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Why pharmaceutical R&D must reinvent itself PAGE 40

John Lechleiter’s take on the human dimensions of medical innovation PAGE 52 • Q1 2010








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Out from the shadows Why the rapid rise of emerging markets will change the pharmaceutical world as we know it.


ccording to PricewaterhouseCoopers’ ‘Pharma 2020’ report, the real GDP of the E7 countries will triple from $5.1 trillion in 2004 to $15.7 trillion in 2020, whereas that of the G7 countries will grow by just 40 percent, from $25.8 trillion to $36.1 trillion. Our cover story looks at how these seven countries – Brazil, China, India, Indonesia, Mexico, Russia and Turkey, along with other under-exploited areas of the globe – represent a huge opportunity for the pharmaceutical industry. Pressure at home from patent cliffs and dry pipelines has even the big players looking for ways to increase their bottom lines while at the same time bringing new treatments to previously unserved populations. It seems like a win-win situation. Other significant opportunities in emerging markets include the chance to further develop new products and establish manufacturing, R&D or other facilities, as well as taking advantage of local skill sets and accelerating time to market. There are pitfalls to beware of, however. The

“Emerging markets are playing a pivotal role in how established companies will move forward and in their growth potential for the future” Simon Friend, Global Pharmaceuticals Leader, PricewaterhouseCoopers (Page 34)

potential for political upheaval and other unforeseen events is arguably higher in certain of these countries than in the West, and could prove particularly challenging for companies unfamiliar with the local markets. Concerns also exist about the solidity of the infrastructures in place, IP considerations and whether proper compliance and regulatory standards can be established. Such challenges seem unlikely to prevent the industry’s continued expansion into these areas. PwC’s report also predicts that in 10 years’ time, the E7 emerging economies will account for 20 percent of sales in the $1.3 trillion pharmaceutical market. What company is going to let that opportunity get away? Elsewhere in this issue, Joe Miletich, Amgen’s Senior Vice President for Research and Development, explains why pharmaceutical companies should continue to innovate, even in these financially straitened times. According to Miletich, while an increase in short-term costs may be unavoidable, it’s important to remember that drug de-

“In the long term, what we fundamentally need as a society and human beings will prevail and the truly innovative things will be rewarded” Joe Miletich, Senior Vice President for Research and Development, Amgen (Page 40)

velopment is a long-cycle business and that in the end innovation will be rewarded. We also hear Eli Lilly CEO John Lechleiter’s take on medical innovation and the critical role it plays in lengthening lifespans and providing livelihoods. He points out that people are innovation’s creators as well as its beneficiaries, and that in order to foster it we need to encourage improved education, increased immigration and more funding for research. As pharmaceutical companies continue to advance into new markets, they would do well to keep these points in mind. Smart people, good research and a healthy dash of innovation are the basis of a successful operation in any market, be it traditional or emerging. n

Marie Shields Editor

“We need to get away from the notion that every drug hitting the same target is equivalent and communicate the potential differentiation of our molecules” Paul Matthews, Vice President for Imaging, GlaxoSmithKline (Page 108)


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CONTENTS_feb10 18/02/2010 11:42 Page 9



Curing the world’s ills? How the so-called ‘pharmerging’ markets will change the future of the industry

Lifespans and livelihoods The human dimensions of medical innovation, according to John Lechleiter

34 40

92 Towards a greener future Mark Rhodes examines the level of environmental awareness in the pharmaceutical industry

When the going gets tough Joe Miletich explains why innovation in R&D is more important than ever

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Who influenced WHO?


Improving enterprise-level productivity

EXECUTIVE INTERVIEW 48 Craig Dobbs, Waters 50 Andrew Thompson, Eurand 68 Nitin Sood, Agilent Automation Solutions 80 Matt Sawtell, GE Healthcare 88 Brandon Pence, Thermo Scientific Hyclone Products 150 Tom Haskell and John Moran, IMS Health


The Lean solution



106 Amy Furlong, ERT 142 Bruce Jones, Disney Institute

64 Lorne Davies, Olympus America Inc. 74 Christina Shasserre, EMD Chemicals 90 Lynn Zieske, Singulex 96 Patrick Lucy, Pfenex Inc. 112 Michael Morales and Bruce Hillman, ACR Image Metrix 124 Alfred Sherk, SherTrack 136 Ethan Smith, Metastorm 144 Chuck Russo, Corbett Accel Healthcare Group

PROJECT FOCUS 114 John Hall, Quintiles 116 Grace 122 Debra Shumar, 3P Partners 134 Paul Dupont, Ropack

60 Who influenced WHO? The controversy surrounding the H1N1 pandemic

78 Leading the way Why California is the worldwide headquarters of biomedical R&D

70 Business minded Raafat Fahim explains why an efficient business model is needed to cope with industry challenges

100 Fixing the failure rate Kamal Shah looks at why most new compounds fail to progress beyond clinical trials

ROUNDTABLE DISCUSSION 85 Software With Amos Dor of Umetrics and Patrick Flanagan of Tripos International

CONTENTS_feb10 18/02/2010 11:42 Page 12




82 Richard Kurtz, Bio-Rad Laboratories, Inc. 152 Eric Opron, Walt Disney World Swan and Dolphin Resort

108 Wedded bliss? Paul Matthews looks at the challenges posed by the marriage of imaging and drug development


46 John McCarthy, Symyx 58 Kim Shah, Thermo Fisher Scientific 98 Scott Dixon, Phase Forward 104 Christene Leiper, Onorach Clinical 126 Grant Howes, Accuri Cytometers Inc. 132 Rebecca Vangenechten and Ivo Backx, Siemens

118 In the driving seat

138 Putting people first

Rene Labatut stays in control of Sanofi Pasteur’s vaccine manufacturing processes

Charles Depasse on the importance of paying close attention to your staff’s needs

128 The Lean solution

146 Feel the force

Carmen Doran and Domingo Traver explain how Lean and Six Sigma are bringing about performance improvements

Why sales force effectiveness is taking top priority

Photo finish 154 Travel 156 Events 158 Snapshot 160 Final word with Byron Hill


Andrew Thompson, Eurand


Craig Dobbs, Waters

In the driving seat



16/2/10 17:01:45

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BRAIN CELLS FROM MOUSE TAILS Scientists at Stanford University have turned skin cells from the tails of mice into neurons that are able to form connections crucial to brain function. The research, which was published in Nature, shows once again that the basic functions of cells can be radically altered by turning on or inserting the right genes in their DNA. The

scientists involved are confident the same technique would work with human tissue. Until recently, it was thought that cellular specialization, or differentiation was a one-way path: pluripotent embryonic stem cells give rise to all the cell types in the body, but as the daughter cells become more specialized, they also become more biologically isolated. Like a tree trunk splitting

first into branches and then into Then Dolly the sheep was individual leaves, the cells were cloned from an adult cell in 1997, believed to be consigned showing that a specialized to one developmental cell could act like an Until recently, fate by physical embryonic stem cell it was thought modifications under certain conthat cellular added to their ditions. In 2007, DNA. According researchers anor differentiation to this line of nounced the crewas a one-way thought, a skin cell ation of induced path could no more become a pluripotent stem (iPS) nerve cell than a leaf could move cells from human skin cells by from branch to branch. infecting them with four stem-





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cell-associated proteins called cludes making connections transcription factors. with and signaling to other One interesting aspect of the nerve cells – critical functions if Stanford study was that it was the cells are eventually to be accomplished without the need used as therapy for Parkinson’s to first turn the skin cells into disease or other disorders. the equivalent of embryonic “This study is a huge leap stem cells. A similar method deforward,” said Irving Weissman, veloped four years ago by Shinya Director of the Institute. “The Yamanaka of Kyoto University direct reprogramming of these in Japan originally showed that adult skin cells into brain skin cells from mice or humans cells that can show complex, could be made into stem cells appropriate behaviors like genand manipulated again to beerating electrical currents and come any cell in the body. forming synapses establishes The new work provides a a new method to study more efficient way to normal and disorWernig’s make neurons from dered brain cell team found that the skin of people function. Finally with Alzheimer’s we may be able of skin cells had and Parkinson’s to capture and changed into diseases. study conditions neurons in just The Stanford like Parkinson’s or two weeks study was led by Marius Alzheimer’s or heritaWernig, Assistant Professor of ble mental diseases in the laboPathology at Stanford’s Institute ratory dish for the first time.” for Stem Cell Biology and The research suggests that Regenerative Medicine. Wernig the pluripotent stage, rather and his team identified 19 genes than being a required touchthat are active in neurons and stone for identity-shifting cells, inserted them into skin cells may simply be another possible taken from the tails of young cellular state. Wernig specumice, using a lentivirus to carry lates that finding the right comthe genes into the skin cells. bination of cell-fate-specific A month later, several of the genes may trigger a domino efskin cells appeared to have fect in the recipient cell, wiping turned into brain cells. Three away restrictive DNA modificagenes were identified using a tions and imprinting a new detrial-and-error process from velopmental fate on the among the 19 that could do the genomic landscape. job on their own. Using these Wernig and his colleagues three genes, Wernig’s team are now applying the same found that 20 percent of the skin process to human cells and cells had changed into neurons Stanford has applied for in just two weeks. a patent on the process. “We actively and directly inResearchers could use the duced one cell type to become a method to turn skin cells from completely different cell type,” a patient with Parkinson’s or Wernig said. “These are fully Alzheimer’s disease, for examfunctional neurons. They can do ple, into neurons with the all the principal things that neugenetic defects that cause rons in the brain do.” That inthe condition.


Demonstrators call for the release of 43 arrested health workers outside the Court of Appeals in Manila, Philippines


Swiss drugmaker Novartis appoints former Head of Pharmaceuticals Joe Jimenez as Chief Executive

The Military Sealift Command hospital ship USNS Comfort anchored off the coast of Haiti, following the recent earthquake

The Bud medical marijuana dispensary in Boulder, Colorado. Since the policy on medical marijuana changed, Colorado’s dispensaries have more than tripled




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PROFILE JAMES CORNELIUS, CHAIRMAN AND CEO, BRISTOL-MYERS SQUIBB James Cornelius was named CEO in September 2006 and was elected chairman of the Board by the company’s Board of Directors on February 11, 2008. Prior to joining Bristol-Myers Squibb, he served as chairman emeritus of the Guidant Board of Directors upon closing of its merger into Boston Scientific in April 2006. He previously served as Chairman and CEO during the merger process and was responsible for the company’s initial public offering and subsequent split-off from Eli Lilly in 1995. “Our vision for Bristol-Myers Squibb is to become a healthcare leader for the future,” says Cornelius. “By uniquely combining the best elements of a leading-edge biotech company with the reach and resources of a major pharmaceutical company, we are transforming into a new kind of enterprise – a next-generation BioPharma leader.” Since 2002 the company has brought nine key products to market for the treatment of serious disease, including two new biologic medicines. “Our focus is helping patients prevail,” says Cornelius. “Moving forward, our strategy will be unwavering.” Cornelius was a member of the Board of Directors of Eli Lilly, a member of its Executive Committee and Chief Financial Officer from 1983 to 1995. From 1980 to 1982, he served as President and CEO of IVAC Corporation, previously an Eli Lilly subsidiary. He attended Michigan State University, where he earned a BA magna cum laude in accounting in 1965 and an MBA in 1967. Cornelius has received several honorary doctorate degrees in recognition of his civic and philanthropic activities in Indiana.




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The FDA has approved GlaxoSmithKline's drug Arzerra (ofatumumab) as a treatment for chronic lymphocytic leukemia, a slowly progressing cancer of the blood and bone marrow. The news of the approval comes as part of the FDA’s accelerated approval process, which allows earlier approval of drugs that meet unmet medical needs. According to reports on Reuters pertaining to the accelerated process, products may receive this kind of approval based on a surrogate endpoint – for example, the reduction in the size of a tumor or the decrease in the number of cancerous white cells. The approval of Arzerra patients with CLL whose cancer is no longer being controlled by other forms of chemotherapy illustrates the FDA’s commitment to using the accelerated approval process to help those patients who otherwise have limited therapeutic options.


Medicines purchased from illegal internet sites that conceal their physical addresses have been found in

50% of cases to be counterfeit


orlistat, as it should have done, and instead contains sibutramine, a substance that was Counterfeits of weight-loss drug Alli removed from use by the European have reportedly been found on sale on Medicines Agency, after early data US-based websites, including showed it may increase the risk renowned auction site eBay. of heart attacks and stroke. The counterfeit The genuine article, which is The websites selling version has been found not to contain manufactured by UK-based the counterfeit drug are GlaxoSmithKline is curbased in the US, but the rently available over the counterfeit packets may as it should have done counter in Britain and claims be available to internaand instead contains sibutramine to help users lose more weight tional patients online. The than dieting alone. However, the UK Medicines and Healthcare counterfeit version has been found not Products Regulatory Agency has to contain warned against the “trend of self-diagnosing and self-prescribing,” calling this practice “dangerous”.



With the acquisition complete, Pfizer now employs 4500 former Wyeth employees at facilDespite declining sales, Pfizer reported a ities in Collegeville and Great Valley. Though Pfizer has already made moves to con26 percent jump in third-quarter solidate quickly now that the profits last year, as cost cuts merger – announced in January offset massive industry Pfizer 2009 – has been finalized. lags. Pfizer Inc., already reported a The company says that the world’s largest pharit plans to announce what maceutical company, has jump in thirdprojects will stay in its rebeen a hot topic in the quater profits search program and what news recently thanks to the gets cut more quickly than the completion of its $68 billion six to nine months companies acquisition of Wyeth, which often take; the time period is expected to be closed in October. Now, with reports showing net income in the firm’s most re- considerably shorter than the painful, drawncent quarter at $2.88 billion – up from out integrations following Pfizer’s buyout of $2.28 billion a year earlier – Pfizer is riding Pharmacia Corp. in 2003 and WarnerLambert Co. in 2000. high again.





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approve Merck’s plan to buy New Jersey neighbor Schering-Plough Merck & Co. has posted a huge Corp. That sale alone saw the profit margin due to higher than company reap an impressive $1.7 average sales and the sale of billion (after tax), but even without a business. it, profits would still The company, have been up 58 whose range of percent from the The sale products inalone saw the year before. company reap an cludes cholesAs a result of impressive terol drugs its profitable year, and vaccines, Merck is moving along with the after tax up from number asthma and allergy eight to number treatment Singulair, two on the pharma posted a net income of $3.42 power ladder, thanks billion, triple the amount it made at in part to its $41 bilthe same time last year. lion acquisition of A large part of that inSchering-Plough. Other come came from the sale successes for Merck have of half of the Merial been the company's new diaanimal health busibetes drugs, Januvia and Janumet, ness so that reguwhich brought in a combined total lators would of $664 million. Meanwhile Singulair sales increased five percent to $1.1 billion.

$1.7 billion

GATES PLEDGES $10 BILLION FOR VACCINES At the reccent World Economic Forum in Davos, Switzerland, revered business tycoon and founder of computer software giant Microsoft, Bill Gates, announced with his wife that they will commit $10 billion over the next decade to help research, develop and deliver vaccines for the world’s poorest countries. According to Mrs. Gates, who announced the initiative last Friday, the vaccines are now the “number one priority” of the Gates Foundation

because of the “incredible impact” they have on children’s lives. Bill Gates added that the next 10 years must be defined as “the decade of vaccines”. The boost comes after a model used by the Foundation and developed by a consortium led by the Institute of International Programs at the Johns Hopkins Bloomberg School of Public Health stated that significantly scaling up the delivery of vaccines in developing countries could prevent the deaths of some 7.6 million children.

AUTISM ARTICLE DISAVOWED A prestigious medical journal has dren. In 2004, as scrutiny and critidisavowed an article it published cism of the study intensified, ten of more than a decade ago linking 13 co-authors of the 1998 autism arautism in children to a common ticle publicly disassociated themchildhood vaccine. The original arti- selves from it. Paul Offit, a vaccine cle raised widespread concern researcher at Children’s about the safety of the Hospital in Philadelphia, vaccine, prompting says at least 12 studies many parents have been done worldwide to worldwide conco-authors of the 1998autism stop vaccinating cluding repeatedly article publicly their children. that the MMR disassociated In 1998, a vaccine does not themselves from it high-profile article cause autism.

10 of 13

published in the British medical journal, The Lancet, announced a link between autism and the MMR vaccine, used against measles, mumps and rubella. There had been no established cause shown for autism, a disorder that affects a youngster’s social skills and ability to interact with the outside world. In the original paper, British gastroenterologist Andrew Wakefield described a small sample of 12 children, eight of whom showed evidence of autism shortly after receiving the vaccine. However, subsequent investigations by British regulators led to charges that Dr. Wakefield falsified data and was paid by the parents of autistic chil-

“We’ve reached the many hundreds of thousands mark of children who did or didn’t receive MMR to see whether risk of autism was greater in the vaccinated group and it wasn’t; consistently, reproducibly, redundantly,” he says. “I think the problem is there are people who simply don’t believe the science. They hold on to this notion that MMR causes autism or that vaccines cause autism much as one holds a religious belief.” Source:


1% of children aged 3 to 17 in the US have an autism spectrum disorder




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MALARIA BREAKTHROUGH Scientists across the globe have long hunted for a vaccine against malaria – a disease that claims roughly one million lives each year. But now, after decades of searching, the creation of a malaria vaccine began to look more and more likely. UKbased pharmaceutical giant GlaxoSmithKline announced it would take the significantly unprecedented step of

sharing its scientific data and laboratories to help fight the good fight against tropical countries. According to reports, Andrew Witty, Chief Executive of the firm and the driving force behind the initiative, said the drug company has a “genuine appetite to change the landscape of healthcare for the world's poorest people.”

RISE IN PRODUCT RECALLS pharmaceutical recalls are due The number of product recalls to incorrectly labeled or packand safety alerts for pharmaaged goods, and nine percent ceutical products and medical are due to compromised devices more than sterility owing to quadrupled in the packaging errors UK between or poor struc2004 and 2008, tural integrity. a new study of pharmaceutical recalls are due to In 2007 the by customer incorrectly labeled or European management packaged goods Commission reagency leased figures reBlueview Group vealing a five-fold reveals. The study, increase in fake pharmaceuticals which pulls together UK govacross Europe, with 2006 seizures ernment and European Union hitting an all-time high of 2.5 figures, shows that over the million items. The worrying infive-year period starting in crease in the incidence of coun2004, recalls and product alerts terfeit drugs and the growing in the pharmaceutical sector sophistication of the lengths that rose from 22 to 94. counterfeiters are now prepared Nearly two thirds of these to go to are a constant source of actions are down to defects in concern for drug manufacturers, the manufacturing or perforprompting ever more research mance of a medical device with into new technologies and strate62 percent of recalls or alerts in gies to protect the pharmaceutithe sector being issued for this cal supply chain effectively. reason. Another 12 percent of


FROM THE VAULT In the Q3 2009 issue of NGP, Chris Viehbacher, CEO of sanofi-aventis, explains his controversial appointment to the position and the need he found to reshape the company’s image. Go to to browse ‘Past issues’ and click on Issue 16, June 2009 and read of Viehbacher’s plan to “bring the outside world into the company and open it up to what’s out there”.

LILLY REVIEW CANCELLED US regulators have reportedly cancelled a review meeting set to decide upon a proposed new indication for Eli Lilly‘s blockbuster antidepressant Cymbalta. According to a notice on its website, the Food and Drug Administration (FDA) has now cancelled the review meeting that was due to take place in light of “new information”, in hope that this new information may prove to be relevant to the benefit/risk balance for the proposed new indication. However, the FDA also main-

tains that it intends to “continue evaluating the application” and is likely to announce future meeting dates for the FDA’s Anesthetic and Life Support Drugs Advisory Committee to reconvene and consider whether Cymbalta (duloxetine) should be recommended for approval for the treatment of chronic pain. The drug is already approved for depression, anxiety, diabetic nerve pain and fibromyalgia, and had third-quarter sales of $790.2 million, up 10 percent.




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GSK JOB CUTS Pharmerging GlaxoSmithKline is expected to announce thousands of job losses. The UK-based pharmaceutical giant is reportedly likely to follow in the footsteps of other drug companies, including key rival AstraZeneca – who announced similar cuts recently – by announcing cuts at the end of this week. Like many big pharma companies, GSK is facing the harsh reality that several of its blockbuster drugs are either about to lose, or have already lost, their patent protection in Western countries, with the US and European governments continuing to bear down on medical costs. The announcement is likely to continue the push by GSK to reduce the workforce in the US and Europe, while continuing to expand in Asia.

DRUG INFO PLEDGE A call for new initiatives to complete Commission proposals that would liberalize European controls on the provision of prescription drug information to patients has come courtesy of Europe’s new Health Commissioner-designate. John Dalli, who is the Commissionerdesignate for Health and Consumer Policy (SANCO) in President Jose Manuel Barroso's new Commission, has told ministers that the current draft directive needs to be reassessed. According to Dalli, “Patients have the right to have access to proper information on prescribed medicines. We have to reassess the proposal and put a better one on the table.” If successful in his nomination, Dalli would also be taking on responsibility for the European Medicines Agency, and in his written answers to the ENVI panel he says he is looking forward to the upcoming evaluation report on the Agency’s functions.

