Pharma March 2012

March/April 2012 ISSN 1746-174X

Volume 8 Number 2

The global magazine for the pharmaceutical and biopharmaceutical industry

Clean Rooms & Contamination Control CO2 Incubators

Outsourcing

Non-Clinical Early Development

Biopharmaceuticals Virus Safety Assurance

LABORATORY SCIENCE CHN Elemental Analysis

w w w. p h a r m a - m a g . c o m

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CONTENTS Follow us on Twitter at http://twitter.com/PharmaMag

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MARCH/APRIL 2012

Contents

FOCUS TOPIC

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Laboratory Science

Contributing Companies: Exeter Analytical (UK)

Ltd, RSSL and TTP Labtech

CHN elemental analysis, leachables and extractables, and achieving successful structure‑based drug design.

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Clinical Trials

Contributing Companies: ERT and Kellman

Industry experts highlight the benefits of centralized ECG data collection, and strategies to improve the enrollment process.

FEATURES

Roundtable Review: Outsourcing Non-Clinical Early Development

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Corrine Lawrence — Via Media UK Ltd

Executives share their insights and experiences of accerlating early development and the role of contract development organizations in achieving that goal.

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Clean Rooms & Contamination Control: Sustaining a Clean Cell Culture Environment Mary Kay Bates and Douglas Wernerspach — Thermo Fisher Scientific

Defending cell cultures from microbial contamination with new technologies in CO2 incubators.

Emerging Markets: China, Unlocking the Growth Opportunity of the Century

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Josée Hulshof, Yue Luo-Fuhrmann and Doreen Dai — Simon-Kucher & Partners

A four-step approach to help companies map out how to fit their local organizations and resources to address the Chinese market.

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Biopharmaceuticals: How are we Doing and what’s Left to do?

Hazel Aranha — Catalent Pharma Solutions

Producing biopharmaceutical products with a high level of virus safety assurance.

March/April 2012

Data Management: Managing Enterprise Database Discovery in Pharmaceutical and Medical Device Litigation

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James Mittenthal — Epiq Systems

Measures to protect proprietary schemas and other intellectual property.

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Legislation: Walking the Social Media Tightrope

Lori B. Leskin — Kaye Scholer

The author discusses the concerns pharmaceutical executives may have as they await the promised further guidance.

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Executive Profile: Focus and Deepen

Dr Ian Muir — Catalent Pharma Solutions

Catalent’s President of Modified Release Technologies talks to Pharma about industry trends and new drug delivery technologies.

REGULARS

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From the Editor: The Green Shoots of Convergence

Corrine Lawrence — Via Media UK Ltd

The emergence of spring makes me ponder about the convergence of the pharma and nutriceutical industries.

06

Comment: Having the Human Touch

Paul Burton — 1HQ

Why pharmaceutical and healthcare companies think about humanizing themselves.

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Nostrapharmus: The Drug Safety Utility — Paying Monthly Bills Versus Building Power Stations Notrapharmus

Nostrapharmus predicts that during the next 5–10 years drug safety operations will become almost completely commoditized.

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Contributors

Editor Corrine Lawrence +44 (0) 771 517 7767 corrine.lawrence@via-medialtd.com Editorial Director Kevin Robinson +44 (0) 1392 202 591 kevin.robinson@via-medialtd.com Art Director/Production Paul Andrews Tel. +44 (0) 1372 364 126 paul.andrews@via-medialtd.com

Account Manager Michael Lund +44 (0) 1372 364 124 michael.lund@via-medialtd.com Financial Officer Cherelle Saunders +44 (0) 1372 364 123

cherelle.saunders@via-medialtd.com

General Manager Miranda Docherty +44 (0) 1372 364 125

miranda.docherty@via-medialtd.com

Content/Marketing Manager Claire Day Tel. +44 (0) 1372 364 129 claire.day@via-medialtd.com

Editorial Advisory Board

The Editorial Advisory Board of Pharma comprises a distinguished panel of experts from various parts of the pharmaceutical industry. They review technical manuscripts, suggest topics for inclusion, recommend subject matter and potential authors, and act as the quality control department for the magazine’s editorial content and direction.

Rory Budihandojo Director, Quality Systems Audit Boehringer Ingelheim Shanghai Pharmaceuticals Co., Ltd

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Patrick Crowley Vice President Product Line Extensions GSK (US) Enric Jo Plant Director Reig Jofre Group Maik W. Jornitz Senior Vice President Global Product Management, Bioprocess Sartorius North America Inc.

Alan Lahaise Key Account Executive Patheon

Ray Rowe Chief Scientist/Prof of Industrial Pharmaceutics Intelligensys/Uni of Bradford

Carlos Lopez Relationship Director Healthcare & Pharmaceuticals Lloyds TSB Corporate Markets

Harald Stahl Senior Pharmaceutical Technologist GEA Pharma Systems Kurt Speckhals Gino Martini Director, Strategic Technologies Senior Director, Supply Chain GSK (UK) Pfizer Inc. Jim McKiernan Chief Executive Officer Geoff Tovey McKiernan Associates GmbH Visiting Professor Maireadh Pedersen Head of Business Development Quay Pharma

Dept of Pharmacy King’s College Wes Wheeler President, WPWheeler LLC

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The publisher endeavours to collect and include complete, correct and current information in Pharma but does not warrant that any or all such information is complete, correct or current. The publisher does not assume, and hereby disclaims, any liability to any person or entity for any loss or damage caused by errors or omissions of any kind, whether resulting from negligence, accident or any other cause. Pharma does not verify any claims or other information appearing in any of the advertisements contained in the publication, and cannot take any responsibility for any losses or other damages incurred by readers in reliance on such content.

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March/April 2012

FROM THE EDITOR

The Green Shoots of Convergence

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t last, the long, dark nights and heavy, grey skies are giving way to warmer climes and lighter days. With lambs skipping in fields, buds forming on the naked branches of trees and tender shoots pushing their way through the dormant earth … spring is definitely in the air, and its telltale signs of new life nourish me with a sense of vigour and well-being. If only I could bottle it — whatever ‘it’ is.

The extra light and heat of the spring sun have beckoned me outside to remove winter’s litter and to prepare the ground for new growth. As a garden dabbler, I’m keenly aware that life is food. Yet food is also medicine; I can vouch for the nutritional benefits of, for example, garlic, watercress, tomatoes, currants, spinach and herbs. A few years ago, I made the decision to turn my back on many of the processed foods on offer in supermarkets. Now, I struggle to make it through a day without a bucketful of fruit and vegetables. Should I find myself in a situation that hampers my access to such ingredients, I can feel my

body rebel as it tries to do something meaningful with ‘food’ that has the same nutritional benefit (and taste!) as an old boot.

Working on Pharma puts me in receipt of many press releases … and I’m seeing an emerging trend — the power of food and its place in our medicine cabinets. Health and food have a long history and are inextricably linked. Food has the power to prevent (or encourage) the occurrence of certain diseases and illnesses; it also has the force to ‘cure’ or alleviate. And this hasn’t escaped the notice of the pharmaceutical and nutraceutical industries. Furthermore, the University of Aberdeen is offering a new Masters degree (Molecular Nutrition) that addresses the links between diet and diseases including cancer, diabetes and cardiovascular disease. How far off is the convergence of the pharma and the nutraceutical industries? Only time will tell. But what I’m really waiting to see is the first bottle of ‘Spring’ — a tonic that energizes, invigorates and puts a bounce in your step.

Corrine Lawrence Editor, Pharma corrine.lawrence@via-medialtd.com

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COMMENT

HAVING THE HUMAN TOUCH Companies and individuals have been humanizing themselves in the public eye for generations. There have been subtle attempts, as well as some less subtle attempts (some with more positive effect than others) across all industries and territories. But, why should pharmaceutical and healthcare companies think about humanizing themselves?

W

hat does it mean to humanize?

The definition of ‘humanize’ — to portray or endow with human characteristics or attributes/to imbue with humaneness or human kindness sheds some light on what it is about and why it can be valuable to the pharmaceutical and healthcare industries.

The one hard question for pharmaceutical and healthcare companies to answer is “why it is important to present ourselves to the public as being in touch with humanity?” Given that those companies produce drugs and develop health solutions to better the lives of patients and consumers, it makes sense to come across to the public as being a caring company; being in touch with humanity implies that you care.

But is it really important for a company to come across as caring? Large pharmaceutical and healthcare

companies seem to think so; there is an increasing shift in the direction of portraying themselves as such. In recent years, for example, pharmaceutical companies have received negative publicity and have been portrayed as an industry that cares less about the patients than it does about making money (and is seen as making lots of it by charging so much for medication). For these companies, humanizing themselves can only help. A visit to any one of the many pharma company website will present you with images of caring hands, caring doctors, caring teams and the list continues. You will feel you are being watched over, which is the message those industries have been trying to portray to the public and professional worlds. Why not, then, go one step further and humanize the company in other ways, especially through a social media channel or other digital channel strategies in general?

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Copyright ©2011 AmerisourceBergen Packaging Group

COMMENT Benefits

So what are the benefits? One particularly important and additional benefit to humanizing a company is that you generate a belief, support and confidence in the parent company itself. Consider Apple and its followers: if there is a glitch in one of their products or software updates, it does not make a significant impact to consumers’ confidence in their products — they believe in Apple products, and a solution, and, therefore, the strong following can withstand any storm that may arise. Although the healthcare industry is much different (and of course,Apple is a unique example that is difficult to fully compare to others), most companies in this industry have a variety of products and product categories so should something should go wrong with one product, a resolute belief in the parent company will help. The drawbacks to this are exposing the parent company as the master brand and failing to give sufficient independence to the product brands. But in the long run, the benefits could easily outweigh the risks as belief in the parent company (or master brand) start to develop a following and support to ride these storms that companies inevitably face at some point. The support to this argument is that when something does go wrong on a particular product, the media will always expose the parent company. Humanizing the company will act as a shield.

It may not protect the company completely, but it can certainly soften the blow.

So how does a pharma company humanize itself? Given that patients trust other patients more than they trust pharma companies, the latter could facilitate this interaction and provide useful information along the way, within any therapy area. Pfizer has successfully done this with the creation of ManMOT.co.uk, a forum where men can interact with other men and, for example, share experiences and get advice from a GP (Mondays mainly). And on the top and bottom of the webpage, there is a simple mention of the word “Pfizer.”

There have been many similarities between the fast‑moving consumer goods (FMCG) and health industries: some experts believe that the pharmaceutical and healthcare industries follow the FMCG industry in certain business areas; for example, the use of social media. The FMCG industry, and others, has taken advantage of this channel of communication and interaction with their consumers not just to sell a product or increase a product’s profile, but also to learn about their consumers and their behaviour. A company’s strategy can be easily customized to their customers’ needs. Ultimately, the realization that a humanizing strategy can benefit the business is a great starting point. The most effective strategy will depend on the needs, size of the company or category, therapy areas, products, history, presence, territories and the target consumer or patient age group.

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LABORATORY SCIENCE

BOOST YOUR CONFIDENCE WITH CHN MICROANALYSIS

Using CHN microanalysis alongside other analytical techniques can provide precise and accurate data on a sample’s composition and purity.

S

ample characterization and purity determination requires a combination of analytical techniques to generate the package of data to fully characterize a sample. This article examines and demonstrates the role of CHN (carbon, hydrogen and nitrogen) elemental analysis and how it complements other established analytical techniques, including nuclear magnetic resonance (NMR) and mass spectrometry (MS), in helping laboratory scientists determine a sample’s composition and purity.

Furthermore, the article will demonstrate how CHN microanalysis can be used to determine sample purity by eliminating “blind spots” sometimes found with other analytical techniques enabling reliable calculation of compound stoichiometries as is required in life science research and development.

Determining Sample Composition and Purity

Research compounds typically produced in synthetic and medicinal chemistry laboratories often require final purification steps using flash chromatography or preparative HPLC. For flash chromatography, the samples are passed over a silica bed and eluted at an appropriate rate to afford separation of the product from by‑products (often structurally related compounds) and impurities. The composition of the mobile phase is adjusted to allow this separation whilst ensuring that the product itself is retained

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Figure 1: 1H NMR spectrum in CDCl3 of 4‑Bromo‑2,6‑bis(benzylthio) methyl pyridine.

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63.944

ppm

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Figure 1

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on the column for the minimum time possible. The product is collected as a solution in the mobile phase, the solvent evaporated off and the product dried.

Under certain mobile phase conditions, the silica gel may become sparingly soluble and trace levels elute with the product. This inorganic contaminant is ‘invisible’ to standard NMR and MS techniques, which could lead to a falsely elevated reaction yield.

Yet, even with very low levels of inorganic impurity (silica gel) in a sample there will be a significant reduction in the percentage carbon, hydrogen and nitrogen levels as determined by CHN elemental analysis.

Similarly, whilst the presence of low levels of residual solvent in a ‘dried’ sample of 4‑bromo‑2,6‑bis(benylthio)methylpyridine was readily identified by CHN elemental analysis as significant deviations from theoretical percentage values, the solvent has little or no effect on 1H NMR or MS data as shown in Figure 1.

In this example, CHN elemental analysis of 4‑bromo‑2,6‑bis(benylthio)methylpyridine should give theoretical carbon, hydrogen and nitrogen values of 58.60%, 4.68% and 3.25%, respectively. Yet, analysis of the sample gave the values of C: 57.51%, H: 4.57% and N: 3.24%. This deviation of 0.4% from theoretical values as measured by CHN microanalysis indicates that the sample is not completely pure. Figure 2 shows how, by the inclusion of 0.5 moles of residual methanol in the calculations, the identity of the parent sample can be confirmed and the presence of trace levels of residual solvent confirmed and identified.

The principles of sample purification employed in reverse phase HPLC methods are similar to those discussed previously in that the sample is introduced onto a silica‑based solid support and separation from impurities with subsequent elution from the column being determined by judicious modification of an aqueous/organic solvent mix of mobile phase. It is common practice to add modifiers such as trifluoroacetic acid (TFA) to the mobile phase to sharpen peaks and improve resolution.

A large proportion of drug candidates, however,

March/April 2012

LABORATORY SCIENCE

Figure 2: CHN Analysis calculations for 4‑Bromo‑2,6bis(benzylthio)methyl pyridine (C21H20BrNS2).

Figure 3: Determination of hard to quantify ‘invisible’ impurities.

