sharing the outcome of the trial as well. The objective was to expand this platform to 26 countries by the end of 2018 (Koester, 2018).

IBM is using a fingernail sensor prototype and machine learning to diagnose Parkinson’s disease based on

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fluctuating changes in a patient’s speech.

It has received a grant from the Michael J. Fox Foundation for Parkinson’s Research for the conduct of Parkinson’s Progression Markers Initiative (PPMI), an observational PD study that has collected a vast amount of anonymous longitudinal data (Ghosh, 2019).

Novartis recently launched the FocalView app which will be used to remotely collect electronic device reported outcomes (eDROs) from 150,000 patients to track ophthalmic disease progression and will also use electronic informed consent and electronic patient reported outcomes (ePROs) (Gruber, 2018).

Challenges Associated with Digital Clinical Trials

While digital clinical trials seem to be the way ahead, there do exist diverse challenges related to digital clinical trials.

These include challenges related to:

• Data privacy and security • Dealing with populations with very low levels of computer literacy • Complex trials involving invasive procedures for which site visits would be essential • Dealing with an elderly population which may not very social media savvy – this may directly impact patient recruitment • The lack of in-patient support • Technology costs associated with running virtual trials • Interventional studies that need to be conducted in a structured setting, such as an intensive care unit or phase I unit – along with early-phase oncology and first-in-human studies • Patient engagement – as the interaction with clinicians decrease, companies have evaluated different options to keep patients engaged. EmpiraMed tested virtual gaming, wherein patient were rewarded by points for each goal that

they achieved (registration, recruitment, etc) and these points could be used for gift cards, etc. However, such approaches could raise ethical issues (Luchhini, 2018).

Advantage, Digital

Digital clinical trials have their own unique advantages: • The costs of patient visits range from US$3000 - US$7000 per visit. For a large multi-centric trial, running over 1-2 years, this could account for close to 60 per cent of the budget. Some of these costs could be offset through the virtual clinical trial model (Mantel, 2018).

• For indications where patients are incapacitated, or they may have challenges traveling to a distant site, the virtual model poses significant advantages in terms of retention.

• The virtual model may in fact be more representative of a patients’ www.pharmafocusasia.com

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The costs of patient visits range from US$3000 - US$7000 per visit. For a large multicentric trial, running over 1-2 years, this could account for close to 60 per cent of the budget.

Some of these costs could be offset through the virtual clinical trial model (Mantel, 2018).

The FDA Perspective

FDA Commissioner, Scott Gottlieb, has strongly advocated the use of digital technology in clinical trials (ACRP, 2018) and has proposed a Centre of Excellence for Digital Health in 2019 (Fassbender, 2018). It also launched the Digital Health Innovation Action Plan in 2018 to enable timely access to high-quality, safe and effective digital health products and the FDA Pre-Cert program, a pre-certification program to work with companies to develop a new approach to digital health technology oversight. The FDA in Dec 18, also as a measure of caution, published a report on the benefits and risks of digital health tools that are not regulated by the FDA as medical devices., since the Cures Act amended the Federal Food, Drug, and Cosmetic Act to exclude certain software functions (such as those

AUTHOR BIO

real-life experience, and the latency of actionable insights associated with the conventional ‘brick and mortar’ model is significantly reduced.

Companies like TriNextX partner with over 80 healthcare organisations across 16 countries, providing access to data of over 135 million patients through a cloud-based federated health research platform called TNX, which can use data from EHRs and run analytics to support the real-time modelling of proposed clinical trial protocols, feasibility studies and patient recruitment (Lynch, 2018 Yeates, 2018).

Sanofi also partnered with Evidation to monitor ‘digital biomarkers‘ in patients to analyse real-world behavioural data to bridge the gap between drug efficacy and effectiveness bey analysing patient behaviour, since 50 per cent of health outcomes are determined by patient behaviour (Staines, R, 2019; Bulik, BS, 2018).

• Subjects evolve from being only data producers to being both data producers and data consumers, enabling them to take more informed decisions regarding their health.

• Social media and mobile apps have literally transformed patient recruitment. Stanford University ran a cardiovascular trial using Apple’s MyHeart Counts App (from the Apple Research Kit - ARK) attracted 11,000 volunteers within one day. Similarly, the mPower app enabled the enrolment of 7,406 people in a Parkinson’s study within six hours: prior to that, the largest study group has been 1,700 (Landman, 2018). Biogen, which used to recruit an average of six patients per week partnered with the My Health Team, resulting in an upward spike in subject recruitment to 800 patients within 2 weeks 37 per cent of sites fail to meet recruitment criteria and up to 10 per cent do not recruit a single patient during a trial. Hence, the use of social media to enhance recruitment has becomes key (Limaye N. and Saraogi, V, 2018).

software intended for use as general wellness software products, certain types of electronic patient records etc) from the definition of a medical device and thereby FDA regulation (Caccomo, 2018).

There is an important need to create a digital clinical trial ecosystem or a continuum, clearly identifying the data flows between all the key stakeholders. Compliance with guidance and regulations such as ICHE6 R2, 21 CFR part 11, HIPAA and the FDA’s draft guidance on ‘Content of Premarket Submissions for Management of Cybersecurity in Medical Devices’, released in October 2018, GDPR is important. Blockchain technology, though still in a nascent stage, is being increasingly evaluated to facilitate interoperability between data contributors enabling all participants to securely maintain their own copies of the data, as per Deloitte (Kent, 2018).

With the cost of managing a study site ranging from $1,500 and $2,500 per month, the potential benefits of moving to a ‘siteless’ virtual clinical trials are significant (Petersen, M, 2018).

Virtual trials and the concept of ‘quantified health’ as described by Dr. Daniel Kraft, Executive Director, Exponential Medicine will probably define the future (Oymaci, 2018). ‘Virtual clinical trials’ or ‘digital clinical trials’ are clearly the destination of the future. Yes, it is of utmost importance to truly focus upon ‘patient centricity’ and ethics.

References are available at www.pharmafocusasia.com

Nimita Limaye (Ph.D Biotechnology) is an industry expert with over two decades of experience working across the pharma-biotech / CRO industry.

She has held senior leadership positions in the industry, led global operations, mentored life sciences technology start-ups, provided advisory services in outlining business strategy and consulted on diverse aspects in life sciences. She currently leads the Life Sciences Practice of Applied Technology Solns Inc. USA.

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Academic Ventures and Professional Service Companies

Partnering issues in early stage drug development The Life science industry has experienced an impressive transformation of its Research & Development (R&D) processes. While Incumbents, including Big Pharma, have progressively committed themselves over the final phases of new drugs’ clinical trials, new entrepreneurial researchbased ventures, have rapidly become the dominant players in the drug discovery and pre-clinical phases. In such an open model for innovation the entrepreneurial opportunity for academic startups is not at all (except a few notable cases) that to try to dominate a market niche in the future, but to sell their technologies to a bigger company for further exploitation. Therefore, to reach a successful drug discovery phase and/or a pre-clinical phase, cooperation with Business expert and Consultants is a live-or-die question for a new pharma ventures..

Roberto Parente, LISA Lab, Department of Management DISA, University of Salerno Rosangela Feola, Technology Transfer Office, University of Salerno Valentina Cucino, PhD Student, Scuola Superiore Sant’Anna

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O

ver the past few decades, life science and pharma have been characterised by a series of radical changes that have been at the origin of an impressive transformation of R&D processes and have made them a favoured scenario for radical change in the innovation paradigm.

The main trigger for these changes was the decline in R&D productivity in the industry during the first decade of the 21st century.

Investment in research and development has now increased substantially: they represent 16 per cent of sales in the period 2000-2010 with a 60 per cent increase in the previous decade. At the same time, the risk associated with the development process is increasing

RESEARCH & DEVELOPMENT

as a consequence of two main factors: the focus of investments in new and riskier therapeutic areas and the more restrictive regulation for drug approval.

In addition to this, the expiry date of patents between 2010 and 2014 have put at risk more than US$ 209 billion in annual drug sales, resulting in US$ 113 billion of sales of unlabelled drugs.

All these challenges have generated two different results: a strategic effect on the pharmaceutical companies, and a structural effect on the pharmaceutical sector.

From a broader point-of-view, the challenges and radical change that characterise the sector require the pharma companies to adopt adequate strategies to manage these risks. Some of the major steps taken by big pharma companies are those of restructuring their innovation model. The traditional model of closed innovation, predominant in the past decade and in which the innovative activities were mainly carried out in-house, has been replaced by a new model called Open Innovation in which collaboration among different actors of the innovation process is the key element. In other words, the innovation model of the pharma industry has evolved from an integrated one to a more open and networked model.

As a consequence, pharmaceutical companies have radically modified the innovation strategies, adopting an approach that promotes relations with the different type of partners (such

as biotech product firms) in order to acquire (inbound open innovation) or to commercially exploit (outbound open innovation) technologies and knowledge.

The growing openness of the innovation model of pharmaceutical companies is only one side of the coin, however. It has been accompanied, and at the same time favoured, by a radical change in the structure of the sector itself, with the emergence of new kinds of actors. The value chain of the pharma industry is now more disaggregated with the presence of different actors involved at different stages.

In particular, new kinds of players, that are small biotech start-ups, showed they were particularly able to capture the entrepreneurial potentials of these changes.