TEVA HITS HIGH Teva Pharmaceutical Industries Ltd, the world’s largest generic maker of drugs, has announced that trading has hit a 15-year high and that annual revenue will double to $31 billion by 2015. As the company has reduced its dependency on the Copaxone multiple sclerosis treatment, its biggest selling drug, it has seen its more profitable branded business more than double. The company’s growth has also been attributed to more opportunities in countries where generics account for a small amount of drug sales, as well as greater government reforms emphasizing cost savings. It hasn’t hurt that $150 billion worth of brand name drugs will be losing their patent protection in the next five years. Teva has also projected a net income of $6.8 billion in 2010.




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FAKE ADVERTISING The Ghana Medical Association (GMA) has called on stakeholders to help it eliminate the practice of fake drug advertising and the reckless use of medical titles, which has characterized the sector of late. The Association has pointed out that The Ministry of Health, Food and Drugs Board, the National Media Commission, and the Medical and Dental Council, should work together to enforce the laws regulating the use of titles, and ban the unregulated ad information available. The President of the Association, Dr. Emmanuel Adom Winful, reminded the general public to be mindful of some of the false claims contained in some of the advertisements being carried by those claiming to be doctors. Consequently, it has reacted against the unnecessary doctorial titles many Ghanaians, especially herbal medical practitioners, have conferred on themselves.




Leading British-Swedish pharmaceutical company AstraZeneca has announced that it is to cut 8000 jobs worldwide as it embarks on one of the biggest shake-ups seen in the industry’s history.

Sanofi-aventis, France's largest pharmaceutical company, is reportedly on track to secure the top spot in the diabetes area, aiming to steal it from current leader, Danish firm Novo Nordisk.

According to analysts, the job cuts are likely to result in the loss of 1500 jobs in the UK, where AstraZeneca has research and development (R&D) operations in several locations. Analysts have also speculated that the pharmaceutical giant will shed as many as 3500 posts from its R&D facilities across the globe as it tries to cut costs.

Reports have surfaced that suggest sanofi has identified diabetes as a top priority in pharmaceuticals and has now established a global division to help the firm achieve its aim of becoming the number one firm in the disease.

The reasoning behind the cuts is to save money. The overall plan is to outsource more of AstraZeneca’s research and development function – a division largely defined as the heart of any pharmaceutical company – to pharmerging markets such as China.

The move comes after the firm's bestselling drug for 2009 proved to be Lantus (insulin glargine), with fullyear revenues reaching €3.08 billion ($4.2 billion), up 22.5 percent from the year previous. Sales of Apidra (insulin glulisine) were also up 38.8 percent to €137 million ($188 million).




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TOP 10

On 12 January, Haiti was rocked by the largest earthquake ever recorded in the area. The incident sparked a call for emergency aid across the world, and now, thanks to Novartis, the pharmaceutical industry is getting on board too. According to reports, Novartis is, through its local organizations in countries throughout the region, set to provide the equivalent of over $2.5 million in immediate emergency aid for victims of the disaster. Reports show that this support will include both direct financial aid to relief agencies working in Haiti, as well as donations of essential medicines, including antibiotic and pain relieving drugs.

Biggest threats to men’s health, according to the Mayo Clinic


ACADEMIC-INDUSTRY COLLABORATION project will focus on developing new animal An international consortium of scientists, led by models which use brain recording and behavioral H. Lundbeck A/S and King’s College London, has tests to identify innovative and effective launched one of the largest ever research drugs for schizophrenia. It will also deacademic-industry collaboration proThe velop the hardware and analysis jects to find new methods for the project will techniques to apply brain imagdevelopment of drugs for schizoing, especially MRI and PET phrenia and depression. imaging, to drug development. It techniques to apply ‘Novel Methods leading to brain imaging to drug will examine how new genetic New Medications in Depression development findings (duplication and deletion and Schizophrenia’ (NEWMEDS) is or changes in genes) influence the rea unique project, bringing together top sponse to various drugs and whether this inscientists from academic institutions with a wide formation can be used to choose the right drug range of expertise, and partnering them with for the right patient. And finally, it will try to denearly all major global drugs companies. velop new approaches for shorter and more effiThe main objective of NEWMEDS is to decient trials of new medication – trials that may velop new models and methods to enable novel require fewer patients and give faster results. treatments for schizophrenia and depression. The


2 3 4 5


7 8 9 10

Heart disease





Type 2 diabetes



Kidney disease

Alzheimer’s disease




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Japan’s leading pharmaceutical company, Takeda, has revealed today that it has signed up Pfizer as a partner to co-promote its blockbuster diabetes drug Actos in China. According to the Japanese drug maker, the pact will increase the number of medical representatives supporting the sales and marketing of Actos (pioglitazone) in the region. The agreement is set to expand the product’s reach by “utilising the territory coverage of Pfizer, the largest multinational pharmaceutical company in China.” Statements on Takeda’s website explain how the drug, used for the treatment of type 2 diabetes, has been sold in China since 2004 by Tianjin Takeda Pharmaceuticals, a joint venture of Takeda Pharmaceutical Company Limited and Tianjin Lisheng Pharmacetical Co., Ltd., a Chinese company. According to the International Diabetes Federation, the diabetes epidemic has the greatest potential to increase in China, because of its population size, rapid urbanization and economic expansion, meaning that a wider use of Actos in China is critical to overcoming the fight against the disease. In fact, the potential to expand the use of Actos is considerable, given that China is estimated to have more than 50 million diabetics by 2025. The deal also highlights Pfizer’s own strategy of expanding its operations in the country and comes less than a month after it announced plans to establish a new R&D centre in Wuhan.

Oregon Freeze Dry, Inc, and its partner that crossover from a variety of commercial areas. Lyophilization is consitently utilized in the EnerG2 have been selected to receive a Department of Energy stimulus grant of $21 development and preparation of drugs, medical million to design, build and manufacture a devices and food products. This successful appliunique carbon electrode material. The plant cation of lyophilization is another example of funded by the DOE grant will be the first US- how two companies took advantage of their cryo based large scale manufacturing operation for and lyo preservation knowledge to customize formulation to maximize the preservation of form these materials making up the key comand functionality. Lyophilization expeponent in ultracapacitors for use rience with materials ranging from in applications such as elecOregon Freeze active pharmaceutical ingreditric vehicles. The facility is Dry,Inc.,and its ents, quick dissolve tablets, adproposed for construction partner EnerG2 have vanced wound care products, on the site of OFD’s existbeen selected to receive a grant of stabilized platelets, vaccines and ing campus. diagnostic kits provides a founOFD’s innovative dation to investigate new delivery thinking and experience system concepts. coupled with the flexibility of Creating or retaining high surface an elegant preservation process provided the right blend of contract services area, bioavailability and solubility can be enEnerG2 needed to rapidly develop and provide hanced with the appropriate expertise in a proposal to the DOE. The breadth of OFD’s lyophilization. Materials that have sensitivities to capabilities and experience manipulating the heat, shear, oxygen and shelf-instability at certain lyophilization or low-temperature, low-pressure temperatures and finished weight are candidates preservation process provided EnerG2 a huge for taking advantage of this technology. At OFD the passion is to utilize its over 45 advantage in savings from proof-of-concept through to commercialization. A unique set of years of lyophilization application in diverse areas intellectual property assets is required to enable to find solutions and develop clients’ products development of defensible products or process rapidly through Quality by Design (QbD).

$21 million


In fact, according to insiders, the health package the House requires approximately New reports have warned that the pharma$140 billion from drug companies to pay addiceutical industry may have to pay out more tional healthcare costs over the next than the $80 billion it agreed to condecade. What’s more, officials tribute to President Barack The House within the pharmaceutical Obama’s health overhaul efrequires industry have warned that forts. The news reportedly reapproximately the version of the bill the flects pressure from the Senate is debating may alDemocrats and their supportfrom drug companies ready pluck close to $100 ers for more money, needed to pay additional billion from drug makers. to cover older and low-income healthcare However, it has also been recosts Americans. It comes amidst reported that proposals that would ports that both Obama and the require drug makers to pay out even more Democrats are desperate to keep the drug inmoney will prove to be a real test for one of dustry on-side, as a crucial ally in the healthWashington’s richest lobbies. Many care debate. This is largely because of the Democrats believe the industry will profit pharmaceutical industry's influence in states when roughly 30 million uninsured Americans where it is a large employer, particularly New gain coverage for prescriptions. York, New Jersey, Connecticut and Indiana.

$140 billion




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A new report by leading consultancy firm PricewaterhouseCoopers (PwC) has warned that factors including changing market dynamics and rapidly evolving healthcare reforms are likely to push up the effective tax rate for the pharmaceutical and life sciences industry. According to the study, Pharma 2020: Taxing Times Ahead, rising tax rates will also be dictated by the impact of the global financial crisis and the diminishing reliance on the blockbuster drug model. The findings of the report warn that such changes in the industry will make tax planning more complicated and challenging for tax executives working for pharmaceutical companies. The survey is based on a poll of 35 senior tax executives from pharmaceutical, biotech and medical device companies and warns that six in 10 tax leaders agree that an increase in the effective tax rate for the pharmaceutical industry is inevitable. In addition to these findings, nearly two-thirds of respondents (63 percent) agreed that the cost of increased taxes on their organizations might be passed on to consumers, unless they find ways to operate more efficiently and transform their approach to R&D and sales and marketing. A total of 62 percent of respondents said they are looking to maximize tax credits and other incentives for R&D.

The head of Almac, Sir Allen McClay, has died aged 80. Sir McClay, who qualified as a pharmacist in 1953, established his first business, Galen, in 1968 and made it one of the world’s leading pharmaceutical and biotech companies. When he retired as President of Galen Holdings, which later changed its name to Warner Chilcott, in 2001 he established a new company, Almac which integrated drug development services, research and manufacturing to about 600 clients. The company quickly established itself as a leading pharmaceutical firm and employs thousands of people in the pharmaceutical industry.


More than

3 million

Americans stutter – about 1% of the population

Sir Allen was knighted in 2005 and for a man of his wealth, was a very generous philanthropist. He set up the McClay Foundation to unite industry and academia, which has a turnover of £167 million ($264 million). He also personally donated £20 million ($32 million) to Queen’s University in Belfast. Ironically, for all his success in the pharmaceutical industry, Sir McClay often described himself as “one of the world’s worst pharmacists.”

NANOTECHNOLGY INCREASES OPTIMIZATION Nanotechnology coupled with proteomic analyses offers the pharmaceutical industry new opportunities to optimize the drug discovery and drug development process. The miniaturization of assays in the nanoscale range will improve cost effectiveness by requiring substantially less sample for any given technique, improve result reproducibility and sensitivity due to the precision of the automation and low nonspecific binding, reduce assay time since the reactants are confined to femto or atto liter volumes, and allow for important new tests that were previously not possible due to insufficient sample material. Dip Pen Nanolithography (DPN) is an established method of nanofabrication that is ready to impact the biological sciences. Using DPN, biomaterials such as proteins, cell extracts or whole cells can be deposited on to surfaces at nanometer resolution. The resulting nanoarrays are made with far less sample and use femtoliters of reactants per spot compared to traditional microarrays, bringing precision, cost effectiveness and high reproducibility to proteomics.

Combining DPN generated nanoarray with the latest generation of fluorescent detection technologies has resulted in the NanoDiscovery Fluorescent System, a new approach to protein analysis and detection developed by the Nano BioDiscovery Division at NanoInk. It is compatible with high-resolution fluorescent scanners and easily accommodates existing assay protocols. The uniformity of the nano features combined with the low volumes and extremely low non-specific binding substantially improves the sensitivity of these assays. This ultimately permits the detection of very low abundance biomarkers from small amounts of biofluids or other precious clinical samples, as well as the detection proteins buried deep in the proteome, with very low or no expression profiles. The NanoDiscovery Fluorescent System opens the door for exciting opportunities towards experiments that were previously not possible, as well as more cost- and timeefficient approaches to drug discovery and development. For more information, please visit


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eCLINICAL EVOLUTION eClinical is ill-defined in today’s marketplace. Many use ‘eClinical’ to simply mean an electronic technology, i.e. EDC; others further differentiate eClinical to mean technology solutions working together to create integrated process-driven solutions. Considering this latter definition, as our clinical trials environment has changed, we can consider three stages in our current evolution of eClinical. Firstly, clinical trials typically employed multiple technologies which meant some data and functionality overlapped. This led to repeated activities and data in multiple solutions, and the requirement to check and reconcile the data contained in each. The first evolutionary step developed was point-to-point data integrations to ensure that data entered in one system was automatically replicated into others – eliminating data duplication issues and redundant activities. Common integrations include provision of study progress data from EDC and RTSM (randomization and trial supply management) systems to CTMS applications. Point-to-point integrations, whist effective, are complex to support and deploy when there are multiple solutions that require connecting. Utilizing a clinical technology integration platform – or middleware hub – is an evolutionary step that enables integrations between multiple solutions to be implemented and supported quickly and efficiently. This approach requires only a single connector between each application and the middleware hub and provides central control and visibility of all integrations in play. We’re seeing further evolution of eClinical in response to the complexity that site and sponsor users face when using multiple technology solutions. A study manager, for example, must access and review reports in multiple solutions to understand the true status and progress of their study. A site user must log in and out of multiple solutions to perform basic workflow. The next adaptation is to focus on how solutions and data can be combined to simplify their use. This can be achieved through product convergence: making functionality that resides in one product available through another. For example, enabling an EDC user to access RTSM functionality – randomization, dispensation, pack replacement – through that product interface, removing the need to access multiple solutions. eClinical will continue to evolve by making the process of running clinical trials simpler. For more information, please visit

STUTTERING GENE FOUND Researchers have discovered a gene linked to stuttering, a speech disorder that afflicts an estimated one million adults worldwide. Scientists believe the finding raises hope that a drug might someday be developed to treat this disabling condition. Researchers say the speech impediment appears to stem from a defect in the gene that regulates the way brain cells break down and recycle waste products. This abnormality interferes with the brain’s ability to process speech. Stuttering causes sufferers to get stuck repeating or prolonging sounds, syllables or

words that interrupt the normal flow of speech. Experts say most children who stutter seem to magically outgrow the disorder. But for people who continue to stutter into adulthood, researcher Dennis Drayna of the US National Institute on Deafness and Other Communicable Disorders says stuttering can be profoundly disabling. “I think in some cases it is hardly even viewed as a legitimate disorder,” said Drayna. “People dismiss it all the time when in fact it’s a clear biological disorder that has very big influences on affected individuals.” The researchers homed in on a single gene, known as GNPTAB, which was defective in 46 members of a large Pakistani family. The abnormal gene also was found in 77 unrelated Pakistanis with the speech impediment. Source:

SEARCH FOR THE BEST DEVELOPMENT MODEL Today, containing costs and maximizing the make this mistake and unnecessarily hire spevalue of each development dollar is critical to cialty expertise or bring them in too early, reassuring that the industry continues to pursue sulting in a loss of time and money. promising new technologies and therapies. What if this asset were paired with severHowever despite our best efforts, as an indus- al other assets in a similar stage of developtry the cost of discovering drugs, developing ment? It is easy to see how a virtual team new therapies and conducting clinical could be constructed with experts who trials continues to soar. If a compado not require full-time employA virtual ny can focus on a particular ment but can be dedicated to team could improve asset, such as a drug candidate the firm for some period of program efficiency at a particular phase, it will be time. It becomes easier to and considerably able to more specifically define make decisions on each asset the skills needed for developbased on data rather than tied development ment as well as how long they are into the context of a company’s costs required, and thereby more accusurvival or long-term stability. A virrately gauge costs. tual team could improve program efficiency Additionally, if the exit is something other and considerably reduce development costs. than developing into a fully integrated devel- Such gains in efficiency could lead to more soopment company, it makes little business sense phisticated financial models with which to to hire full-time personnel. It would be difficult manage risk across product portfolios while to predict the level of involvement needed from helping promising therapies reach patients the new hires while also ensuring sufficient more quickly. bandwidth to deal with inevitable challenges of For more information please visit a development program. Yet many companies



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“We know that it is a risk factor but we can’t attribute the rise in Autism is a complex disability autism to the shifting trend tothat affects a person’s ability to wards having children later in life,” she says.. Older communicate and inmothers are known teract with others. to face increased There are Women who gave birth after risks for having many theories children with geabout what netic disorcauses it, and were nearly twice as ders, the latest has likely to have a child with autism and to do with a genes mother’s age. are thought Researchers from the University of to play a role in the California looked at millions of entire autism specparents, and found that women trum.

age 40

who gave birth after age 40 were nearly twice as likely to have a child with autism as a woman under 25. But the increased risk is small: only five percent of the increased risk is attributed to maternal age. Researcher Janie Shelton was the lead author.


J&J RECALLS PRODUCTS The world’s largest consumer healthcare company, Johnson & Johnson has voluntarily recalled more than 500 products that are available over-thecounter, including brands such as Tylenol, Motrin and Rolaids. The recall was issued after reports of an unusual odor emanating from the products. It is similar to the issue that saw a mass Tylenol recall last year, damaging the product’s reputation. The odor has been described as an “unusual moldy, musty, or mildew-like odor that, in a small number of cases, was associated with temporary and non-serious gastrointestinal events.” In a

statement, J&J stated that some consumers had experienced nausea, stomach pain, vomiting and diarrhea. The recall, which will involve calling back products from all over the world including the United Arab Emirates and Fiji, will also involve the Benadryl allergy drug and St. Joseph’s Aspirin. According to J&J’s McNeil Consumer Healthcare division, the smell is caused by the presence of trace amounts of a chemical called 2,4,6-tribromoanisole (TBA), which can result from the breaking down of a chemical found in wood pallets and other packaging and transport materials.

EXPANDING PRODUCT SECURITY Given the growing sophistication on-dose, multi-layered, brand proof pharmaceutical counterfeiters tection technology that enables manand illegal diverters, it is becoming ufacturers to authenticate and trace more apparent that multi-layered every single dose. NanoGuardian's approaches to protecting medica- NanoEncryption technology postions are becoming a necessity for sesses intrinsic layered security feapharmaceutical manufacturers. In tures at the overt, covert and forensic an article titled ‘Fake level and is applied directly to tablets, Pharmaceuticals’ from the January capsules, vial caps and prefilled sy4, 2010 issue of Science and ringes. Since NanoEncryption techTechnology, David Shore, Assistant nology always remains with the Director of Global Security specific dose, even after nufor Europe at Pfizer, merous repackaging efsaid, “Any new seforts, it provides Any new curity features for brand integrity, security feature only packaging only protection and lasts about last about 18 confidence that months before traditional, onbefore counterfeiters counterfeiters can package technolocan produce produce mimics.” gies cannot alone mimics Additionally, counterprovide. Although packfeiters are adding small aging security features provide a amounts of the correct active ingre- vital barrier to counterfeiters and illedient to their counterfeited versions gal diverters, there is mounting eviin an attempt to fool API detection dence supporting the need to protect methods. These are the extremes to patients, brands and companies by which counterfeiters and illegal di- implementing new strategies that inverters will go to fool authorities, clude on-dose security features. By healthcare professionals, manufac- implementing a technology like turers and patients. NanoGuardian’s NanoEncryption These disturbing trends merit a technology, manufacturers can aunew approach by pharmaceutical thenticate and trace each and every manufacturers to extend pharmaceu- dose from plant to patient and theretical security features beyond the pack- by significantly increase their defense age and on to the medication itself. against the costly, and potentially NanoGuardian’s deadly, consequences of counterfeit NanoEncryption technology is an and illegally diverted medications.