Figure 4: Exeter Analytical Inc.’s Model 440 CHN analyser.

% of element

Figure 2

Figure 3

How CHN Elemental Analysis Works

Figure 4

often have multiple basic ionization sites that are readily protonated and the presence of TFA may cause association to these sites at ratios not easily determined. TFA has a molecular weight of 114.03 and even at subunity ratios this will have a significant impact on the mass of sample taken whose mass itself may only be 300–400. This problem is even more significant in the case of peptides and proteins; they contain multiple basic nitrogen atoms within the molecule, each of which is susceptible to protonation and association. Using the TFA salt (CF3CO 2H) of the diuretic amiloride (C6H 9N 7OF) as an example, Figure 3 demonstrates how %C, H and N changes with stoichiometry and how simple calculations and graphical representation can allow accurate determination of sample composition for dosage calculations or interpretation of biological activity.

March/April 2012

In CHN elemental analysis, samples are weighed (1–2 mg) into a tin capsule that is supported within a nickel sleeve. The prepared samples are then placed into an autosampler that is purged with helium — chosen for its chemically inert characteristics relative to the tube packing reagents, and its very high co‑efficient of thermal conductivity. The tin capsule containing the sample is introduced via a ladle into a combustion tube held at 975 °C in a pure oxygen environment causing the tin capsule and sample to undergo flash combustion with an exothermic reaction at 1800 °C. These conditions, along with an option of variable combustion time create conditions such that even the most thermally resistant sample will oxidize. The products of this combustion process pass over a series of specialized reagents held in the combustion tube, which are ordered such that complete oxidation of the products is assured with conversion of the sample’s elemental carbon, hydrogen and nitrogen to carbon dioxide, water, nitrogen gas and nitrogen oxides. These combustion products are subsequently flushed through a reduction tube packed with copper, held at 620 °C, where nitrogen oxides are converted to molecular nitrogen and residual oxygen is removed.

In Exeter Analytical Inc.’s CE440 analyser (Figure 4)

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LABORATORY SCIENCE Figure 5: Combustion train in CE440 elemental analyser.

Barbara Mason

Fore more information

Barbara Mason Operations Manager Warwick Analytical Service Exeter Analytical (UK) Ltd Tel: +44 247 632 3223 barbara.mason@exeteranalytical.co.uk www.warwickanalytical.co.uk

the combustion and reduction tubes (the combustion train, Figure 5) are orientated in a horizontal geometry to prevent build‑up of sample ash.

To ensure total homogeneity, the mixture of combustion gases is pulsed into a mixing volume enabling a faster formation of a homogeneous mixture. Using a pressure transducer, the pressure in the mixing volume is measured until a pre‑set pressure has been reached. The combustion products are then sealed in the mixing volume for a defined period of time after which a known volume of the combustion product mixture is released. This known volume of combustion mixture then passes through a series of traps where H 2O and CO 2 are completely absorbed, with high precision thermal conductivity detector filaments located before and after each absorption trap. The difference between the output of each set of detectors before and after absorption can be seen to be proportional to the trapped component to allow determination of the carbon and hydrogen content, with the remaining gas containing only helium and

nitrogen. Comparing this against a helium reference produces the nitrogen concentration.

Conclusions

Using CHN elemental analysis alongside analytical techniques such as NMR and MS, with an understanding of the synthetic pathways, generates with a much higher degree of certainty the quality of compounds being produced. This in turn affords a greater degree of confidence in the decision‑making processes based around a product’s performance further down the R&D path.

CHN elemental analysis is fast, easy to use, and can provide precise and accurate data on a sample’s composition and purity. The versatility of the technique ensures that it is amenable to a wide range of life science sample types, including crystals, amorphous solids, peptides, proteins and, when used in conjunction with appropriate sample handling techniques, can even accommodate volatile samples such as colloids and gels.

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LABORATORY SCIENCE

LEACHABLES AND EXTR ACTABLEs Pharmaceutical packaging serves many functions, but its primary role is to protect its contents. The process and pack jointly represent a system that is designed to deliver a pharmaceutical product free from contamination and external influence. So it has to be acknowledged that the very systems that are designed to preserve and protect pharmaceutical products can also, occasionally, be the cause of problems that affect quality, compromise stability and even put patient safety at risk.

T

he danger — where it exists — comes from chemicals that leach out of packaging materials and find their way into products.

There is a similar risk associated with factory items such as rubber seals or plastic pipes. Leaching describes the passage of chemicals from an item into the drug product during normal conditions of storage and use, whereas extractables are chemicals that can be ‘forced’ out of packaging under stress. Both possibilities need to be tested for, and hopefully, discounted.

Identifying Problems

For more information Julian Rae Senior Associate Principal Scientist Pharmaceutical Chemistry RSSL Tel. +44 118 918 4000 enquiries@rssl.com

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Testing is advisable at the earliest stages of drug development. No company would wish to have a new product launch delayed because it is unable to provide regulators with evidence that a relatively inexpensive closure system is appropriate and safe.

The various Pharmacopoeia set out a whole battery of tests for assessing the contamination risk presented by packaging materials and closures. Such contaminants could include chemicals that • Compose the packaging material (for example, plastic monomers).

• Are used in the production of packaging (for example, metal catalysts).

• Are external to the packaging (for example, moisture from the air).

The testing required, however, differs depending on the material in question, the manner in which it was made and the use to which it will be put. Polypropylene, for example, is not a uniformly consistent material and it is necessary to know which additives have been used in its manufacture to determine which tests to apply. It is unsurprising, therefore, that the compendial methods do not provide all the answers. A competent laboratory (and a concerned client) will want to develop and validate bespoke methods that will provide product/packaging‑specific results that can be used in support of submissions for approval of a new drug system or medical device.

Analytical Investigations

If ‘packaging’ chemicals do contaminate a product, or degrade the active during a stability study, they will cause an out‑of‑specification (OOS) result. That does not mean,

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however, that every OOS result is caused by contamination from packaging. All possibilities must be investigated.

Modern chemists have a wide range of sophisticated analytical instruments at their disposal for investigating OOS results. Technologies such as liquid chromatography– mass spectrometry (LC–MS) and gas chromatography– mass spectrometry (GC–MS) are hugely powerful in isolating and identifying trace amounts of nonvolatile and volatile contaminants, respectively. Fourier transform infra‑red spectrophotometry (FT‑R) may also be used, and inductively coupled plasma mass spectrometry (ICP‑MS) and atomic absorption spectrometry (AAS) will be used for identifying metal elements. Conversely, modern supply chains are also extremely complex, and will involve excipients and APIs coming into contact with a myriad of containers and surfaces during storage and distribution, as well as during processing and packing.

For the laboratory charged with the investigation of ‘what went wrong?’ it is important to have a thorough understanding of the production process and its potential vulnerabilities, as well as the specifics of the packaging.

Many hours of fruitless sampling and testing can be avoided if the client can provide these details, though it still needs the laboratory to understand what it is being told! On the flip side, it greatly helps the client if the laboratory can present and interpret its results in a meaningful way, rather than merely presenting a stack of numbers. Communication is key to reaching a rapid conclusion about where a fault lies, and in implementing a quick resolution.

Conclusion

Without the proven quality of packaging, the pharmaceutical industry would simply not exist. That said, it is important to accept that problems with extractables and leachables can arise from time to time. Hence, it makes commercial and ethical sense to thoroughly test the packaging and product together as early as possible in the drug development process to ensure that they are suited, and to repeat these tests before sanctioning any change in product formulation or packaging specification. Similarly, when problems arise, rapid, investigative analysis is essential, and it helps to use a laboratory with a good experience of emergency investigations.

March/April 2012

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of laminar-flow monitoring, they measure flows from as low as 0.05 m/s (standard velocity wN of air, based on standard conditions of 20°C and 1013.25 hPa). Due to the optional high-precision calibration, the measuring accuracies are within ±1% of the measured value. The users can choose between the thermopile and ‘dumbbell head’ sensor models.

The thermopile sensor of the SS 20.415 simultaneously offers the option of detecting the direction of flow. Thermopile sensors are distinguished in particular by their mechanical sturdiness and extremely quick response time of 10 ms. The aerodynamically optimized dumbbell head sensors of the SS 20.515 are particularly easy to clean, even when switched on. A coated design also allows their use in aggressive media. Both sensors are suitable for disinfection with alcohols such as isopropanol and with H2O2.

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LABORATORY SCIENCE

ACHIEVING SUCCESSFUL STRUCTURE‑BASED DRUG DESIGN The development and commercialization of new medical drugs is a complex and costly process, and increasing pressure is being placed on effective research to accelerate the rational design of compounds. This review discusses the process of structure‑based drug design, highlighting the problems surrounding the structural determination of biological targets by X‑ray crystallography. It also presents an effective solution enabling the crystallization process to be successfully incorporated into the automated drug discovery process.

S

tructure-based drug design has proven to be effective in nearly all aspects of drug discovery, enabling the development of inhibitory compounds that bind directly to a biological target involved in a disease pathway.

Determination of a protein’s 3D‑structure provides valuable information on the exact shape of its active site and the conformational changes that occur upon ligand binding. Such insights allow the rational design of compounds, optimized for binding specificity and affinity, thereby enhancing drug efficiency and eliminating unwanted side-effects.

Determining the structure of biological macromolecules

by X‑ray crystallography can be a lengthy, complex and costly procedure. Optimal crystallization conditions vary for individual proteins or protein families, and screening involves numerous trials, varying buffer conditions, precipitants and dilutions. Furthermore, following successful crystallization, issues involved in scale‑up and deciding whether a crystal is viable for structure determination can also be time consuming.

Using traditional manual techniques for crystallization set‑up and optimization, successful production of diffraction quality crystals can take months. The manual process of protein crystallography can be a major bottleneck in the drug discovery process. Today’s drug discovery industry, however, employs a wide range of automated liquid handling and screening technologies for biological assays and compound screening that do not compromise experimental flexibility or data quality.

This review discusses the requirements for effective automation of protein crystallization from screening through to scale‑up for crystal harvesting and structural analysis.

Implementing an automated nanoliter liquid handler can often resolve issues commonly associated with the manual set‑up of crystallization screening trials, offering consistent, accurate volume dispensing and drop placement.

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Crystallization Screening Process

The process of protein crystallization can be divided into three discrete stages: initial screening to produce hits; optimization to define conditions for reproducible, stable crystal formation; and finally, scale‑up for the production of crystals large enough for X‑ray data collection.

Using automated liquid handling procedures for crystallization screening and scale‑up alleviates repetitive and time‑consuming manual pipetting.

Primary Screen Set-Up Because of the often limited amounts of protein available, the ability of an automated liquid handler to accurately dispense nanoliter volumes of protein and buffer (in the 100‑nL range), without the risk of contamination, enables a larger range of screening conditions to be studied. The ability of automated liquid handlers to cope with the viscous nature and variable surface tensions of

March/April 2012

LABORATORY SCIENCE screening buffers and additives have also been a concern.

By using positive displacement technology, whereby liquid is drawn up using a piston inside a cylinder unit, it is possible to accurately dispense nanoliter volumes of varying viscosities and surface tensions. In addition, disposable tips eliminate potential cross‑contamination of samples.

Accurately placing drops of screening solution on top of protein drops, whether using the sitting or hanging drop technique, is a repetitive task that is prone to manual error.

Low volume drops have to be placed accurately so that the protein and the screen drops coalesce and are not distorted by the edge of the crystallization plate’s subwell. Liquid handlers that can accurately and reliably place drops have increased the speed and success rates of crystallization screening programmes.

Optimization Following the initial screening phase to establish one or more conditions for successful crystal formation or nucleation, optimization may include the incorporation of additives, which enhance crystal stability and/or conformation. During the process of crystal formation, optimal conditions for nucleation of a crystal may differ to those required for its subsequent growth. To optimize the quality and reproducibility of crystals, it can be beneficial to seed crush early phase crystal samples from one set of

conditions into a second set of conditions. This process is termed micro‑seeding and can be easily done using automated liquid handling instrumentation.

Conclusion

Using automated liquid handling procedures for crystallization screening and scale‑up alleviates repetitive and time‑consuming manual pipetting, and the associated potential errors. The ability of robust and high calibre liquid handling robots to accurately and consistently dispense multiple nanoliter volume samples enables large screening studies to be done. By maximizing the number of screening conditions per protein sample, optimizing crystallization conditions and enabling faster scale‑up, the structural biologist can address complex biological questions quickly and efficiently.

The successful automation of crystallization using robots such as TTP labtech’s mosquito Crystal and LCP has significantly improved the process of protein crystallography and facilitates high‑throughput drug discovery. The discipline of X‑ray crystallography is now accessible, not just to a select group of specialist scientists, but to multidisciplinary teams working in structural and molecular biology. This allows them to determine 3D structure and thus develop drug compounds with high efficacy and minimal off‑target effects.

Wendy Gaisford PhD

For more information Wendy Gaisford PhD Scientific Writer TTP labtech www.ttplabtech.com

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CLINICAL TRIALS

THE MULTIPLE BENEFITS OF CENTR ALIZED ECG DATA COLLECTION

Continual developments in technology are helping to provide solutions for data inconsistency and inaccuracy in the analysis of electrocardiograms (ECGs). The regulatory requirements for digital submission of data have put additional focus on centralization of cardiac data. A study of investigative sites conducted by the Tufts Center for the Study of Drug Development (CSDD) revealed that more than 50% of respondents predict that during the next 5 years the increased usage of the centralized method will be significant. An explanation for this adoption of centralization can be linked to the multiple advantages it offers comparison with the decentralized approach. In addition to being more economically viable for companies, this approach significantly increases data quality and offers greater consistency for clinical trials.

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ardiac safety concerns are cited as a particularly prevalent reason for withdrawing drugs from the market, making changes to labelling and postponing, or refusing, regulatory approval. If one or more of these occur, it can result in significant cost for a company in the short run and reduced revenue in the long run. To monitor accurately the cardiac safety of new compounds, sponsors require precise and high quality ECG data, which is sometimes unavailable through a decentralized model. Using a decentralized model can often produce fragmented and inconsistent ECG data collection and analysis, because it is done across multiple investigator sites using local ECG machines. Inconsistent results can frequently occur because of the variation in instrument models using different algorithms for calculations that are then evaluated by multiple clinical personnel of varying experience.