By deploying valuable technical expertise, lower costs, less cumbersome organisational structures and the ability to hyper-focus on one (or a few) specific areas that show promise, these companies have demonstrated the ability to make incredible scientific advances (Christy J. Wilson, in Pharma R&D, March 27th 2018) and they are playing a key role in the creation of new knowledge and technologies in the sector.

The growth rate of this eco-system of small biotech companies is very strong worldwide, and their development has conditioned the innovation strategy of big pharma companies and the organisation of the drug development process of the sector.

Incumbents, including big pharma, have progressively committed themselves over the final phases of new drugs’ clinical trials. They maintain their key role in the management of the more advanced and expensive phases of clinical

development and commercialisation on the final market of these new targets.

Start-ups and new entrepreneurial research-based ventures have rapidly become key players in the drug discovery process and pre-clinical phases. Thanks to their previous scientific knowledge, sometimes with the support of financial professionals specialised in high-risk investment, these spin-offs have proved particularly effective in the operations of identification and preclinical validation of new therapeutic targets.

However, in an open model for innovation, the entrepreneurial opportunity for academic biotech startups is not at all (except few notable cases) than to try to dominate a market niche in the future, but to sell their technologies to a bigger company for further exploitation.

The business model of these small biotech companies, with few exceptions, normally consists of the sale of their technologies that have reached a certain stage of development, to big pharma.

Therefore, to reach a successful drug discovery phase and/or a pre-clinical phase, that is the necessary level of development to be attractive to big pharma, for a new venture is a liveor-die question and at the same time a very challenging issue.

In fact, in addition to financial restrictions that generally this kind of firms have to face, there is a more ‘strategic’ aspect that needs to be considered concerning the choice of ‘key activities’ and processes on which to focus the attention and to direct efforts and resources during the initial stages of development. While clinical phases in the drug development process are quite well defined due to strict regulation rules that oversee the possibility to go forward, the pre-clinical phases are not. This means that judgement from the targeted buyers of the technology is the only benchmark against which pre-clinical projects struggle to

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Investment in research and development has now increased substantially: they represent 16 per cent of sales in the period 2000-2010 with a 60 per cent increase in the previous decade.

demonstrate their proof of concept validity. In other words, due to the industry’s organisation, the validation process of a new therapeutical target takes shape inside an entrepreneurial body that don’t know ex-ante who will judge its robustness and according to which benchmark they will express his judgement.

Cognitive representation of (rugged) competitive landscapes of the pharma industry is, therefore, a key activity to better define the entrepreneurial opportunity and to represent a clear model of relationships between strategic choices and expected payoffs.

The problem is exacerbated by the team composition of the academic start up, that often miss management competencies. Integration of these competencies by the beginning in the founding team is quite complicated and notwithstanding some excellent experiences in the US and Europe about the so-called “founding angels”, this integration often remains a will.

To overcome these difficulties, “in most cases, what start-ups need most is something akin to “mentorship” from large pharma firms and industry organisations1”.

For those having onboard an external investor, an experienced mentor, having reached these steps means successful completion of a valuable milestone 1 Christy J. Wilson, in Pharma R&D, March 27th 2018

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and could be the necessary condition for a new startup in order to reach the necessary development to intercept the interest of a big pharma company.

This is why growing numbers of professionals try to intercept the entrepreneurial teams in a more or less difficult step of their development process in order to help them in arranging their pathway to a potential deal for the technology.

Business developers, strategic consultants and so on can offer that “cognitive representation” and expertise in order to drive and manage the development of the young biotech start-up. However, if necessary, the match between these two kinds of subject, biotech start-ups and professional/external consultants, is not simple to realise.

Two separate kinds of a mismatches are the main sources of pitfalls in entrepreneurial/managerial cooperation in drug development: 1. Knowledge bases of both parties and absorptive capabilities 2. Distribution scheme of incentives and contracting forms.

The first one concerns the different backgrounds and knowledge bases of startups on one hand, and external consultants, on the other. The founders of an academic spin-off are typically university professors, research-centre faculty members, doctoral students,

PhDs or research fellows, with a strong technical background and a full knowledge of the technology they develop. On the positive side, they own the intellectual capital related to the new technology and have the necessary scientific skills to develop further the technology on which the spin-off is based. On the negative side, they often suffer the so-called ‘technological myopia’, that is the inability to go further than the technical and technological aspects of the project to capture the market and economic implications.

On the contrary, the external subjects generally have significant experience in new ventures, competences, and networking in the business development of new ventures, necessary to drive the entrepreneurial development of the project; but they do not have the needed skills to address and to face the technological uncertainties arising in the early stages of development.

In this context, a problem of informational asymmetry emerges, making the match between the two subjects very complex. More specifically, we can observe two kinds of informational asymmetry (Parente et al., 2011).

The first one referred to as ‘hidden information’, occurs when one party to a transaction is aware of information that is not known to the other party.

For example, a group of inventors being intimately involved with the creation of the technology and its development possesses more information than the external subjects –who might find it difficult to access the relevant information even through the process of due diligence. In some cases, researchers– inventors do not disclose the features of their invention because they do not have confidence in investors and fear to lose the economic benefits and rewards that could result from commercial exploitation.

The second type of informational asymmetry, described as ‘hidden action’, occurs when one party to the transaction

RESEARCH & DEVELOPMENT

based on the results of scientific research.

In most cases, technologies developed introduce radical innovations, usually with a predominant component of tacit knowledge and general purpose type.

The founders of an academic spin-off spend a great deal of time and effort on additional technical development in the early stages of a new company, focusing their activities on the proof of concept and prototypes. These characteristics create many difficulties in identifying a priori the possible technology developments and, consequently, the difficulty of determining the real value of the entrepreneurial idea. The market risk relates to the fact that academic spin-offs often propose new technologies for which there can be a high degree of uncertainty about being accepted by the market. This is why those technologies are invented as a product of academic research (science push) and, often, not as the result of efforts to meet specific customer needs (demand pull). A market application must be found for inventions, but this requires data collection and generation of information about customer needs and

how these could be satisfied, as well as obtaining and incorporating customer feedback about the products that make use of new technologies.

The solution to these problems could be found in the definition of mechanisms of participation of inventors and investors in the company able to intercept the needs of both.

More specifically, the prevision of a risk-sharing approach from external consultants could be a possible solution.

Aware of their difficulties in attracting external financial resources, academic startups in general are well disposed to integrate the entrepreneurial team, leaving an equity share of the company with the objective to acquire the necessary and missing competencies.On the other hand, for external consultants, the assumption of entrepreneurial risk should be balanced through a mechanism of allocation of decision-making powers and the introduction of monitoring and incentive systems in order to enforce the commitment of researchers– inventors in the academic spin-off.

Roberto Parente is Professor of Innovation and Entrepreneurship in the Department of Management and Innovation Systems at the University of Salerno. His research interests are mainly related to high tech start-up from academia. He is currently in charge of the Direction of the LISA Lab, which offer unique opportunity to connect an ecosystem of people and organizations involved in Technology Transfer initiatives.

AUTHOR BIO

is unable to observe actions taken by the other party. For instance, the work of a group of inventors might generate results that cannot be observed or verified by others and which are important to the development of the technology and the performance of the new venture; but, contrarily, by reducing such efforts, the inventors would reduce the probability of entrepreneurial success and the efficient use of the capital employed. The group of inventors might make certain decisions autonomously, and the costs resulting from these decisions would be borne by the investors or other external subjects involved in the project. This type of a problem can lead to moral dilemmas and agency conflicts — the ‘informed’ party has an incentive to act according to self-interest, even if such actions impose high costs and risks on the other party. That agency conflicts and costs may be especially important in high-tech startups, where potential investors are faced with the difficulty of assessing and developing the potential of the new technology. The agency conflicts and costs could discourage external subjects from participating in the spin-off.

With regard to the second problem, i.e. distribution scheme of incentives and contracting forms, generally an external consultant and/or business development manager, charge a fee for services mechanism of payment.

This system is very difficult to access for a young startup because they often lack the financial resources necessary to acquire external services in order to develop the project and to transform a promising technology into a successful business. Young startups, in general, suffer from a systematic lack of financial resources and face several difficulties in attracting them from external subjects, such as venture capital.

This is particularly true in the initial stages of development because of the technological and market risks they have to face. Technological uncertainties very often occur in new spin-offs

Rosangela Feola is Technology Transfer Manager at the TTO of University of Salerno and research fellow of Lisa Lab (Laboratory for innovative entrepreneurship and academic spinoffs) at the University. Her research interests are mainly related to entrepreneurial university, technology transfer process, and the role of innovative start-ups in emerging sectors. She is co-authors of several national and international publications on the same subjects.

Valentina Cucino is a PhD Candidate in Innovation management at Scuola Superiore Sant'Anna. Her research activities focus on the relationship between university and industrial sector and the technology transfer in the field of life sciences. Since 2012 she has been a member of Lisa Lab (laboratory for innovative entrepreneurship and academic spinoffs) at University of Salerno.

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MICRONEEDLE ARRAY PATCHES The way forward for the management of diabetes

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The development of successful ‘smart insulin’ in glucose responsive ‘closed loop’ insulin delivery system is already taken into research basically to deliver insulin in response to increased glycemic levels, which may provide optimal glucose control with negligible patient’s effort and also tend in improving the quality of life in diabetic patients.