18 months


Stuttering affects

four times as many males as females


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Autism is the fastestgrowing developmental disability, with a

1148% growth rate

COMPANY INDEX Q1 2010 Companies in this issue are indexed to the ďŹ rst page of the article in which each is mentioned. 3P Partners 122, 123 Accuri Cytometers, Inc. 126, 127 ACR Image Metrix 112, 113 Aerotek 8, 149 Agilent Automation Solutions 68, 69, OBC Ambit Biosciences IFC, 77 Amgen 40 Aventis Pasteur 70 Bio-Rad Laboratories, Inc. 82, 83 BioProcessing Inc. 45 Celgene Corporation 100 Corbett Accel Healthcare Group 144, 145 Disney Institute 142 Eli Lilly and Company 52 EMD Chemicals 74, 75 ERT 106, 107 Eurand 10, 50, 51 European Vaccine Manufacturers 60

Finesse Solutions, LLC 66, 67 Frost & Sullivan 146 GE Healthcare 80, 81 GlaxoSmithKline 60, 92, 108 Grace 2, 116, 117 Halloran Consulting Group 15, 28 IMS Health 150 Meettheboss 76 Metastorm 136, 137 Missouri Partnership 160, IBC Nabi Biopharmaceuticals 70 NanoGuardian 30, 31 NanoInk, Inc. 26, 27 New Jersey Economic Development Authority 159 Norwich Clinical Research 103 Novartis 60 Novartis Pharma Technical Operations 128 Nycomed 34, 138

Olympus America Inc. 64, 65 Onorach Clinical 104, 105 Oregon Freeze Dry, Inc 25, 33 PACE 60 Perceptive Informatics 28, 29 Pfenex Inc. 96, 97 Phase Forward 98, 99 Pilgrim Software 6 PricewaterhouseCoopers 34, 78 Quintiles 63, 114, 115 Roche 60 Ropack 134, 135 SAGE 60 Sanofi Pasteur 118 SanMed 146 SherTrack 124, 125 Shire 34 Siemens 132, 133 Singulex 90, 91 Symyx 46, 47

Thermo Fisher Scientific 13, 58, 59 Thermo Scientific Hyclone Products 88, 89 Transgenomic 73 Tripos International 84, 85 Umetrics 85, 87 University of Florida 141 Waters 4, 48, 49, 121 Walt Disney World Swan and Dolphin Resort 152, 153 World Health Organization 60

OREGON AD.indd 1

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With emerging markets poised to contribute more than 50 percent of the pharmaceutical industry’s growth in the next year, many companies are looking to expand their international presence. Marie Shields takes a look at what this means for the future of the industry.


hina, India, Brazil, Mexico, Russia, Turkey, Indonesia – these are the top so-called ‘pharmerging’ markets, and they and others like them could hold the key to the future growth of the international pharmaceutical industry. Two years ago, PricewaterhouseCoopers produced its ‘Pharma 2020’ report, analyzing industry trends for the next 10 years, and these seven countries – called the E7 – play a crucial role in that vision of the future. According to the report, “The real GDP of the E7 countries will triple from $5.1 trillion in 2004 to $15.7 trillion in 2020, whereas that of the G7 countries will grow by just 40 percent, from $25.8 trillion to $36.1 trillion. Their wealth relative to that of the G7 will rise from 19.7 percent to 43.4 percent over the same period. “In 2004, the E7 countries spent 0.94 percent of their GDP on prescription medicines (although the precise percentage varied from one state to another). They collectively accounted for eight percent of the $518 billion global market. The G7 countries, by contrast, spent 1.31 percent of their GDP on medicines and accounted for 79 percent of all sales. “If all 14 countries continue to spend the same proportion of their GDP on medicines as they do now (and if their GDP grows as we have projected), the global pharmaceuticals market will be worth about $800 billion in 2020, and the E7 countries will account for about 14 percent of sales.” Simon Friend, PwC’s Global Pharmaceuticals Leader, confi rms that this view has not changed. “The industry has been in a watershed mode for the past few years, and to some extent is starting to work its way out of it. But there are huge pressures on it from a number of different angles, and the most critical or fundamental is, where are the new products coming from? “Compounding the pipeline issue, you’ve got patent expiries. We predicted two years ago that $157 billion of sales would come off patent by 2015. We’re now some way into that. It’s very real and companies are struggling to work their way through it in the absence of significant new products coming through.” These challenges are forcing pharma companies of all sizes to change their business models – exploring the potential of generics and how to leverage the biotech space, for example – and one of these new models, perhaps the most important one, is expansion into emerging markets. Ann Brady, Vice President of New Market Development for Shire, confi rms that her company is moving in this direction. “The traditional model within 35

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Mark Rothera is Vice President for Europe, the Middle East and Africa for Shire’s Human Genetics Therapy business.


Mazen Darwazah is Vice Chairman of Hikma Pharmaceuticals.

Jostein Davidsen is General Director for Nycomed Russia-CIS and Senior Vice President, Nycomed.

Ann Brady is Vice President of New Market Development for Shire.

pharma has been dominated by Western developed markets, treating Western diseases. In recent years we’ve seen a trend for big pharma, as they have come under pressure with regard to patent expiries and a lack of pipeline, to move commercialization activities beyond the developed markets.” Shire is a specialty biopharmaceutical company focused on helping people with serious diseases, wherever they are in the world. Brady continues: “The world is becoming more connected and as an industry, we do need to look at global development, and specifically for Shire, that’s where we are directing our business. We’re looking beyond just what will service the developed Western market.”

Dealing with diversity It’s one thing to say you’re moving into emerging markets, and quite another to deal with the practicalities involved. The seven countries that make up the top of the emerging market list are obviously vastly different from each other in terms of geography, population, culture and political situation. There is no such thing as a generic ‘emerging markets policy’ – each country requires its own specific plan, which brings with it its own challenges. How then, does a company choose which new market to invest in? As Nycomed’s Jostein Davidsen points out, the top 10 companies will most likely invest in all of them, while for mid-sized and smaller com-

Simon Friend is Global Pharmaceuticals Leader, PricewaterhouseCoopers.

panies, it’s often a matter of history. “It has to do with the history of the different companies, the history of Nycomed being, for example, active in the Soviet Union for 20 years. We had a footprint there from an early stage and we automatically built on that. “When it comes to countries like Turkey or Mexico, if you were not there in the early days, maybe you’re reluctant to go in later. It will cost much more, of course, and in some of these markets you may well have to go in and acquire local companies, only by that time there is not much left to acquire, so it is much more difficult.” As General Director for Nycomed Russia-CIS and Senior Vice President, Nycomed, Davidsen has been involved with the company’s operations in the country since the Soviet days, and has seen the region rise to play a key role in Nycomed’s growth strategy; so much so that the current aim is to have Russia-CIS represent 38 percent of the company’s growth in 2013. That doesn’t mean there won’t be challenges along the way, as Davidsen explains: “Entry costs are high, although there is relatively less expense on the registration of products and on clinical trials. But office premises are much more expensive here than in other parts of Europe, and the cost of media campaigns and TV campaigns for over-the-counter products has risen dramatically. And then are unforeseen events that can have a negative impact.” Unforeseen events are indeed a potential downside of moving into any new market, but particularly so in markets where the political situ-


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ation or other factors may be unfamiliar to the investing company. As Mazen Darwazah, Vice Chairman of Hikma Pharmaceuticals, puts it: “You need to understand the local culture. Often, when you’re a multinational company, you think globally and you act globally. Working in this part of the world you have to think globally and act locally. “You have to understand the barriers of entry. You have to understand the perception that the healthcare community has in a particular country, so you have to work with them on the basis that these are local requirements in terms of dosage forms, pricing and delivery of goods. “You also cannot work in a country, and then when there’s a crisis or a civil war, leave that market. This is what happened for example in Algeria, when there was a civil war and all of the multinationals left. You cannot go into a market in the good times and leave when there’s a crisis. You have to stay in a long-term partnership.” Hikma started out as a Jordanian company 32 years ago, so its perspective is a little different from that of European or US-based companies. Having concentrated on the immediate surrounding markets of Lebanon, Syria, Iraq and Saudi Arabia for its fi rst 10 years, the company then expanded into other parts of the Middle East and further afield, and has a presence today in 42 countries in 18 markets. Th is history of moving from an emerging market outward rather than the other way around has given Hikma an interesting insight into the complexities of doing business in different parts of the world, as Darwazah explains: “Egypt, for example, is a $2.2 billion market, while Bahrain is a $40 or $50 million market. To make a fi le for registration for a product takes the same time in terms of preparation for both countries. You cannot say, ‘I want one fi le for all the Arab countries.’ It’s an accumulation of the registrations and an accumulation of the time that you spend in countries where you get your market share and you gain your footprint in those markets.” PwC’s Simon Friend points out that this tremendous variation is not something that is unique to emerging markets: “The reality is that this is also the case in developed parts of the world: the US market is very, very different from the markets in Europe, for example. It may be changing in the US at the moment, where you will end up with a much greater percentage of the industry being funded by government, but right now US healthcare is still largely private, whereas in the UK and other economies, it is very heavily a government-funded market. “The other thing to bear in mind is, who is actually buying? That is transforming the way in which the sales and marketing functions are

being designed for the future, away from the traditional model of going out to the physicians and leaving samples. “The influence of physicians has declined, because the buying process is becoming increasingly binary. You need to get to the payer and get behind the payer’s mindset and understand what the payer’s economics are. And that applies equally in the emerging and the developed world; you need to know who are the real influences and what sort of sales forces you need in the future. “One of the interesting things for domestic companies in countries like India, China, Brazil and Central Eastern Europe is that the best thing they can do is not to follow the western model. If the view is that the western model is broken, why would you try to replicate it?”

Looking for advantages Given the number and nature of the challenges involved, you may wonder why companies would bother moving into emerging markets at all. The benefits do, however, outweigh the challenges. “Those markets are becoming increasingly attractive in a number of different ways,” 37

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says Friend. “Emerging markets are playing a pivotal role in how established companies will move forward and in their growth potential for the future. Part of that is in terms of where the money sits, and if there is a growing purchasing power in some of these emerging markets there in itself lies a market potential. That’s why companies are looking to build their footprints in those marketplaces, where the demand for branded drugs will start to increase in the same way that it has done in the developed world. “Equally, there are other significant opportunities in emerging markets from an industry perspective – whether it is around the further development of new products, or establishing manufacturing, R&D or other facilities. These environments are increasingly attractive because of the skill sets that exist there, and the speed at which they can accelerate and get to market. “There are still concerns about the infrastructures in place, about the IP considerations and about the ability to properly establish compliance and regulatory standards in these areas, which will require proper monitoring and resources to ensure that companies are not exposing themselves to undue risk.” Friend cites the rise of homegrown companies in these markets as the force behind regulatory and in-

frastructure improvements that may help to draw the big international companies in: “The domestic companies are building and growing and establishing themselves in the larger world. They’re no longer small offshoots. They’re starting to become well-established companies with well-established products that are competing against others in the more developed environment. “The infrastructure that is starting to be put in place to support domestic companies provides great support for the Western companies to come in behind and have a more security around what is happening. For example, in India where they put in new IP legislation in 2007 or 2008, the issue there around policing it is still exists. Does that mean you wouldn’t go there? I don’t think it does. What we’re seeing with many companies building a presence there, is that you just have to go in with your eyes open. “In China, we know that from a counterfeit perspective, the authorities are working hard and have identified the pharmaceutical industry as one where they need to ensure that the IP is protected. They are taking steps in the right direction.” These potential pitfalls will not be enough to stop the industry’s major and niche-market players from making the move overseas. Shire, for one, has set itself a goal that will be driven by expansion into non-traditional markets: it aims to be the most valuable specialty biopharmaceutical company in the world by 2015. “An important part of achieving that goal is the diversification of our revenues across a bigger geography globally,” underlines Mark Rothera, Vice President for Europe, the Middle Opportunities for orphan diseases East and Africa for Shire’s Human Genetics Therapy business. “Th is means not just the Mark Rothera, Vice President and General Manager revenues that we’re generating, but the qualfor Europe, Middle East, and Africa for Shire Human ity of those revenues and the sustainability of Genetic Therapies, explains how specialized therapies them that will build value.” are making inroads into new markets. “We have a broad ‘rest of world’ defi nition,” adds Shire’s Ann Brady. “Today our revThe division that I’m in is specifically focused on very rare diseases, enue base is very heavily weighted to the US, and we’re very much involved with products that benefit from the the orphan and we need to diversify that. We need to look drug legislation, where you’re looking to bring products to market for a very small in geographies beyond the US, Canada and the patient population as compared to some of the broader specialty products. major European markets. Our defi nition is exIn this context, it’s interesting to look at the Europe and Middle East and tremely broad in that it encompasses Central Africa arena, because of the enlarged European Union with 27 markets, and the and Eastern Europe, Latin America and Asia fact that there is this umbrella intention related to the orphan drug legislation. Pacific. So we have a huge opportunity to inCountries in the Central and Eastern European regions that are now part of the crease our presence in many of the developed EU are looking to adopt some of the practices that Western European countries markets within this ROW defi nition. have had in place for a while. This includes the implementation of rare disease “In addition, the traditional emerging plans for those countries, and the opportunity is for patients with these rare markets are a significant component of our diseases to have access to premium-priced but very innovative and very targeted ROW activity. As a business, we will be tarproducts for these conditions. geted in our expansion here. We’re not saying Places like Poland and the Czech Republic and others within Central and we’re going to every one of these markets, and Eastern Europe are playing an increasingly important role. We’re also opening nor are we saying that we are going to invest up in Turkey and we have an office in Russia. These are countries where it is also directly in these markets. We need to target possible to bring in premium-priced products for very rare disorders, where the our rollout into new geographies on the basis health authorizes are willing to entertain that for a small patient population set. of our portfolio and how we may best optimize value for our global business.”

The global pharmaceuticals market will be worth about $800 billion in 2020


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Nycomed’s Davidsen also foresees emerging markets playing a big role in his company’s future. “In terms of Russia-CIS, we have a tough year behind us in 2009,” he explains. “Russia was very negatively affected by the global fi nancial crisis – GDP was minus nine percent. It is expected that this year we will achieve a GDP of between one and three percent. The oil price is helping here, and, of course, any industry in Russia is very much dependent on macroeconomic elements; much more than in any other Western country. Many things are oil-price dependent, which is now looking much more stable. “The prediction for the Russian pharma market is that we will have slight growth this year. The challenging factors for this market are the state regulations and the new laws related to medicine and the price regulations that are in the later draft stages, about to be accepted and decided in the national assembly and signed off by the president. We don’t know exactly what the impact of these regulations will be, but again it is a major move toward a more regulated marketplace. “Nycomed is also strong in some Latin American and South American countries like Brazil, Argentina, Mexico and Venezuela. We are also looking at China, and attempting to get a better foothold in India and in Asia, although for the near future, Russia-CIS and Latin America will play the most dominant role.” Despite the challenges involved, it seems clear that increased pressures on pharmaceutical companies at home, combined with the attrac-

E7 countries The seven major emerging economies as defined by PricewaterhouseCoopers, with their predicted economies in 2050 (US$) People’s Republic of China: - 70,710,000,000,000 India: - 37,668,000,000,000 Brazil: - 11,366,000,000,000 Mexico: - 9,340,000,000,000 Russia: - 8,580,000,000,000 Indonesia: - 7,010,000,000,000 Turkey: - 3,943,000,000,000

tive earnings potential of emerging areas, will drive further investment into these new markets. After all, according to the forecast by PwC’s ‘Pharma 2020’ report, in 10 years’ time, the E7 emerging economies will account for 20 percent of sales in the $1.3 trillion pharmaceutical market. Any company worth its salt won’t be able to sit back and let that opportunity slide away. „

Europe vs the US Do European companies have an advantage over their US counterparts when it comes to seeking out new markets?

Mazen Darwazah, Vice Chairman of Hikma Pharmaceuticals: European companies sometimes are more flexible in terms of their size. The MENA market, for example, represents only two percent of the dollar value of the final market worldwide, and it’s divided into 18 different countries, so it’s very fragmented. If you’re a very big company and you want to go into this market, you have to decide whether it’s worthwhile investing and putting in all that infrastructure. European companies tend to be smaller and they know how to work in small markets, where big companies may work better in bigger markets. This’s why we’ve seen more European companies in this part of the world than American companies. That’s the basic difference, and because the US market is currently 40 percent of the dollar value of the world market, why should they spend time on a two percent dollar market when they have a bigger market in their own backyard? Jostein Davidsen, General Director for Nycomed Russia-CIS and Senior Vice President, Nycomed It’s difficult to say. Historically, when it comes to Russia-CIS, in Soviet times there were no American companies active here at

all. There were mostly European companies: German, French, Italian. European companies still have perhaps a closeness to this emerging market. Today, of course, all the big US companies are here and they have had good business development over the years. But I think that in the Russia-CIS marketplace, the European companies have an advantage in being a frontrunner because of that history. Simon Friend, Global Pharmaceuticals Leader, PricewaterhouseCoopers I don’t think one can draw any particular conclusion that a US-headquartered company is at a disadvantage from a Europeanheadquartered company, because they’re all pretty global in outlook and approach and have footprints all over the place. If you’re moving into a new market and you’re leveraging relationships there, the more fundamental issue is, do you trust the people you’re working with? You only need to get burned once or twice before you think, ‘I’m not going to go there. I’ll go somewhere else.’ The more an environment becomes developed and the more experience a company has in building trust there, chances are that if that trust is built, it will go back. 39

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Joe Miletich tells NGP why it’s more important than ever for pharmaceutical R&D to pursue the highest levels of innovation.


oe Miletich is clearly a man who loves his job. His enthusiasm shines through as he talks about his current responsibilities as Senior Vice President for Research and Development at Amgen, and also when he talks about his past positions. Miletich certainly boasts a varied career background: after completing an MD and a PhD in molecular biology at Washington University, he trained in internal medicine at the University of California, San Francisco, then went back to Washington University where he was a faculty member for 18 years. In 1999 he moved into the pharmaceutical industry, taking a position at Merck in the toxicology group before heading up the company’s worldwide pre-clinical development. Miletich joined Amgen in 2002, and for the first four years was responsible for discovery research all the way through the first introduction of medicines into people. Since 2006 he has focused on translational medicine. To top it all off, he is also a board-certified clinical pathologist. This wealth of experience should come in handy as he shepherds Amgen’s R&D through what are shaping up to be some turbulent years for the industry. Like most top 20 pharma companies, Amgen rode the wave of blockbuster success in the late 1990s and early 2000s, but now finds itself staring at the twin threat of patent expiries and a lack of big earners coming out of the drug pipeline. Amgen’s answer is to “reignite” its innovation engine. But what does this actually mean? In its broadest sense, any change can be labeled as innovation. As Miletich points out, you’re not going to get very far by doing things the same way they’ve always been done. In this way, innovation is essential to a company’s survival.

things that are acting against that larger goal. The first is a fear of being reckless and having an insufficient regard to safety; and the second is a concern about how we are going to pay for it, because it’s very costly to be this innovative. “The only reason people might be reluctant to be highly innovative now is because of a worry that we’re at a temporary phase where the concerns about safety and reimbursement have become so prominent in our thinking that what we would normally expect as rewards for innovation might not be there.”

Against the odds Miletich believes it is more important than ever to be innovative in the current climate. He underlines the obvious fact that discovering and developing drugs is a long-cycle business: the time from an original idea until a drug reaches the market might be 12 or 15 years. Companies work constantly to reduce that time, yet at the same time ever more stringent safety and efficacy requirements act to increase it. He remains optimistic, however, that the need for innovation will win out in the end. “In the long term,” he says, “what we fundamentally need as a society and human beings will prevail and the truly innovative things will be rewarded. When you think about this as a long-cycle business, as a company we need to pay attention to that and bet heavily on it.

This is an unusual time to be in the pharmaceutical industry: our fears and concerns are at a peak at the same time that our hopes and aspirations are also at a peak His definition of the term ‘innovation’ as it is used in the current context of drug discovery means not just bringing in change but bringing in change at a very significant level: changing the practice of medicine and changing what people understand and believe about what can be done in disease conditions. “That’s the highest level of innovation when you’re in the drug discovery and development business,” says Miletich. “You want to change the way people think about a disease and make things possible that weren’t possible before. “I think society truly wants our industry to focus on the highest level of innovation, but in our current climate there are a couple of

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“That doesn’t mean we won’t do anything that isn’t the most highly intranslate that original idea. You also have to understand how to make a molnovative thing we can think of. There are very practical benefits to being inecule at large scale, how to formulate it and what the attributes are that will novative on a less expansive scale, and we do make improvements to become important in human biology, and how you would recognize if you medicines. We’ve done this in the past, and we’ll continue to do so where it needed to change something. brings benefit. “You have to incorporate all you learned from your pharmacokinetics “It’s all in how you weight your portfolio. We weight our portfolio so that and drug metabolism studies to know and appreciate the characteristics of roughly two-thirds of what we’re doing are highly innovative things. those molecules and how they behave, and you certainly have to unIt’s a conscious choice. We make the choice to do that and then derstand all of your toxicology assessments so that you can set ourselves up so that we can find people in our own reclearly make a weighted judgment about what risk you will MORE THAN search labs and in all the connections we make with small expose patients to and become very convincing and fluent companies and with academic collaborators around the and provide appropriate scientific evidence about the world – find those innovative insights that will help safety factor that you’re employing when you embark on change the practice of medicine.” those experiments. PATIENTS HAVE A major focus of Miletich’s role at Amgen is to over“Even more than all of that, when you integrate RECIEVED AN AMGEN see the translation of drugs from discovery through early your learning from all of these different sciences that go MEDICINE stage clinical trials. He points out that at Amgen, translainto what molecule you want to make and how it performs, tional medicine is not limited to early clinical trials and bioas well as what actually happens when you do this in biology, marker research. you can learn a great deal more. You can learn a great deal about “Of course we have a terrific medical sciences group that places an enorhow things work in the human body.” mous emphasis on biomarkers and we concentrate on our experiments in Miletich and his team work to integrate the different sciences needed to people to discover whether that fundamental idea that we started with back move a candidate molecule forward and develop it with the optimal properin the research labs actually does have enough impact in human biology to let ties for a potential human therapeutic, in order to learn as much as they can us change the practice of medicine. about what goes on in human biology and to carry out the most informative “But that’s not the only thing that’s important when you’re trying to experiments. They then use that information to make judgments about how



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to weight the portfolio and where to make the investments that are the most likely to pay off with the greatest benefit to people.