Pharmaceutical companies worldwide, therefore, are increasingly recognizing the important benefits associated with centralized ECG collection. In February 2010, the Tufts CSDD published research results regarding the industry adoption of centralized cardiac safety laboratories and perceptions from key stakeholders.1 According to the report, 97% of the respondents rated central laboratories as being accurate and 90% rated them as being efficient. Looking ahead, 89% of respondents expected the use of centralized ECG to increase in 5 years. The increasing adoption

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of centralized cardiac safety laboratories has been triggered to a high extent by the latest regulatory developments and pressure on the biopharmaceutical companies to reduce cost.

Current Legislation

FDA, the European Medicines Agency (EMA), Health Canada and the Japanese Ministry of Health have adopted the current ICH E14 guidance for industry, which provides recommendations to sponsors concerning the design, conduct, analysis and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization.2 This assessment should include testing the effects of new agents on the QT/QTc interval, and collecting cardiovascular adverse events. The investigational approach used for a particular drug should be individualized, depending on the pharmacodynamics, pharmacokinetic and safety characteristics of the product, as well as on its proposed clinical use.

The guidance recommends performing a thorough ECG trial (TET) and if any cardiac safety concerns are raised, later phase trials will require more robust or intense ECG collection. A key requirement of the ICH E14 guidance is that a proof of concept, providing evidence that a centralized ECG system can be successfully used, must be done prior to commencing a TET trial. The guidance also stipulates the use of centralization in cases where cardiac safety concerns are raised.

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CLINICAL TRIALS

Reduced Costs

Amy Furlong

The 2010 Tufts research revealed that only 33% of all ECGs are collected using a core laboratory.

This low percentage reflects sponsors’ and CROs’ misconception that collecting ECGs locally is cheaper than the centralized approach. In reality, the ‘hidden costs’ of data capture at site and associated data cleansing result in higher total costs than using a core laboratory. The findings of the research showed that it could cost up to $245 for a single decentralized ECG to be collected. This fee excludes the internal costs to the sponsor for data cleaning and reconciliation associated with a decentralized, paper approach.

When using a decentralized model, the majority of collection, transcription, cleaning and interpretation of ECG data are conducted by the sponsor and the individual monitoring site. As a consequence, sponsors must pay a considerable ECG acquisition fee, which includes charges for technician time and the use of ECG machines at the investigator site. Additional fees for cardiac specialists to provide over read of the ECGs are also incurred based on the experience of the specific study Investigator. By following a centralized approach, this fee is substantially reduced as all work is outsourced to a single provider. In addition, the digital collection equipment supplied by leading core laboratories provides an easy‑to‑use interface to reduce data entry errors and collect, transfer and store data electronically.

Accelerated Analysis Time

References

1. www.ert.com/ knowledge-series/ 2. www.fda.gov/downloads/ RegulatoryInformation/ Guidances/ucm129357.pdf

For more information

Amy Furlong Executive Vice President and Chief Operations Officer ERT Tel: +1 215 972 0420 info@ERT.com www.ERT.com

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When using a decentralized model, ECG studies are conducted within a variety of investigator sites using local ECG machines. Combining all collected ECG data from the different sites can be time‑consuming, as each site will need to manually transcribe data from paper printouts and data reconciliation, which negatively affects the decision‑making process. Using a centralized model can dramatically accelerate analysis time as it employs standardized ECG data collection processes. This promotes early detection of cardiac risk and so reduces the risks of wasted time and cost of a potentially unviable drug compound. There are many case studies demonstrating that the collection of digital data improves quality and timeliness of data … and ECG data are no exception.

Enhanced Data

When relying on local ECG analysis, there are many factors that may influence the interpretation of ECG

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data and introduce variability and inconsistency of results. Centralized cardiac safety services minimize potential bias and facilitate confidence in the quality and consistency of results. All ECG data are collected digitally using high resolution, validated systems, thereby eliminating common transcription and misinterpretation errors. Many core laboratories also use systems that can automatically check for missing visits or demographic changes, further improving data quality, integrity and consistency.

Qualified individuals assess all interval duration measurements (IDMs) and a qualified cardiologist — who is trained to follow standardized procedures, which are continually validated through a quality control programme — evaluate every ECG. These standardized processes provide cleaner and more accurate and reliable data. The improved confidence in the accuracy and quality of ECG data enables sponsors to make more informed internal decisions regarding the compounds under investigation.

Access to Innovation

Pharmaceutical companies rely heavily on the use of innovative technologies to facilitate continued success. A centralized cardiac safety approach enables sponsors to implement the latest technological advancements, including lightweight and compact ECG machines, which have a significantly smaller footprint than their predecessors. As a result, the challenges associated with more traditional heavy and expensive instrumentation are removed. New ECG systems are easier to maneuver and are cheaper to ship and store. In addition, the compact size of the state‑of‑the‑art instruments provides a better ‘technical’ service, offering more consistency and improved accuracy whilst effortlessly and seamlessly integrating with computer systems through a web application. Furthermore, enhancements in the collection of data to provide real‑time data integrity checks to obtain clean data as early as possible are also provided.

Conclusion

Pharmaceutical companies worldwide are increasingly recognizing the value and advantages of centralized ECG data collection for cardiac safety purposes.

The centralized approach promotes compliance with current legislation, and benefits sponsors by offering improved data accuracy and reliability, significant time and cost savings and access to the most advanced ECG technology.

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CLINICAL TRIALS

TAMING THE ENROLLMENT MONSTER IN CLINICAL TRIALS Enrollment shortfall is an endemic problem in clinical trials. Nearly 80% of trials fail to enroll on time — a costly and unnecessary burden on the process. Better management, however, can improve this poor statistic.

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rug failures are an inevitable part of Big Pharma’s landscape, with major Phase III failures all too common.

Most recently, Pfizer took yet another hit when biotech partner Medivation threw in the towel for its once‑promising Alzheimer’s drug, Dimebon, following a failed 12‑month study of the drug and two failed Phase III studies. This January, Pfizer took the opportunity to bow out of its partnership, writing off its $225 million upfront and $500 million milestone programme for what proved to be another embarrassing pipeline failure.

Costly drug failures such as Medivation’s aren’t always blameless. Delays in clinical trial recruitment are a major part of the problem. And what begs a close look is the role contract research organizations (CROs) play in those delays, which so often delay or jeopardize drug approvals.

How bad is the problem? At least 30% of clinical trial sites fail to produce a single, randomized subject, and 90% of trials fail to enroll on time. With study management and monitoring accounting for more than 25% of clinical R&D budgets, sponsors and CROs need to acknowledge that these line items and their escalating costs are directly linked to cycle time duration.

There’s a significant deterrent built into today’s industry to reduce this cycle time duration. Large CROs are vast public companies with revenue goals and shareholder expectations. They are measured in part by increasing ‘man hours’ they put into a clinical project thus increasing revenues. Driving innovation or investing in new technologies that shorten time, therefore, is bad for them. Slowing the clock adds to the CROs’ coffers. With many CROs and drug companies ‘joined at the hip’ in master service agreements, there’s little recourse for CROs that err because contracts specifically prohibit another CRO from getting a piece of their business.

Having worked both sides of the clinical trial arena, during my career in Big Pharma I realized the functional service provision (FSP)/CRO model needed to change.

In part, the gravy train and less stringent regulations raised all boats; but with all pharma companies being squeezed today, CROs need to address the enrollment problem or they’re going to imperil future success, as well as jeopardize lives with costly delays in trials for otherwise promising medicines.

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Here’s an example of a recent situation that’s all too common: A CRO informed their biotechnology sponsor company that its prostate cancer drug trial would require only 6–8 months for enrollment, but by the eighth month, only 17 of the 80 patients needed were enrolled. At that rate, the trial was going to take four times longer than what was projected, meaning the costs will increase 400% — good for the CRO, but not so good for the customer. Ironically, the biotechnology company isn’t going to terminate this CRO — that’s too costly. So the sponsor has already burned millions of dollars and valuable time because this CRO didn’t complete its upfront diligence.

The industry currently addresses problems by adding more people instead of innovation. Yet the solutions are out there and there’s a compelling case for implementing them. After all, for the past 15–20 years the trend has been for pharma companies to reduce their R&D financial risk by outsourcing trial enrollments.

In the US, approximately 10,000 trials are being conducted every year and 37,000 are started annually, according to clinicaltrials.gov. There’s big money involved, on both sides: At least one of every three treating physicians conducts such trials as a second revenue generator. Conducting clinical trials can be so lucrative that some doctors do so the expense of a regular practice. This is a cozy relationship for doctors and the sites, but carries paralyzing costs for drug companies. Sponsors invest several thousand dollars to locate each doctor, incentivize participation and then tie up as much as $50,000 to open a site, with additional carrying costs to keep them open as they under perform. So, how is the innovative, agile CRO working in partnership with its pharma clients to enroll a trial more quickly and efficiently to tame the clinical trial financial monster?

Improve Protocol Definition at the Outset

Today, the sponsor developing the protocol typically implements a high number of protocol amendments, which causes delays. The approach to data is antiquated and site selection is still a manual process with redundant data collection.

During my time on the sponsor side, protocols would come across my desk saying, “You have to find me 200 doctors that want to run a cholesterol trial,” and

March/April 2012

CLINICAL TRIALS we would put together a questionnaire and prestudy evaluations. Then we would meet a doctor who would respond: “The way this protocol is written is clearly not the way anyone practices medicine.” In short, the inclusion criteria were impossible to meet.

Drug companies have a fine-tuned endpoint analysis.

Take, for example, pancreatic cancer, with a mortality rate of 3–5 years; by asking “Will this patient be alive in 5 years?” enrollment goals can still be met and patients found quickly and more efficiently, simply by tweaking the language or criteria.

Pay Closer Attention to Study Sites

The site selection and activation should be a data‑driven evaluation process that ensures the most qualified sites are rapidly contacted, qualified and initiated to facilitate accelerated enrollment. With 20% of sites typically enrolling 80% of the subjects, it makes better sense to select more physicians from the 20% bin, which can be determined beforehand. Most CROs fail to pursue this strategy.

More Upfront Planning in Site Research

A good CRO invests more upfront strategic planning and site research, choosing regions or countries to meet regulatory, commercial, and clinical and timeline requirements. It might take 3 months to start a US study, but 8 months in China. China might, however, have a higher incidence of that disease, whereas the US doesn’t. Or, within the US, you might find that a gum disease you’re targeting is prominent in the northeastern part of the country, so doctor recruitment wouldn’t be conducted in California. This is all critical information in trial site selection that can shave millions in time and costs from trials. The effective CRO will summarize the feedback from specific countries studied, conduct historical benchmarking on a country or region, and deliver clear, concise forecasts on a global study, a region, a country — all before recruitment starts.

With this specific upfront work, a CRO can refute the protocol or potentially advise the sponsor that the trial can be completed in shorter time if the protocol were written properly.

Select the Most Optimal Sites and Close the Low Enrollers

CROs should conduct a specific protocol feasibility study surveying investigators from multiple strategic data sources in targeted areas. This also helps to finalize a country list, document the enrollment forecast, and provide a specific timeframe as to when the clinical trial application will be sent to the regulatory agencies — because some countries are specific. Health Canada, for instance, one of the more aggressive timeline regulatory

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agencies, advises sponsors and CROs that they will have a study reviewed within 30 days.

More Creative Outreach Plans

A risk-based, study outreach plan should be developed with target leading and lagging indicators to ensure return on investment (ROI) includes a mix of direct mail, television radio print and Internet. Materials need a clear call to action. The provider should have a call center and web‑based tracking solution to manage leads from first call to subject randomization. A specific plan is essential and flexibility is imperative.

Modify Recruitment Outreach Early and Often

Drug companies will invest heavily for recruitment upfront running television advertisements with a national call number, as well as newspaper and web advertising.

During the first or second week of recruitment, it is essential to track and benchmark which media have the greatest impact — this is largely determined by where the patients come from. The costly TV component may not be as effective as the less expensive website or banner ad. There’s an old marketing adage that says: “Half of my advertising dollars are wasted, I just don’t know which half.” Spot on tracking using software technologies, such as the enrollment tracking and projection software from Y‑Prime, will help better target ad spending so that it can be fine‑tuned more quickly and effectively to ensure the trial is enrolling on schedule.

Weekly Performance Reviews

Too much time passes too quickly in the enrollment process; weekly monitoring, however, ensures problems are identified quickly. A firm review time each week keeps all parties on track to measure progress and ROI, as well as tweak the recruitment budget.

The ultimate vision should be for the sponsor and CRO to revamp key study planning and start‑up activities to yield accelerated enrollment. This is achieved by developing a protocol specific feasibility survey distributed to regional physicians via electronic survey, for protocol assessment and enrollment estimates.

Conclusion

Maintaining the status quo seems to have fared better in pharma than most other industries would permit, with sponsors wedded to legacy, antiquated solutions and cozy relationships, rather than embracing newer, robust eClinical solutions. With so many millions on the line, clinical trial sponsors and their CROs need to rethink and re‑engineer their enrollment processes.

Playing the same game when the rules have changed is a flawed strategy.

David Kelly

For more information David Kelly President Kellman Pharmaceutical Services www.kpslife.com

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OUTSOURCING

OUTSOURCING NON-CLINICAL EARLY DEVELOPMENT

Global bio/pharmaceutical companies have been on a desperate mission to turn the productivity of their R&D operations around. As the sector moves into a new phase, executives from Big Pharma and contract development organizations (CDOs) came together at Via Connect’s roundtable to share their insights and experiences of accelerating early development and debate the role that CDOs have in achieving that goal.

Internal versus External

The roundtable opened with a debate about maintaining in‑house activity versus outsourcing. Paul Deutsch of UCB Pharma said that the company has decided to increase outsourcing (its long‑term goal is to outsource manufacturing as well as process R&D and other supporting functions), but it also wants to maintain internal expertise so that it can fully understand all the technical aspects. The company balances what it can do with the resources it has against what needs to be done.

By contrast, Bayer HealthCare, which is involved in early stage chemistry and isn’t particularly known for outsourcing, would like to. But, as Ingrid Reinkober explained, previous attempts to outsource were relatively unsuccessful with respect to technology transfers; as people left the companies in question, Bayer felt that its knowledge was being spread throughout the industry.