Ashish Wadhwani, Head, Department of Pharmaceutical Biotechnology, JSS Academy of Higher Education & Research - College of Pharmacy Baishali A Jana, Senior Research Fellow, Indian Council of Medical Research (ICMR)

D

iabetes Mellitus (DM) is a chronic life-threatening disease just like cancer or any other disease whose incidence has become doubled in recent years. In diabeties patients, the use of intensive insulin therapy was found to reduce long term vascular complications and some evidence also highlights the increased risk of both hyperglycemia and hypoglycemia. Islet transplantation has significantly increased over the past decade, yet there are issues of immunosuppressive drugs and the unavailability of adequate pancreatic donors. Nowadays, novel insulin analogues have improved pharmacokinetics profile corresponding to endogenous basal and prandial insulin secretion more strongly.

However, despite advances in insulin formulations, external insulin infusion pumps, glucose control still remains a challenge. Patients with diabetes do not achieve their glycemic targets which, therefore become a major hurdle for the development of insulin therapy.

Diabetes

Diabetes, which causes uncontrollable increase in blood glucose levels, is globally one of the most prevalent chronic diseases. It is a metabolic disorder which either causes permanent lack of insulin production from the pancreas (type 1 diabetes) or a condition where the cells fail to respond to insulin due to

dysfunction (type 2 diabetes) which later elevates the blood glucose levels.

Insulin is a hormone which is synthesised and secreted from the pancreas to meditate the metabolic reaction involving glucose. In the absence of insulin, the cellular system cannot accurately convert carbohydrates such as sugars, starches, or other foods into energy which is used by the body. These factors in due course result in many complications, such as cardiovascular disease, chronic renal failure, retinal damage, nerve damage, and microvascular damage. According to the reports given by the World Health Organization (WHO), Around 180 million people globally are affected by diabetes and as estimated, the number will increase over 350 million by the year 2030. In the human body, insulin and glucagon are counter regulatory hormones that play a vital role in regulating blood glucose levels. Either excess or shortage of glucose in the blood is known as a metabolic disorder.

History reveals that diabetes emerged around 2000 B.C, which was discovered by Wells and Lawrence. The discovery of insulin and its functionality was in the year 1921, and continuous glucose monitoring was introduced in 1999. Despite many difficult situations, recent engineering is being focused on many advancements towards individual

components that can be combined into closed loop systems that can facilitate a controlled blood glucose levels in a predetermined amount and time under defined conditions without any human input. Diabetic patients are recommended to check their blood glucose levels and take periodic insulin for better management of blood glucose levels. However, patients often do not follow the suggestion as per prescribed as there is a lot of pain, intense stress for repetitive blood collection and insulin shots. These complications lead to various severe diabetic problems like cardiovascular, kidney disease, stroke, blindness and nerve degeneration. In addition, insulin over treatment causes a sudden drop in blood glucose concentration which may cause seizures, unconsciousness and even death. Initiation of continuous glucose monitoring in the early 1960s was landmark which was led by the first production of hospital based commercial artificial pancreas.

Intravenous sensing of glucose and insulin delivery combination was developed in the late 1970s. For many decades, automated closed loop insulin delivery also referred as an ‘Artificial Pancreas’ has been an important difficult goal, also now for researchers in treating diabetes. In the past 10 years, research into an artificial pancreas that is on the closed loop delivery system has gained significant interest and focus has been done on the subcutaneous route for glucose measurement and delivery. This will further help in advancing more towards interstitial glucose monitoring and thereby increasing the use of this combination.

Closed Loop Insulin Delivery System

This closed loop delivery system will perhaps happen gradually, and would have benefits like glycemic control, and thereby the ability to temporarily shut off of pump to overcome the situation like maintaining glucose levels between the meals and exercise. A plethora of biosensors have been developed www.pharmafocusasia.com

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Continuous glucose sensor

Control Algorithm

Glucose level

Subcutaneous insulin pump

Fig 1 Schematic illustration of the flow of information in a closed- loop system.

which enables in providing diagnostic information regarding a patient’s health status. Many different types of sensors have been investigated and a 2010 review by Toghill and Compton gave a great insight into enzymatic and non-enzymatic electrochemical glucose sensing approaches studied over the past decades. Now, non-invasive spectroscopic methods for glucose detection have also been growing in popularity with Raman and Infrared Spectroscopy gaining particular attention.

However, the main challenge that still remains is the creation of biosensors for daily use by patients in a personalised monitoring format. Recently, several reviews focusing on sensor integration developed into wearable platforms have been published. Therefore, a novel method which will be pain and stress -free in monitoring glucose levels and maintaining homeostasis accurately is highly desired in the management of uncontrolled diabetes. This article solely focuses on recent advances towards noninvasive and continuous glucose monitoring devices with a particular focus planned on monitoring glucose concentrations for diabetics.

Body Access Routes

The information flows in a closed-loop system where the continuous glucose sensor sends control algorithm which 40

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pumps adequate insulin into the body to maintain the glycemic levels, it showned in figure 1.

Currently there is no artificial pancreas approved and available in the market. The artificial pancreas may contain functionally integrated components that will moreover continuously sense glucose levels, thereby determining appropriate insulin dosage and also delivering insulin in proper time. Several components related to artificial pancreas have been developed which includes, the use of glucose sensor and insulin pump which is linked via wireless communication system for adequate glucose monitoring and parental delivery of insulin in diabetic patients. Currently available intensive therapy has been found to vary in managing glycemic levels by the use of the closed-loop system. This helps in regulation of glucose levels in diabetic patients. Glucose levels are continuously monitored without any requirement of patient's input. Measuring glucose levels looked promising with minimum invasive methods for outpatient glucose monitoring. Existing commercially available sensors are directly inserted into the subcutaneous tissues that measures electric current, generated by the oxidation of glucose via the enzyme glucose oxidase.

For the development of artificial pancreas; till date different types of the glucose sensors, along with four available types

of insulin algorithms and insulin delivery systems are in the research phase. The ultimate focus is on the development of a combination of better glucose monitoring and insulin delivery technologies by way of an algorithm into an automatic closedloop system. This development results in the decrease in glycemic variability and fewer hypoglycemic conditions. Hence, the procedure is painless as compared to needle pricking to monitor glucose levels and deliver insulin for effective management of diabetes.

Artificial Pancreas

An ‘Artificial pancreas’ is a technology which stimulates the secretion of insulin in response to elevated glycemic levels. It is a closed-loop system which monitors the glucose levels in blood and triggers the insulin release to regulate and maintain glycemic variability without obstructions. It is considered to be a potential advance system in regulating glycemia and thus improving quality of life. A closed-loop system is a combination of glucose monitoring module and insulin release sensor.

Continuous monitoring of this glycemic level is basically enabled by blood-glucose tests and then accordingly adjusted insulin shots can lead to reduced use of artificial pancreas or closed-loop insulin delivery called as “Smart” insulin patch. ‘Smart’because it releases insulin according to the body’s need. This combines the use of glucose sensor which monitors glucose levels and insulin sensor which pumps insulin via the controlled algorithm as per the glucose readings. This system mimics the role of β cells to regulate the blood glucose levels. However, gathering accurate signal feedback of the glucose level and thereby maintain the glycemic variability still remains an important challenge for such a device. A chemical approach such as use of insulin-loaded matrix in a glucose sensor with a relevant actuator could be beneficial in the closedloop system for the release of insulin.

The changes remain to demonstrate a strategy which could manage both fast

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Microneedle as Artificial Pancreas Device System

Other modified applications for closed-loop insulin delivery include microneedles via transdermal route.

Microneedles have been found to be versatile and researchers are now focusing on development of different microneedles based on metals or polymers comprising of an enzyme such as Glucose Oxidase (GOx) as sensor along with insulin.

These have been known to passing small amount of insulin through microneedles via auxiliary pumping systems thus maintaining quantitative control and providing continuous delivery. In recent years, human skin has become very popular method for monitoring glucose. The Glucowatch was developed as a wearable device was initially brought to mark for noninvasive continuous monitoring glucose to measure glucose levels, but due to its limitation the product was removed from the market in 2008.

The concept of Microneedle was used for the development of a glucose sensing patch, since this approach can offer minimally invasive methods for biosensing. "The miniaturized device spans a total area of 6x6mm in which it contains 200 hollow microneedles (300micrometer in length with a 50x50 micrometer lumen). Three screen-printed electrodes were used for quantifying glucose concentrations in the interstitial fluid including a Pt- C working electrode covered with a layer of cross-linked bovine albumin serum and glucose oxidase. The sensing device was attached to the skin by an adhesive layer contouring the perimeter of the sensing pod. Detection was performed upon glucose diffusion into the microneedle array wherein GOx could react to produce hydrogen peroxide"1. This microneedle patch allows the patch to be in constant contact with the skin, 1 https://www.mdpi.com/1424-8220/17/8/1866/htm

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providing permanent access to the interstitial fluid and thus enableing this device to operate continuously.

Due to this short length of the microneedle there is precise penetration for interstitial fluid sampling, thus it does not reach the dermis layer. Moreover, as the microneedle penetrate the skin, contamination by sweat is also avoided.

Tests have shown that this device can operate successfully for upto 72hrs with only 17minutes lag time caused by the passive diffusion of analytes from the blood into the interstitial fluid matrix.

Limitations such as clogging, distortion of the shape upon the penetration of the skin can affect the dynamics of the sampling. However, this novel device holds great potential for noninvasive continuous glucose monitoring. Scientist Zhi and his team further developed the technology by encapsulating the sensors in a thin film which gave the benefits of fast analyte transport through the device.