Forging ahead Producing breakthrough drugs that radically change the way we look at disease might be every R&D team’s dream, but what about the challenges in bringing that drug to market? Only about one in every 10 drug candidates that enter clinical trials are eventually approved by the FDA, and the cost of all these failed drugs is another major challenge for the industry. How can pharma companies raise their success rates and cut down the amount of money spent conducting trials for drugs that never come to market? “Companies may understandably try to reduce drug discovery and development to a methodology that can be repeated for project after project,” Miletich says. “There is great efficiency in doing that so you don’t relearn how to do things, and we do that when it is appropriate as well and have no qualms about it. Where things are repetitive and we can learn to do them in a repeatable, efficient fashion, we do that at every opportunity. “Every one of these innovative projects, however, is a new adventure. It’s a pioneering discovery, and in order to optimize how much you can do with the resources you have you need to make decisions all along the way about what your level of investment is going to be. “That means that when you integrate all this information that’s coming in in real time as you’re in this early stage of drug development, you should have a sense, if you’re paying attention to all the information you have, about

what your likelihood of success is, and about what your potential for doing good in how many people might be. My firm belief is that you should adjust your investment to those opportunities as you see them in real time. “You don’t just set up a drug discovery and development organization and turn a crank. You learn how to turn the cranks very efficiently where it’s important, but you continuously review your portfolio and continuously monitor what the opportunity actually looks like relative to your original idea and adjust your investments accordingly.” Miletich says that when this is done well and a good stable of candidates is selected at the very beginning, a fraction of these emerge quite early as having very promising characteristics. These can then be invested in heavily and pushed aggressively and quickly, thanks to the conviction that this drug should be developed and made available as fast as possible. “With some, another fraction, you find the idea simply wasn’t good enough or your molecule wasn’t good enough, and when you find that early you can stop that investment, rethink what you want to do, and see if there’s an adjustment you can make. Then there’s a group in the middle, which can encompass 40-50 percent of the molecules, where you discover that there’s something else that you need to understand before you can gage the value of the opportunity. For these candidates, you adjust and modify your investment and decide what that next piece of information is to allow you to make a decision about whether it’s worth investing in or not. “You have to manage this portfolio in a very dynamic way. When you do that, you’ll increase your overall success rate, and you’ll increase the efficien- 43

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cy of the resource base you use. I’m optimistic that in another five or six years “Fractures there can often be problematic, not healing adequately or takwe will be able to point back and say it did result in an improved success rate.” ing too long to heal. We’re investigating AMG-785 to see if we can improve Although Miletich makes this process sound quite straightforward, in rethe speed or quality of healing in that setting.” ality it is anything but. He explains that for a typical project at this stage there Amgen has a large number of therapeutic candidates in phase II trials in can be as many as 1000 different work streams. His oncology, as well as a portfolio of molecules being team could be working on 30, 40, or 50 different studied in a variety of inflammatory and autoimprojects and many of those work streams are intermune diseases, including an extensive program of Happy anniversary connected, so that one that’s about to begin depends molecules in asthma. The company recently licensed In 2010 Amgen celebrates its 30th on the results from another one that has just been a molecule from Cytokinetics and is studying paanniversary, having been completed. This makes managing this resource base tients with severe congestive heart failure to improve established as a corporation on in real time an incredibly complex project manageheart function. April 8, 1980. Since then, the ment task. “We’ve also recently introduced an antibody company has grown to become one called AMG-145, which helps us lower cholesterol of the world’s leading independent On target levels in patients that can’t otherwise reach target,” biotechnology companies. The use of biomarkers is often touted as an esMiletich says. “We’re in phase I studies with that sential weapon in this struggle to cut waste by enmolecule. So we’re making some meaningful ven• More than 17 million patients suring more drugs hit their targets, but Miletich is tures into the cardiovascular arena, again where we’re have received an Amgen quick to point out that biomarkers are not magic using mechanisms that have never been explored in medicine bullets. “Biomarkers are just tools,” he says. “They human biology, to do things in ways that were never • The company has a presence in allow you to gage whether you’re doing what you possible. We continue to have new efforts in dianearly 50 countries wanted to do and whether it’s as impactful as you betes, such as the deal we concluded in December • Its focus is on discovering, wanted it to be. with Array BioPharma to license their glucokinase developing and making human “Sometimes when people talk about biomarkactivator, which is a very promising molecule that, if therapeutics ers, they make it sound as though they can solve all it is successful, will allow treatment of diabetes in a • It specializes in innovative our problems, and that it’s the biomarkers themnew and meaningful way.” medicines for serious illness and selves that are important. But in fact the important When asked how he sees pharmaceutical R&D is a pioneer in protein thing is deciding what you want to do, what your developing over the next couple of years, Miletich therapeutic manufacturing idea is, whether it works and whether it is impactsmiles, and calls it an intriguing question. “In one ful. Biomarkers help you determine whether you’re sense if you take the pulse of the industry, there are doing that or not, and you have to have a full toolset pressures there that are unprecedented: concerns of biomarkers to do that. around safety, around reimbursement, around the “One of the things that might not be evident to productivity of the industry as a whole. people who aren’t familiar with the business is that “At the same time, from someone in my position while in human medicine we have a large number the prospect of doing important things for patients of tests that are available through physicians and who suffer from grievous illnesses has never, ever hospitals and we have a lot of imaging tools, those been better, and it feels like a very unusual time to be tools, assays and tests were developed for very spein the pharmaceutical industry: our fears and concific purposes and often don’t answer the questions cerns are at a peak at the same time that our hopes we’re asking now. and aspirations are also at a peak, and no one knows “So we have to set up new assays, new tools, new tests, and we have to unhow this will play out. derstand how they perform in populations of people. All that work has to start “If you look at previous examples of how humankind has reacted in other very early on because it can take years to set up. Our goal is to always have situations that are even remotely parallel to this, I would say that there will be those tests and assays in place by the time we are ready to do that experiment tremendous advances, and there will be some things that we can’t predict that in people.” will take place in ways we can’t foresee. My guess is that some time over the All of this hard work has resulted in some interesting drug candidates next 10 years we might see some consolidation in the industry, but we’ll also moving through Amgen’s pipeline, including an osteoporosis drug known as see some winning scenarios emerge out of the next four or five years of effort. AMG-785, which is now in phase II trials and about which Miletich is very Those companies that are nimble and can adapt and that aren’t afraid of the excited. “We’re investigating AMG-785 along with our partner UCB, to find opportunities will manage to be highly successful even though there are great out what dose and schedule of this new therapeutic will enable us to restore a concerns about the pressures on the industry at the moment. good level of baseline bone health to women with moderate to severe osteo“I hope, and will work diligently with all of my colleagues here at Amgen porosis, and we’re also studying it in a phase II trial where we’re looking at to ensure, that we are one of those companies that emerges with the success very hard-to-heal fractures. In particular, we’re looking at fractures that haprate that’s necessary to move on to even greater things.” n pen in the tibial plateau, the top of the lower leg bone. Joseph Miletich is Amgen’s Senior Vice President for Research and Development.



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In a time of shrinking budgets and constrained resources, the ELN is helping life sciences R&D groups of all sizes do more with less. Scientists with whom we are working claim a 20 percent increase in productivity is through efficiency gains in experiment setup, calculations, planning and documentation, along with the ability to find information instantly and ‘clone’ previous experiments. Most importantly, deploying a single ELN across many disciplines – and the entire R&D spectrum – improves R&D productivity by letting all scientists collaborate in an orchestrated workflow process. Given the shifting priorities within today’s R&D environment, a rapidly deployable, highly configurable ELN also provides the operational flexibility to start new projects, define new processes and transfer resources rapidly and easily.

Deployment and collaboration R&D organizations have traditionally relied on a conventional license-based soft ware model for acquiring ELN applications, but today’s economic and competitive pressures are leading many organizations to consider a new model in which the ELN is hosted offsite and accessed as a subscription-based service online. Under this model, all that scientists need is an internet connection and a password to gain instant access to a shared ELN that is fully supported and maintained by the supplier. The hosted ELN is a great option for small and mid-size life sciences labs, biotechnology companies and academic project teams. They do not have to purchase expensive soft ware licenses or manage extensive server banks with security, redundancy, data backup and maintenance. They also do not have to support resource-draining system administration teams and the change control documentation required by system auditors. How an online hosted ELN helps scientists do The research expenditures required to carry out specialized testing in today’s market are burdensome. As a result, to reduce costs and more with less in the lab. By John McCarthy shorten the path to more robust, promising pipelines, life science teams of all sizes are partnering with ife scientists and lab managers are increasoutside organizations that offer specialized expertise. ingly embracing electronic lab notebooks In essence, this move to collaborative outsourcing is (ELNs) for many reasons. First and foreenabling labs to do more with others. most, today’s highly configurable ELN The hosted ELN is especially valuable in supsupports the diverse needs of the many porting transparent partner engagements. When a life science disciplines that must collaborate to bring partner performing initial screening or animal studies small molecule drugs and biologicals to market, and for an R&D lab returns its results in a shared, hosted the right ELN does this without requiring expensive ELN environment, the R&D lab doesn’t just receive a customization. The ELN has proven itself vastly supespreadsheet of data. The lab also accesses the protocol, rior to the paper notebook as a truly effective tool for semethodology, sample preparation and other related incurely documenting the design, execution, analysis and formation used by the partner, thereby gaining a much reporting of experimental information in the context of broader and deeper view into the overall context of the John McCarthy is VP Product researchers’ workflows. Furthermore, centrally accesoutsourced project. By linking into a shared, hosted Management Strategy with Symyx’s software business unit. sible and searchable notebook repositories enable life informatics environment, multi-disciplinary virtual Symyx electronic laboratory notebook, decision support, scientists to share information and improve experiment teams can quickly and easily access the same informascientific database and hosted design by taking advantage of their colleagues’ insights. tion, use the same methodologies and work together informatics offerings give researchers immediate access to Today’s ELN consolidates experimental data, reduces more effectively. „ critical workflow applications and information. Symyx powers R&D errors, enhances workflow productivity by driving laboratories with information consistent processes, simplifies regulatory compliance, that generates insight, enhances For further discussion, please see our longer online article on collaboration and drives today’s flexible ELN for multidisciplinary life science teams at protects intellectual property (IP) and drives collaboraproductivity. For more information about the company visit, tion within and across labs.

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Real-time data for manufacturing Craig Dobbs describes definitive technologies for PAT and QbD initiatives. Of all of the analytical techniques that are currently applied as process analytical technology (PAT) tools in solid-dosage manufacturing, why is liquid chromatography of particular importance in drug development? Craig Dobbs. Several analytical techniques can be used in PAT – liquid chromatography, mass spectrometry, near infrared spectroscopy and Raman spectroscopy to name a few. Th roughout a therapeutic compound’s lifecycle, liquid chromatography (LC) is the only advanced analytical technology that is routinely used in every phase of the process: in discovery, research, development, manufacturing, qc/release and post shipment stability monitoring. The amount of meaningful information produced by LC systems during this process is nothing less than a gold mine of data. It is imperative that such LC analytical data is secured, easily archived and searchable, can be quickly cross-referenced and overlayed, and is instantaneously available to support decision-making processes. The concept of a long-term, historical database focused specifically on full characterization of a therapeutic molecule is at the central core of the USFDA’s

laboratory to monitor reaction progress, or to specifically measure individual parameters like IPM purity or concentration. During a single in-process LC analysis, a remarkable breadth of information can be extracted: raw material consumption, IPM purity, IPM concentration, even the presence of low-level or trace concentrations of impurities can be measured and quantitated down to 0.01 percent. If a trace compound negatively impacts a critical quality attribute of the IPM, LC is the ideal technology for monitoring its presence. Leveraging all of this information is critical to understanding where your process is relative to the defi ned design space within a QbD strategy. Are there limitations in applying traditional LC as a PAT tool? CD. What generally keeps traditional LC from being adopted directly onto the manufacturing floor is that it simply takes too long to generate a result. LC may produce data with unrivaled breadth, specificity, sensitivity and accuracy – but off-line QC Lab sample-to-answer times are typically in excess of four to six hours. That reality is rapidly changing. With new at-line and on-line analytical LC tools, manufactur-

“In the current Six Sigma environment of manufacturing, facilities are constantly searching for process improvements to drive overall efficiencies and productivity” Quality by Design Initiative (QbD). LC is the single analytical technique that supports QbD by consistently producing the same type of easily referenced and interpreted data from anywhere in a drug product’s lifecycle. The manufacture of an active pharmaceutical ingredient is invariably a solution phase based process, which is the ideal sample matrix for LC analysis. Analytical LC testing of inprocess material (IPM) is routinely performed today in an off-line manufacturing QC

ers can make a measurement, generate information and make a decision in real-time or in less than five minutes. Real-time LC capability was realized in 2004 when Waters Corporation introduced UltraPerformance LC, or UPLC technology. The ACQUITY UPLC System was the market’s fi rst real-time LC, followed by ACQUITY UPLC H-Class System for easy LC to UPLC migration in discovery and development labs. UPLC technology now extends to automated direct on-line and at-line IPM

As a Senior Manager for both Biopharmaceutical Business and Process Analytics at Waters, Craig Dobbs partners with industry experts to develop technology solutions that address process analytical needs in manufacturing, as well as in the development of biotherapies.

analysis on the manufacturing floor with the PATROL UPLC System. PATROL UPLC is the first and only real-time LC system specifically designed for this environment. How can PATROL UPLC technology address manufacturing business pressures? CD. In the current Six Sigma environment of manufacturing, facilities are constantly searching for process improvements to drive overall efficiencies and productivity. Because of the throughput challenges that LC presents as described above, as well as resource and cost issues, the technique is not usually considered an appropriate candidate for manufacturing floor deployment. Realizing these limitations but desiring the many analytical benefits of LC, the PATROL UPLC System began as a collaborative effort between Waters and a major pharmaceutical company to deliver real-time speed, sensitivity, specificity and accuracy to the manufacturing floor, with a focus on making it reliable and rugged with a simplified operator interface appropriate for the environment. The flexibility and automation engineered into the system was implemented to address existing SOPs, provide a continuum of real-time UPLC technologies across the entire drug development cycle, and convert a once considerable manufacturing bottleneck into a competitive advantage. „ For more information on the PATROL UPLC System, visit


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Understanding emerging markets Andrew Thompson shares his thoughts on preparing for success in emerging markets.

As economic, demographic and social changes sweep through the developing world, pharmaceutical companies are looking beyond the leading industrial nations (the ‘G7’) to the growing potential of emerging markets. What is the potential for pharmaceutical products in emerging markets? Andrew Thompson. PriceWaterhouseCoopers estimates that the GDP of the ‘E7’ – the seven major emerging countries that include Brazil, China, India, Indonesia, Mexico, Russia and Turkey – will triple over the next decade, and by 2020 could account for close to 14 percent of a projected global pharmaceutical market of $800 billion. Further, disease profi les in emerging markets are evolving to more closely resemble those of developed countries, shift ing from infectious disease control to management of more chronic conditions such as cancer, diabetes and respiratory and cardiovascular disease. According to the World Health Organization, in the US only 12 percent of deaths from cardiovascular disease occur in working-age people, compared with 28 percent in Brazil, 35 percent in India and 41 percent in South Africa. There is a growing market for products that address unmet medical needs in these countries – and those that also enhance therapeutic benefits such as dosing regimens and targeted dosage forms (such as via drug delivery technologies) greatly increase the potential for commercial success. Pharmaceutical companies seeking to market their products in the first world generally face a stringent approval process. How does the regulatory environment in emerging markets compare, and how can companies prepare? AT. Generally, regulatory dossiers such as a US Food & Drug Administration (FDA) approval or a EU Certificate of Pharmaceutical Product (CPP) meet the standards of developing countries, and could over time become the benchmark for regulatory approval in emerging markets. With more than 20 products sold in

over 50 emerging countries since 2002, Eurand has demonstrated success and experience in providing technologically advanced products to partners addressing unmet medical needs in these markets. Eurand’s successful record with the FDA, including recent approval of several products, has resulted in strong data packages that can help streamline registration timelines for these partners. The launch of a once-daily formulation of the muscle relaxant cyclobenzaprine in Korea in September 2009, for example, came just 17 months after finalizing the

Despite increasing similarities to the developed world, emerging markets present their own unique challenges. What other considerations must companies make before planning to enter an emerging market? AT. Review of emerging markets is a very dynamic process, and perceptions and direction can often change. Companies seeking to succeed in these markets must be armed with substantial information, prepared to create local partnerships for the long term, and willing to be flexible and creative in their planning.

“Disease profiles in emerging markets are evolving to more closely resemble those of developed countries, shifting from infectious disease control to management of more chronic conditions” licensing deal with a major local pharmaceutical company, Daewoong, in April 2008. Approved by the FDA in 2007 and marketed in the US by Cephalon as AMRIX (Cyclobenzaprine Hydrochloride ExtendedRelease Capsules), the product uses Eurand’s Diff ucaps technology and reduces the need for patients to take multiple daily doses of cyclobenzaprine while improving the safety profi le and tolerability of the drug by reducing the levels of somnolence associated with the standard immediate release (IR) drug formulation. In addition to Korea – a pharmaceutical market that increased 8.5 percent from 20072008 – Eurand has also fi nalized deals with local companies to market cyclobenzaprine ER in Turkey, South Africa and Israel, where growth over the same time period was 12.9, 7.8 and 5.3 percent, respectively.

Eurand’s experience has led to the development of an intensive process for assessing each market, working closely with local partners to leverage their understanding of market dynamics. Key factors in this process include assessment of the region’s healthcare system, trading environment and taxation issues; the local competitive landscape, therapeutic class analyses; as well as a review of regulatory, pricing and reimbursement practices. With the right information, the right products and the right partners, companies that make the investment now can successfully tap into the great potential of emerging markets. „ Andrew Thompson is Vice President of Commercial Operations at Eurand. He has 25 years of experience in international marketing and operations in the pharmaceutical industry, including increasingly senior positions at ICI Pharmaceuticals, Glaxo Wellcome and Spanish pharmaceutical group Almirall. In 2007 he joined Eurand, where he is responsible for the company’s pharmaceutical technology business outside the US.


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Lifespans and livelihoods In this address given to Town Hall Los Angeles in January, CEO of Eli Lilly and Company John Lechleiter looks at the human dimensions of medical innovation.


s we embark on a supposed fresh start in this new decade, we bring some baggage with us. We face immediate problems such as double-digit unemployment and fiscal crises at the state and federal levels, long-term challenges that include the rising costs of healthcare and retirement in an aging population, and growing pressures on the underpinnings of the American economy. Some pundits and prognosticators say America’s decline is inevitable. Of course, a decade ago, people predicted that Y2K would bring on the Apocalypse, and as we meet here there are always those predicting the ‘big one’ that will finally send a big chunk of California into the Pacific.


But I’m optimistic about our nation’s successful journey through the ‘teens’ and beyond, as long as we carry with us and safeguard the key to so much of our prosperity and health… and that’s innovation. It’s no exaggeration to say that innovation is the wellspring of California’s – and our nation’s – greatness. Whether cars or airplanes or rockets; or agriculture, computers or medicines; innovation has fueled unprecedented prosperity. California itself has brought the world the high-tech wonders of Silicon Valley – the ‘right stuff’ that fueled our aerospace leadership – green technologies, a booming biotech sector, and of course, the movies! At Eli Lilly and Company, we’ve staked our future on innovation. As healthcare undergoes radical transformation, we’re in the midst of the most

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sweeping changes in our company’s history, which involve a new structure and new ways to do R&D, all aimed at speeding the flow of new and better medicines to patients. It’s no exaggeration to say that every single day we’re intensely focused on cracking the nut of medical innovation. But I’ve learned that we also have to keep making the case for innovation, to sustain an environment where new ideas can flourish, where innovative solutions can make life better for everyone, where creative thinking is nurtured and invention is rewarded, which all raises the question: Why do I have to defend innovation? What’s not to like? It’s not that people oppose innovation, but they take it for granted – or unwittingly undermine the ecosystem required for innovation to flourish. I can tell you, based on the experience of a company that invests some $4 billion a year in R&D, that innovation doesn’t just happen. And the conditions must be right – starting with the essential aspect of a society that appreciates and rewards innovation. We tend to think of innovation in terms of technology, science, labs, but innovation is essentially the application of human ingenuity to improve human life. To fully appreciate innovation, we have to see and understand clearly its benefits for humankind. I want to draw your attention to those human dimensions of innovation. I’ll focus on bioscience innovation – speaking from the perspective of a research-based pharmaceutical company – but I believe my remarks will also apply more broadly to innovation of all kinds.

Transforming lives Let me begin with the first human dimension of innovation – lifespans. We’ve added a decade to lifespans in this country, just in my lifetime. Has there been any more important accomplishment in this period? A key reason why we’ve gained this extra decade is innovation. In fact, an independent study found that just one area of medical innovation – the launches of new medicines – accounted for 40 percent of the increase in life expectancy during the 1980s and 1990s. Indeed, throughout the past century, medical innovation transformed the basic expectations of human life that had prevailed since the dawn of civilization. More and more death sentences were lifted: think of antibiotics for infections, vaccines for conditions such as polio, and more effective treatments for a growing number of cancers. For example, the five-year survival rate for all cancers diagnosed between 1996 and 2004 is 66 percent, up from just 50 percent in the mid-1970s. More than 11 million Americans with a history of cancer are alive today. Other dread diseases became manageable chronic conditions, such as diabetes, heart disease and HIV/AIDS. Between 1995 and 2005, annual deaths from HIV/AIDS dropped 70 percent. And countless maladies barely under-

“We know when budgets are tight, there’s always a temptation to cut R&D. We also know that our future depends on innovation and we try to resist that temptation” stood or described in 1900 – things like severe sepsis, osteoporosis, schizophrenia and auto-immune disorders – are being brought to heel by medical interventions. Six years ago, my predecessor, Sidney Taurel, spoke to this forum on the social implications of longer lives. Sidney made the point that we’ve added not only to life spans but also to what some call “health spans,” that is, years of life without a disabling condition. This means more people who are active, engaged, working, contributing to social progress in myriad ways. We’re determined to keep this progress going. Today, America’s biopharmaceutical companies, including Lilly, have a robust pipeline of potential new medicines – nearly 3000 compounds in development, some 40 53

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percent more than we had 10 years ago. These molecules hold the potential to treat some of our most pressing unmet medical needs, and to increase ‘health spans’ even more.