The transition from research into clinical development is a significant development process. Speaking for Pfizer, Kurt Speckhals explained that managing the point of technology transfer and hand off from their research lines into their ‘pharmasci’ lines is challenging. It is often best done through internal collaboration with a team of scientists within pharmasci who are well connected across the disciplines of chemical development, formulation development and analytical development.

So far, the company has been unable to find that close collaboration between those scientific lines for early clinical development activity externally. “You can find specialists who are good at one or two of those three components, but bringing them together is the advantage we have by using our internal resources,” Speckhals said.

Aptuit has built the Indigo model (an accelerated drug development programme), which is probably relevant for smaller‑scale companies that lack the internal resources, but tends to be difficult to scale to the size of the Pfizer portfolio. Given that Pfizer has the resources, the company keeps these capabilities in‑house.

Successful drug development depends on good interaction between scientists in the difference segments of the process. Tim Tyson of Aptuit noted that, in the past, there have been companies with component‑level capability; but some, including Aptuit,

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now offer integrated drug development, which requires experienced people working together. The considerable amount of rationalization happening throughout the industry has found some companies, such as Aptuit, acquiring that integrated capability from Big Pharma — they have taken on a whole integrated R&D centre wherein people have spent 25–30 years working for one company doing integrated drug development. These people know each other and drug development issues.

Tyson described drug development as “a mixture of science and art” — the ‘art’ being the management of experienced and capable people … and getting them to work together effectively.

Representing a complete rethink of the process is Eli Lilly, which has developed an alternative model that depends heavily on outsourcing. The company’s Sherman Whitfield explained that for 135 years they did everything in‑house. But, given the $1.3 billion costs and 10–12 years that it takes to come up with a new drug, the company wanted to find a way to speed up its process and reduce costs. The resultant strategy is what the company calls its ‘fit net’ business model.

Whitfield explained: “We believe there are people outside Lilly that have the capabilities, expertise and technology to do things better than us.” Building on this belief, the company is intentionally outsourcing to speed up the process and reduce costs. Whitfield added: Our molecules are our babies and we want our babies to grow up to be billion‑dollar babies. To get these babies to grow, we need some outside help; nobody wins by letting them sit on the shelf waiting to grow.”

Internal Resistance

Despite the availability of capable people who can do the job externally, resistance can come from within.

According to Axel Sinner of Deloitte Consulting: “Pharma companies don’t like to acknowledge that, internally, they are not good enough to outsource.”

Frequently, R&D people employ a step‑by‑step process whereby the outcome defines the subsequent step. There is little or no upfront planning of how the outcomes will be handled, which makes it difficult when outsourcing — an unforeseen change in a project requires renegotiation at

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OUTSOURCING

a contractual level. Sinner advised that good outsourcing comes from forward planning and deciding in advance what exactly needs to be achieved. The outsourcing partner will then know what is expected. The contract should start with a plan that takes into account the various outcomes. This can be met with internal resistance from people who are more comfortable with the stepwise approach. They need to be convinced that seeing the full story, with possible alternatives, means they will be far more effective earlier. Thinking ahead is a good policy for all companies, even those that don’t outsource.

Volatility in Early Development

It is essential to build a high degree of quality into portfolios early on, but the inherent volatility in early development also calls for flexibility and speed. Alex Robertson of AstraZeneca explained that the company takes a portfolio approach to early development rather than just focusing on individual projects. He said: “When you have a team of multidisciplinary scientists and business people working on a project, face‑to‑face communication is clear and easy; people get a direct understanding from portfolio and project teams about the relative issues and opportunities. It is very easy and quick to switch resources to reprioritize one thing and move on to another, especially if you are working outside of a contractual framework.” Robertson said that having an internal model makes it easier to be highly responsive; it also affords the opportunity to expose attrition points in the development programme. Furthermore, this flexibility and responsiveness enables the company to delay decisions to invest until they get the required clinical signals.

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Global R&D Networks

Most major pharma companies have global R&D networks, but to what degree are people who are involved in early development really co-located at one site or have had to work out ways of co‑ordinating across large distances? According to Robertson: “For AstraZeneca, it’s a combination: in some cases, everyone is co‑located, whereas in others, because of a particular R&D footprint, they have people from different functions working in different places.” The most important thing, he stressed, is “clarity of role, having a joint purpose in your early development teams and working together with clear outcomes.” Geographical differences make this difficult, but not impossible.

So, if it’s possible to work across large geographical distances internally, can’t the same be done with a CRO? Kurt suggested that Pfizer’s fragmentation of resources is quite different compared with its research units, which are highly dispersed and located in various global locations for strategic reasons. The company’s pharmasci resources are primarily centralized to two locations: specifically, they have a team of about 12 scientists and two managers who do all their formulation work, from toxicology formulations for drug safety to first‑in‑human formulations and up to proof‑of‑concept. This small team can work with these research units and manage that volatility. The other piece of the equation is downstream.

That same group is closely connected to three clinical research units that Pfizer operates around the world — one in the US, one in Belgium and one in Singapore — and through that close coupling downstream they can work with the pharmacists and the clinicians in the clinical research units and further allow them to do the

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OUTSOURCING most with the API as quickly as possible. For Pfizer, it’s important to the linkage in both directions across the value chain. Aptuit tries to reflect how companies manage their projects. The company, therefore, assigns an experienced project manager to integrate the team, which is sometimes one company or multiple companies, with Aptuit’s resources. This strategy helps to focus on outcomes and the delivery of milestones, and to keep people informed. It is a project management system with a focus on the customer

both sides are trying to make materials to get to the marketplace.

But, I think, from two different perspectives.

Sponsor versus CRO Perspectives

Sponsors and CROs usually have different perspectives, particularly regarding timeframes and frequent changes in priorities, and the issues these cause for both parties.

Having gone from Cambrex (a service provider) to UCB (a pharma company), Deutsch shared his insights on this topic. “Clearly, both sides are trying to make materials to get to the marketplace. But, I think, from two different perspectives,” he said. Pharma companies try to progress something from a gramme scale — taking it through toxicology studies and clinical trials — to market as quickly as possible. The CMOs, which are a business service, as well as a partnership, have to react to this. During the early stages, either party can’t really invest too much in the long-term: developing a fully commercialized process when you’re just going to be making toxicology material adds time and costs upfront. The pharma company needs to spend as little as possible upfront regarding the long-term — it should consider what is necessary to get to the next step and do just enough in parallel so that the next step isn’t delayed.

Deutsch noted, however: “The problem is how to line up

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all the supporting things that need to be done in advance.

Whether it is done internally or externally, how do you prepare, for example, the API or biologic beforehand?

This takes a lot of time and requires difficult decisions to be made, such as when to invest: do you do it upfront, at risk way in advance, or do you wait until you have some positive indicator and accept the time delay?” The day‑to‑day interactions within pharma companies enable them to do this internally, he explained; but, to have that detailed and personal interaction with an external party is much more difficult … and yet, “you are trying to get them to react to what you need.”

Experience of working with other people builds up a knowledge of who you can depend on to react quickly to what’s needed and who will handle the associated difficulties. Again, this is far from simple — negative results can generate a phone call to halt proceedings. At a technical level, this can be dealt with, but frequently the difficulty lies with the party dealing with business and money. The occurrence of certain events can make things extremely difficult for both the technical and the business teams. Adding to the debate on ‘perspectives,’ Speckhals explained that within Pfizer, pharmasci is also responsible for the delivery of all its clinical supplies.

“In this dynamic context, early clinical programmes, even though they’re externalized, need us to be able to reprioritize work quickly with strategic partners in that area. Schedule transparency is, therefore, essential,” he said. The company shares both committed and confirmed demand, as well as any emerging soft demand, across the full portfolio on a regular basis, with its pack/label strategic partners. This gives the partners, in aggregate, a sense of what’s going on; they may not know what is assigned to them, but they can see the workload to the same degree of transparency as the sponsor. Speckhals concluded that these models are necessary when outsourcing in areas with uncertain and highly variable demand.

Robertson highlighted AstraZeneca’s approach.

“After looking at the spectrum of activities we have supporting early development, we usually target the most simple activities externally, and keep the more complex ones internal — we invest an internal resource where we can get the biggest return on our dollar.”

This approach, though, requires effective project management and the client needs to be clear in what it asks the CRO or CMO to do and vice versa. “They’re looking for a partner who proactively interacts and can effectively manage a piece of work,” he added.

AstraZeneca tends to follow this approach primarily because of the priority and the speed associated with early development … and it still has a large amount of internal resource assigned to that. There was some agreement that to outsource more of these activities, companies would want fewer, but deeper, relationships.

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OUTSOURCING The likely increase in information sharing about the upcoming demands and the enhanced understanding of a partner’s capacity provides a deeper understanding of the projects across those two companies.

From a CRO perspective, Tyson highlighted two issues that affect them. The first is capacity and capacity planning. The work that Aptuit does in this early space usually takes 2–4 months. Consequently, they have the pressure of having to constantly win work to fill their capacity. And so the company has to build systems and processes to deal with that. The second issue is efficiency and effectiveness. Aptuit has significantly more work than other individual companies because of the type of work that it does — they touch about 2000 molecules on an annual basis and there are about 10,000 in development at any particular time. Working with 20% of all molecules in development, therefore, gives them a significant amount of knowledge that generates efficiency and effectiveness improvement that, says Tyson, “we share with all the customers that we deal with. This level of involvement in transactions and processes has helped the company to understand inherent inefficiencies, improve them and then share that knowledge.”

Why Outsource?

Reinkober asked whether the primary focus on outsourcing is time/speed and full-time equivalents (FTEs) or is it knowledge and expertise? As CEOs of big pharma companies request more efficiency and better innovation, what does this mean for the discovery department?

Sinner responded that there has to be a mindset change.

Rather than waiting for clinical trial results to determine the potential of a molecule, discovery should consider the outcome of whatever it touches early on. Discovery teams need to consider how a target can be ‘better,’ instead of ‘just as good as.’ Any other approach is “just playing and not working for new products,” explained Sinner. ”With respect to outsourcing, this means gathering all the intelligence in the company to decide what the targets are, why they think a particular target could be better and so on. The amount of intelligent work and thinking that has to be done internally is increasing and, therefore, requires more resources. Toxicology studies, for example, can be outsourced to free up some internal resources.” Answering ‘why do we think something is better?’ highlights potential new pathways, which makes outsourcing easier and identifies what is expected from a partner. This change of mindset cannot happen overnight, but it’s a process that needs to be started.

Knowledge and Expertise

Knowledge and know‑how has been critical to service providers’ offering. Some pharma companies, however, have developed unique areas of expertise in‑house, which makes it difficult for a CRO/CDO to contribute

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to. For example, material science capabilities is an area within Pfizer that has a substantial function; it allows the company to consider, early in the process, solid state chemistry, polymorph selection, salt selection and screening processes. These capabilities are integrated within the pharmasci development processes … they are not ‘optional.’ In addition, some of Pfizer’s scientific efforts, even in early development, focus on using predictive tools and computational methods to progress the science. Instead of doing stepwise development and experimentation, the company uses tools, such as accelerated stability, assessment protocols and material sparing formulation approaches, to test (and confirm) predictions, which then enables it to complete its filing and move development along at a faster pace. Speckhals said that these tools and capabilities are probably, to some degree, available in the market, but “not in an integrated manner as we have them assembled internally in pharmasci.”

CDOs/CROs have often focused on project management to speed up the process, but some scientific approaches can also achieve this. Jan‑Olav Henck, CSO of Aptuit, explained that when he previously ran SSCI, he worked with about 800 clients worldwide — ranging from “an extremely conservative big pharmaceutical company in Japan — who had no tolerance for risk — up to two men and a molecule in a garage in California, with a completely different risk profile.” According to Henck, clients rarely seemed to have a strategy in place or knew what they wanted. He explained that to support a development activity in an integrated fashion as described

by Speckhals, the service provider needs to have all the pieces in place; but the sponsor doesn’t always have their pieces in place. From an organizational point of view, the handovers within those organizations are not well managed, and from a strategic point of view, it’s not well understood what the different departments within the companies want to accomplish. Service providers can better help those clients who have a good understanding of what they want to accomplish.

Vendors can offer a variety of tools or programmes early in the process and try to really understand what the various challenges presented by a molecule may be. Patheon’s programme — SoluPath — is designed to improve the bioavailability of compounds with poor solubility by testing, in parallel, multiple formulations. By screening multiple cutting-edge technologies in parallel, the programme delivers rapid results and identifies the best drug delivery solution to increase bioavailability in human studies. It was noted that although a lot of the large companies have internal capabilities, current industry pressures have forced many to make decisions that are not necessarily what they want to do, including significantly downsizing their material science capability.

For many of the larger pharma companies it is imperative

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OUTSOURCING

to have the capability, knowledge, scientific resource and expertise to do this critical phase of development.

Tyson added: “I think the larger companies will have an increasing need to have somebody or some alternatives to just considering in‑house capability because of the pressures we face.”

It seems the range of technologies available to deal with materials engineering is creating many opportunities for CROs and CDOs, who are carving out niches in this area. Tyson believes that the breadth of talent that wasn’t necessarily available externally in the past is now significantly increasing. Aptuit has the capability to make decisions on leads through a lead optimization programme that includes mathematical modelling.

“Those types of resources are now being acquired and are available via vendors, and will be essential to do some of the work that is being done internally,” concluded Tyson.

Robertson said that he had seen a mindset change during the last couple of years — there is a greater focus on the right kind of molecule, the right sort of patient groupings and the right kind of developments. He has seen this change at AstraZeneca and suspects it is common across the industry because of the pressures it’s under. Linked to that, the company has also invested in areas such as physical science because of the importance of building quality into a portfolio. The company recognizes, however, that it can’t be the expert in every technique in

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every scientific innovation. So AstraZeneca understands that it is going to have to access some of the specialist science outside; yet, they have invested, funded and have the right kind of scientists and people to be able to drive that process from within.

The stop/start nature of early development is another challenge in establishing successful outsourcing relationships. How do you develop a business model that enables both parties to work together meaningfully without long gaps because a molecule has died and there is nothing behind it? Sinner offered that when a company has the internal flexibility to do things in parallel, it is relatively easy to shift resources when a kill signal is detected. Within a partnership, such incidences rarely have a negative impact on the internal/external scientific relationship; flexibility, however, also needs to exist between the contact handlers. “In my experience, contracts are usually rigid with regard to requirement; for example, if a molecule fails to show the desired outcome, it needs to be killed. Afterwards, a lot of resource is used to renegotiate that contact. Better business comes from outsourcing partners when flexibility is built into the contract at the beginning of the relationship — including a good understanding of the potential kill points. The contact may take more time to word but, it will save time and resources in the long run and so reduce the overall contract handling costs,” he advised.