This approach might be designed for pancreatic islet transplants which are known treatment procedure for Type 1 diabetic patients. Microneedles can be safe for maintaining artificial pancreas environment thus increasing the system reliability, decreasing the feeling of pain

AUTHOR BIO

response of insulin administration along with tremendous biocompatibility.

and also implementing a systematic closed-loop delivery system on insulin.

The smart insulin patch could be a game changer as it can be placed anywhere on the body to detect increase in glucose level (Figure 2).

Conclusion

This article highlights the benefits of a closed-loop system and thereby encourages the developments of an artificial pancreas. The ideal medication would be the biological cure where the β cells, which are damaged, could be replaced with healthier ones. The innovation of artificial pancreas could bridge the gap until a total cure is obtained. The majority of patients still struggle to achieve the optimal blood glucose levels; even with the sophisticated insulin pumps and continuous glucose monitoring devices.

The artificial pancreas may become a more convenient and superior mode of insulin delivery. An intravascular device that can be implanted and which can sense glucose and deliver insulin to maintain optimum glycemic levels would be a safe, easy, pain-free and a reasonable method for the management of diabetes in near future.

Ashish Wadhwani did his M. Pharm and Ph.D in Pharmaceutical Biotechnology from JSS University, Mysuru. After completing his Ph.D, he worked as Research associate at National AIDS Research Institute, Pune for DBT-ICMR joint project. He has handled couple of projects as PI/Co-PI from Government of India and published papers in peer reviewed high impact factor journals. He has presented several papers at international forums and received various awards. He has 40 research papers and 22 National/ International presentations in his credit. Currently he is working as Head, Department of Pharmaceutical Biotechnology, JSS Academy of Higher Education & Research – College of Pharmacy, Ooty, Tamil Nadu, India.

Baishali A Jana is Senior Research fellow from Indian Council of Medical Research (ICMR), New Delhi pursuing her Ph. D under the guidance of Ashish D Wadhwani, Head, Dept. of Pharmaceutical Biotechnology, JSS Academy of Higher Education & Research College of Pharmacy, Ooty on the project entitled ‘Microneedle- A Closed Loop Transdermal drug delivery system for the Management of Diabetes’ with an aims to develop microneedles that are assembled on a transdermal patch to overcome the limitation of both Injectable and Oral drugs. She has vast experience in the area of Microbiology and Biotechnology.

MANUFACTURING

Systematic Framework for Implementation of RTD-based Control System into Continuous Pharmaceutical Manufacturing Pilot-plant Pharmaceutical tablets have been traditionally classified as good (within specifications) or bad (out of specifications) based on offline measurements of representative samples. Several assays based on tablet samples are necessary to ensure product quality and must be satisfied before releasing the tablets into the market. However, there are no methods and tools available that can be used for real time assurance of tablet drug content.

In this work, a framework for the implementation of a tablet diversion system based on Residence Time Distribution (RTD) is presented. The proposed diversion system is essential to assure the drug content of the tablets produced via continuous manufacturing. A tablet diversion system is created according to the introduced framework, and the proposed diversion system is implemented in a commercial control platform, where its functionality is demonstrated using the developed RTD model.

Ravendra Singh, C-SOPS, Department of Chemical and Biochemical Engineering Rutgers, The State University of New Jersey

R

esidence Time Distribution (RTD) is a probability distribution function that describes how long a fluid or powder element spends inside a given operation. Currently, the Continuous Manufacturing (CM) is evolving as a preferred platform for pharmaceutical products involving solid dosages forms. Therefore, the pharmaceutical industries are going through a

paradigm shift from conventional batch manufacturing to advanced ContinuousManufacturing (CM). However, the RTD-based diversion system is desired for continuous pharmaceutical manufacturing to assure the drug contents of the tablet to be released to the market.

The objective of this work is to demonstrate the implementation of RTD-based tablet diversion system into

a novel continuous direct compaction pharmaceutical tablet manufacturing pilot-plant.

Process and Pilot-plant description

The continuous pharmaceutical manufacturing pilot-plant has been built at C-SOPS, Rutgers University that has been adapted by industries. This process has been extensively studied. The snapshot www.pharmafocusasia.com

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MANUFACTURING

of the pilot-plant is shown in Figure 1.

The process and pilot-plant description has been previously reported.

Implementation of RTD-Based Diversion System

A systematic framework has been developed to guide the implementations of diversion systems based on RTDs (see Figure 2). It is known that the residence time distribution of a system is characteristic of its unit operations.

Hence, the plant setup needs to be defined before any RTD determination efforts occur. It is also important to establish the type and location of the PAT sensors. Once the plant configuration is fixed, the boundaries of the rejection system must be defined. The downstream boundary should be chosen based on the closest location, downstream of the unit operation producing undesirable products, where the diversion gate can be installed. The upstream boundary is 44

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The RTD-based control system can be used to divert the out of specification tablets produced during continuous pharmaceutical manufacturing.

dependent on the closest PAT sensor upstream of the unit operation.

The installation of the diversion gate and its integration with the control system starts with the definition of the kind of actuation used to operate the gate. Most commercially available systems have either electric or pneumatic

actuation. Once the gate is installed, it is necessary to understand any transport delays between the actuation in the control system and the actual actuation in the gate. This delay must later be incorporated in the RTD of the system.

As previously mentioned, RTDs are heavily influence by material flow properties and process parameters. An RTD is only valid for the formulation and processing parameters at which the experiments were conducted, and extrapolations are rarely valid. For this reason, the next two key steps in the framework are fixing the powder formulation to be used and fixing any process parameters that can influence the mixing or the mass flow rate of the system.

The most important step in the implementation of the tablet diversion system is the experimental determination of the system’s RTD. The last steps in the framework involves fitting an RTD model

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MANUFACTURING

Local Level Control

Supervisory Feedback Control

Supervisory Feedforward Control

Local Level Control RTD-based Control Figure 1 Continuous direct compaction continuous tablet manufacturing pilot-plant

to the experimental data and tuning the diversion system. Model fitting is done to obtain a clean RTD, without noise, that represents the system. Once the model is obtained and integrated, the

Define plant setup

Define process parameters

tuning of the diversion system occurs. In this step, the safety margin of the RTD prediction is determined. This margin can be tuned by tightening the nominal limits for diversion by a tuning constant.

Bound diversion system

Conduct RTD experiment

Install rejection gate

Fit RTD model

Results and Discussions

Three simulated scenarios have been created to demonstrate the implementation of the RTD-based diversion system in a commercially available control

Define Formulation

Tune diversion system

Figure 2 Systematic framework for implementation of RTD-based diversion system.

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and only returns to its normal state 6 seconds after the input concentration value is brought back to 9 per cent. This scenario replicates a situation where a traditional delay based diversion system would achieve the same performance as an RTD-based system.

Conclusions

It is essential to assure the drug concentration of the tablets before releasing it into the market. A combination of traditional feed forward/feedback control strategy together with a tablet diversion system can be used to achieve this. The RTD-based control system can be used to divert the out of specification tablets produced during continuous pharmaceutical manufacturing. A systematic framework to implement the RTD-based control system has been developed and applied to the continuous pharmaceutical manufacturing process. The proposed systematic framework supports the paradigm shift of pharmaceutical tablet manufacturing from conventional QbT-based batch-wise production to QbD-based continuous production.

Acknowledgements

This work is supported by the National Science Foundation Engineering Research Center on Structured Organic Particulate Systems, Rutgers Research Council and U.S Food and Drug Administration (FDA).

References are available at wwww.pharmafocusasia.com

Figure 3 Demonstration of diversion system

AUTHOR BIO

platform (Figure 3). The NIR signal has been simulated using an input parameter block and the F(t) coefficients used in this demonstration correspond to the response of a first order system.

In the first scenario (Figure 3a), a pulse with 10 seconds duration and 1 per cent magnitude was applied to the system. The pulse spreads across the tablet press according to the RTD resulting in predicted concentrations that do not trigger the rejection mechanism. This result is a clear example of a situation where an RTD-based diversion yields a better performance than the traditional time delay based diversion system. The second scenario (Figure 3b) consists again of a pulse with 10 seconds duration but with 12 per cent magnitude. The larger magnitude results in a disturbance that violates the concentration limits and triggers the diversion system for approximately 17 seconds.

When a step disturbance with a magnitude of 3 per cent is applied to the system (Figure 3c), the diversion system is triggered after two seconds 48

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Ravendra Singh is Research Assistant Professor at C-SOPS, Department of Chemical and Biochemical Engineering, Rutgers University, NJ, USA. He is the recipient of prestigious EFCE Excellence Award from European Federation of Chemical Engineering.

He is PI/Co-PI of several projects funded by FDA and pharmaceutical companies. He has published more than 61 papers, written 12 book chapters, presented at over 98 conferences and edited one pharmaceutical book.

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CUSTOMER CENTRICITY ON SOCIAL MEDIA

ARE THERE LESSONS FOR PHARMA FROM OTHER INDUSTRIES? Big pharma is gradually and progressively riding the social media bandwagon with a host of tactics towards listening, analytics, engagement, brand promotions, and much more. This has meant successful handling of the regulatory hurdles — what to share, what not to share, how much to share and most importantly the safety events that need to be reported. But even as all of this is afoot, companies are generally observed to be reticent in embracing social media wholeheartedly. While companies in other industries may only fret over a social media faux pas because it can potentially lead to public embarrassment of sorts; for pharma, social media could be unforgiving, not to mention the regulatory implications it can have.