Leading in biosciences There’s a second human dimension of innovation, the importance of which is on par with health – and that’s livelihoods. Just the one area of innovation I’ve been discussing – bioscience – provides good jobs to 1.3 million Americans. Bioscience is a 21st century knowledge-based industry paying an average salary of around $75,000. When most people think of Los Angeles, science might not be the first thing that comes to mind, but LA boasts one of the largest concentrations of bioscience employment in the country. A study by Battelle Memorial Institute, based on 2006 data from the US Bureau of Labor Statistics, counted 70,000 bioscience jobs in the Los Angeles metropolitan area. The study estimated that every job in biosciences supports nearly five additional jobs in the economy; so, with the multiplier effect, as many as 400,000 jobs in the LA metro area are tied to bioscience. Today the US biosciences sector leads the world. In fact, it is just the kind of knowledge-based industry we need to build our economic future. But leadership can be lost. Absent policies that maintain the right conditions for innovation to flourish, we risk losing our advantage and squandering our potential. The pursuit of innovation is a very difficult, very high-risk venture. If innovation is to take root and grow, it requires a combination of elements I referred to earlier as an ‘ecosystem’ – and I believe this is a good analogy. The first element of this ecosystem is an atmosphere in which innovation can thrive – the air and sunshine – a society that understands and appreciates

When compared with students in 57 countries around the world, US 15-year-olds rank 23rd in science literacy and 32nd in math literacy


scientific inquiry and innovation, and free markets where innovators can expect to be rewarded for the risks they take and the value they create. The second element – the nutrients for innovation – come in the form of monetary investments. For investors to take the risks associated with innovation, they must have a fair shot at earning a return if the work is indeed successful. That requires solid protection of intellectual property and a fair, rigorous and transparent system of regulation. In addition to better prepared teachers, we need to give them more support, beginning with curricular materials based on sound research. Lilly is supporting research by the National Science Resources Center – an affiliate of The National Academies and the Smithsonian Institute – to develop a handson, inquiry-based approach to teaching science in Indiana. And we’re working with I-STEM to improve science kits and make them available to teachers throughout the state. The third and most important element – the seeds of innovation – equate to talented people and their ideas. Ultimately, innovation grows from the human mind. So far, I’ve spoken of people as the beneficiaries of innovation, but it’s equally important to understand that we are the source, as well. We need to remind ourselves that human beings, with their talent and energy, their creativity and insights, are a priceless resource – but a resource that is woefully underdeveloped in this country, even as we congratulate ourselves for maintaining – still – the world’s largest knowledge economy.

Better education In keeping with my focus, I want to call attention to three policies necessary to allow these seeds of innovation – human talent and ideas – to take root and grow. Those three policies are: broad improvement in science and math education in our grade schools and high schools; immigration laws that allow and

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n important policy to promote innovation is immigration policy that allows and encourages top scientists to choose to work in the US. Let me explain why this is so important. In pharmaceutical research, only one molecule in 10,000 ever makes it to the market as an approved medicine. One discovery, one insight over the course of years can mean the difference between success and failure for an entire research program. So, just as we look for the most promising molecules, we also look for the very best scientists. Today, many of the top candidates are not US citizens or even permanent residents. This includes candidates emerging from US graduate schools – and, again, it’s not surprising in light of US science education. To stay and work in this country, skilled foreign nationals typically need H1B visas, but the number of those visas has been subject to impossibly low limits in federal law. Since Congress last raised the annual cap in 1990, US GDP has grown by nearly two-thirds, and the demand for skilled workers has risen commensurately. We’re not talking about big numbers. At Lilly – a top 10 global pharma company – we currently employ a grand total of 230 people in the US on H1Bs and other temporary visas; that’s about one percent of our US employee population. Yet those folks are vitally important. They account for a significantly larger percentage of our senior-level scientific work force, and they make vital contributions that otherwise would not be made. At Lilly, we’ve typically had success with only about 75 percent of our H1B visa applications, because once the low limit has been exceeded, we’re subject to a lottery like every other potential employer. And that’s not all. It takes an average of five years for the Lilly employees we sponsor for residency status to obtain a green card. This kind of delay causes a great deal of anxiety and uncertainly for prospective immigrants, including promotions and careers on hold, and significant difficulty traveling outside the US while green-card applications are pending. We believe that the uncertainty and frustration of the

encourage top scientists to choose to work in the United States; and a well-funded basic research infrastructure within academic and government labs. Let’s begin with science and math education. No matter how you look at the statistics, the United States is falling short, especially at the high school level. In international comparisons, American 15-year-olds perform poorly in science and math literacy. When compared with students in 57 countries around the world, US 15-year-olds rank 23rd in science literacy and 32nd in math literacy. And we’re not meeting our own goals for student performance in these fields. On the National Assessment of Educational Progress, only half of 12th graders are at or above a basic level of achievement in the sciences, and average scores for 12th graders in the sciences actually declined nationwide from 1996 to 2005.

immigration process are driving away prospective candidates before we ever see them. In fact, our nation is experiencing a trend where a significant number of talented foreign nationals who come to our universities and corporations simply return home, which is what you’d expect under these conditions. Whether or not Congress takes up comprehensive immigration reform, we must fix the policies that are driving away talented people who want to live here and contribute to our economy. This does not require drastic changes, just a sensible increase in visas for these highly skilled immigrants and a shorter, simpler process to get a green card. To those who argue that these immigrants are taking jobs

from Americans, I respond that they’re contributing to strong businesses that help create jobs and drive innovation right here in this country. According to the Wall Street Journal, between 1990 and 2007, 25 percent of US companies started with venture capital had an immigrant founder. It surely beats the alternative: talented people returning to their native country or going elsewhere to start or help a foreign firm to compete against us. You want a job-killer? That’s a job killer.

A recent review of science education ranked California – along with my home, Indiana – among states with what was described as “middling performance”. California is among relatively few states that showed improvement in science scores between 2000 and 2005. The ACT admissions test reported that fewer than one-third of students who took the test in 2008 were ready for college-level biology – both nationwide and in California. These kids are the future scientists we’ll need to discover new treatments and cures for our toughest medical problems. But, not surprisingly, the number of US students pursuing bachelor’s degrees in science, technology, engineering and math – the so-called ‘STEM’ fields – is far below what will be needed to meet future demand. Broad understanding of math and science is essential, first of all, so that young people across our society have an opportunity to participate in 55

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the high-tech economy of the future. Further, as the technology sector grows, the Baby Boom generation retires, and shortages emerge in particular fields, we will need a large cohort with basic scientific skills to prepare for these jobs. Meeting these needs will require continued significant attention to improving K-12 science and math education across our country, and I believe that both the public and private sectors must be involved. Let me cite just one key imperative: Better preparation and support for teachers in STEM subjects: teachers who know their stuff and can get students excited about math and science. In too many schools, teachers lack strong subject-matter knowledge in these fields. When I think about my own decision to pursue a career as a chemist, it was two devoted high school teachers who inspired me and put me on the right path. Yet even the best-prepared teachers too often lack necessary curricular support, beginning with materials based on sound research. To that end, Lilly is supporting an effort by the National Science Resources Center to develop a hands-on, inquiry based approach to teaching science in Indiana. President Obama recently announced a public-private initiative to improve STEM education, building on existing philanthropic programs to expand teacher training, and to place math and science teachers with advanced degrees in hard-to-staff schools. This is just what the doctor ordered. Ultimately, what we need is not an intensive program to produce an elite cadre of brilliant scientists, but a common effort as a society to develop whole new generations of Americans with knowledge and skills in math and science – a large pool from which great scientists and breakthrough ideas will emerge.


Research funding Another policy imperative is a well-funded basic research infrastructure within academic and government labs, through increased funding for the National Institutes of Health, the National Science Foundation and other agencies that pursue and support basic research, as well as the training of young scientists. Academic and government research has historically operated synergistically with the private biopharma sector, often supplying the raw material, such as insights on disease processes and leads on promising molecules, which industry works to translate, develop and commercialize. Real federal funding for research declined over the past five years – and the decline hit basic research in government and academic labs. During this same five-year period, by comparison, R&D spending by biopharmaceutical companies grew 22 percent in real terms. The American Recovery and Reinvestment Act – the ‘stimulus bill’ – provides substantial funding for the National Institutes of Health, the National Science Foundation and other agencies involved in health research. While that infusion of funding is welcome, what’s more important is sustained federal support for basic research. At Lilly, we know when budgets are tight, there’s always a temptation to cut R&D. We also know that our future depends on innovation, and we try to resist that temptation. We need the same commitment at the federal level. Inconsistency in funding means that grants dry up, projects are cut short, and progress is disrupted. In addition, too many prospective research scientists see the attendant uncertainties of a career in basic science, and look for other opportunities. Our nation’s innovation engine works best when we’re firing on all cylinders. The indispensable role of government is to support basic research, along

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with translating and transferring knowledge to the private sector. US companies, in turn, apply that knowledge to develop and commercialize innovative products that create value in the market. What’s required is not some new Manhattan Project but rather a long-term commitment to funding for basic research, to attract more outstanding scientists to that research and keep them engaged in productive work throughout their careers, whether those careers take root in academia, government laboratories, or the private sector. A few years ago, a business reporter offered a startling description of the business that Lilly is in: “Drug research,” he said, “is quite possibly the least efficient endeavor in the world of business. It’s the equivalent of hiring thousands of art students and funding decades of work in hopes that once in a while one will paint a ‘Mona Lisa.’” Now that comes across as a sobering thought, except that Lilly scientists do produce those Mona Lisas! And the portrait they paint is the face of every patient who benefits from the medicines they create. We’re determined to paint more masterpieces – longer lives, healthier lives – through medical innovation. Clearly, at a time when we’re up against some big economic and fiscal barriers, protecting innovation might be seen as a luxury. Yet who among us can witness the impact of cancer, Alzheimer’s disease, and other scourges and say, “We have all the medical innovation we need”? In fact, innovation may help us overcome fiscal as well as medical and technological challenges; in a world of increasingly constrained budgets, scientific innovation is likely to create new and less expensive treatment alternatives. Furthermore, bioscience innovation is truly an active ingredient in the economy of our nation; a source of enhanced livelihoods and of good jobs and incomes based on American economic and technological leadership in this high-tech field. It can and must also be an active ingredient in any recipe for healthcare reform, representing as it does a huge part of the solution to our healthcare challenges. Without innovation, we’re not going to be able to provide more effective healthcare to a rapidly aging population; we will be defenseless against scourges such as Alzheimer’s disease; the staggering health crises that linger in the developing world will get worse, not better, and America’s most fundamental competitive advantage will indeed decline.

Optimistic outlook Fortunately, I’m an optimist. Being involved in the hard, often frustrating work of innovation requires optimism. But it generates optimism, too, because we’ve seen diseases conquered, pain relieved, lives saved by our work. One of the most inspiring aspects of my job is the chance to meet faceto-face with patients whose lives have been touched by Lilly medicines. In a Christmas photo on my desk is the face of a young man, a Lilly employee, who had been saved from imminent death not two months ago by a Lilly medicine … and the faces of his wife and son. We stand on the brink of an enormous opportunity to harness new scientific knowledge that could make a further, substantial contribution to

human health. It is no understatement to call this the ‘Century of Human Medicine’. And medicine is just one of many fields where dedicated people are pursuing exciting innovations to improve life for people around the world. We’re fortunate to live in a time and place where we can choose to devote substantial resources to such endeavors. We owe it to future generations in this country, and to people around the world, to ensure that we create and sustain a viable ecosystem for innovation as a matter of highest priority. We must continue to build a society that appreciates and rewards innovation, maintains a strong legal and regulatory infrastructure, and most of all, prepares and encourages talented people to pursue innovative science. All of us who care about innovation should be insistent about high-quality K-12 education, especially in math and science; immigration laws that allow skilled scientists to work in the US; and steady long-term funding for basic research. Through a commitment to innovation, founded on a deep appreciation for what innovation contributes to human lives, we can overcome the very serious problems that face us today and prepare for the challenges of the future: securing livelihoods and enhancing lifespans for Americans in this new decade and for generations to come. n © 2010 Eli Lilly and Company. Reprinted with permission. John C. Lechleiter is Chairman, President and Chief Executive Officer, Eli Lilly and Company 57

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Improving enterprise-level productivity By Kim Shah


n an environment of extreme cost containment, integrated informatics solutions contribute significantly to today’s pharmaceutical manufacturing laboratories that require increased product quality and compliance with strict regulations, as well as improved efficiencies that can lead to reduced costs. Modern LIMS (laboratory information management systems) serve as common platform frameworks that other informatics solutions, instrumentation, enterprise systems and enterprise communications tools can plug into to share common functions, without having to build them from scratch for each product. These systems are capable of storing data and methods in a safe and consistent way, thereby ensuring ultimate data security and integrity as well as effective processing distribution. As a consequence, scientists and researchers are able to easily access data in order to make better-informed decisions in a faster and more reliable fashion. Adopting a comprehensive enterprise-level integration approach to streamline business processes can alleviate some of the challenges facing modern pharmaceutical manufacturing laboratories. In response to market growth indicators, Thermo Scientific CONNECTS helps bridge the gap between laboratory-generated data and the enterpriselevel information that is required for mission-critical management decisions. Because our company is uniquely positioned to offer this enterprise-level so-


lution set, Thermo Scientific CONNECTS allows our customers to more fully integrate the work of the laboratory across the organization and to expand the business of science from the lab throughout the enterprise. We are also able to capitalize on our ongoing partnership with industry leaders such as Microsoft and Oracle, as well as newer entrants to the integration discussion, like secure document management systems or ELN resources. CONNECTS provides both the integration of instruments and systems, and the interoperability necessary to transform laboratory data into relevant business drivers. In facilitating this enterprise-wide integration of systems, management will have the information they need for early insight into how pipeline drugs or compounds are progressing on a routine basis, as well as the critical data they need before, not after, any point of crisis that may affect operations, shareholder value or the safety of the consumer.

“Adopting a comprehensive enterprise-level integration approach to streamline business processes can alleviate some of the challenges facing modern pharmaceutical manufacturing laboratories�

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mation about quality and analysis values. In order to leverage the full benefits We are engaging with our customers in dialogue that will facilitate manof modern ERP solutions, GPSG Brazil needed a solution to interface the agement-level discussion about the necessity of integrating all of the sources LIMS with SAP so that the LIMS feeds data into the ERP. of potential data, including the laboratory and all related instrumentation, enBy interfacing the LIMS with its ERP, GPSG Brazil can expedite the data terprise systems like MES (manufacturing enterprise systems), PIMS and ERP flow between the lab and the manufacturing functions, streamline data han(enterprise resource planning), and enterprise communications tools like dling, and integrate data collection and reports. GPSG Brazil needed a validatSharepoint, BizTalk or document management systems. ed product that provided sufficient flexibility to deliver all the requirements In the ideal situation, this end-to-end integration of the entire enterprise that a pharmaceutical plant has, such as data security and consistent quality will facilitate better data correlation and collaboration, end-to-end report gendata; a centralized repository for the quality management data; fast and accueration, and more secure data exchanges, with the goal of providing managerate data storage and recovery, and all the industry functionality. ment with a dashboard view of the key business metrics essential to running Seamless integration of laboratory instruments to the LIMS and of the the business. LIMS to the existing ERP systems at GPSG Brazil ensures full regulatory comPharmaceutical manufacturing operations, contract manufacturing orpliance at a lower cost. CDS/LIMS integration ganizations (CMOs) and active pharmaceutical ingredient also supports and enables the periodic auditing manufacturers (APIs) are highly regulated and required to of the supplier certification system utilized by the control the quality of their analyses according to specific FDA company to guarantee the quality of its raw maguidelines, which apply to electronic format records that are terials. created, modified, maintained, archived, retrieved or transThe LIMS/CDS solution achieves quick and mitted in their laboratories. accurate transfer of high volumes of data, inThese regulations are valid even for records that are not creasing sample throughput and improving labused in a submission, such as training records and SOPs. As oratory productivity. Since the LIMS provides a consequence, one of the major challenges facing the inincreased traceability, the system enables easy dustry is the need to use validated CDS (chromatography and quick access to background data associated data systems) and LIMS that enable compliance with stanwith batches, allowing for automated batch condards and procedures enforced in this highly regulated entrol. In the case of failed data, CDS/LIMS intevironment. gration allows scientists to track both the original For pharmaceutical manufacturing companies today, a failed result and the actual chromatograph in the key business driver is the availability of a coherent strategy system. This enables users to find out if there was that can integrate data from LIMS, CDS, ERP, MES, ELN Kim Shah is Vice President, Marketing and Business Development, Thermo Fisher an operator error or a serious issue that would (electronic laboratory notebooks) and other sources across Scientific. Shah has more than 20 years’ experience in high tech marketing and impact the quality of the product, so as to take all the enterprise. management. Prior to joining Thermo of the appropriate action to protect consumers. Fisher Scientific in November 2006, he served as Vice President of Marketing and Solutions The integrated system detects changes in the Channel Development at Convoq. He has held leadership roles at Inso Corporation, Global Pharmaceutical Supply Group (GPSG) Brazil, a production line, determining new analyses to be Lotus Development and Micrografx, and unit of Janssen-Cilag Farmacêutica Ltda., Johnson & Johnson, made. Chromatograms can be viewed during the co-founded e-tractions, Inc., a provider of strategy and implementations of online has taken advantage of the latest connectivity opportunities in analysis and the workbook can be customized, in marketing campaigns. its São José dos Campos laboratory complex in São Paulo. order to view the analytical results. All required GPSG Brazil has adopted Thermo Scientific CONNECTS, an modifications may be performed in advance, integration solution that provides the connectivity for laboratory instrumenpreventing unnecessary and time-consuming rework. tation and informatics software, enterprise systems and document manageThe integration of laboratory and enterprise systems has enabled GPSG ment tools, enabling a fully integrated pharmaceutical manufacturing Brazil researchers to view information that was previously only available in environment. data reports. As a result, delivery of results has been accelerated since fewer Every month, GPSG Brazil’s manufacturing plant processes more than steps are required within the analysis process. 10,000 analyses to assure the quality of nearly 2000 samples of raw materials, Enterprise-level integration is crucial in today’s business climate, where packaging materials, semi-finished and finished products, water and stability. near instantaneous response is required by pharmaceutical companies to proThe site is fully equipped with an incoming laboratory plus microbiologic, tect the public and the environment. With CONNECTS, our goal is to bring chemical, analytical development and research and development laboratories. key business knowledge originating in the laboratory to management at all The manufacturing plant handles both solids and liquids, including Tylenol levels of the organization. The integration of the entire enterprise will facili750 mg tablets, Tylex tablets, Nizoral tablets, Tylenol drops, Nizoral cream and tate better data correlation and collaboration, end-to-end report generation shampoo, and imported products such as Eprex, Risperdal tablets. and more secure data exchanges, with the ultimate goal being to provide manGPSG Brazil selected a Thermo Scientific LIMS solution to deploy in its agement with a dashboard view of the key business metrics essential to runlaboratories to ensure integration with corporate enterprise resource planning the business. n ning package, SAP R/3. Between the production plant and the laboratory that analyzes data from production, there is a need for regular exchange of inforFor more information, visit 59


Who influenced Is it better to overestimate the threat of a virus and spend millions on vaccines that may not be needed, or make a misjudgment in the other direction and cause millions of unnecessary deaths? By Jodie Humphries


n April of last year, the World Health Organization (WHO) was informed of human infections caused by a new H1N1 virus. The report was classified as being of ‘immediate concern’ because the genes contained in the virus were from animal influenza viruses, establishing that the virus was very different from the usual seasonal human influenza viruses. On 11 June 2009, WHO announced that the virus would now be classed as a pandemic, because the virus had spread through 120 countries. It was

predicted that the H1N1 virus would affect billions of people, and kill thousands. To date, there have been more than 14,000 laboratoryconfi rmed deaths worldwide.

Media speculation In recent months, however, there has been speculation that due to WHO’s ties with the pharmaceutical industry, the extent of H1N1 was exaggerated. It has been suggested that there was no need for WHO to call the virus a pandemic, an action that resulted in many countries changing their health priorities to accommodate the thousands of patients that were expected as a result. Th is, in turn, prompted governments to spend millions on contracts with drug companies to procure large quantities of the H1N1 vaccine. But, as argued by Dr. Keiji Fukuda, Special Advisor on Pandemic Influenza to the Director General of WHO, “The H1N1 pandemic is not the same as seasonal influenza and differs in major respects. Large outbreaks occurred outside the usual season for influenza. The virus caused a striking and unusual pattern of severe illness and deaths in younger people, with many deaths caused by viral pneumonia: an especially aggressive form of the condition – and this pattern is not typically


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WHO? seen during seasonal influenza.” Fukuda’s arguments came on behalf of WHO at the Council of Europe hearing ‘The handling of the H1N1 pandemic: more transparency needed?’, held in late January. Ultimately, WHO’s collaborations with the industry provide better access to high-quality and affordable medicines, vaccines and diagnostics. Medical interventions, including antiviral drugs, vaccines and diagnostic tests, have long been recognized for their role in mitigating the health impact of an influenza pandemic. In fact, WHO itself states that “pharmaceutical companies play an essential role in this regard and WHO has engaged with them to pursue its public health objectives.” As such, in responding to the pandemic, WHO drew on advice from a standing body of experts, the Strategic Advisory Group of Experts on Immunization (SAGE), which advises WHO on vaccine use. Members of SAGE are likewise required to declare all professional and fi nancial interests, including funding received from pharmaceutical companies or consultancies or other forms of professional engagement with pharmaceutical companies. The names and affi liations of members of SAGE and of SAGE working groups are published on the WHO website, together with meeting reports and declarations of interest submitted by the experts.