March/April 2012

OUTSOURCING

Adding to Sinner’s comments, Speckhals explained that prior to pharmasci’s involvement, they have an outsourcing group that focuses on discovery outsourcing. It is a dedicated function called ‘external research solutions’ and the company has progressed a lot of things externally in the biology, chemistry and ADME screening areas. This raises two points: one is the importance to have a function that is dedicated to building these processes, managing the contracts and managing the interface with the supply partners; the second is the contracting approach. This is where there is huge volatility, but the portfolio is very large, broad and dynamic; the contracting approach, therefore, is not at the candidate level, but is based on FTE commitments to the strategic partners. This can be effectively managed because of the substantial amount of work that is strategically outsourced, and that is a lesson that can be applied to the CMC (chemistry, manufacturing and controls) space. “You have to be outsourcing a significant portion of the portfolio to be able to apply those types of contracting approaches. We haven’t used those recently in the pharmasci service lines because our proportion of internal versus external doesn’t really warrant that kind of contracting solution,” Speckhals concluded.

There is a distinction between doing the right thing versus doing things right; often, there is a lot of focus on doing things right. It was noted that some companies

March/April 2012

have found with FTE contracts that they spent a lot of time just making sure they’re using the FTEs they had contracted for. Tyson identified with this and said that the molecules they’re working on are more important than people and people hours. “In our business we’re trying to get to an answer quickly — good or bad. If it’s bad, we want to reallocate resources; if it’s good, we want to allocate more resources to that particular molecule.

Both organizations need to be incentivized to come to quick decisions. For us, failure means that we don’t have any more work. If the decision, therefore, is to stop a molecule, we replace it with others that are in the pipeline.

This is our experience of successful relationships — it helps us to arrive at the right decision and ensure some continuity of work.” Another option, according to Robertson, is open‑book costing, which falls somewhere between the FTE and more competitive bidding model.

This alternative can speed up the contractual process but requires a good, stable relationship to work.

Conclusion

The industry is experiencing some incredible change dynamics, which are forcing companies to rethink how drug development is done. Outsourcing is going to be a key component to drug development and finding ways to develop strategic partnerships and identify core skill capabilities will be essential to its success.

Panel Members

• Paul Deutsch: Senior Director, Chemical Process Development, UCB Pharma.

• Kurt Speckhals: Senior Director, Pharmaceutical Services, Pfizer.

• Ingrid Reinkober: Vice President, Strategic Sourcing Raw Materials and APIs, Bayer HealthCare.

• Tim Tyson: Chairman and CEO, Aptuit.

• Alex Robertson: Director, Sourcing Pharmaceutical Development, AstraZeneca.

• Axel Sinner: Senior Manager Strategy and Operations, Life Science and Healthcare, Deloitte Consulting.

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31

CLEAN ROOMS & CONTAMINATION CONTROL

SUSTAINING A CLEAN CELL

CULTURE ENVIRONMENT

Working in a cell culture clean room is an effective way to minimize microscopic threats. Unfortunately, micro‑organisms are our constant companions, and so pose a constant risk. Taking advantage of new technologies in CO2 incubators can combat micro‑organisms that jeopardize cultured cells.

D

References

1. E.A. Grice, et al., “A Diversity Profile of the Human Skin Microbiota,” Genome Res. 18, 1043–1050 (2008).

2. G. Grass, et al., “Metallic Copper as an Antimicrobial Surface,” Appl. Environ. Microbiol. 77(5) 1541–1547 (2011).

3. D. Roe, et al., “Antimicrobial Surface Functionalization of Plastic Catheters by Silver Nanoparticles,” J.Antimicrob. Chemother. 61(4), 869–876 (2008).

For more information

Mary Kay Bates Global Cell Culture Specialist Laboratory Equipment Thermo Fisher Scientific Douglas Wernerspach Global Product Manager — CO2 Incubators Laboratory Equipment Thermo Fisher Scientific www.thermoscientific.com/co2

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ifferent Class/ISO/BSL/Grade levels of clean rooms require different protection and containment strategies, which are partly determined by whether you are protecting yourself or your product. If you are culturing cells for production, then your goal must be the protection of your cells. But are you doing all you can to defend your cell cultures from microbial contamination?

A key consideration is your CO2 cell culture incubator. The CO 2 incubator provides an ideal environment for cultured cells to prosper, but it is also a natural place for bacteria, viruses and fungi to colonize and grow. For the majority of these micro‑organisms, people are the source of the problem: a recent study revealed that humans carry 10,000 micro‑organisms/cm2. 1 Therefore, although it is clearly important to follow established protocols to limit opportunities for contamination of your work area, you should also consider utilizing a CO 2 incubator that can help protect your precious cultured cells from contamination that enters the clean room with staff.

Contamination Control Choices

Modern CO 2 incubators offer a range of contamination control methodologies, which can be classified into two categories: elimination and prevention. Contamination elimination methods include automated cycles that run overnight in an empty incubator and effectively sterilize the chamber. Methods that help prevent contamination of the interior aim to eliminate micro‑organisms in an ongoing manner.

Contamination Elimination The most effective automated method to eliminate any micro‑organisms from the interior of the incubator is high heat sterilization. Several CO 2 incubator manufacturers offer this option, but beware: similar technologies do not produce the same results.

Look for data proving effectiveness using standard test micro‑organisms, performed by independent third‑party laboratories. In addition, check the fine

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March/April 2012

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Innovative Sample Storage Technologies print: some incubators require the removal of sensors and other internal parts prior to running the cycle; this means you have to sterilize and return these parts afterward, with the risk of re‑introducing contamination into a clean incubator.

Other automated methods, such as chemical sterilization, can be problematic — chemicals used to sterilize the incubator require special handling, and any remaining residue can be toxic to your cultured cells. Also, these methods have spotty effectiveness, as any microscopic areas that are uncovered will not be sterilized, leaving micro‑organisms to fight another day.

Contamination Prevention A popular approach for airborne contamination is to create a clean room environment inside the incubator, using high efficiency particulate air (HEPA) filtration. Effectiveness is highly dependent upon design, so check the time required to filter the entire chamber to establish Class 100/ISO 5 level conditions. Depending on the manufacturer, this can be as fast as 5 min.

For a worry-free method to prevent microbial colonization of your cell culture incubator, consider an incubator interior that is itself antimicrobial. Solid 100% copper surfaces have a long history of proven effectiveness against a wide variety of germs. Some incubators offer internal components that are made of copper alloys, but research proves that no alloy is as effective as solid copper, which can eliminate 10 7 Escherichia coli, Staphylococcus aureus and many others in 90 min or less. 2 Copper is effective for the life of the incubator and requires no extra maintenance. It is completely safe for cultured cells, as the copper ions only kill on contact and do not become airborne. Although copper interiors may not look shiny, cells will be highly protected and you will spend more time working, less time cleaning.

Recently, silver has emerged as the newest antimicrobial surface to be incorporated in the CO2 incubator. Silver maintains its beautiful appearance, much like stainless steel, and requires no maintenance.

Although silver coatings have proven to be effective against a number of bacteria and biofilms, the effects are not as rapid as copper.3 Some manufacturers offer customized CO2 incubators with clean designs for more intensive clean room applications, including specialized low particle release insulation or HEPA filtration for the air exhausted from the electronics area. Choosing a CO2 incubator that will both prevent and eliminate microbial contamination can extend clean room defences.

March/April 2012

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EMERGING MARKETS

CHINA, UNLOCKING THE GROWTH OPPORTUNITY OF THE CENTURY The article looks at the management of a highly fragmented payer landscape in China for the pharmaceutical industry. A four‑step approach is outlined to help companies map out how to fit their local organizations and resources to address the Chinese market.

T

he size of the Chinese pharmaceutical market has recently surpassed Germany’s. It’s now the world’s third largest pharmaceutical market by sales, after the US and Japan.1 With a population of 1340 million (compared with 312 million in the US and 128 million in Japan) and a GDP growth of 9.3% in 2011 (compared with the US 2.6% and Japan 0.1%), it is clear that China will emerge as one of the growth engines of pharmaceutical industry for generics and innovative treatments.2,3 With such a convincing outlook, it’s unsurprising that pharmaceutical companies are looking to expand into China.

Successful expansion in China, however, is challenging and raises many questions: Where exactly is the strong growth coming from? What’s the opportunity of patented, innovative medications and how to approach the market of established products? HHow can companies penetrate the public reimbursement market and how can they do this in the cash market? Which layers of the income pyramid should be targeted and which geographic regions should be prioritized? Most importantly, what does this mean for business strategies and the magnitude of the corresponding investments?

Until now, as multinational companies launched a new product in China they typically targeted the high‑income cash‑paying segment, mostly in densely populated regions. This ‘top‑of‑the‑pyramid’

Level of income

Example: Patient prioritization in China

High

All patients Uninsured: Province 1

Mid

Insured: Province 1

Low Insured:

Uninsured: Province 2

Province 2

Figure 1: Example of patient prioritization in China.

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Priority:

Figure 1

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High

Medium

Low

approach makes sense against the background of a burgeoning middle‑class with increasing income; but China is a rapidly developing market. Although a growing population is covered by health insurance with improving service levels, innovative drugs are still largely self‑paid. Many companies are wondering whether they are (still) doing the right things in this country or whether the current approach leaves significant market potential untouched. A four‑step approach can help to systematically understand the payer environment, devise target approaches to different stakeholders and unlock the tremendous opportunities that China offers.

Define China’s Payer Universe

With a highly fragmented payer landscape and complex funding dynamics, it’s important to first agree on terminology. In China there are two main groups paying for medications: Out‑of‑pocket (OOP) patients and third‑party institutional payers. In this article we reserve the term ‘payer’ for third‑party institutional payers (both public institutions and private insurance companies), and refer to OOP patients for the self‑pay market.

OOP patients pay for a large, yet rapidly falling share of healthcare expenditure (35.5% in 2010, from 60% in 2001). 4 Pharmaceuticals, however, are predominantly paid OOP (roughly two thirds of total pharma expenditure) and innovative drugs are normally self‑paid. OOP patients are by no means homogeneous stakeholders. Different income levels are associated with different mindsets and value perception. Other variations in patient profiles, such as insurance status, are easily overlooked. As a result of the co‑pay mechanism, the insured patient may still have to pay a significant amount of their medical expense out‑of‑pocket. This group of patients is gaining importance in China, and they require a different approach than the uninsured population.

Third-party institutional payers include government, hospitals and the small yet growing private insurance sector. Government (including employer paid social security) currently pays for almost one third (31%) of drug expenses —

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EMERGING MARKETS

mainly inexpensive generics. According to the Health Minister, approximately 90% of the Chinese population is now covered by some kind of public insurance. 5 Reimbursement schemes, however, differ; although central government defines national reimbursement lists, the locally applicable list is at the discretion of provincial/municipal governments.

Operating under opaque laws and regulations, payers rely on relationships and short‑term budget impact in their decision‑making.

Prioritize the OOP Patients and Payers

The second step is to prioritize the different types of OOP patients and institutional payers. This helps to increase productivity of the field forces. Multiple criteria for prioritization exist. Is it profit or revenue maximization, a global expansion or penetration strategy, or market optimization of a specific brand?

Companies need a clear strategy before commencing, because prioritization will profoundly impact the flow of resources.

OOP patients can be prioritized by income level, insurance status, location and so on (Figure 1). A ‘high‑income’ employee in Shanghai is typically well‑covered by insurance. He or she might be looking at rather limited OOP payments for an innovative treatment. Yet, an OOP patient from a less

the reputation of the manufacturer and preference for imported medicines from Western countries also play a significant role.

March/April 2012

Figure 2: Decision‑making criteria of patients (Simon‑Kucher China Project example).

CONCEPTUAL

Patients’ relative decision criteria importance when deciding to take a medication Recommendation from my doctor How well the drug works (its efficacy) The drug’s side effects What I pay for the drug Reputation of the drug manufacturer Recommendation from my friends/ family My opinion of the drug Recommendation from my pharmacist 1

Not Important

2

3

4

5

Very Important

Figure 2

developed region can be well off and able to afford high‑priced drugs.

Institutional payers may be prioritized by their size, influence or degree of accessibility. Provincial payers may be more accessible, whereas national payers have greater impact, but usually less accessible.

Segment OOP Patients and Payers

by Attitudes and Behaviour

With priority groups identified, the next step is to segment OOP patients and payers based on their attitudes and behaviours. The goal of segmentation is to understand the different decision making criteria to address them accordingly.

For OOP patients, low price is certainly a motivator, yet the reputation of the manufacturer and preference for imported medicines from Western countries also play a significant role. The most important decision driver for a patient is the physician’s prescription (Figure 2).

Patients trust the physician to make the right decision for them, not only clinically, but also economically.

In crowded major hospitals in cities with millions of residents, physicians see so many patients per day that they only have a few minutes for each consultation.

They usually, therefore, keep the treatment discussion short, and can anticipate the patients’ willingness to pay when making treatment recommendations. Compliance to physician advice is very high, especially when a serious disease is concerned.

Institutional payer behaviour is driven by factors such as expanding coverage of basic medical care and improving its quality, along with rational budget management. Real‑world clinical outcomes and market uptake are seen as indicators

References

1. www.chinadaily.com.cn/ business/2011-08/03/ content_13043302.htm 2. http://esa.un.org/unpd/wpp/ Excel-Data/population.htm 3. http://web.worldbank. org/WBSITE/EXTERNAL/ COUNTRIES/ 4. J. Chen, “Challenges Cloud Chinese Pharma Prospects in the Year of the Dragon Today,” Scrip, 10 February 2012.

5. C. Zhu, Health Minister China, China Science and Humanities Forum, 2011.

6. Xu Hengqiu, Anhui Province Deputy Director of Health.

7. S . Lee, “When Old Dogs Meet New Tricks — 2011 Academic Marketing Recognition Ranking for International Pharmaceutical Companies in China,” Pharmachina 7 (2011).