But when looked at closely, it can be seen that social media is no safe haven for other industries as well.

All industries see consumer outrage over any issue that affects them but companies don’t always shy away from confronting this. So is there a message for global pharma that needs to be heeded?

Awani Saraogi, Analytics Consultant

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I

magine checking into a hotel late in the night but not being able to get the room you had so carefully chosen because the call centre didn’t align with the hotel on the specification! Customers in such scenarios find themselves at a loss for venting out their frustration and social media seems a good refuge. Industry specific review portals and social networking sites are flooded with such comments from customers. Companies across most industries have developed their response and engagement strategy for handling such scenarios. Responding to the customer’s post with an immediate apology and following up till the issue is resolved fully is the goal that most companies target for. Though even with this the end result may not always mean a happy or satisfied customer but the company is at least able to showcase that it cares.

Given the prevalence of social media in our lives today, there is a lot being discussed on Social media etiquette — whom to respond to, whom not to respond to, how to handle trolls and who is a troll in the first place. But in the pharma industry defining anything in black and white is difficult because its illness and patient safety that we are dealing

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Engaging on Social Media – What Other Industries Do

with. But given this, it's more so important that companies heed to what patients are writing, their sentiment and underlying emotions, address their concerns as best as possible and even then if there is further negativity at least not delete those posts. A drug which has come to the market post a proven positive benefit risk profile has some value in being there; but it’s also a fact that the likelihood of its benefits and the severity of side effects would vary from patient to patient. Those who experience severe side effects are likely to react just as we do when we don’t get the service we expect from a brand but removing these negative posts from the social media pages amounts to not showing any empathy towards a patient who needs help and that surely can’t leave a positive image for a brand.

So how do companies in other industries handle social media comments, appreciation and crisis? In most industries the benchmark is for customer service to be present all through the buying cycle and definitely long afterwards. “Nowadays, consumers expect brands to offer help way before they’ve decided to buy, and long after they’ve made the purchase..” says Joel Chan on mention.com. In this setting, even the well-meaning reticence of pharma companies is likely to be construed as lack of empathy. So how do brands in other industries really engage?

Experts believe being transparent and empathising with customer concerns is the key. Below is an approach followed

by AXA, a leading insurance company based out of Paris, for handling Social Media comments. The team works with the goal of touching/responding to every post that is made even if negative and then transparently posting data on their performance. This strategy helps reassure a customer that whatever be the nature of complaint at least she is heard.

In other industries as well the practice continues; consider the Social Media stalwart airline, KLM, which was also one of the pioneers in the space. KLM Social Media support runs with a team of 300+ agents who handle 180,000 messages weekly. KLM though has come a long way from just providing prompt responses to its customers on Social Media channels and now also leverages the vast record of interactions for enabling better services and improving the overall customer experience like helping with lost and found items by just engaging on Twitter.

Chobani, an American yogurt brand takes the job of Social Media Customer Service even further through bespoke responses and taking several other measures for driving customer delight.

In one particular case when a customer posted a positive comment thanking the brand for their Yogurt which helped her healing post a wisdom tooth extraction, the company replied requesting for her address so they could ship a ‘get well soon’ www.pharmafocusasia.com

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note. It may be a very small gesture but it goes a long way in driving customer perception and engagement.

Handling positive or neutral scenarios may be simple but what do these brands do when confronted with negative sentiment? Zappos social community manager, Jessica Oberst says, “We truly care about our customers, and when there has been a loss of service, we bend over backwards to understand exactly what has happened, take strides to make improvements in an effort to prevent future losses of service…”. This may not be possible in each case or every time, because customers are just as prone to be on the erring side as a brand could be.

But it is important for a brand to take the right steps to handle such situations well else it could lead to spiraling negativity on Social Media channels. Some of the best practices and social media dos and don’ts in such scenarios are: • Don’t delete such comments from the page unless it’s a clear case of trolling or is profane or anathema to the brand ethos • It’s important to appear engaged and respond to the customer genuinely • Stay true to what you commit or promise and ensure full closure • Try to take the conversation offline There could be many more such best practices to keep sight of, the key focus being empathy and stepping in the shoes of a customer (patient) who has had a negative experience.

Engaging on Social Media – WHAT PHARMA CAN DO

For a patient or their caregiver, who is also a customer and has experienced this service in other industries, these are the benchmarks in customer-centricity, service available at the fingertips and on the go. So when dealing with an illness and an uncommunicative brand or pharma company, the experience can be even more frustrating. Some pharma companies are taking cognisance of this reality and can be seen responding actively on social media channels.

GSK’s global Twitter handle for instance (@GSK) can be observed replying to 52

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patient and caregiver posts, similarly Abbott is observed engaging with its @ AbbottGlobal, Pfizer with its @pfizer handle10 and a lot more. Like Jay Baer, Social media expert from Forbes says, “A lack of response is actually a response.

It’s a response that says, ‘We don’t care about you very much’.”

While Pharma brands are taking baby steps and developing well rounded social media engagement strategies, the key tenets which are noticeable in other industries need to be well imbibed.

Negative comments may look bad on a brand’s page but deleting them does not quite stop the comments or resolve the issue. A patient or caregiver who is looking for empathy or seeking advice may wander to other forums where there is extensive interaction leaving room for the negativity to grow and the entire reason for which a brand has chosen to be there on social media, to showcase that it cares is lost.

When used effectively, social media on the contrary offers an opportunity for building a better perception. What brands like Chobani and KLM do are but small cues for the art of possible. If a patient is posting repeatedly with frustration on disease burden it may help if she is re-directed to any prevailing support programs and if there is none then a small gesture of support can go a long way in managing a positive perception.

Another social media engagement tenet that is well adhered to by companies in other industries but not so much in pharma is posting customised,

user-specific responses. Most companies tend to post generic responses for issues that can’t be resolved immediately or which will take some time for the executive to circle back and provide full closure on. In case of pharma this may well mean almost every other complaint or issue but in such cases a customised, patient-specific response even if it means an honest apology can go a long way in building a better perception. After all, patients and caregivers despite their predicament, are rational human beings barring a handful individuals who may make it a habit to stay negative. In cases where there is an ongoing issue and a deluge of comments on social media, it may be difficult for a social media team to keep up with customised responses.

Infact, in such scenarios, most posts may just have the same message or be of a similar nature, so in such cases posting a pre-approved standard response that acknowledges and apologises may work just as well. Like Nicole Klemp, social media expert from Sales force says, “Have a plan in place and official statements drafted”.

The third key tenet is the response time itself, responding within the first one hour being the goal here. For a pharma company this means aligning a lot of other steps internally (operationally).

While in other industries, companies may choose to empower their front line executives enough to make the right judgment and post a response, in pharma, due to the likely regulatory implications, most companies would be

INFORMATION TECHNOLOGY

queasy posting a non-standard response which has not gone through a chain of approvals internally. In such a setting posting customised responses within the hour may be ambitious, even unreal, in some cases but why not try to determine the shortest feasible response time which could be anything within a day’s timeframe? If this still looks ambitious then a company also has to realise that social media in today’s context is serious business and if negativity on social media can have serious ramifications for a company then trying to create or maintain a positive perception may require a little more investment and effort.

The last one here is not a key tenet or even a best practice, it’s just a simple step that companies across several industries take to earn brownie points or bring in that wow factor – responses posted by senior company executives sometimes even for simple issues but mostly in times of major negativity. This may be a hum and haw subject as it’s not easy to implement, after all would this mean that in cases where a patient’s health is seriously impacted would an executive come to acknowledge who dropped the ball. In most cases infact no one may have actually, it may just be the nature of the disease or limitations of the treatment itself so this is still in the grey, a difficult to tread space!

Social Media Trolling and How Best to Handle It

Are there social media trolls in pharma as well, if so, how should a company deal with it? The jury may still be out on how to best deal with trolling on social media but experts lay out some best practices.

For instance, Jay Baer, author of Hug your Haters, advises readers to apply the “Rule of Reply Only Twice” and not to

engage in a constant dialogue. In the pharma industry, it’s difficult to discern trolling as compared to other scenarios but there are some scenarios when we know that it’s not genuine complaint or even a patient/caregiver who is posting.

Such as when individuals start posting negatively on a jingle that a brand may have used in its digital ads or on the frequency or content of the ads. In such scenarios we know that it’s not a genuine patient or caregiver and given this the rules of trolling can apply.

In Conclusion

For ages, companies across industries have been creative and thoughtful in how to achieve customer delight. The advent of social media gave way to a plethora of tactics and even more room for the creativity to bloom but at the same time it has its perils, the major one being the choice and the power that a customer has to express what she doesn’t approve of. So it’s a tight rope walk and a constant balancing act for a company to stay relevant but not draw public ire. For a pharma company, the opportunity that social media brought came with even bigger risks, wider exposure to regulatory scrutiny, but also an opportunity for patients and caregivers to look for empathisers when the brand doesn’t listen. It’s also a scenario where a pharma company can reap the benefits of social media with a thoughtfully chosen but patient-centric social media engagement strategy. If showing the customer or a patient that “we care” is the key then who can know this and practice this better than a pharma company, in letter and in spirit?