Yet there can be no denying that the pharmaceutical industry has seen a rise in profits as a direct result of the H1N1 pandemic and the resulting sudden demand for vaccines. CSL Limited saw its profits rise 63 percent above 2008 levels by June 2009, while GlaxoSmithKline had benefited from a 30 percent jump by the third quarter. Roche, maker of the preventative drug Tamiflu, enjoyed a 12-fold leap in profits from the second quarter of 2008 to the same period in 2009. What’s more, and perhaps most critically, at the hearing Dr. Wolfgang Wodarg, a medical expert specializing in epidemiology and the former Chair of the PACE Sub-committee on Health, stated, “WHO basically held the trigger for the pandemic preparedness plans; they had a key role to play in deciding on the pandemic. Around $18 billion was spent on this worldwide.” There is some debate over whether this is an issue of blame. At the hearing, and speaking on behalf of the pharmaceutical industry, was Dr Luc Hessel from the European Vaccine Manufacturers, who said, “The vaccine industry merely did what it was asked to do. The industry’s role is to produce safe vaccines in a timely manner and respond to governments’ requests. It is governed by stringent international health regulations and rigorous safeguards against confl ict of interest. Decision-making regarding vaccine needs can only be based on the best available data at the time.” Nonetheless, swine flu has ended up being one of the most expensive public health crises ever, as – in the midst of a global recession – gov-

H1N1 Facts and figures Vaccine Orders and Consumption Number of cases have slowly been declining, resulting in governments having a huge surplus of the vaccine and cutting their initially large orders from the pharmaceutical companies.

France Ordered 90 million // used 5 million United Kingdom Ordered 90 million // used 23 million United States Ordered 251 million // used 160 million

Estimates vs. The Actual Number of Deaths

Est. 50,000

Est. 90,000

Actual 3,068

Actual 392

The United States

The United Kingdom

It was estimated that up to 30-40% of both the UK and US would become ill within six months of the situation of a pandemic being announced. Official figures of confirmed cases were much lower. 61

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The 10 countries with the highest number of swine flu deaths (confirmed cases // confirmed deaths)

United States 113,690 cases // 3068 deaths

Canada 25,339 cases // 426 deaths

United Kingdom 28,456 cases // 392 deaths

Russia 25,339 cases // 602 deaths

Turkey 12,216 cases // 627 deaths

Mexico 69,949 cases // 986 deaths

Brazil 58,178 cases // 1632 deaths

China 120,940 cases // 737 deaths

India 28,810 cases // 1229 deaths

Argentina 11,458 cases // 617 deaths

Sources: WHO, ECDC, BBC, Financial Times

ernments spent millions on vaccines that now may not be needed. And because of this, drug companies are reaping the benefits.

Far from over Despite the fact that WHO says the pandemic isn’t over yet, with more infections – and deaths – still to come, many nations are nevertheless attempting to cancel pending orders for H1N1 vaccines. France, for instance, which had ordered 90 million doses of the vaccine, more than was needed to inoculate its entire population of 60 million, has so far used only five million doses and now wants to cancel 50 million and sell the rest. Similarly, the Netherlands has a 19 million-dose order on sale to other countries, while Germany is in talks with manufacturers to halve its order of 50 million doses and sell off millions of others. Switzerland, Spain and Britain are also considering giving away or selling the millions of doses that they have received or have on order, while the US, which has so far only distributed 160 million of the 251 million doses it purchased to doctors, hospitals and other healthcare providers, has yet to make a decision on whether it will have an overflow and what it will do with any surplus. The main reason for the extra vaccine is simply that demand fell far short of what was originally expected. And now, after governments

have spent billions of dollars on vaccines that are seemingly not needed, some politicians and health professionals are looking to hold someone accountable. Dr. Fukuda, however, argues that, “WHO is confident of the scientific validity of its recommendations. The labeling of the pandemic as ‘fake’ is to ignore recent history and science and to trivialize the deaths of over 14,000 people and the many additional serious illnesses experienced by others.” He certainly has a point: while the number of cases might be declining, the fact remains that more 14,000 people died as a result of the virus. In the US alone, initial estimates put the projected death toll at 90,000, while in the UK the figure was expected to be 50,000. While the actual figures haven’t reached these numbers, the effects of swine flu are still very real. Was the seriousness of the swine flu pandemic exaggerated? Perhaps, but it would be wrong to jump to the conclusion that this was done to line the pockets of the world’s drug-makers. On the contrary, the speedy development and delivery of vaccines could be one of the main reasons that the pandemic hasn’t reached the dizzying heights of infection that were initially expected. After all, a pandemic remains a pandemic whether it results in 14,000 deaths or – like the Spanish Flu in 1918 – 50 million. „

“Many nations are nevertheless attempting to cancel pending orders for H1N1 vaccines”


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9/2/10 09:18:52


Helping bring products to market faster

Lorne Davies explains the importance of digital imaging in research.


harmaceutical and biotechnology laboratories are under increasing pressure to help bring drugs and healthcare treatments to market faster. But the process of isolating and testing lead candidates is fraught with difficulty. Digital pathology and virtual microscopy are valuable during every key step of the discovery process and are being adapted more and more by companies doing pharma and biotech research. The first research area that can be streamlined using virtual microscopy is the examination of hundreds or thousands of animal slides that are generated for each study. Until recently, a pathologist or other clinical professional prepared each slide, put it on a microscope, decided which area to review first, looked into the eyepieces, counted cells or made other observations, and finally, recorded the findings in a spreadsheet, analysis tool or LIS system. The user then moved to the next area of the slide (or next magnification) and repeated the sequence. This process was repeated with each animal, slide and region. Today, using new virtual microscopy tools like the Olympus VS110 slide scan-


ning system, glass slides are delivered to a technician who scans them once. Numerous pathologists can review the slides simultaneously, each at various magnifications, with automatic logging of batch, animal, slide, location, magnification and other metadata, along with each reviewer’s findings. The slides are instantly accessible, so instead of delivering boxes of slides first to one pathologist and then to another, any number of pathologists anywhere in the world can be called upon to review them, vastly increasing the potential for rapid and expert review and analysis. Adding the capacity for parallel review to the workflow has saved some companies enough time to allow for additional pathology reviews. Furthermore, since original glass slides are not passed around, they can be archived, while accurate, clear digital images are available for future research without the risk of breakage or loss. Each pathologist’s review is also streamlined. Onscreen whole slide review using multiple magnifications and areas of the sample allows for greater speed, less risk of error, enhanced data archiving and retrieval, fewer ergonomic issues, and access to expert pathologists wherever they are located.

Virtual microscopy offers additional benefits beyond the laboratory. For instance, it offers the company the potential to more easily deepen and draw on the knowledge they have amassed about the compounds or treatments they are considering. They can now go back to review a molecule or a whole class of molecules, using the database to relate their findings to other studies. In addition, digital imaging and review allow both qualitative and quantitative analysis. Image analysis, for instance, adds data points to help minimize subjectivity and reduce the number of independent analyses needed to arrive at an end result. Whole slide stereology is a technique that allows the rigorous quantification of lung alveoli, brain neurons or other features as part of the research process. Both image analysis and stereology provide more than data endpoints; they also can help save valuable time in the research process. At the Osteoarthritis Research Society International (OARSI) meeting in Chicago in 2004, one major international pharmaceutical company reported that it took 15-30 minutes to annotate each image using traditional microscopy tools, but with the virtual microscopy system, they were able to shorten review time to under 30 seconds per image, giving the company a remarkable 30-60x time saving over the older method. Automated data management tools also help reduce repetitive and manual processes, even as they increase data traceability. Virtual microscopy and digital pathology are helping today’s pharma and biotech companies bring new products to market with greater speed, enhanced connectivity, stronger validation based on scientific principals, improved quantification and increased traceability. The next frontier in digital imaging in the field may be the development of multimodal systems that will deliver brightfield, fluorescence, darkfield, differential interference contrast (DIC) and more in an integrated package. n Lorne Davies is Group Manager, Strategy and Product Management, Clinical Digital Imaging at Olympus America Inc. He is responsible for virtual microscopy research and planning throughout the US and Canada. A veteran of two decades in the microscopy, pharmaceutical and scientific instrumentation fields, he has been with Olympus since 1998.


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Does size really matter in single-use applications? By Barb Paldus


oday, there is a great deal of marketing noise touting the 5000 L single-use bioreactor. The direction of single-use vendors (in increasing vessel size) appears to be in direct contrast with the evolution of market needs. Consider that the landscape of biotechnology-based drugs is evolving from a small number of high-volume blockbuster cancer drugs to larger numbers of more targeted drugs for smaller populations. Focusing on large therapeutic areas such as cancer, but acquiring approvals for multiple related orphan indications, has proven to be a good strategy for many drugs. The result of this diversification in monoclonal antibody drugs is a need for flexible manufacturing facilities capable of rapid product changeover at smaller volumes, as opposed to high-volume, capital-intensive facilities focused on the high-volume production of a single drug. Similarly, facilities built to develop and manufacture biosimilars can benefit from high-yielding, robust new cell lines and therefore do not require the same production volumes. Moreover, biosimilar product facilities must minimize capital expenditure, and diversify the risk with multi-product capability. These drivers, namely multi-product capability, rapid scale-up and capital efficiency, have driven the adoption of single-use systems by the cell culture community. Because single-use bioreactors are still a relatively ‘new’ area, vessel design continues to evolve, as do new processes such as perfusion. Furthermore, single-use automation systems are designed to be flexible in both hardware and soft ware for easy product changeover, so that they naturally lend themselves to the incorporation of new sensors, new types of vessels, new control algorithms, and new cell culture methods. It is precisely this flexibility and ease of use that is expected to propel single-use system adoption in the future.

The recent proliferation of single-use bioreactor designs has focused primarily on aeration methods, as well as optimizing the uniformity of mixing and temperature. Th is becomes more and more difficult to achieve in volumes of 2000 L or more, whereas it is relatively straightforward and low risk in smaller size vessels. The advent of new sensors will allow additional data about the bio-process to be obtained and new algorithms to be developed for improved control and titer. In contrast to electrochemical sensors that vary up to four times in length depending on vessel size, the same optical pH and dissolved oxygen sensors can be used in 1 L or 2000 L single-use vessels using a clever port design.

“Focusing on large therapeutic areas such as cancer, but acquiring approvals for multiple related orphan indications, has proven to be a good strategy for many drugs” Moreover, single-use optical sensors such as Finesse’s TruFluor pH and DO sensors can be manufactured to a well-defi ned set of tolerances that assure reproducible and predictable performance parameters. As a result, all measured values are obtained using the same sensor and the same performance specifications, so that the bio-process engineer can be assured that the measured process values in scale-up and scale-down studies are completely consistent, and any variations between the processes are a result of fluid mechanics in different sizes of vessels. In this case, literally, size won’t matter.

Additionally, because single-use bags allow easy modifications and additions of new ports, it is much easier to introduce new measurement technologies in the process as they become available in the market. As a result, it is anticipated that the process analytical technologies (PAT) initiative will be much more useful for single-use technologies than for traditional stainless steel platforms. Because the measurement technologies will be independent of reactor type and size, their testing and validation should actually become much easier, with greater repeatability of results and consistency in measurement during scale-up and scale down. Finally, owing to more robust cell lines, whose productivity can yield tens of grams of product per liter, bioreactor size of single-use vessels for the production of most biologicals is not expected to exceed 2000 L. Most single-use production systems today are a 1000 L stirred tank configuration that mimics a stainless steel reactor in geometry, but can be designed to have a more homogeneous cell culture environment. Th is size of reactor allows manageable handling of the bioprocess bags, while matching (with the increased titer) the capacity of a typical production Protein A chromatography column. Realistically, handling bags larger than 2000 L carries significant risks to both the product and personnel involved. In the end, size will matter. What will matter is that the bioreactor is ‘just right’. To that end, with further increases in titer and the downstream bottleneck in chromatography, the industry may indeed fi nd that ‘small is beautiful’. „ Barb Paldus was most recently the CTO of Picarro, a company she founded in 1998. At Picarro, she was responsible for technology strategy, research and business development, which led to a solid-state Cyan laser product in 2003 and cavity ring-down spectroscopy products in 2004. Paldus is currently a partner at Skymoon Ventures. She received both her PhD (1998) and MSEE (1994) degrees in electrical engineering from Stanford University, and her BS (1993) in electrical engineering/applied mathematics from the University of Waterloo.


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Rise of biologics Nitin Sood explains the expansion of automation trends in life sciences. Can you explain current automation trends within the life sciences sector? Nitin Sood. The automation trend we are seeing is a shift in emphasis away from small molecule lead identification with its larger and more static automation systems toward flexible, bench top stations to support target identification and the development of new biologic therapeutics, or NBEs. Th is is consistent with the broader industry move toward biologics and the need to have high quality and well-characterized targets. Biological drugs offer greater target specificity, improved safety profi les and open up new possibilities in disease treatment and prevention not addressable with conventional therapeutics. As such they are an attractive addition to the pharma portfolio, commanding a premium price with reduced competitive pressure, especially from the generic threat that looms for small molecule drugs. Within five years, half of marketed drugs are expected to be biologics, and the industry is moving to sustain and expand NBE discovery. We expect to see our business shift accordingly, moving to the earliest stages of drug discovery. Automation will be a key component in reducing cycle time, developing high quality targets and getting quality biologic candidates into the pipeline faster. What are the challenges and benefits of expanding automation beyond HTS workflows and what tools can pharmaceutical companies use to achieve this? NS. The challenge is in being able to understand the fundamental differences between screening for active chemical entities versus developing quality targets and viable NBEs. In order to address target ID and biologics discovery, automation companies need to begin thinking beyond simple throughput concerns to the more sophisticated idea of reducing cycle time. Reducing cycle time means a greater emphasis is placed on the quality and

certainty of results, on the science that is driving discovery. That science changes rapidly and the automation must have the flexibility to respond. At Agilent, we are known for robust, low-footprint automation that can be easily repurposed as the need changes. Another challenge is that reducing cycle time means having a deeper understanding of the science and the steps involved to getting a sound result. That pushes us to consider new applications and assays. In traditional lead identification, we essentially address one step of a workflow. The basic operation is plating

Which are the best methods for companies to use in automating their genotyping workflows and their siRNA screening? NS. That’s the beauty of a flexible automation platform. The science drives the automation, not the other way round. If it is feasible and sound scientifically, we can fi nd a way to adapt and advance the automation to work with the application. And the automated methods we have already developed to support PCR and next generation sequencing are being leveraged by our customers to support the increasing investments in pharmacogenomics research.

“Automation will be a key component in reducing cycle time, developing high quality targets and getting quality biologic candidates into the pipeline faster” compounds, transferring compounds to assay plates and reading. Now consider what goes into a target ID workflow. We have a customer doing functional genomics using a lentiviral system. They create vector libraries, produce virus, transfect cells and assay the cells. They use an Agilent BioCel system to automate the whole process, so the system does nucleic acid prep on the Agilent Bravo liquid handler, manages the pipetting and incubations involved in the transfection, through to high-throughput flow cytometry. The system has to orchestrate those various steps at the level of both hardware and soft ware, which is quite impressive. Th is customer has cut their project time, gets high-quality data from the system and uses between one and two resources per project when they previously used eight to 12. And they were able to redirect those resources to develop the science that will give them a competitive advantage in the marketplace.

How do you see automation developing within pharmaceutical R&D in the next few years? NS. We see that there will be a continued emphasis on developing quality targets and biologic therapeutics. That will mean automating a variety of applications in genomics and protein analysis – something we already do but which we expect will take up the bulk of our business in the next few years as HTS investments level off. And we see publicprivate partnerships playing an increasingly important role, as more target development unfolds in universities and private research institutions. We’re looking forward to the challenges and innovations that this will drive in the near future. „ Nitin Sood is the General Manager of Agilent Automation Solutions and has served in this role since July 2009. Sood brings a wealth of business experience and market expertise to his role. He has held leadership positions in leading life science companies, including Applied Biosystems and Agilent Technologies.


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Raafat Fahim of Nabi Biopharmaceuticals explains why a more efficient business model is needed to cope with the increasing challenges of the industry.


aafat Fahim has long been a fi xture in the pharmaceutical industry. Prior to his role at Nabi Biopharmaceuticals he held a 14-year tenure with Aventis Pasteur before it became a part of sanofi, and it was here in the leading vaccine manufacturer of the world that he cultivated his concept of developing research to market. By converting research findings into manufactured solutions and implementing them into the market, Fahim found a more efficient business model to cope with the rising industry challenges. He attributes much of his thinking to his time at Aventis Pasteur: “It certainly provides a wide scope of experiences that I’m using today in my current role as Chief Executive of Nabi – a biotech with a vaccine development pipeline. In this I am able to interact and use my experience in the many areas that Nabi needs, both research and development, as well as from a business development perspective,” he explains.

Challenges Now is the time a wealth of experience is needed to respond to the industry’s challenges. Bioinformatics are enabling researchers to identify more numerous and complex targets than ever before, and pharmacies are finding that they’re also unusually constrained in their ability to turn research findings into manufactured solutions through the market. Although R&D is much further ahead in its game than manufacturing and not facing the constraints of regulatory processes, it still has its hindrances. Fahim explains that on a daily basis certain things may work in a good way but are often unable to be applied in practice due to regulatory constraints; the rigorous side to this is ensuring that manufacturing continues consistently and in a compliant way. “Compliance is one of the biggest elements facing biotechs. They innovate very well, but then when it comes to regulations and compliance the brakes are put on their development simply because of the need for a rigor in manufacturing. These are the kind of things that one faces on a daily basis. Having the technology is one thing, but what you can do with it is another. For the most part pharmaceutical companies, and in my case vaccine companies, have understood, digested and accepted that it’s a reality and are coping with it reasonably well.”

Fahim points to the example of this occuring: a concept can be invented in a short period of time but then it often takes five or six years to go through the various stages of regulatory and compliance process. “You can have an idea of what works or what you’ve tested in the lab and in small animals and maybe discovered in a couple of years, but then it takes you another six years to get to the stage where you can apply for marketing authorization,” he explains. Th is is usually a problem for small biotech companies and this is often an area in which they don’t excel, he says, as the company is unlikely to be developed for manufacturing or engineering but for discovery and research; what Fahim describes as “the fun part.” The problem is a practical one that all biotech companies face and each must endure the necessary length of time to go through the regulatory process to arrive at the fi nal stage.

“So many companies have gone bankrupt, even though they have a very good product, because they are unable to continue to develop” “The best advice one can give is to realize what you don’t know very early on,” says Fahim. “Most companies, when they get early successes in research and discovery, think and believe that now they can do anything and don’t recognize that getting through the next stage of manufacturing, compliance and the regulatory process is actually a completely different set of expertise that you need to start preparing for earlier. That is probably one of the biggest problems facing most small biotech companies, that they don’t realize early enough what they don’t know and the experience they lack within the company.” This is not the only challenge facing small biotech companies; the pharmaceutical industry also has to face problems within pharmacies’ supply chain. Fahim notes efficiency as one challenge. The pharma industry, although it has grown substantially in recent years and is recognizing it is now well established, still remains far less efficient than other indus-


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“To me innovation is about meeting a huge unmet medical need with huge market potential”

tries. He points to the automotive industry, as well as the chemical and food industries and the success in these in getting the supply chain down to the minor details. “For a long period of time, the pharmaceutical industry enjoyed a reasonable return on investment and a reasonable margin for their product, and they were less concerned about cost and efficiency. They recognized that a few years back, but are not yet at the stage that they could be or should be, from my perspective anyway,” he says. “There is no doubt it will change. That I can guarantee you because with the pressure on the pharmaceutical industry to control costs, they are now recognizing and facing quite a bit of a challenge to become more efficient. They are actually coping with it now and addressing it in a big way. They are taking the right steps, maybe a bit later than they should have; but nevertheless they are doing that now.”

Efficiency Driving efficiency within Nabi is of primary importance to Fahim. Still in the development stage, the company is preparing itself for consistency in manufacturing and preparing for commercialization. The first stage is ensuring the drug can be produced correctly and with equality.The second stage is then to drive consistency. Nabi has not yet had to face the second stage, but Fahim has already begun examining it; his previous role with Aventis Pasteur taught him to approach such issues very carefully.

“I started to look at that and see how we can do it in the future but I don’t have to face it for another two-to-three years or so, fortunately for me. The most important thing for us now is to make sure we can do it and to make sure that I can produce the material. Efficiency becomes a secondary issue at this stage but planning for efficiency is definitely important. “We’re now looking at the supply chain, what is the best way to handle the various contract manufacturing organizations that you’re working with to make them more efficient then to be responsive to the needs that we have in the future. So you can consider that we are in the planning phase, as opposed to the implementation phase today,” says Fahim.