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EMERGING MARKETS

Josée Hulshof

Yue Luo-Fuhrmann

Doreen Dai

For more information Josée Hulshof Director Simon-Kucher & Partners Josee.Hulshof@Simon– Kucher.com

Yue Luo-Fuhrmann Senior Consultant Yue.Luo-Fuhrmann@SimonKucher.com Simon-Kucher & Partners Doreen Dai Consultant Simon-Kucher & Partners www.simon-kucher.com

36

of clinical value. Therefore there is usually a gap of several years between a new product launch and reimbursement. Furthermore, regions vary drastically in their economic development, as do political and economic motivators. As part of the healthcare reform, central government encourages a bottom‑up approach to pilot programmes locally.

A deputy director of health stated that the guiding principle of reform in his province is, “When drug prices are low, the common people benefit.” 6 In other provinces, awareness has grown that over‑emphasis on price bidding by local governments has become a critical issue for drug purchase tenders, especially for essential drugs. This is generating alarming consequences, such as free‑falling drug quality and rising shortages of low‑cost medicines. 4 Simon‑Kucher’s experience indicates that grouping OOP patients and institutional payers in segments of similar behaviour can increase effectiveness of payer engagement significantly, particularly in countries such as China.

Develop a Tailored Approach for Each Segment

With patient segmentation in mind, it’s logical that market access activities should be tailored to the respective segments. As resources are always stretched, proper prioritization and segmentation is indispensable to optimize resource allocation.

Whilst doing so, it may emerge that the field force has a suboptimal geographic scope, or that gaps exist in required competencies or some simple payer management tools may be lacking (Figure 3).

To succeed in China, a company must adjust its organization to the country‑specific challenges.

This raises questions such as: Are the affiliate functions mirroring headquarters or do they consider the specificities of China? Is there a toolbox available to address OOP patients in a different way than the well‑informed institutional payers in a G7 country? The differences between such tools may be as large as that between a voucher and a cost‑effectiveness model.

A recent study surveyed thousands of physicians in China, questioning their perception of the level of professionalism in pharmaceutical academic marketing conducted by major multinationals.7 Results showed that despite sizable investments, a number of prominent companies are poorly recognized. Although it is proven in Western markets that academic marketing is quite effective, apparently many companies have not yet found the best way to maximize the effect of such resource‑consuming activities. Whilst this is true for physicians, it is even more so for institutional payers.

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Payer interaction performance matrix

+

Payer reception

Figure 3: Example of a payer management tool — payer interaction performance matrix.

_

C Re-evaluate strategy

A Strategy and tactics on target

D Improve strategy and tactics

B Re-evaluate tactics

Achievement of objective

+

Figure 3

As a result of the developing nature of the healthcare system, reaching out to Chinese institutional payers is much harder than in mature markets. The team must be able to deal with high levels of uncertainty and lack of transparency. It may be necessary to have an in‑company public affairs expert monitoring policy developments and advising colleagues in charge of market access and marketing about payer communication, engagement planning and strategic orientation. A strong payer field force that knows their payers and that can properly engage with them is a must for successful implementation of access strategies. Particularly in China, sophisticated payer strategies require cross-functional teamwork. Access programmes aimed at OOP patients cannot be developed without input from the marketing group. Regulatory affairs should be a strong ally at all times in the path to success. Payer‑inclusive brand planning and uptake planning is a joint effort between pricing and market access, marketing, medical and regulatory affairs.

Conclusion

The four steps outlined may be applicable for any country; the China‑specific input, however, makes the difference. Organizations need to break free of the conventional definition of payers and begin with correctly defining ‘payers’ in China. After establishing the basis, proper prioritization and segmentation becomes possible, which can then be translated into actionable engagement plans.

As China’s market continues to expand and global pharmaceutical companies increase presence in China, this approach helps to systematically prepare for a successful expansion strategy; one that targets previously unaddressed parts of the Chinese market and unlocks the growth opportunity of the century.

March/April 2012

March/April 2012

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37

BIOPHARMACEUTICALS

HOW ARE WE DOING AND WHAT’S LEFT TO DO?

To understand the full spectrum of modern therapeutic agents, it is necessary to study the development and safety of biopharmaceuticals. The author discusses the risk assessment and processes used to produce biopharmaceutical products with a high level of virus safety assurance.

I

nterest in smaller biotech companies has accelerated because of a decline in the number of big pharma blockbuster drugs and the fact that many of the latter have gone off patent or will soon do so.1 Traditionally, the two industries were distinct from each other based on their approach to drug discovery and the materials they use. Pharmaceutical companies typically employ combinatorial chemistry and informatics to develop small molecule drugs (new chemical entities [NCEs]), from chemically defined raw materials, whereas the biotech companies use genetically engineered biological systems to produce large‑molecule therapeutics/new biological entities (NBEs) (Table I).

The distinction between the types of companies that produce pharmaceuticals (small molecules) and biopharmaceuticals (large molecules), however, is blurring rapidly. Members of both industries have come to realize that they need each other to succeed.2 The impetus for pharma companies to combine into one entity producing both small- and large‑molecule therapeutics, stems from biotech firms’ need for the expertise and manpower of big drug companies in bringing drugs to approval and in marketing them thereafter. For their part, the large pharmaceutical enterprises have noted that the success rate in FDA approval is now higher in the biotech sector compared with nonbiotech products. The Tufts Center for the Study of Drug Development analysed average approval rates from 1993 to 2004 for investigational drugs first tested in humans. The 32% success rate for biotech molecules was substantially higher than the 13% approval rate observed for the small molecule therapeutics. Of the large molecules, monoclonal antibodies comprised the largest group (47%).3 Furthermore, annual sales of biopharmaceuticals, which are presently estimated to be approximately $100 billion, are expected to grow two to three times faster than conventional small‑molecule compounds during the next 5 years.4 The impetus for both types of companies to converge is fueled even further by the fact that major advances in cell line development, bioreactor design and purification techniques have led to a 7‑fold increase in global protein output from mammalian cell cultures alone from 2000 to 2005 (500 kg versus 3600 kg).5

38

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Current and Future Safety of Biopharmaceutical Products

Safety Record to Date Advances in genetic engineering and the impressive ability to produce new therapeutic proteins in large quantities are tempered by well‑founded safety concerns.

Biopharmaceuticals have an elevated degree of heterogeneity and structural complexity (Table I). They are produced using living organisms and may be augmented with reagents (for example, serum, transferrin, growth factors) derived from those and other animate systems (Table II).

Consequently, contamination with endogenous and adventitious viruses may occur via raw materials used in production, purification reagents, viral load associated with the cell line or as a result of flaws in the manufacturing process (breach of good manufacturing practices [GMP]).

Furthermore, the production of biopharmaceuticals often requires a minimum of 10 stages in their manufacture. All told, these stages could necessitate the use of 18–30 unit operations associated with hundreds of process parameters; it is, therefore, necessary, to identify what constitutes a critical process parameter (CPP) as a change in any one of them could affect any or all of the downstream operations.6 The combination of these factors requires the use of unique approaches to achieve an acceptable purity‑to‑impurity ratio (that is, risk–benefit analysis) because analytical techniques used for characterizing chemically synthesized drugs are not directly applicable to biopharmaceuticals. Nevertheless, regulatory agencies mandate the same level of quality and safety assurance for both types of therapeutic agents.

From their inception, biopharmaceuticals have had an excellent safety record despite the attendant risks; for example, there have been no reports of iatrogenic pathogenic virus transmission through administration of biopharmaceuticals derived from recombinant cell lines.6 The record, however, is not flawless — Genzyme experienced an occurrence of viral bioreactor contamination in June of 2009.7 Product inventories were insufficient to meet projected demand for Cerezyme, resulting in significant patient morbidity and loss of revenue for the company. Such occurrences also raise regulatory and legal concerns, as well as requiring the shutdown of the facility or, at minimum, the production process. There have been other reports of safety breaches affecting bulk harvests because

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Lynn Perlmutter Head Global Product Communication and Training Bayer Healthcare

Chris Preti Vice President Patient Engagement GlaxoSmithKline

Terri-Lynn Ledger Senior Product Manager, Patient Programmes Amgen Canada

Elizabeth Oyekan Pharmacy Quality and Medication Safety Leader Kaiser Permanente

Laura Cranston Executive Director Pharmacy Quality Alliance

Edwina Rogers Senior Director Patient Centred Primary Care Collaborative

Top Stakeholder:

David Williams Chief Marketing Officer PatientsLikeMe

www.pharma-mag.com www.eyeforpharma.com/pcusa

March/April 2012

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BIOPHARMACEUTICALS

Table I: Some differences between new chemical entities (small molecules) versus new biological entities (large molecules).

Table II: Source materials and products that must be evaluated for viral safety.

New chemical entities

New biological entities

• Synthesized by controllable, proven methods

• Derived from/created in living systems

• Synthetic reagents and raw materials

• High level of structural complexity

• Quality determined by the degree to which chemical structure and purity specifications are met

• Product is defined by both its specifications and the production process • Determination of ‘absolute’ as well as ‘relative’ purity presents analytical challenges

Table I

of the inadvertent introduction of adventitious viruses; these were, however, detected during in‑process testing and did not affect patient safety.6 Risk Assessment Complete elimination of risk in any situation with multiple interacting systems is impossible to achieve. For biopharmaceuticals, zero risk would translate into absolute absence of residual pathogenicity and extraneous agents.

Limitations in detection methods preclude the possibility of proving total clearance of viruses. The excellent safety record in biopharmaceuticals production has been achieved by using several overlapping processes directed at eliminating or inactivating viruses and other adventitious agents. Each process is mandated per regulatory guidelines to operate by a different mechanism of action to help ensure virological safety of biotherapeutics.

Overall, safety is commonly approached with the principle of achieving a level of risk that is as low as is reasonably practicable (ALARP). Accordingly, a level is set below which risk is judged to be tolerable. The principle of the ALARP approach is used on a case‑by‑case basis; for example, low concentrations of infectious virus in plasma products are not tolerated, nor are virus‑contaminated source materials. High levels of endogenous retrovirus, however, are judged to be acceptable in certain cell lines, such as Chinese hamster ovary (CHO) cells because they are noninfectious and safety concerns are chiefly theoretical.8 Determining how much risk is acceptable requires negotiation of a complex decision tree. Compared with their small‑molecule counterparts, assessment of causality and management approaches are significantly different for biopharmaceuticals. Benefit–risk assessment for a drug (NCE) typically involves collating a body of data in search of evidence beyond a reasonable doubt that an adverse event is/is not attributable to the drug. In contrast, with biotherapeutics, each discrete reported case of potential virus transmission must be viewed as a possible indicator of an infectious batch, and carries with it some level of probability that the disease may be transmitted to large numbers of patients.8

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The Safety Triad

Appropriate Sourcing The continued and improved safety of biopharmaceuticals will probably be achieved by the current and continually evolving three‑step process: • appropriate sourcing • documentation of virus clearance (virus validation studies) by steps in the downstream purification process • in-process testing.

In terms of source materials, the value of starting production with the highest quality ingredients is self‑evident and certain continuous cell lines, such as CHO cell lines, the workhorse of the industry for production of monoclonal antibodies and other recombinant proteins, are well characterized.8 Validation and In-Process Testing Source materials contaminated with pathogenic infectious virus cannot be used. Yet, because of limitations associated with virus detection, the steps that comprise the manufacturing process must be capable of removing/ inactivating any theoretical viral load. There are several orthogonal processes (that is, operating by independent mechanisms) that are known to reduce viral threat. These processes include both inactivation (heat, detergents, low pH inactivation) and removal steps (chromatography, filtration for virus removal), which are part of the biologics manufacturing process. The results of each step are evaluated (validated) using worse‑case conditions, which theoretically demonstrates the minimum clearance or inactivation the given process can provide.

Optimally, viral validation studies confirm the operating conditions selected, as well as document their efficacy in achieving the expected performance of the processes used. Validation studies only achieve an approximation of the true situation, but they serve to isolate critical process parameters (CPP) regarding viral clearance and help to establish a design space that can be used for setting operational limits and worst‑case scenarios. Although conducting validations at both extremes of the process may be preferable, this approach

March/April 2012

BIOPHARMACEUTICALS

• Animal blood, plasma or other tissues

• Indirectly animal-derived (for recombinant insulin, growth factors)

example,

• Human blood, plasma or other tissues

• Raw materials (for example, serum, transferring, growth factors, hormones

• Insect cell lines

• Monoclonal antibodies

• Mammalian cell lines

• Clotting factors

• Avian cell lines

• Immune system modulators

• Transgenic systems (for exmple, goats, cows, sheep)

• Vaccines

• Polyclonal anitbodies

• Excipients — human/animal derived (for example, albumin, gelatin)

Table II

is rarely used because of its cost and the lengthy amount of time required for testing.9 Virus clearance studies are a key component of the overall approach recommended to establish the safety of biopharmaceuticals. The ultimate bioclearance claim is related to robust study design, relevant testing regimens and the correct interpretation of the data. Safety validation of production and virus clearance processes coexists with, and is supplementary to, in‑process testing. Aside from fulfilling a regulatory requirement, validation studies minimize production failures by providing assurance of the product’s consistency and safety. By extension, validation studies also help to maximize production.

Once the overall procedure used to manufacture the biopharmaceutical has been shown (validated) to achieve required safety and efficacy standards, changes in production procedures cannot be made following regulatory approval.

Typically, separately evaluating each of the steps and then summing the amount of clearance seen for the whole process establishes adequate viral safety of the end product.

Although this technique has limitations, it is currently the only practical means of addressing a complex situation.9 Safety assurance is extended through time by testing each batch before releasing it for use by patients (also referred to as in‑process testing).

Careful risk assessment, followed by rigorous application of the safety triad processes has proven to be a viable means of manufacturing biopharmaceuticals with acceptable risk– benefit ratios. Although it may be a complex procedure, therein lies its strength. Its intricacy and redundancy provide the flexibility that will be needed to encompass the production of the increasing number and complexity of future biopharmaceuticals.

Conclusion

The lack of any cases, to date,of iatrogenic transmission of pathogenic virus in recombinant therapeutics

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should by no means generate feelings of complacency.

It does, however, provide some indication that the current encompassing approach to biopharmaceutical safety, with the customized risk–benefit evaluation, is a viable approach.

In addition, virus safety assurance of biologicals is far from being a stagnant field of endeavour. Clearance and inactivation methods are evolving at an increasing pace.