References are available at www.pharmafocusasia.com

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CPHI JAPAN 2019 Awani is an Analytics Consultant with 14 years experience across industries, including Pharma and Healthcare. Next gen analytics services including digital media analytics has been her area of interest and focus. She has supported several Fortune 500 clients in these roles.

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IOT AND AI CREATE ‘SMART’ DIGITAL ASSISTANTS OPENING NEW POSSIBILITIES FOR DRUG DEVELOPMENT

Nobody challenges the fact that Artificial Intelligence (AI), Internet of Things (IoT), Real World Data (RWD), and Blockchain will fundamentally impact drug development.

While there are many emerging solutions, there is limited experience in applying these solutions in the real-world. In this paper we focus on how IoT and AI technologies can be integrated into a patient-centric digital platform and practically applied to enable new approaches to trial execution, while opening the way to a new generation of products.

Isabelle de Zegher, Vice President, Integrated Solutions, PAREXEL Informatics

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2

017 was the year where pharma realised that Big Data could dramatically increase the value of data produced during drug development or coming from Electronic Medical Records (EMRs) and medical devices. In 2018 it became clear that AI technologies could unlock much of the value of Big Data; 2019 is the year where we have everything in our hands to leverage Big Data, IoT and AI to deploy solutions that fundamentally

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affect the full drug development lifecycle, reverse the continuous growth of drug development timelines (25 per cent higher in 2018 versus 2012, reaching a startling 12 years on average) and bring new therapies to the market sooner and smoother.

The IoT refers to the ever-growing network of physical objects — beyond computers, smartphones and tablets — that contain electronics, software, and connectivity allowing these things to connect, interact and exchange data via the Internet. Gartner estimated the total number of IoT devices to be 8.4 billion in 2017 and predicted an increase to 20 billion by 2020; Intel, meanwhile, projected a growth up to 200 billion by 2020, which equates to nearly 26 smart devices for each human.

The Internet of Health Things (IoHT) is an application of the IoT for health-related purposes, enabling remote patient data collection. These devices range from a simple monitor to a smartwatch and lately into e-textiles; they allow to collect parameters such as

activity, sleep, temperature, heart rate, glucose, oxygen and many others, in near real-time, offering a broad range of capability to monitor patients. These devices are playing an increasing role in disease prevention and control, and in managing chronic diseases.

AI is a field of computer science that aims to mimic human intelligence with computer systems. It includes a set of mature technologies that have been evolving for more than 30 years in healthcare and other industries; they include Machine Learning (ML), Natural Language Processing (NLP), Knowledge Base Systems (KBS), and Robotic Process Automation (RPA). In the last 5 years, there has been increased use of ML driven by the introduction of the cloud with high processing power, and increased access to Big Data: the computer learns by detecting patterns in a set of training data and is then able to predict outcomes from newly acquired data. As processing power is being moved with “edge” devices, ML algorithms will increasingly be running from the edge, decreasing the

need to exchange the large volume of data needed for ML algorithms. RPA and more specifically bots — such as ALEXA or SIRI —building on speech recognition, cognitive services and machine learning are increasingly part of our daily life; if we customise bots with medical content, they could become very useful medical personal assistants adapted to the context and needs of the patient.

There is a clear intersection between IoT and ML. IoT is about connecting machines that generate large amount of real-time data and making use of these data. AI-Machine Learning (AI-ML) is about learning from data and simulating intelligent behaviour; it needs vast volumes of data to increase their predictive value. By integrating IoT and dedicated AI-ML algorithms, we create a ’connected intelligence’ rather than just connecting technologies. Adding a bot-based personal assistant leverages even further the value of IoT and ML, enabling intelligent and personalised interaction with the patients and creating a ‘smart assistant.’

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Combining IoT and AI in an Intelligent Patient Digital Assistant

The difficulty with emerging technologies is to understand how to apply them in the real world to maximise their value. In the pharma world, we believe that IoT and AI can best be combined in an Intelligent Patient Digital Assistant (IPA) with the components described below.

The Sensors(IoT) capture information directly from the patient — or from the patient’s home. Usually, data are collected hourly or daily (e.g., glucose, blood pressure) leading to few megabytes (MB) of data. In some cases, like monitoring of patient neurological conditions based on movement, data are collected continuously and can range to several gigabytes (GB)1 per patient per day.

1 1 Terabyte (TB) = 1000 Gigabytes (GB); 1 Gigabyte (GB) = 1000 Megabytes (MB).

• A document with the text included in this paper would be less than 0.5 MB. •Classical EDC studies would consume 5 to 20 GB per

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The Patient Personal Assistant combines within a single app all the functions needed to support a patient in his/her daily life. The major difference between the Patient Assistant and a set of integrated apps, is that it builds on AI-Bot technologies to adapt to the patient context and needs; it keeps learning and adapting to the patient preferences as it interacts with him/her and increase the sense of familiarity and ‘caring’. It could include different modules. The Engage module is the core of the Bot, managing patient interactions and informing the patient on his/her disease and on the trials, while keeping him/her engaged in a treatment or in a clinical trial; this module can be extended with eConsent. The Collect module would function as a context-dependent, adaptive electronic Clinical Outcome Assessment/ eCOA).The Wearable module displays study (based on the number of patients)

any specific information directly from the sensors. The Monitoring module manages messages, warning or alert, coming from the predictive AI algorithms; it ensures that the patient understands the message and checks he/she takes the necessary actions, based on the context.

The Patient Personal Assistant could include other optional intelligent modules such as the Organiser to help with scheduling visits to a hospital, book a taxi, order food, call somebody, in the same way an ALEXA or Google Home support people at home. The eMedication module supports the patient in taking medication properly; ideally, it should be linked to a medication dispensing system with Radio Frequency Identification (RFID) technology that allow to confirm if a pill has been taken out of the box or not.

All the information coming from sensors — and potentially other sources such as from the Patient Assistant Collect module — is sent into a centralised

INFORMATION TECHNOLOGY

Organizational & Regulatory Challenges (in green) and technology challenges (in blue) in the implementation of an Intelligent Patient Digital Assistant Component

Sensors (IoT)

Patient Assistant

Predictive Analytics

Integrated Data Store

Integrated platform

Challenges

Trends & Remediation

Limited sensors available for clinical research (while they are many for Fitness)

Develop own sensor in collaboration with hardware providers

Limited experience in deriving meaningful clinical outcome from sensor data

Define new clinical endpoints derived from sensor data (e.g. variation in movement in ALZHEIMER derived from activity monitors)

Need of regulatory approval for sensors, if used to collect clinical endpoint

Partners with regulators & identify new approaches

Device management (registration, configuration, shipping, trouble shooting, return, ..)

Develop supply chain management services with understanding of national custom rules

Accuracy of sensors not always proven and documented

Request evidence and if needed test sensor in controlled environment

Limited power/battery charge forcing patient to recharge periodically

Include recharge period when designing protocol

Interoperability (different connectivity and communications options)

Agree on standards

Security and risk of breaching patient confidentiality

Requires IoT industry-wide security measure

Amount of data - in case of near-real time data collection, too large for normal telecommunication capabilities

Ad hoc discussion with data communication providers

Ethical approval for ‘adaptive’ content in eConsent and patient information

Partners with regulators/ERB & identify new approaches

Risk of bias in data collected through eCOA if this is too much adaptive and context dependent

Balance the value of adaptation to the patient versus risk of bias, while designing eCOA questions with Bot technology

Cost to develop and configure knowledge content for each new clinical trial

Manage content in a re-usable way to ensure scalability

Include AI technologies (speech recognition, cognitive services…) to ensure personalisation

Maximise use of existing technologies (ALEXA, SIRI, MS Bot framework,)

Integration with sensors

Agree on standards

Data Privacy issues limit possibilities to share & use data needed for ML

New approach to data sharing (like for organ sharing, with opt-in is the default in some countries)

Amount of data needed to ensure high quality in results

New approach in ML to limit waste of data

Availability of skilled resources to develop

Check in other industries- like aeronautics- and train staff internally

Potential Bias in ML based on training data set

Ensure consistency between patient population and ML model / training data

Cost to keep Terabytes (TB) of data gathered from sensors over 15 years

Partners with regulators to define new approach for long term archive for Big Data

Meet regulatory requirements of a ‘Software as a Medical Device’

Partners with regulators

Process change in trial execution and product development

Deploy change management program – including sites and patients, not just pharma

Limited knowledge of software product development in pharma industry

Partner with software providers

Develop Edge Computing device with local processing power

Table 1

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integrated data store in the cloud and further analysed. Compliance monitoring checks if a patient is wearing/using the sensors properly by tracking unexpected patterns: for instance, if a patient with muscular dystrophy puts his sensor on his dog, the system will quickly detect that there is an unexpected pattern and will flag an alert. Predictive analytics uses similarl ML to detect specific bad conditions such as risk of heart attack, hypoinsulinemia, asthma crisis, or epilepsy crisis, learning from data from previous patient populations and comparing with the patient data. The algorithm can then generate an alert to the patient directly and/or to the treating physicians or to family.

One major limitation in this model involves the ability to communicate large amount of data needed for the ML algorithm over the net. For instance, activity data collected continuously (10 to 100 times/second) can easily grow to several GBs to be transferred per patient per day.

This requires telecommunication capabilities not always available in cities, let alone in rural areas. With edge computing, we can expect the emergence of IoT devices that will be capable to run and maintain ML algorithms locally and only send critical data for audit and archival.