Economic recession There are certain challenges that face every pharmaceutical company, regardless of size or stage of development. The economic recession impacted the ability of companies to ensure the security or consistency of supply chains and has driven home the need for efficiency in a big way. Pharmaceuticals and biotechs may be two completely different industries but the challenges they face both derive from the same financial dilemma. The pharmaceutical industry has seen the big issue of control of costs and pricing of pharmaceuticals whereas within the biotech industry this is much more dramatic. The pharmaceutical industry is still reasonably profitable but the biotech industry is less so. 71

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“The pharmaceutical industry is one of the industries that has been least impacted, so to speak, by the fi nancial crisis, although they are facing the challenges themselves. For biotech, however, it is dramatic,” says Fahim. “If a biotech company now wants to raise money for the next stage of development or discovery they are doing, it is almost impossible to get anybody to back it up now. “So many companies have actually gone bankrupt, even though they have a very good product, or sold their companies or products at a significantly reduced price simply because they are unable to continue to develop. Th at’s a major problem that we’re currently facing. We were fortunate that we had cash in the bank so I didn’t have to go and raise money otherwise I could be facing the same fate as others have.” Without money in the bank Fahim explains that the situation is nothing other than a crisis. He advises that if a company has prod-

dependent on their own organic growth for innovation. It is clear that they have failed miserably. “They have a huge infrastructure that makes the cost of innovation very, very high, stifles innovation with the various committees, and the various triage of projects that they have. On the other hand, the biotech has shown, categorically, that it can develop very fast and in a nimble way. That’s why they’ve been gobbled up by the big pharmaceutical companies, be it the products or the companies as a whole. So there is no doubt that biotech has driven innovation over the past 15 years and will continue to do that in the future.”


Innovation is essential for a company to stay ahead of the game: it has proved to be a critical piece of the drug discovery model. Fahim explains that at the center of Nabi’s innovation is a drive towards areas that are of significant unmet medical need and that are unique. “I can go and discover the next antibiotic, but guess what; there’s a lot of other companies doing the same thing. “The best way for a biotech to be unique, and survive and strive is to get into areas where there’s still significant unmet medical need but is not very crowded. The vaccine that we are looking at within Nabi, which I consider to be a very good example of that is a nicotine vaccine. uct but no cash, the most feasible move would be for them to partner “There are still 1.3 billion people smoking in the world and we know with larger pharmaceuticals that may be interested how bad smoking is. And, therefore, a nicotine vaccine, in their technology. Th is is often easier said than which is a unique technology and a unique drug is a done, with large pharma companies wanting to take huge unmet medical need with huge market potential. advantage of the smaller company is dilemma and We are the leaders; so obviously, we have found that area wait for the price of such a deal to become cheaper. to be attractive very early on. Without public funding or private backing there is “The other vaccine we have is against the flu coccus little option other than a partnership. aureus, which is the super bug everybody hears about. One big issue shaping the industry is the number Again, there is no vaccine on the market for it, so it’s of acquisitions that have been conducted recently, a huge unmet medical need, has huge market potential Pfi zer and Wyeth being just one example. But is this and is not in a crowded area. To me innovation is about proving to be a help or a hindrance during these difmeeting a huge unmet medical need with huge market ficult times? Fahim states that he prefers to be the potential, so you can make your mark in the field.” optimist, advocating that the trend is not necessarily Driving and managing that level of innovation Raafat Fahim is President and a bad thing and not one that will necessarily stifle inthroughout the company is Fahim’s responsibility as Chief Executive Officer, Nabi Biopharmaceuticals. He most novation. “It may actually make it more efficient,” he CEO. The best way to do this, in his opinion, is to ensure recently served as Chief Operating Officer and General Manager. His says. “And in the current realities of price control of that the scientists have enough freedom to develop the career includes 14 years with Aventis pharmaceuticals, that is a very good thing. That’s one concepts and ideas they have, although this is often Pasteur where he developed several vaccines from early research to way to cope because the pharmaceutical industry has prohibited by the constraints of costs and resources. If marketed products. been inefficient so far. possible, this is the model he believes to work well. A “To drive efficiency is very good. Now, does it very heavy structure will stifle innovation, which is to impact negatively on innovation? It potentially may have a negative be avoided at all costs. impact, but the overall impact would be positive, in essence, and would Fahim explains that efficiency is the future; the most important drive more efficiency in the pharmaceutical industry. It’s not a bad trend. development for the pharmaceutical industry over the next few years It depends how far it goes. You don’t want to end up with one huge pharis to drive efficiency and become lean in the supply chain. He argues maceutical company in the world, and we have regulations in place to that the examples of extracting a lot more cost out of the current state prevent that from happening.” of inefficiencies are plentiful. “It’s a wise thing for the pharmaceutical Ensuring that smaller companies can still compete against these industry to start paying even more attention than they are today to merged giants is innovation, says Fahim. He notes that there is no longer the current potential for more price controls over the industry. Th at any doubt that large pharma’s ability to drive innovation fast or wide becomes, probably, one of the biggest things they need to look at careenough is stunted compared to the past. “Each one of them was fully fully,” concludes Fahim. „

“The best advice one can give is to realize what you don’t know very early on”


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EMD ED P_7jan10 18/02/2010 14:10 Page 74


Needles and haystacks Individual parameters often do not meet the usability criteria that would make them ideal candidate biomarkers but by combining multiple characteristics, it is possible to develop a firm basis for decision-making, both in drug development and the clinic. By Christina Shasserre

Safety profiling

Multiple organ and system toxicities, including hepatotoxicity, cardiotoxicity, immunotoxicity and nephrotoxicity, are evaluated prior to use of a potential therapy in humans. Due to their potential utility, the use of biomarkers in drug safety testing was included in several projects under the auspices of the Critical Path Initiative (CPI), which is the “…FDA’s national strategy for driving innovation to modernize the sciences through which FDA regulated products are developed, evaluated, manufactured and used.” One of the first successful projects was the development of a set of biomarkers that can effectively detect whether a compound of interest can cause damage to the kidney or nephrotoxicity. Through collaboration with the public-private Predictive Safety Testing Consortium (PSTC), both the FDA and EMEA have listed seven biomarkers for kidney damage as being useful in determining kidney damage. As more CPI projects come to fruition we can look forward to firmer guidance on biomarker identity and application in safety testing, with the ultimate goal of lowering the cost of drug development and reducing the number of late development/post-marketing failures due to toxicity concerns. Time brings technological advances, new ideas and shifts in our understanding of biological systems, and so the number and biomarkers that are available will increase. Just as the use and type of biomarkers have progressed from age/height to blood pressure and heart rate and on to molecular biomarkers, we can expect novel parameters to be discovered, validated and ultimately put to effective use. We look forward to the evolution of biomarkers and their increased application. Perhaps they are the vanguard into our personalized medical future – but for that we need more than one haystack. n

Evaluating the safety aspects of lead compounds is an essential step in drug development.

For more information on CPI please visit

iological markers, or biomarkers, are measurable characteristics used to distinguish normal biological processes from altered ones. In the clinical setting, protein biomarkers present in serum or plasma are often measured using one of the traditional ELISA/EIA-format tests. Results from these routine tests are used in diagnosis, prognosis, determination of disease stage, risk assessments, and in determining whether the subject will respond positively (or negatively) to a planned course of treatment. Disease-associated biomarkers identified by primary research are typically altered in only a subset of patients, and most are modulated in multiple diseases or biological states and so lack the specificity required for a diagnostic or prognostic test. The poor utility of most single analytes as diagnostic biomarkers has led researchers to seek disease-specific protein distribution ‘fingerprints’. Used together, a panel of biomarkers has the power to better discriminate a specific disease and can potentially do so at an earlier stage. The application of biomarkers at the point at which it makes a tangible difference to human health and wellbeing has its roots much earlier in the drug and diagnostic development process. Multiplex biomarker assays have key advantages in that they require less sample material, provide time and cost saving through parallel throughput and provide a level of flexibility that fits into many discovery and development workflows.


Drug development In the research environment, the use of single and multiplex technologies is critical to the success of most projects. The analysis of key biomarkers involved in specific biological pathways or processes gives researchers a rapid and accurate snapshot of the disease state and whether a candidate compound is effective. More specific tests can give rise to mechanistic insights on the mode of action of compounds, as well as the condition itself.


Christina Shasserre is General Manager and Head of Global Biosciences at EMD Chemicals, an international organization serving the global market by providing specialty chemicals for pharmaceutical, biotech, cosmetic, automotive, plastics and various industrial applications.

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California Biomedical_4August 18/02/2010 13:18 Page 78


Leading the way The highlights presented here from PricewaterhouseCoopers’ California Biomedical Industry 2010 Report outline why the state is the worldwide headquarters of biomedical research and development.


alifornia is the world headquarters for biomedical research and development. The state is home to the largest concentration of biomedical companies in the world and one in six of the 1.6 million biomedical jobs nationwide. Its companies, universities and research institutes are dedicated to delivering biomedical innovation in the greatest areas of unmet medical need. The California biomedical industry spans the full range of technologies and entities whose ultimate goal is the improvement of public health, human therapies and the quality of life for patients around the world. California entered 2010 with its highest unemployment rate in postwar history, 12.5 percent, and economists and political leaders worry that payrolls will not bounce back to 2008 levels for years to come. California’s biomedical industry delivers high-wage jobs that drive the economy and are crucial to the state’s economic recovery. The average annual wage for the biomedical industry across the state in 2008 was nearly $75,000, as it was in 2007.

The biomedical industry continued to add jobs in 2008, employing nearly 274,000 Californians and growing by approximately 24,000 jobs since 2004. The industry was not only a pillar in the overall state economy but a significant player in local communities throughout the state as well. The largest concentration of industry-related jobs was in the San Francisco Bay Area. Companies and academia there employed nearly 54,000 people. Los Angeles County companies and institutes employed more than 44,000 people, while Orange County recorded over 30,000 biomedical industry jobs. San Diego County rounded out the top four clusters with 23,000 industry positions. Examined by sector, the overall biomedical employment in the state included approximately 112,000 people in the medical devices, instruments and diagnostics sectors. That number represented about 41 percent of the overall total jobs. Biopharmaceutical companies employed the next largest segment, with more than 81,000 jobs or about 30 percent of the total. The state’s academic research centers employed more than 43,000 people in life sciences positions for approximately 16 percent of the total. Wholesale trade accounted for nearly 32,000 personnel or about 12 percent of the state’s biomedical employees. The remaining 5400 employees or two percent worked in the laboratory services sector.

Product development California remains an important source of the scientific innovation that creates the commercial value of biopharmaceutical products and the benefits they bring to patients around the world. At the end of August 2009, there were some 869 products in the California biopharmaceutical pipeline. The state’s pipeline includes products that California companies originated or invested in to address a broad range of diseases. The California biopharmaceutical pipeline represents about 15 percent of the total worldwide biopharmaceutical pipeline of 5850 products. Global sales of all biotechnology and pharmaceutical products reached $719 billion in 2008, reflecting growth of 5.4 percent over the prior year. Of this total, biologic products contributed about $120 billion. Biologics can include products such as vaccines, blood and blood components, gene therapy, tissues, monoclonal antibodies and recombinant therapeutic proteins created by genetic engineering. The top six disease focal areas comprised 86 percent of the California pipeline, with oncology research and development remaining on top with 272 products. Central nervous system disorders were next with 117 products, followed by immunological and inflammatory disease (110 products), infectious disease (109 products), cardiovascular and blood diseases (70 products), and diabetes and other metabolic disorders (66 products).


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The figures Investment California’s life sciences companies continued to expand through 2008 (most recent data available). Total revenues from the state’s biomedical sectors of $75.9 billion marked a nearly two percent increase over the $74.5 billion generated in 2007. Most of the revenues were attributed to product sales by such California headquartered biopharmaceutical powerhouses as Genentech, Amgen, Gilead Sciences and Allergan, as well as medical technology leaders Edwards Lifesciences, Gen-Probe and Illumina. Venture capital drives many of the country’s innovative new companies. All told, venture capital investments in the United States totaled $28.1 billion in 2008 and $17.7 billion in 2009. In both years, half of the national total was put to work by California companies. Venture capital fueling the state’s industries in 2008 totaled more than $14 billion through over 1600 deals involving more than 1300 companies. In 2009, nearly $9 billion was put to work via more than 1100 deals and over 900 companies. The largest beneficiaries in the state were the biotechnology, medical devices and equipment, semiconductor, media and entertainment, and telecommunications industries. Yet the biomedical industry, which combines biotechnology and medical devices and equipment, secured the bulk of the investment dollars at approximately $3.5 billion in 2008 and $2.6 billion in 2009.

California Biomedical Average Wages by Sector (2008) $108,93

Biopharmaceuticals Wholesale Trade

$80,130 $57,314

Medical Devices, Instruments & Diagnostics


Laboratory Services


Academic Research

Source: Bureau of Labor Statistics Quarterly Census of Employment and Wages and Company Specific SEC filings.

California Biomedical Employment by Sector (2008) Medical Devices, Instruments & Diagnostics Biopharmaceuticals Academic Research Wholesale Trade Laboratory Services

“The biomedical industry is one of the most recessionresilient sectors in California” Source: Bureau of Labor Statistics Quarterly Census of Employment and Wages and Company Specific SEC filings.

Opportunities and challenges The biomedical industry is one of the most recession-resilient sectors in California’s hard-hit economy and a critical driver of innovation, job growth and revenue that will help lead the state to economic recovery. In fact, among respondents to the most recent California Healthcare Institute (CHI) and PricewaterhouseCoopers (PwC) California Biomedical Industry Survey, most (64 percent) had expanded or sustained their workforce over the previous year. Looking forward, the respondents to this year’s CHI-PwC Survey remained confident in their ability to sustain and grow their California-based operations over the next two years. California remains a magnet for grants from the National Institutes of Health (NIH). In 2008, California received NIH grants worth more than $3.15 billion. The Golden State’s share was approximately 40 percent more than that of Massachusetts, the next highest recipient. California has averaged approximately 15 percent of the total NIH grants over the past decade, and was awarded 15.1 percent of the total in 2008. n

Number of Biopharmaceuticals in California Product Pipeline 400


350 300 250

217 194

200 150 100







0 Preclinical

Phase I

Phase II

Phase III

Source: IMS Health R&D Focus, July 2009 79


Optimizing your laboratory assets GE Healthcare’s Matt Sawtell looks at the tools pharmaceutical companies can use to ensure they maximize their R&D dollars. Pharma companies are striving to reduce costs without affecting quality, yet few have capitalized on the optimization of their laboratory assets. Why is this the case? Matt Sawtell. The pharma and biotech industries have for a long time focused on driving cost out and continuous improvement in manufacturing, through widespread adoption of Lean and IT initiatives. However, there has been minimal focus on adopting these best in class approaches in R&D, leaving pharma companies at the ‘early adopter’ stage when it comes to laboratory asset management. On the vendor side, companies in this space have been slow to evolve away from the standard service delivery structure. The step change needed now is to adopt an outsourcer/ Chief Technology Officer approach. Th is would enable pharma companies to realize the value of a combined technology, IT, Lean, process and business intelligence offering in the management of laboratory assets in R&D. Once this approach is adopted both the vendor and pharmaceutical company can form a true strategic partnership, ensuring each operational project makes an impact not only on hard cost savings and simplification of operating models, but also significantly improves the efficiency and productivity of scientists to focus on core activities.

Although R&D is project-based and therefore more difficult to process map than manufacturing, there are many opportunities for improvement. The key initially is to gain visibility of every process and laboratory asset, including a complete understanding of where all assets are, how often they’re used and moved, and the workflows they’re used in. At GE Healthcare we have created an effective life sciences services solution, built around a change acceleration program (CAP) enabling fast and effective change, combined with data-driven decision making which provides a roadmap of when, how and where to drive that change. In addition, as these programs cover the entire lifecycle of an asset, support is offered right through from purchase planning to disposition.

What benefits does a complete laboratory asset management program offer? MS. The industry is being advised to streamline R&D groups to small focused teams with more emphasis on ensuring R&D dollars are spent on drug development rather than non-core activities. Pharma is looking to outsource more of these non-core activities and a complete lifecycle laboratory asset management service will enable them to take advantage of integrated services, technologies and tools, going way beyond an extended service contract.

as asset tracking, spend and asset utilisation analysis, they have certainly not maximized the benefit these tools can bring. Going over and above this, GE Healthcare’s asset management service programs offer resources such as analysis of workflow and waste, data analytics designed to measure service quality, and benchmarking data to ensure spend, service levels and other variants, which are best in practise. Rather than supplying simple service level analysis, business intelligence gives insight into how assets are used, and an understand-

What tools can companies use to optimize the management of their laboratory assets? MS. Although many pharma companies have already adopted measures on a low level, such

ing of their value if unused, to support decisions around redeployment or disposal. In addition, insight into fi nancing options and advice on asset purchase enables companies to really maximize CAPEX. How do you see the area of laboratory asset management developing in the future? MS. The current economic environment is forcing pharmaceutical companies and their suppliers to think differently about how to drive performance and make their business model more agile. With M&A activity showing no signs of easing off, all companies are looking to redefi ne their business practices in order to address both present and anticipated future market challenges. Laboratory asset management providers need a deeper and faster adoption of learnings from other industry sectors such as the aircraft industry through reliability centre maintenance, IT outsourcers’ service agnostic approach and industry partnerships to enable IP

“Once this approach is adopted both the vendor and pharmaceutical company can form a true strategic partnership" creation. Service organizations are morphing into ‘services’ solution providers, offering consultative tools, technologies and change processes to become a more integral part of the pharmaceutical operating model. In this environment, strong organizations will thrive under the challenge of producing more aligned services and solutions. As Darwin once said, “It is not the strongest of the species that will survive, or the most intelligent. It is the most adaptable to change.” „ Matt Sawtell is Director of Global Operations, Scientific Asset Services – Life Sciences at GE Healthcare.


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Step up to the MIQE When it comes to real-time PCR in drug discovery, Richard Kurtz believes that MIQE guidelines will help create a clear path.


ver the years, polymerase chain reaction (PCR) has evolved into a readily automated, high throughput quantitative technology. Realtime quantitative PCR (qPCR) has become the industry standard for the detection and quantification of nucleic acids for multiple application, including quantification of RNA levels. But a lack of consensus among researchers on how to best perform and interpret qPCR experiments presents a major hurdle for advancement of the technology. This problem is exacerbated by insufficient experimental detail in published work, which impedes the ability of others to accurately evaluate or replicate reported results. In extreme instances, incongruous pre-assay conditions, poor assay design and subjective data analysis methods have led to the publication of irrelevant or misleading data. The original 2002 paper on measles, mumps and rubella (MMR) provided evidence that supported a link between the MMR vaccine and autism. Later examination established the original conclusions were based on flawed real-time PCR data. Subsequent publications have convincingly demonstrated there is no plausible link between the vaccine and autism, but the debate and doubt continues outside of the scientific community and MMR vaccination rates have dropped in several countries. Accurate qPCR testing can help companies avoid pursuing the wrong compound or target. Providing sufficiently detailed reports of experimental design in early stage drug discovery research can potentially save millions of dollars by not wasting man-hours or reagents. The Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) standards can help companies and researchers avoid these drug development pitfalls. MIQE’s goal is to restructure the current approach to qPCR data reporting into a consistent format that encourages detailed auditing of experimental processes, analysis and results whereby the technical quality of the work and


reliability of the conclusions can be evaluated. Implementing these guidelines is imperative in continuing the growth of qPCR into an accurate and reliable nucleic acid quantification technology. MIQE promotes the careful examination of qPCR results to enhance integrity of submissions to peer-reviewed journals, consistency between laboratories and experimental transparency. Adoption and compliance of these guidelines will help researchers more accurately report data and replicate experiments, ultimately saving time and money. When it comes to providing scientists with the tools to be MIQE-compliant, Bio-Rad Laboratories, Inc. is paving the way. Recently,

direct import of data from the system to the software. The combined solution provides researchers with the flexibility to handle both small and large experiments as well as combine data from different experiments using qbasePLUS software as the repository database. As the industry continues to recognize the importance of the MIQE guidelines it will become increasingly necessary to ensure that laboratories and corporations are following them. Simplifying compliance facilitates not only drug discovery and development, but basic biological research. Investing in a qPCR system and failing to follow guidelines that will ensure that quality data is being produced may result in a wasted investment.

“Quality data is paramount for the successful development and potential approval of a drug candidate” Bio-Rad entered into an arrangement with Biogazelle to exclusively distribute the qbasePLUS data analysis software with its CFX96™ and CFX384™ real-time PCR detection systems, a program that enables users to annotate their experiments with MIQE-compliant experimental details. The qbasePLUS software in combination with these real-time PCR systems provides customers with improved accuracy in their qPCR experiments and speeds up standardized data analysis. qbasePLUS software allows for the elimination of erroneous data, normalization to remove sample-specific non-biologic variation, and inter-run calibration, which can remove the technical variation between samples analyzed in different runs. By enhancing the reliability of the qPCR data, qbasePLUS conforms to MIQE. Using the CFX96 and CFX384 real-time detection systems with qbasePLUS software accelerates research through automated, fast calculations and

It can be anticipated that additional qPCR vendors will soon offer solutions to assist researchers in maintaining MIQE compliance. Top instrument makers and reagent vendors are supporting the thought leaders working to expand MIQE awareness and compliance. Bio-Rad has trained sales and support staff to help researchers comply with the guidelines. They share this training through educational meetings focused on MIQE. Quality data is paramount for the successful development and potential approval of a drug candidate. Following MIQE will help strengthen the quality qPCR data needed to move a candidate forward. Plus, it may avoid the devastation of finding out the focus was on the wrong target or having a drug candidate fail. n Richard Kurtz is Senior Marketing Manager at Bio-Rad Laboratories. Prior to joining Bio-Rad, Kurtz served as Field Applications Manager for MJ Research Incorporated. Kurtz earned his PhD from Northwestern University and a BA in Molecular Biology from Colgate University.