By 2020, 90% of biopharmaceuticals available today will be off patent, but indicators of the accelerating development and approval of biopharmaceuticals strongly suggest that there will be a robust production of many newer biotherapeutics that will be on patent by that time.4 Advances in safety procedures will proceed in lockstep with the continuing development of biopharmaceuticals.

Such an effort will be necessary because newer biopharmaceuticals are likely to change in character and be associated with different sets of risks, particularly as new contaminants are likely to be discovered. Of an estimated 150,000 viruses, only 5000 have been detected to date, and viruses are constantly evolving.10 In addition, new blood‑borne virus infections are being reported and each will need to be addressed in safety analyses and purification processes.

The unrelenting potential for the appearance of new viruses is enhanced by the dissolution of global boundaries. Pathogens can now travel to locations that were not previously considered indigenous to them.

Because of this globalization and the many viruses still undiscovered, vigilance and the ability to clear even the viruses we cannot yet detect must remain high. Ultimately, patient protection is paramount.

Current indications are that as new threats to safety appear, the in‑built flexibility and evolutionary nature of risk management strategies will be able to continue to ensure the safety of biopharmaceuticals.

References

1. http://pharmexec. findpharma.com/ pharmexec/Sales/IMSPredicts-Plateau-in-GlobalGrowth/ArticleStandard/ Article/detail/563063?cont extCategoryId=43775 2. www.bizjournals.com/

sanjose/stories/2003/06/23/ focus3.html 3. J.A. DiMasi, et al., “Trends in Risks Associated with New Drug Development: Success Rates for Investigational drugs,” Clin. Pharmacol. Ther. 87, 27–277 (2010).

4. http://uk.reuters.com/ article/2010/07/02/ biosimilar-drugs-idUKLNE6 6102R20100702?rpc=401 &feedType=RSS&feedNam e=stocksNews&rpc=401 5. http://lifesciencedigest.

com/2010/07/11/ monoclonal-antibodycompanies-commandpremiums/ 6. www.contractpharma. com/issues/2011-11/ view_features/virus-safetyof-biopharmaceuticals/ 7. http://lifesciencedigest.

com/2009/07/20/ genzyme%E2%80%99 s-manufacturing-disruptionhighlights-investmentopportunities-in-lysosomalstorage-disorders/ 8. H. Aranha, “Virological Safety of Biopharmaceuticals: A RiskBased Approach,” Bioprocess Internat.

(Suppl), 17–20 (2005).

9. w ww.pharmtech. com/pharmtech/ data/articlestandard// pharmtech/252002/22567/ article.pdf 10. P.P. Pastoret, “Human and Animal Vaccine Contaminations,” Biologicals, 38(3), 332–433 (2010).

For more information

Hazel Aranha PhD, RAC Manager Viral Clearance & Safety Catalent Pharma Solutions hazel.aranha@catalent.com www.catalent.com

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DATA MANAGEMENT

MANAGING ENTERPRISE DATABASE DISCOVERY IN PHARMACEUTICAL AND MEDICAL DEVICE LITIGATION Conducting litigation in the pharmaceutical industry takes special efforts when it comes to both data discovery and intellectual property protection.

Understanding the technical and business aspects of database systems, and the steps one must follow to properly undertake litigation and the accompanying database discovery in the pharmaceutical industry is critical to success.

P

harmaceutical product litigation in US courts involves highly complex data that pose unique challenges for discovery — the pretrial phase in lawsuits in which each party obtains evidence from the opposing party through various means, including requests for document production and depositions. Data for discovery in everyday litigation typically includes email and custodian documents, but in pharmaceutical litigation, material often includes unusual data types, such as enterprise databases that manage information in categories such as clinical trials, sales, adverse events, medical inquiry and FDA filings. This information is stored in intricate proprietary systems and off‑the‑shelf packages that include sophisticated workflows and connectivity capabilities.

Discovery of this information is a multistep process that involves understanding the technical and business aspects of each system, as well as the manner in which it is developed, maintained and operated. Protection of this information outside the corporate firewall is far more complex than for traditional forms of custodian data.

Producing Enterprise Databases as Documents or Standard Reports

Requesting parties, provided with source database data in static reports, have argued that they should be afforded the same analytical capability available to defendants, such as the ability to statistically analyse adverse reactions to drugs.

This raises several issues.

A traditional method of collecting from enterprise systems is to run ‘front end’ reports into a document format and process the reports with an eDiscovery vendor.

Requesting parties, however, are now challenging the sufficiency of this method. Reports arguably do not give them the same analytical functionality that defendants have and, therefore, courts often mandate production “in the format in which it is maintained.” If enterprise systems have been identified as containing relevant information, the traditional industry response has been to

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treat databases as exceptions. Resisting discovery with the argument that the “data is not reasonably accessible” is, however, not holding water in today’s environment.

This ‘native’ concept does not lend itself well to the consideration of complex enterprise systems, regardless of whether they are large‑scale enterprise resource planning (ERP), financial, human resources, messaging or manufacturing systems.

In these cases, the native repositories are rarely produced as a whole. Instead, relevant records and their metadata are extracted from the enterprise database, prepared, reviewed and produced in an agreed‑upon format. Each system is unique, but all may be approached and assessed using a defined methodology, summarized below: • Take stock of databases that contain relevant information. Identify systems, platforms and application functionality at both the operational and business levels, and document the nature of the information stored within each database. Be sure to include legacy and proprietary data sources.

• Understand how various systems inter‑relate. Systems can contain derived data that is retrieved from other data sources. Identify where data redundancy exists and eliminate it by tying data to its original source.

• Narrow the number of unique databases. In pharmaceutical companies that are the result of mergers and acquisitions, multiple repositories may perform overlapping functions in slightly different ways.

Furthermore, although systems may be migrated and replaced, legacy data may remain behind.

• Identify relevant data and the selection process during meet and confer sessions.

• Reach agreements concerning specific data elements to be retained in the database production, production formats, documentation and scheduling.

• Develop extraction methodologies and scripts, and quality‑check the extracted data.

The following sections outline the major issues involved in producing these materials in native format.

March/April 2012

DATA MANAGEMENT STRAP

Interpreting the Request and Interacting with the Requesting Party

As a preliminary matter, the production request must be vetted to confirm that there is a need to take measures apart from traditional discovery. The requesting party may have awareness of certain systems as a result of a course of dealing, a meet and confer, interrogatories or the deposition of a Rule 30(b)(6) witness. As another example, because US‑based manufacturers of medical devices are subject to FDA regulations for quality systems (CFR 21 Part 820), such recordkeeping systems are specifically mandated, and, therefore, are generally known to be targets in certain cases.

Further steps toward qualifying the request for production include an application of relevant time frames and related products. The relevant databases in many large corporations may include multiple versions of such systems as adverse events and sales data, stemming from retired systems and corporate acquisitions. Linked applications such as workflow tools and supporting reference tables must be evaluated for relevance as well.

Meet with both ‘business’ and ‘technical’ owners of these systems well in advance to allow the collection

March/April 2012

professional to interpret the provenance of the data for later certification, assess volumes, obtain permissions, determine costs and time frames, address confidentiality and licensing issues, collect all applicable documentation, and understand the exact nature of how the system is used in practice. This will set the stage for negotiations with the requesting party. The goal of any production is to offer only the responsive, nonprivileged materials — but especially difficult in cases involving large productions of structured data is ensuring that the producing party does so without revealing intellectual property (IP). The meet and confer may include a ‘quick peek’ at the database schema to establish relevant elements. Database schemas may involve hundreds of columns, tables and millions of rows of data. Requesting parties have become increasingly sophisticated at understanding these underlying data structures and building their own electronic hosting systems for the benefit of plaintiffs acting in concert.

The legal team must prepare to estimate the cost of the effort and associated time frame, and determine who shall bear it. They must determine which portion of the database plaintiffs are actually entitled, what must be redacted, as well as which ancillary or third‑party data must be included.

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DATA MANAGEMENT They must also determine whether third‑party aggregate data (for example, industry analytics from IMS Health) must be produced. A complete and verifiable cost document becomes an important component of interactions with the requesting party and for motion practice.

Managing and Documenting the Process within the Corporate Enterprise

In pharmaceutical eDiscovery, the collection team is rarely in a position to capture enterprise data directly. The process involves a co‑ordinated effort with teams of internal IT, security and risk, legal, business, and records personnel to secure the information on the corporate side of the firewall, execute the collection whilst maintaining chain‑of‑custody and data integrity, and document the process defensibly.

Business owners must often participate in the process of documenting their systems and workflows, and those materials must then be vetted with legal before becoming actionable. Typically an iterative process is required to create the correct queries for the desired extractions, determine the right data sets, and confirm time frames (including an examination of archival and backup practices).

Because of the project-orientation of the typical corporate IT department, discovery data collection may be subject to IT department priorities. Creating timeframes for these projects should inform negotiations with the requesting party. In certain instances, there may be alternative means to obtain the information (such as restoring a backup tape versus querying a data warehouse versus querying a live system) that may vastly affect the cost and time frames.

Processing and Preparing Enterprise Data for Review, Redaction and Production

James Mittenthal

For more information

James Mittenthal Vice President Consulting Service Epiq Systems Tel. +1 212 710 6933 jmittenthal@epiqsystems.com www.epiqsystems.com

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At this point, the data passes from the corporation to the law firm, vendor, or other eDiscovery professional. It should be accompanied by sufficient documentation to allow the preparer to understand the format and data elements, but lines of communication should remain open. The preparer must create an environment by which the material can be loaded for assessment, processing, review and production.

If there are multiple versions of the repository, they must be aligned and consolidated; for example, an adverse event database from one supplier may include a column called CASE_NOTE and another may include a column called CASE_DESCRIPTION. The preparer must determine whether these columns refer to the same information and should be combined.

The preparer must also analyse the data for missing or incorrect information. Although it is not the preparer’s responsibility to ensure the quality of the inbound data, he or she must be prepared to speak to the condition of the data.

Ultimately, the data are processed into a format whereby it can serve the purposes of the discovery process, such as ad hoc

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query and reporting by the producing party, review by the attorney teams, and production in the format mandated by the case order or negotiation.

The production plan must also take into account third‑party sources of information and their licensing (such as built‑in MedDRA dictionaries that help define coded entries), as well as confidential, proprietary or EU/HIPAA or otherwise protected information. The redaction process must consider not just obvious forms of patient identification (such as social security number), but also other elements that may readily identify a patient, such as the name of the doctor coupled with the related patient zip code.

Many of these functions, such as staging an inquiry platform on a secure Web server or creating a turnkey redaction system for the attorneys, require substantial custom programming and provision for thorough audit trails. Complex hierarchical systems such as the format for the electronic Common Technical Document used to transfer regulatory information can involve extensive programming to present the material to attorneys for review. Prior to production, the data sets must be subjected to a consistent and auditable quality control process. The creation of appropriate affidavits and other documentation by the preparer forms an important part of the production effort.

Protecting Data, Confidentiality and Corporate Know-How Outside the Firewall

Inside the corporate firewall, enterprise data may be protected through a variety of means: physical security, database, network and application security, encryption, tightly controlled conditions for access including time constraints, audit trails, numerous supporting computer applications, business rules and policies, and compartmentalized job functions. Once the data is reduced to a transportable format for discovery, many of the safeguards are severed from the electronic information. Notwithstanding legal safeguards such as protective orders, nondisclosure agreements and confidentiality designations, the legal team must enact creative safeguards to protect the information beyond the life span of the case.

Conclusion

The pharmaceutical industry is highly regulated and highly litigious, so it’s in each company’s best interest to learn as much as it can about discovery to ensure it is remaining in compliance with the rules governing the process. Although discovery within the pharmaceutical industry can pose a challenge, following the best practice recommendations set forth here can ensure the process progresses smoothly — from identifying and working with internal stakeholders to structuring data production formats to ensuring the security of data — and the company’s IP — once it’s been produced.

March/April 2012

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LEGISLATION

WALKING THE SOCIAL MEDIA TIGHTROPE

Recent advancements in technology pose a host of opportunities for pharmaceutical manufacturers, but also a potential quagmire for regulatory or liability compliance. FDA’s recent draft guidelines for companies on responding to requests for off‑label information, were updated specifically to address requests made through social media. But the draft guidelines address only one small part of the complex issues surrounding social media, leaving companies to walk a fine line between regulatory compliance and litigation liability.

P

harmaceutical marketing — from a purely legal perspective — used to be simple and the rules relatively straightforward. When marketing to doctors and other healthcare providers, drug companies were bound by the FDA‑approved label as to what they could say about the safety and efficacy of their product. Courts applied the “learned intermediary” doctrine, holding that a company’s duty to warn was directed to the doctor, not to the ultimate patient.

But then things changed: direct‑to‑consumer advertising added a new twist to the way consumers viewed pharmaceuticals; new regulations were put in place; and courts began questioning the way the learned intermediary doctrine was applied. Technology advanced beyond television, radio and print. Internet websites introduced banner advertisements. Instant messaging and chat rooms led to commenting on articles, and to Facebook, MySpace, Twitter and other social media sites. As Dan Bryant of Red Dog Communications recognized in Pharma, social media and the Internet represent a unique and evolving platform for both communicating important health information to the public, and providing a means for people to discuss and seek out important information about their health, diseases and treatments.1 Yet, as these advances in technology move into the mainstream, FDA regulations and the law have lagged behind. Companies are now hungry for guidance on critical issues unaddressed by the draft guidance: what obligation does the company have for monitoring third‑party sites and correcting information?

According to Google’s presentation to FDA at its November 2009 public hearing, 111 million individuals searched on Google using health‑related keywords between October and December 2007. A September 2010 survey by Pew Research Center found that 80% of Internet users — or 59% of US adults — look online for health information.2 As consumers and healthcare professionals increasingly turn to online resources for information about prescription drugs, manufacturers have waited — and with increasing urgency, advocated — for a comprehensive framework for the dissemination of information via social media. FDA responded with a 2‑day public hearing in November 2009, where it solicited input on a broad range of issues, including adverse event

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reporting, parameters for the use of hyperlinks, and the ability of manufacturers to post corrective information on discussion forums. Following the hearing, the FDA Center for Drug Evaluation and Research (CDER) indicated that it would publish proposed guidelines. The year came and went without publication, and observers took note when the proposed document was omitted from CDER’s 2011 Guidance Agenda. Instead, CDER listed a planned guidance on “Responding to Unsolicited Requests for Prescription Drug and Medical Device Information, Including Those Encountered on the Internet.”3 Even that limited document was ultimately scaled back.