Applications & Benefits of the Intelligent Patient Digital Assistant

The Intelligent Patient Digital Assistant (IPA) is a ‘remote’ support agent for a patient, providing contextual and adapted information, monitoring patient condition and providing adapted feedback — and potentially health alerts — whenever needed to the patient or to external people, family, treating physician, health care call centre. In clinical research this enables the implementation of patientcentricity in clinical trial execution and opens possibilities for developing a new generation of products, combining drug and technologies.

The IPA described above can be extended to support clinical trials by adding sites and investigators with a

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Clinical Trial Management System (CTMS), integrating data collection from a classical Electronic Data Capture (EDC) system and/or from the EMR and by including data export functions, enabling delivery of a Clinical Study Report (CSR).

This extended platform can be used to support new approaches to clinical trial execution, envisioned by pharma for a few years now.

• As the platform allows for ongoing monitoring of the patient, pharma companies may build a case for regulators to put their drug product much faster on the market, under conditional approval.

• By introducing an IPA capable of adapting to the patient context, the platform supports patient-centricity and provides new possibilities to improve patient compliance.

• Thanks to the sensors (IoT), the platform allows for remote monitoring of the patient, a key technology enabler for virtual / remote trials, allowing the patient to remain at home rather than visit the site regularly and, therefore, increasing his/her comfort and readiness to remain in a trial.

• And finally, thanks to the predictive analytics module linked to bot that can regularly adapt advice and/or treatment to the patient specific data and context, personalised medicine becomes affordable at a wider scale.

The other major area of opportunity for pharma is the possibility to develop new products combining digital technologies with drug product to bring a new generation of services to the healthcare market. As an mHealth device, the IPA can be used for patients affected by a chronic disease or elderly people who are at risk of a dangerous clinical events (e.g. crisis of epilepsy or COPD), but do not necessarily require constant support and follow-up. The IPA can collect information and monitor the patient in the background, while at the same time assuring the patient and family that he/she is in ‘safe’ hands. Apple is already tackling this market, coupling the Apple Watch with the iPhone and expanding functionalities

to acquire data from both devices, and adding new apps residing on the iPhone.

A first application could be the result of their partnership with Janssen2 in Atrial Fibrillation. In this new model, instead of developing drug products as standalone, the industry can start to think how to combine their drug with sensors, bots and additional ML predictive capabilities within an Intelligent Patient Digital Assistant; this helps improve patient safety while also increasing compliance and efficacy — and therefore value — of a treatment delivered just in time to the patient. In addition, such products can save millions of hospitalisation costs, a valuable economy for most countries with ever increasing healthcare cost.

Challenges in Implementation

While there are major benefits for the Intelligent Patient Digital Assistant, its implementation will not go without challenges as displayed in the table below.

There are organisational, regulatory and technical challenges that will require additional innovation and new ways of thinking, as well as new or adapted regulations.

These aren’t insurmountable challenges. And while it will require hard work and collaboration between many different stakeholders to resolve them, the benefits (patient safety & comfort, increased efficacy with more personalised treatment, decreased cost) far outweigh the effort. We suggest, however, you avoid trying to solve all the problems at once; it is better to start small, find solutions to small problems and bring value step by step.

Conclusions

There is no question that both the healthcare and the pharma markets need new approaches to treatments as the current costs are not sustainable while the patient population is ageing, and chronic diseases are increasing. Digitisation could be a core driver of the change.

2 https://www.biospace.com/article/j-and-j-and-appleteam-up-for-heart-health-program/

INFORMATION TECHNOLOGY

a recent survey3 of 500 IT professionals including 100 top IT executives suggested that “IoT and AI are the most popular technologies currently in use, and top of the list for further investment for businesses seeking increased efficiency and competitive advantage.” The trend applies to life science too with an increasing number of new entrants in digital healthcare with products leveraging IoT and AI. Apple is probably the most aggressive example, but there are many new players coming up every day; they are skilled innovators, flexible, often linked

to prestigious universities and supported by venture capital. Not all of them will succeed but the competition is becoming fierce. In a January 2018 report4 on why digital strategies fail, McKinsey mention that “disruption is always dangerous but digital disruptions are happening faster than ever” and they predict that existing business models will be replaced by new digital business models, where “bold movers (attackers and agile incumbent) survive and rise”. Pharma and CROs are the incumbents of clinical research; now is the time for them to be agile and not just think digital but act digital.

3 https://sadasystems.com/blog/sada-systems-2018-techtrends-survey

4 https://www.mckinsey.com/business-functions/digitalmckinsey/our-insights/why-digital-strategies-fail

AUTHOR BIO

Combination of IoT and AI — Machine Learning & Bot — creates ‘smart’ machines simulating intelligent behaviour, making informed decisions with limited human intervention and offering personalised interaction. An Intelligent Patient Digital Assistant as described in this paper can boost productivity of clinical staff, decrease the cost of clinical trial execution and improve patient comfort while keeping (and even improving) quality of care; it is particularly suited to monitor and support treatment of chronic disease and elderly population. And while they are challenges toward implementation at regulatory, organisational and technical levels, they can be overcome with a stepped approach.

One key question is how fast we will be able to introduce these types of platforms in a highly regulated and conservative industry. There is a growing interest in combining IoT and AI across markets:

V2_ half page avec titre_Pharma Focus Asia - X-Pure - Feb 2019 vectorized.indd 1

Isabelle de Zegher is Vice President Integrated Solutions at PAREXEL Informatics and technical lead for PAREXEL E2E Data Standards program. She has 25 years’ experience in Life Sciences, including extensive work on CDISC standards. Dr. de Zegher holds a MD (UCL, Belgium) and an MSc in Medical Information Sciences (Stanford University).

2/4/2019 2:13:04 PM

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THRUCOOL BY SIA

A dedicated cold chain services Singapore Airlines Cargo focuses on various industry verticals i.e. airmail, charter services, perishables and live animal transportation etc. How do you drive your company towards greater innovation and stay updated to the ever-changing/evolving market needs?

SIA: Apart from keeping abreast of the recent developments in the market, we also actively reach out to our customers to understand their needs and preferences, and learn more about their latest developments. In addition, we participate in trade conferences and community-based events to exchange ideas and learn from our industry partners.

Please enlighten us with the key features of your new product'THRUCOOL'.

SIA: THRUCOOL offers dedicated cold chain services and strives to provide the highest quality handling for time-sensitive and temperature-controlled pharmaceutical shipments to maintain their integrity throughout air transportation. The launch of THRUCOOL is driven by SIA’s awareness about the importance of pharmaceuticals to the broader community and the growing complexity in their handling requirements. From the launch of the COOLRIDER product in 2000, to becoming the first airline in Asia-Pacific to be awarded the IATA CEIV PharmaCertification in 2017, pharmaceuticals has always been one of SIA’s key verticals.

To achieve the objectives of THRUCOOL, SIA partnered with SATS, Cargologic and Qantas Freight to launch a ‘quality corridor’ along the Zurich-Singapore-Sydney route as an initial offering. The partners were inducted after meeting the stringent criteria set by our pharma quality team, based on standards adopted from IATA ‘s CEIV Pharma programme.

This ensures that the quality of our pharmaceutical handling remains consistent, safe and secure throughout its journey.

The quality corridor is set to expand to other key export and import markets from 2019 onwards to further strengthen the THRUCOOL product.

As part of THRUCOOL’s offerings, thermal covers are implemented on mix-loaded shipments as an additional layer of protection from external factors to prevent temperature excursions during carriage. Active tracking devices, which allow for real-time monitoring of shipments’ location and temperature are approved for carriage on all SIA flights. SIA has also been

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working closely with SATS to identify hotspots and tighten the operational gaps in the Singapore hub’s handling processes.

The launch of THRUCOOL reassures SIA customers of our commitment to handle pharmaceuticals with utmost care and reliability. THRUCOOL serves as a platform to constantly seek out innovative ideas to enhance our service offering.

How do you meet the exact requirements of your customers while transporting life-saving pharmaceutical and healthcare shipments via THRUCOOL? SIA: Firstly, we work closely with our customers to ensure that the requirements (especially storage conditions) of the pharma shipments are communicated clearly during the booking stage and stated clearly on the airway bills. This reduces the possibility of mishandling as a result of unclear instruction to our ground handling agents.

Secondly, and most importantly, we work closely with our ground handling agents across our network to understand their facilities, capabilities and processes, to ensure that they are able to handle these life-saving pharma shipments. If gaps are identified, we will work with them to address these gaps either by tightening the handling processes or formulating mitigation efforts to reduce or eliminate the impact of the gaps. Furthermore, with a good understanding of our network capabilities, we are able to better advise our customers on the service level expected at origin and destination.

Transporting pharmaceutical and healthcare products through THRUCOOL demands a rigorous logistics approach. What are the special precautions that you take for Pharmaceutical and healthcare transportation?

SIA: Since the launch of THRUCOOL, we have identified hotspots, where temperature excursions are most likely to happen, across our supply chain and worked hard to address them. We tightened the handling process to reduce the shipment’s time exposure at tarmac and implemented thermal covers for selected shipments in specific lanes to reduce the possibility of temperature excursions.

What is the most in-demand segment for Singapore Airlines Cargo?

SIA: Much like the healthcare segment, our perishables accounts have seen healthy volumes benefitting from our cold

chain capabilities which ensure that our shippers’ produce stay fresh and uncompromised throughout their journey with us.