Published in the Federal Register on the last business day of 2011, the Draft Guidance has been narrowed to address only unsolicited off‑label information requests. Far from a comprehensive guide for dealing with social media, the Draft Guidance discusses social media issues solely within the confines of existing policies regarding off‑label communications.

FDA’s distinction between ‘solicited’ and ‘unsolicited’ requests reflects the reality of the distinction between company‑created, sponsored or controlled online content versus third‑party created and controlled content. For example, in defining the distinction between ‘solicited’ and ‘unsolicited’ requests for information, in addition to traditional means of requesting information, FDA considers a scenario where a firm “asks or otherwise encourages users to post videos about their own uses of its product on third‑party video‑sharing sites.”4 Information requests triggered by such a posting, according to the draft, would be considered ‘solicited’ requests. Other activities that could lead to ‘solicited’ requests about off‑label use include • encouraging bloggers to write about off‑label uses of a product.

• announcing results of a study via Twitter “suggest[ing] that an off‑label use...is safe and effective.”4 • maintaining a website that enables users to peruse a company’s standard responses concerning off-label uses.

These guidelines do not, however, cover any disclosure requirements to the public about the company’s control concerning these various activities.

Perhaps most interesting — and least satisfying — is FDA’s advice regarding information requests posted to public online forums. Although acknowledging that “it can

March/April 2012

LEGISLATION be in the best interest of public health for a firm to respond to unsolicited requests for [off‑label] information...that are made in public forums,” such interests appear secondary to FDA’s reservations about making off-label information “available to a broad audience and for an indefinite period of time.”4 Accordingly, the Draft Guidance directs that substantive responses to publicly posted off‑label information requests — if the manufacturer should choose to respond at all — should be provided only to the specific individual who requested the information as a private, one‑on‑one communication.

(Emphasis added.) A company may issue a public response on the online forum, but it “should be limited to providing the firm’s contact information and should not include any off‑label information.” (Emphasis in original.) Any public response should also disclose the company’s involvement, convey that the question pertains to an unapproved use, and refer to the current FDA labeling. The current guidelines make no distinction among the diverse forums where prescription drug products might be discussed, whether on

It is unclear whether FDA still intends to issue a more comprehensive document on social media. a site targeted specifically to healthcare professionals or a patient- or consumer‑oriented website.

Also unanswered by the Draft Guidance is the need for parameters governing public correction of online misinformation. The Draft Guidance governs responses only to ‘requests’ or ‘questions,’ not affirmative statements.

A company seeking to correct online statements about off‑label uses would appear to be left unguided. Faced with online testimonials pertaining to off‑label uses of its product, — for example, a Wikipedia entry that has been edited by others to provide information that is not compliant with existing advertising and labeling rules or public social media comments incorrectly attributing off‑label use of a product to the manufacturer — a company would be understandably confused, and rightfully concerned about

March/April 2012

FDA’s reaction (possible regulatory enforcement action) to any public response on the one hand, and a potential increase of liability for failure to warn, and so on, on the other. This leaves manufacturers walking a difficult tightrope without a net. Finally, the draft guidance does not address the question of adverse event reporting. A key issue during FDA’s public hearing on social media was the obligation of a company to monitor, report and follow up on adverse events posted on the Internet. It is patently unfair to expect a company to monitor the entire Internet for adverse events.

So What’s Next?

It is unclear whether FDA still intends to issue a more comprehensive document on social media, or whether the issues under consideration since 2009 will be addressed slowly by piecemeal. If, however, change is possible, the changes that drug and medical device companies would probably like to see include the following: Although companies cannot police the whole Internet to ensure that third‑party statements are correct — making any requirement to monitor unrealistic and impossible to meet — there needs to be freedom and flexibility in a company’s ability, where in its judgment it is appropriate, to correct information posted by others without permission on a site they control (for example, on a Facebook page created by the company), whether there is a formal ‘request’ for information or not. From a liability perspective, the company may indeed be obligated to make such corrections.

Given the real public health dangers and lack of accountability posed by nonregulated advertisers, bloggers and online content creators who provide information about prescription medications on‑line, FDA should encourage manufacturers’ legitimate, FDA‑regulated contributions to the discussion as a source — sometimes the only source — of reliable information.

FDA’s draft guidance attempts to create a single set of rules to govern all promotional activity, regardless of the medium. But there is an obvious need to differentiate Internet and social media from traditional forms of promotion and communication. Unlike traditional print or broadcast advertising, Internet and social media users have a great ability to control, alter and respond to the promotional messages and other product information they receive. Manufacturers’ primary concern should be that individuals have access to accurate and responsible information.

FDA should acknowledge the additional difficulty in following up on adverse event reports in the online space. Even if a potential adverse event is identified, given the anonymity prevalent on the Internet, and even if the four required elements for reporting are present, there will likely be no reliable means to follow up to obtain additional information — or even to determine the veracity of the posting.

Lori B. Leskin

References

1. D. Bryant, “Pharma Adverse to Social Media?” Pharma 7(6), 6 (2011).

2. www.pewinternet.org/

Commentary/2011/ November/Pew-InternetHealth.aspx 3. www.fda.gov/downloads/

Drugs/GuidanceCompliance RegulatoryInformation/ Guidances/UCM285145.pdf 4. Guidance for Industry: Responding to Unsolicited Requests for Off‑Label Information About Prescription Drugs and Medical Devices — Draft Guidance (December 2011).

For more information

Lori B. Leskin Partner and Co‑Chair of the Product Liability group Kaye Scholer LLP lleskin@kayescholer.com www.kayescholer.com

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EXECUTIVE PROFILE

FOCUS AND DEEPEN

Catalent recently acquired Aptuit’s Clinical Trial Supply assets. How will this benefit the company and its customers?

Many large and mid-size pharma companies are looking to consolidate the number of suppliers they use to relatively few, trusted partners that have the expertise to serve a number of their development and supply needs. This acquisition will make us a strong Number 2 player in the clinical trials space and enables us to support the trend toward more global clinical trials. The acquisition also strengthens our position as the Number 1 global partner for drug development and formulation services. Complementing this acquisition we have recently completed cold storage capacity investments at our sites in the US and in Germany, and we are expanding our analytical services footprint in the UK and Germany.

Supporting customers’ clinical trials is pivotal to many aspects of their products’ successful ongoing development. It is important that we demonstrate to customers how we are able to optimize development, so the effective integration of these assets into our wider offering is clearly essential. We aim to optimize development timelines for our customers and we will continue to invest so that we are better able to react to change and reliably meet development milestones.

I’m confident we can demonstrate the benefits to customers.

Many companies are downsizing and consolidating to focus on core capabilities, yet Catalent has been expanding. How does this reflect the company’s long‑term strategy?

Some companies have pursued an aggregation strategy, adding semi‑related services to broaden their offerings and ‘touch-points’ with customers. This strategy requires diversity in physical resources and skills, yet because the customer–supplier relationship is broad rather than deep it is difficult to economically sustain all these services; particularly at times when customers take more tasks ‘in‑house.’ This is not the case with Catalent as we pursue a ‘focus and deepen’ strategy, occasionally choosing to part with valuable, but non‑core businesses. We work diligently

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Dr Ian Muir, President of Modified Release Technologies, Catalent Pharma Solutions, talks to Pharma about the company’s expansion strategy, its response to trends in customer demand and the adoption of new drug delivery technologies. to improve efficiencies, using resources to deepen development and delivery capabilities in those areas that remain.

We’ve seen benefits in close integration with our partners to provide novel solutions that meet the ever more challenging requirements of the drug development landscape. Companies should expect a strategic delivery technology partner to solve real problems through formulation and dose form optimization, and we combine these solutions with manufacturing and packaging innovation to create drugs that are effective and payer‑friendly. Acting as one through a deep, focused understanding, both parties can take ownership of real challenges and new ideas, as well as co‑invest in improved products.

When companies operate as real partners, they create more value for all.

Is Catalent planning to make further acquisitions; if so, what can you tell us about these?

We plan to continue to expand our capabilities in drug development and formulation, and in supporting clinical trials on a global basis. Whilst specifics cannot yet be revealed, these areas will require significant global investment.

What trends have you seen emerge in customer demand and how does Catalent expect these to evolve?

Customers are increasingly looking for their strategic partners to address significant unmet needs. Globally, we are seeing a shift from drugs being professionally administered to self‑administration or administration by relatively untrained professionals.

March/April 2012

EXECUTIVE PROFILE

Dr Ian Muir

A provider that is able to offer solutions based on technology can create value early on in the development process.

There is also the ongoing need for formulation improvement to improve bioavailability, convenience or the therapeutic profile of the drug.

A provider that is able to offer solutions based on technology can create value early on in the development process and so address the big unmet needs. The resultant products may improve patient adherence, lower drug costs within developed markets and increase access in developing countries.

Orally administered vaccines, for example, are significantly easier to administer to children, and

March/April 2012

are generally more stable in transit and storage. It is reasonable to anticipate then that they may be taken in less accessible, rural areas such as India and China, important emerging markets of more than 1 billion people each. Oral vaccines can also be administered without the aid of a nurse or doctor.

Formulation improvement may also increase patient adherence. Better solubility, permeation and absorption of drugs can be achieved through technologies that change the site of absorption or time of release, thus making the base drug or biologic molecules more effective. More precise targeting can also reduce side-effects; one of the primary drivers of intentional patient nonadherence.

The quest to improve patient adherence is driving greater reimbursement pressures and considering these pressures from the start hasten development.

Current reimbursement pressures are driven by the assessments of private insurers and governmental healthcare systems such as the UK’s National Institute for Health and Clinical Excellence and US Centers for Medicare & Medicaid Services.

Their increased focus on comparative effective research suggests a more holistic approach to the overall understanding of how drugs benefit patients throughout life. Understanding early on how to design ‘payer‑friendly’ drugs pays off.

What new technologies has Catalent employed recently and how have these helped your customers?

Catalent is continually offering new options in drug delivery to help our pharmaceutical partners bring better treatments to market faster. We achieve this through in‑house development and by partnering with expert companies worldwide.

Through partnering with Sanwa Pharmaceuticals, we are able to globally launch OSDrC Optidose technology that could prove to be a major advance in bringing controlled release or combination product to market through its ability to accommodate multiple API cores in one easy coating step. This drug delivery technology is already fully developed and has been commercially proven in Japan. It will significantly improve therapeutic and drug delivery release profiles beyond the capabilities that can be achieved currently, and enables us — and our partners — to offer better treatments to patients.

We also partnered with Pantec for the exclusive worldwide development rights to Lyopan fast dissolve technology. Lyopan offers the potential for improved taste‑masking capabilities, and may increase the range of drugs and consumer products that can be used in a fast dissolve tablet. Fast dissolve tablets ease swallowing and can be taken without water, thus potentially improving patient compliance.

For more information Dr Ian Muir President of Modified Release Technologies Catalent media@catalent.com

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NOSTRAPHARMUS

THE DRUG SAFETY UTILITY PAYING MONTHLY BILLS VERSUS BUILDING POWER STATIONS

Against a backdrop of stringent safety requirements and rising cost pressures, global drug safety groups within pharma companies are keenly looking on delivering ‘more with less’ and refocusing their efforts on what is considered as ‘core.’

T

For more information

nostrapharmus@wcigroup.com

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raditionally, drug safety groups have operated as drug safety factories, which incurred significant capital expenses in building infrastructure related to technology, processes, people and other operational investments. Technology solution providers also built systems that were licensed to sponsor companies, where internal IT infrastructure groups managed these applications and safety databases.

The rapid evolution of the Internet in the late 1990s has changed the business landscape. Although pharma was a little late to adapt to this changing technology, the concept of outsourcing became prevalent. During 2000–2010, global pharma companies spent significant time and effort to outsource several key aspects of drug safety operations. This transition in methodology also forced drug safety database vendors to develop newer models of solution platforms. Software as a Service (SaaS), with superior and secure cloud‑based technology spread rapidly to drug safety organizations.

Pay‑as‑you‑go models started to evolve. The mindset of ‘price per case’ was beginning to get discussed in conference rooms more often and marked a paradigm shift for drug safety groups, where refocus happened.

Drug safety groups started to emphasize their time and resources on risk management, signal detection and emerging markets; less was spent on drug safety operational issues, technology investments and running the factories.

Nostrapharmus predicts that during the next 5–10 years drug safety operations will become almost completely commoditized. Sponsor companies will demand transactional pricings from their vendors.

Vendors will, in turn, benefit from higher case volumes through new media such as social networks, mobile smart phones, emerging nations, and a more aware and educated public who will recognize drug safety issues in a comprehensive manner. The age‑old challenge of under‑reporting of adverse drug reactions will improve.

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There will be higher case volumes to be managed.

Clearly, technology vendors will further enhance their solutions and offerings and become more ‘utility’ companies than software or technology providers.

Monthly invoices will be mailed to customers on ‘number of cases consumed’ and, maybe, an auto‑pay system will facilitate transactions. Of course, sponsor companies will have strict service level agreements with their vendors for quality of service, timeliness, compliance, security and data privacy. Drug safety groups will reorganize and align to be able to provide oversight, diligence and ensure process confidence.

Data will move seamlessly and securely in the cloud and advanced signal detection capabilities will be possible. Healthcare data exchanges with common information models will become prevalent, thus making medicine safer for patient treatment. The concept of ‘Data is Universal’ will become popular.

Industry will share data across therapeutic areas with the sole objective of improving patient safety. When the world of medicine changes, associated solution and technology providers will be forced to adapt and innovate accordingly, otherwise they risk running out of business. This will challenge traditional technology companies who are so used to making revenues through licences and support. Clearly, this is an opportunity for industry partnerships and consolidations — revenue share between technology companies and service providers will become critical. This has happened in other industries and life sciences companies will follow this model during the next 2–10 years.

Nostrapharmus concludes: “All this change is good.

It will refocus and repurpose pharma, to where it truly belongs — science and medicine. Pharma will stop building massive power stations and will start paying monthly bills.

Of course, this change will make the world a better and safer place. It is truly amazing how technology can save lives, improve quality of life and spread the philosophy of ‘global healthy citizens.’

March/April 2012

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