What steps you take to ensure delivery with highest standard for your pharmaceutical-related shipment?

SIA: We have an in-house training programme on pharma to ensure that our staff are adequately trained to provide the required support for pharma shipments. Furthermore, we have a pharma representative from each of the regions serving to drive the development of pharma handling.

What all it takes for you to provide unbroken cold chain transportation from origin to destination?

SIA: Teamwork and communication. Each party (from the shipper, agent, carrier, ground handling agent and consignee) has to work together and communicate effectively.

Do you provide consignment status to your customers while using THRUCOOL? What all details are included in the status report?

SIA: Customers can find out the consignment statuses of their shipments with ease by using our track and trace service that is available online.

In the next three years, which geography will provide the maximum revenue contribution for Singapore Airlines Cargo?

SIA: Currently, Europe is the biggest contributor and we expect it to continue in the next three years. However, we are confident on the growth of Singapore, Australia and India in the coming years.

MS ONG GEOK SUAN GENERAL MANAGER KEY ACCOUNTS & VERTICALS Ms Ong has extensive experience in the air cargo industry across key strategic and commercial roles where she oversaw profit optimisation across SIA’s cargo network, and managed regional sales performance in China, Southwest Pacific, and Singapore.

She now focuses on establishing partnership programmes for key accounts and driving vertical offerings and revenue across targeted industry segments.

Advertorial

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Books

Drug Delivery Systems (Advances in Pharmaceutical Product Development and Research)

Practical Pharmaceutical Engineering

Author(s): Rakesh K Tekade

Year of Publishing: 2018

Author(s): Donald R Kirsch, Ogi Ogas, Madelyn Fernstrom

Year of Publishing: 2019

No. of Pages: 556

Year of Publishing: 2018

No. of Pages: 575

Description: Engineers working in the pharmaceutical and biotech industries are routinely called upon to handle operational issues outside of their fields of expertise.

Traditionally the competencies required to fulfill those tasks were achieved piecemeal, through years of self-teaching and on-the-job experience—until now.

Practical Pharmaceutical Engineering provides readers with the technical information and tools needed to deal with most common engineering issues that can arise in the course of day-today operations of pharmaceutical/biotech research and manufacturing.

No. of Pages: 304

Description: Drug Delivery Systems examines the current state of the field within pharmaceutical science and concisely explains the history of drug delivery systems, including key developments. The book translates the physicochemical properties of drugs into drug delivery systems administered via various routes, such as oral, parenteral, transdermal and inhalational. Regulatory and product development topics are also explored. Written by experts in the field, this volume in the Advances in Pharmaceutical Product Development and Research series deepens our understanding of drug delivery systems within the pharmaceutical sciences industry and research, as well as in chemical engineering.

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P H A RM A F O C U S A S I A

ISSUE 34 - 2019

Author(s): Gary Prager

Practical Pharmaceutical Engineering is an indispensable “tool of the trade” for chemical engineers, mechanical engineers, and pharmaceutical engineers employed by pharmaceutical and biotech companies, engineering firms, and consulting firms. It also is a must-read for engineering students, pharmacy students, chemistry students, and others considering a career in pharmaceuticals.

The Drug Hunters: The Improbable Quest to Discover New Medicines

Description: The Drug Hunters is a colorful, fact-filled narrative history of the search for new medicines from our Neolithic forebears to the professionals of today, and from quinine and aspirin to Viagra, Prozac, and Lipitor. The chapters offer a lively tour of how new drugs are actually found, the discovery strategies, the mistakes, and the rare successes of drug hunters from the US, UK, Germany, and other nations. Dr. Donald R. Kirsch infuses the book with his own expertise and experiences from thirty-five years of drug hunting, whether searching for life-saving molecules in mudflats by Chesapeake Bay or as a chief science officer and research group leader at major pharmaceutical companies.

Analysis of Safety Data of Drug Trials: An Update Author(s): Ton J Cleophas, Aeilko H Zwinderman Year of Publishing: 2019 No. of Pages: 217 Description: The current edition was particularly written for medical and health professionals and students. It provides examples of modern analytic methods so far largely unused. All of the 16 chapters have two core characteristics, first they are for current usage, second they try and tell what readers need to know in order to understand the methods. Step by step analyses are given and self-assessment examples are supplied. Each chapter can be studied as a stand-alone.

Drug Wars: How Big Pharma Raises Prices and Keeps Generics off the Market

Biocontamination Control for Pharmaceuticals and Healthcare

Author(s): Robin Feldman, Evan Frondorf

Author(s): Tim Sandle

Year of Publishing: 2017 No. of Pages: 159 Description: While the shockingly high prices of prescription drugs continue to dominate the news, the strategies used by pharmaceutical companies to prevent generic competition are poorly understood, even by the lawmakers responsible for regulating them. In this groundbreaking work, Robin Feldman and Evan Frondorf illuminate the inner workings of the pharmaceutical market and show how drug companies twist health policy to achieve goals contrary to the public interest. In highly engaging prose, they offer specific examples of how generic competition has been stifled for years, with costs climbing into the billions and everyday consumers paying the price. Drug Wars is a guide to the current landscape, a roadmap for reform, and a warning of what is to come. It should be read by policymakers, academics, patients, and anyone else concerned with the soaring costs of prescription drugs.

Year of Publishing: 2018 No. of Pages: 374 Description: Biocontamination Control for Pharmaceuticals and Healthcare outlines a biocontamination strategy that tracks bio-burden control and reduction at each transition in classified areas of a facility. This key part of controlling risk escalation can lead to the contamination of medicinal products, hence necessary tracking precautions are essential.

Regulatory authorities have challenged pharmaceutical companies, healthcare providers, and those in manufacturing practice to adopt a holistic approach to contamination control. New technologies are needed to introduce barriers between personnel and the environment, and to provide a rapid and more accurate assessment of risk. This book offers guidance on building a complete biocontamination strategy.

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PRODUCTS & SERVICES Company........................................................................Page No.

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

STRATEGY ACG Engineering..........................................................................41

CLINICAL TRIALS Qatar Airways................................................................................27

Airbridgecargo..............................................................................21

Vetter Pharma-Fertigung GmbH & Co. KG...................................33

Cantel Medical............................................................................IBC Matcon..........................................................................................15 Qatar Airways................................................................................27 SIA Cargo.......................................................................... 09, 60-61 Swiss World Cargo.......................................................................19 Turkish Cargo............................................................................OBC Valsteam ADCA Engineering........................................................03 Vetter Pharma-Fertigung GmbH & Co. KG...................................33 RESEARCH & DEVELOPMENT ACG Engineering..........................................................................41 Akzo Nobel Chemicals (India) Ltd.............................................. IFC Matcon..........................................................................................15 Novo Nordisk Pharmatech A/S.....................................................45 Rousselot......................................................................................59

MANUFACTURING ACG Engineering..........................................................................41 Akzo Nobel Chemicals (India) Ltd.............................................. IFC Bachem AG...................................................................................53 Cantel Medical............................................................................IBC Lonza.............................................................................................05 Matcon..........................................................................................15 Novo Nordisk Pharmatech A/S.....................................................45 Rousselot......................................................................................59 Suez Water Technologies.............................................................47 Valsteam ADCA Engineering........................................................03 Vetter Pharma-Fertigung GmbH & Co. KG...................................33 INFORMATION TECHNOLOGY Rousselot......................................................................................59

SUPPLIERS GUIDE Company........................................................................Page No.

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

ACG Engineering......................................................................... 41 www.acg-world.com

Qatar Airways............................................................................... 27 www.qrcargo.com/qrpharma

Airbridgecargo............................................................................. 21 www.airbridgecargo.com

Rousselot..................................................................................... 59 www.rousselot.com

Akzo Nobel Chemicals (India) Ltd............................................. IFC www.kromasil.com

SIA Cargo..........................................................................09, 60-61 Siacargo.com

Bachem AG.................................................................................. 53 www.bachem.com

Suez Water Technologies............................................................ 47 www.suezwatertechnogies.com

Cantel Medical........................................................................... IBC www.mcpur.com

Swiss World Cargo...................................................................... 19 www.swissworldcargo.com

Lonza............................................................................................ 05 http://pharma.lonza.com/

Turkish Cargo........................................................................... OBC www.turkishcargo.com

Matcon......................................................................................... 15 www.matconibc.com

Valsteam ADCA Engineering....................................................... 03 www.valsteam.com

Novo Nordisk Pharmatech A/S.................................................... 45 https://novonordiskpharmatech.com/

Vetter Pharma-Fertigung GmbH & Co. KG.................................. 33 www.vetter-pharma.com

To receive more information on products & services advertised in this issue, please fill up the "Info Request Form" provided with the magazine and fax it.

1.IFC: Inside Front Cover, 2.IBC: Inside Back Cover, 3.OBC: Outside Back Cover

CANTEL MEDICAL Cantel Medical Asia/Pacific Pte Ltd Asia: · Asia: [+65] 6227-9698 For more information email us at info@@cantelmedical.com.sg or visit www.mcpur.com

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THE WORLD'S HEALTH IS IN THE SAFE HANDS OF TURKISH CARGO As the cargo airline that flies to more countries than any other, we carry all your health and wellness needs, from pharmaceuticals to medical supplies without ever interrupting the temperature-controlled cold chain.

turkishcargo.com www.pharmafocusasia.com

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