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Using IT to improve success rates NGP gathers some of the industry’s leading experts to discuss how information technology can support and develop the discovery process. As the pharmaceutical industry changes in response to unprecedented challenges, how must the information technology supporting the drug discovery process evolve and be redefined in order to improve research productivity and success rates? Amos Dor. As the pharmaceutical industry changes, the information technology supporting it must be able to keep up. Advanced sensors are needed to gain information about the materials being used, the process they go through, and their results. This investment in sensors, however well intentioned, doesn’t add value without the means to collect, store and understand


Amos Dor is the Umetrics US Manager at MKS Instruments in San Jose, California. He manages marketing, business development, application, operation, and sales for North America, South America and Israel. He has 20 years of broad experience in management, marketing, business development and engineering in start-ups and large organizations.

Patrick Flanagan is Chief Operating Officer for Tripos International and leads the organization’s commercial efforts. Prior to joining Tripos, his career included strategic sales and business development for leading companies in the healthcare, software, and consulting fields including Baxter International, Allegiance Healthcare and A.T. Kearney and Oracle.

the data they provide. IT must be able to support this data explosion with databases, networks and advanced data analysis tools. The analysis tools especially need to be trustworthy and intuitive to maximize benefits from their use. Multivariate analysis becomes even more important when the number of variables being considered increases. Correlations between variables must be considered, and it is very difficult to see correlations between more than four or five variables at a time when they are looked at individually. To truly optimize productivity and success, the majority of time and resources should be focused on decision-making based on relevant information, instead of on how to collect and plot the data. Patrick Flanagan. All pharmaceutical organizations have their own data stores and data access applications. Standardizing on an extensible product that fulfils their data requirements reduces costs and allows internal IT groups to focus on adding value rather than supporting the base platform. Introduction of data standards makes data more readily capturable, sharable, and understandable and ultimately valuable. The tangible benefits of adopting/moving to a product-based solution are straightforward: reduced cost of ownership, focus of internal resources on delivery of higher value scientific capabilities, and reduced burden on the scientist of tedious data manipulation tasks. The less tangible benefits offer a vastly higher value and productivity gains to the scientist and project leadership: increased focus of scientists on the meaning of their data and delivering the next progression in their project rather than on how to move data around their computers, and improvement in the use and interpretation of data. In the current climate, pharmaceutical drug development must increase its productivity. How can the more widespread use of technology support tools help streamline and improve discovery processes? 85

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PF. Technology support tools, made available across the enterprise and utilized in daily workflows, can enable true knowledge management. Scientists need to get to their data as soon as it is available, so timely data entry and simple delivery are critical requirements. Data must be presented in the way scientists want to see it, so analysis tools must be a click away, and require no further complex data manipulations, avoiding the need for data transfer and loss of context, and data access and analysis capabilities must be integrated with all the applications that are required for an entire workflow. Logistical data such as synthesis and test dates need to be accessible to better understand and improve research processes, and cross-project datasets need to be readily accessible so progression decisions can be made earlier with greater objectivity. Capabilities to mine corporate information beyond the scientists’ current project provide the key to realizing corporate knowledge.

PF. Tripos’ Benchware Discovery 360 (D360) is a powerful system that allows every researcher in a life science organization to access and analyze discovery data and easily share their findings with project teams. Using D360, scientists gain simple access to everyday logistical data queries, as well as in-depth data mining and analysis capabilities. In addition to productivity gains achieved by reducing the amount of time spent formatting, manipulating and manually transferring data, D360 users report that they are able to perform analyses they simply couldn’t do prior to implementing D360. Pfizer recently globally adopted D360 under a unique agreement where we are adopting valuable elements from their organic system (RGate) and adopting them into D360, providing a leading technology to Pfizer scientists while leveraging investment in their legacy system to reduce cost and create a modern, best-ofbreed platform for drug discovery and development. Previous to its acquisition by Pfizer, Wyeth selected D360, and worked extensively with Tripos over a five-year period to develop the application to meet the needs of Wyeth scientists.

“Technology support tools can enable true knowledge management”

How do you see the use of software in pharmaceutical R&D developing

Patrick Flanagan

AD. When drug development includes Quality by Design (QbD) from the beginning, resources can be focused where they will be the most beneficial. Umetrics’ Design of Experiment (DOE) software, MODDE, can be used to reduce the amount of experiments needed, while at the same time, provide as much information as possible from those few experiments. DOE helps decide which variables to control, find the optimal setting, and ensure the process is robust enough to keep quality consistent. It also helps to transfer the product from development to production. Knowing the range of settings that will keep quality consistent before handing the process to manufacturing can reduce the time it takes to qualify and validate the process. Also, the data from the design can be combined with historical data from manufacturing to monitor the process and to do quality predictions in real time. What software tools can discovery scientists use to help organize, analyze and visualize ever-increasing amounts of data, enabling them to make better, faster decisions? AD. Advanced multivariate analysis tools like Simca-P+ from Umetrics can help increase productivity in several ways. First, you can quickly create an overview of all the data showing trends, groups and outliers. You can use this overview to see which observations are similar to each other (or to the group average) and which are not. Second, you can look for correlations in the data. Using the variable plots, you can see which variables are positively or negatively correlated with each other or with your quality measurements. If you see groups or outliers in the data, you can quickly drill down to the variable contribution plot, which shows which variables are causing the groups to separate or the outlier to be different from the main population. Within minutes, you can get an overview of the data, compare two populations of data, or see which variables are predictive of quality.


over the next five to 10 years? PF. We believe that use of software that provides improved capabilities in the ability to predict successful outcomes – like optimizing lead compounds, predicting off-target effects, and managing attrition – will play an increasingly important role in pharmaceutical R&D. Additionally, the integration of data from discovery through clinical and beyond should allow the process of discovery and development to become more cohesive and efficient, moving towards informatics support of translational efforts from hypothesis through to patient outcome.

“In five to 10 years, drug discovery will rely even more on data” Amos Dor

AD. In five to 10 years, drug discovery will rely even more on data and the information you can get out of that data. The ability to collect data from complex experiments will increase, and it will become even more imperative to be able to quickly understand the story that data is trying to tell. Process analytical technology (PAT), including online multivariate process monitoring, will take a larger role in drug manufacturing. With online process monitoring, batches are supervised to see if any measured variables are different than normal. If so, an alert is automatically generated so action can be taken to prevent the batch from being lost. Companies will be able to monitor products from research and development all the way through to delivery to customers. They will be able to provide a complete history for all delivered products. Because of this and other benefits mentioned previously, the FDA will be even more encouraging about implementing programs like QbD and PAT. Companies who haven’t implemented this type of process and quality control will be the exception and will have a more difficult time competing with those who have. n


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Thermo Scientific Hyclone Products ed_4August 18/02/2010 13:58 Page 88


Optimizing cell culture performance Brandon Pence talks to NGP about achieving maximum output from process optimization collaborations. In your opinion, what are the main challenges currently facing biopharmaceutical drug development? Brandon Pence. Moving products to market quickly remains the challenge of any company, in particular those developing biotherapeutics and vaccines. Additionally, as new biologics are developed for more specialized applications, the demand for yesterday’s large manufacturing plants with tens of thousands of liters in bioreactor capacity is diminishing. The ability to quickly manufacture products in a cost-effective manner, and in many cases locate the manufacturing facility in the region where the end-product will be supplied, is becoming key to the market performance of the biologic. To accomplish this, more biopharmaceutical manufacturers are turning to single-use systems for liquid preparation and handling, cell culture manufacturing and bulk intermediate storage. The advantages of single-use systems have been widely documented over the past few years and include manufacturing cost reduction, rapid production turnaround timelines and maintaining a consistent contact surface throughout the manufacturing process flow. With the expanded range of applications for single-use systems, ease of implementation is another critical factor. At Thermo Fisher Scientific, we are placing technology experts in the field capable of working directly with our clients on identifying opportunities to utilize single-use systems all the way from the development of initial application protocols through their integration and qualification. How can biopharmaceutical companies increase the productivity of their protein-based drug production? BP. Matching cell expression systems with the raw materials consumed and the equipment used in the bioproduction process can significantly improve titers, elevating overall efficiencies for manufacturers. However, achieving this productivity improvement requires a balance between providing the right nutritional components in the form


of complete cell culture media and feed supplemization collaborations is the ability to take results ments for the cell platform selected with the optiand implement them globally. This includes selectmization of the bioreactor production process. In ing a partner with global manufacturing sites and a many cases, titer improvements are a function of history of providing and supporting products customizing the nutritional components for the placed into various regions. One important element specific cell clone and then developing the right that is often overlooked is identifying a partner castrategies for delivering those nutrients. pable of providing the right degree of collaborative We believe that having subject-matter exactivity. This activity may involve onsite technical perts with the right process monitoring technolodiscussions and support, project management and gies enables us to analyze the communication, and coordinatcomplete cell culture process ing studies at research facilities and provide customized relocated at the partner’s headsponses to our clients’ needs. In quarters. many cases, these customized responses influence the type of How do you see the area of cell culture media and supplecell culture-based biotheraments used, as well as the propeutics developing over the tocols for operating production next few years? bioreactors. Through practical BP. An emerging trend in cell application of this approach, culture science will be the dewe’ve been successful in partvelopment of more personalnering with biopharmaceutical ized biotherapeutics instead of Brandon Pence is the Associate manufacturers to achieve prolarge blockbuster drugs. These Director of Market Management ductivity improvements greater will require smaller producfor Thermo Scientific Cell Culture and BioProcessing. In his current than two-fold compared to trations systems as they will take role, Pence is responsible for ditional production systems.

global strategic business efforts primarily aimed at improving the tools utilized in bioprocessing systems, biotherapeutics and vaccines manufacturing.

What should companies look for when choosing an external partner to help optimize cell culture performance and achieve maximum results from their research? BP. Having the right technologies and applications resources is obviously important. We have taken a leadership position in the bioprocessing industry by integrating cell culture nutrients (sera, media and supplements) with single-use handling and production systems, including the Thermo Scientific HyClone Single-Use Bioreactor. This enables us to partner with companies in developing complete cell culture systems. Another critical factor to be considered for achieving maximum output from process opti-

advantage of existing cell culture productivity improvement technologies as well as have refined dosing requirements for a smaller patient population. As such, personalized biotherapeutics manufacturers will require an ability to customize the delivery of key raw materials and production systems to ensure robust and efficient processes. Additionally, the emergence of biosimilars as patents expire on existing blockbuster biotherapeutics could have a profound impact on the biopharmaceutical industry. Utilizing strategic partners capable of providing the right technologies will enable both biosimilar manufacturers and novel biotherapeutics developers the ability to constantly be at the forefront of their respective domains. n


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SINGULEX_4August 18/02/2010 11:47 Page 90


An indispensable toolkit Lynn Zieske explains the importance of biomarkers in the drug development process.


iomarkers are indispensable toolkits for drug discovery and development, covering nearly all classifications of analytes such as proteins and metabolites, genetic markers, DNA, RNA and many others. They are widely used in virtually all therapeutic areas including cardiovascular (cardiac troponin I), neurology (amyloid beta 40, 42), oncology (VEGF, Akt-1, PSA), metabolic (insulin, GLP-1), and inflammatory (cytokines and chemokines) diseases. Researchers need responsive biomarkers to serve a variety of different purposes. During drug discovery, biomarkers are used to identify and qualify drug candidates, determine potencies, validate targets and to determine mechanisms of action (MOA). During pre-clinical development, biomarkers are used to demonstrate PK/PD and to evaluate drug safety and efficacy, enabling early decisions on drug candidacy to be made with more reliability. During clinical trials surrogate biomarkers are used to identify and track disease progression. It is important that these biomarkers discriminate and distinguish between study populations and that methods used to measure them can quantify sub-

tle changes caused by drug intervention. Biomarkers are also used to develop diagnostic tools or to validate another surrogate biomarker. Some biomarkers can identify populations for risk stratification that can be used for diagnostic monitoring and predictive tests. The preeminent goal during drug discovery is to optimize the balance between drug efficacy and toxicity. Reproducible and sensitive surrogate biomarkers are instrumental in devising an optimal therapeutic index. Surrogate biomarkers are needed as indicators of disease severity and drug efficacy. Additionally, specific markers responsive to drug toxicity can be monitored in relation to the efficacy of dosage. Knowledge of the stability of these biomarkers in normal populations helps to provide a framework for comparison. With an accurately established baseline of the biomarker, one can observe significant changes over baseline beyond underlying biological variation. Many biomarkers can be used to monitor disease progression, however it is important that technology capable of measuring these biomarkers in a healthy population exists. Significant concentration changes compared to baseline are then indicative of deviation from normalcy. By longi-

tudinally monitoring the progression from a healthy to diseased state, then conversely from a diseased to healthy state, one could determine the efficacy of a given therapeutic intervention. Thus biomarkers can serve as valuable indicators of disease severity and can be measured to provide clinical evidence for drug efficacy. Technologies used to measure biomarkers span across a wide range of platforms. For example, Singulex has developed ultra-sensitive immunoassays for many proteins such as cytokines, chemokines, growth factors, transcription factors, hormones, regulatory proteins such as troponin, and metabolites such as cAMP. Development of such ultra-sensitive immunoassays addresses the lack of sensitive detection methods commercially available on the market. Without the requisite

“Many biomarkers can be used to monitor disease progression, however it is important that technology capable of measuring these biomarkers in a healthy population exists� assay sensitivity, it is not possible to accurately establish baseline levels of specific biomarkers present in the sub-picogram/mL range. Furthermore, small incremental concentration changes (approximately 50-250 fg/mL) possibly linking to disease progression cannot be measured with statistical confidence. Increased assay sensitivity thus enables the clinical utility of biomarkers, empowering the researcher with the ability to gather vital data in evaluating drug efficacy, dosing or treatment regimen. n Lynn Zieske serves as Vice President of Commercial Solutions for Singulex, where he promotes the adoption and innovation of Singulex technology in the life science marketplace. Zieske brings over 20 years of experience in life science product development and marketing strategy, helping to bring innovative products to customers.



9/2/10 09:20:05


Towards a

GREENER FUTURE GSK’s Mark Rhodes examines the level of environmental awareness in the pharmaceutical industry.


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s we become increasingly aware of our impact on the planet, environmental consciousness is growing across many sectors. Big pharma may not immediately spring to mind as having the greenest of business models, but Mark Rhodes, VP Sustainability Pharmaceutical and Consumer Healthcare for GlaxoSmithKline, believes the industry boasts quite a high level of awareness around environmental issues. “I think there is quite a high degree of awareness,” he says. “We’re a very compliant industry, so pharma tends to follow things like environmental regulations and health and safety regulations. There is strong knowledge around compliance and policies and procedures. “The gap that we have that makes us different to other industries, such as the car industry, is that we need to ask ourselves how we can be more sustainable when we don’t have a customer demanding sustainable products. It’s very different to somebody buying a car and wanting something with a low fuel consumption and low emissions. We don’t have anybody saying to us, ‘We want your pharmaceuticals, but we want them greener.’ It has to be driven internally. “Generally, people tend to trust their doctors. If a doctor says, ‘Th is is what I’m going to prescribe you for your illness,’ they accept it and don’t question whether there’s an option that has a better environment profi le. A good example is dry powder in respiratory devices versus aerosols. They have very different environmental profi les, but the patient will tend to be very conservative and want to stick with what they’ve got. And the doctor will not necessarily prescribe based on environmental impact. Even though the molecules might be the same, it’s just the way they’re presented that is different.” Th is can pose a challenge to those charged with making their business more sustainable, but they do have one advantage: as Rhodes puts it, everyone who is internal to the company is also a member of the public. “Everyone has their own personal feelings about recycling. They may recycle at home; why shouldn’t they do it at work? Or they may choose a low-emission car at home, so why are they working in a factory with very high emissions? They’re not different people when they’re at work. You have to harness that enthusiasm and channel it and get everybody together to share their ideas. In fact, sometimes they want to go further than perhaps we in the environmental group want to go, because we see the challenges and we know the problems.” When asked whether he thinks there will come a time when pharmaceutical companies will promote themselves based on their environmental records, Rhodes points to the UK’s National Health Service as an example of a higher consciousness within the health sector. “The NHS has published their own carbon footprint, and they’ve shown that pharmaceuticals are a major part of that,” he explains. “They have to take 80 percent of the carbon out of their system, which includes the supply

chain. They’ll be asking us about the options for a low-carbon respiratory medicine, and then we can have a discussion with them around dry powders versus aerosols and so on. They will then have to think about how they will transition from aerosols to dry powder, for instance.” Yet making these kinds of changes is not necessarily going to be easy, and involves instituting some long-term thinking from the very beginning. “If we were going to develop new molecules in the respiratory arena,” Rhodes says, “we need to ask whether we should be developing them in the future in aerosols, or should we stick to dry powder because we know carbon is going to be an issue? We’re going to be constrained, we’re going to be taxed, there are going to be issues with cap and trade. We have to realize that the choices we make now in R&D can have an enormous impact on our product portfolio in five or 10 years’ time. “So irrespective of the supply chain, there’s the whole point around what delivery mechanisms you’re going to have. In the supply chain, it’s a question of asking the right questions of the suppliers; for example, asking them what the carbon footprint is of the service they provide, or of a certain packaging material. Then we need to start asking what the options are to reduce or improve it. “It’s quite possible they’ve got something sitting on the shelf that they offered us five years ago and we said, ‘No, we don’t want that.’ And now we’re saying, ‘Actually, we might want that. We’ll have a discussion about it now.’” Rhodes points out that in some cases it may take suppliers a few years to develop more sustainable options. Th is may result in the offer of exclusivity for a certain period of time, and then the option to open the new product or material to everyone else. Because there is an upfront investment involved, they need to see some returns. Th is again ties into the idea of taking a more long-term view, rather than just viewing it as a one-time transaction.”

“We’re a very compliant industry, so pharma tends to follow things like environmental regulations and health and safety regulations. There is strong knowledge around compliance and policies and procedures"

Strategic moves In his role, Rhodes fields queries from colleagues working to make improvements in environmental sustainability. “They may say, for example, ‘We’re reducing the amount of packaging we use in a carton. Can you help us describe the environmental benefit of that change? We know how much cardboard it is, we know how much we’ve saved, but how does that equate to the carbon we produce, or the amount of trees or water we use?’ “Our brands are now also starting to work on sustainability strategies, because clearly people don’t go into a shop and buy two pounds of GSK. They go in and buy Aquafresh toothpaste, or a pack of Panadol. 93

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“Within its consumer division, GSK has created a 100 percent recycled plastic soft drinks bottle, and several consumer facilities have achieved zero percent to landfill” Th is puts more pressure on the brands to think about their sustainability strategies, which could be from how to design their packaging, what ingredients they’re using, where they’re sourcing them from, and whether they are sustainable. They may aske: What’s the difference between FSCcertified cardboard versus SFI-certified cardboard? Which one is better? Which one do we want? Can you help us with that? “We help with the technical aspects. They manage the projects, because it’s their brand, and clearly they’re the ones who own the budget and it’s their PNL. Our role would be to guide them in that, give them the tools and advise them on things such as: recycled equals so much, virgin might be something else, what the difference is between cardboard and plastic.” Rhodes says the VP Sustainability role within GSK is quite new, although he himself has been doing environmental management since 1990; the main difference being that this once consisted mainly of an auditor visiting the factories, writing policies on the environment and checking that they were being followed. The auditor would look at whether the factories were putting waste in the right place, managing effluent, and complying with the laws. “The shift in terms of this role is that now it’s much more around the product,” Rhodes underlines. “Environment health and safety management is one group in terms of operation, but now we’re also looking at

the impact of the product on the environment. The upstream impacts the downstream impacts which supplies are we using, are they ethical, are they not ethical? That’s the difference.” The other change, of course, is the much greater awareness among the general public about environmental issues, such as climate change, and the effects of excess carbon being created at all stages of the manufacturing process. As Rhodes points out, back in the 1990s, ideas about the environment tended to focus on “the smokestacks” – the direct impact of factories on air quality. Now things have become much more strategic. “We can see the beginnings of the need to internalize the external costs of carbon, where we’re going to have to start paying for carbon, whether it’s in the packaging that we use, the ingredients we buy, the increased cost of oil and so on. We have to be much more strategic with the environment – again, it’s looking longer term. “A project for the environment might have a payback of five to seven years. In the past, we wouldn’t have approved that. We would have said, ‘Two years is our criteria.’ But now we’re saying actually, spend it now, because it will save you an awful lot of money later on.” Ironically though, Rhodes says that when it comes to tackling climate change, it’s often the smaller things rather than the big, newsworthy projects that make the difference – the boring things that no one sees and no one wants to talk about: turning lights off, improving air handling, improving air conditioning, changing boilers. “Those are things that people don’t interact with and don’t get very excited with. You put a couple of solar panels on the roof and they all think you’re doing a great job. That will cost you $90 a ton to recover the carbon, whereas you get your sales fleet to drive a little more efficiently and it will cost you 10 cents a ton. And you’ll get that saving instantly.”

Nutritional goals In addition to its pharma division, GSK also has a consumer division, and within that a nutritionals business, and each of these is in a


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different place when it comes to an environmental strategy. The nutritionals division began work on its environmental strategy a few years ago, setting targets not only on energy and water, but also on working towards making their packs 100 percent recyclable, as well as having 50 percent recycled material in their packs and looking generally at sustainable sourcing. “You take a product like the drink Ribena in the UK,” Rhodes says, “which is a very old product and has a strong heritage. Consumers want to link to that product and feel that they can trust it. And, of course, they’ve got a choice. When they get to the shelf in a supermarket they could have Ribena, they could have Robinsons, they could have ownbrand labels. So you want to build that trust, which is why it makes sense for nutritionals to move quicker on some areas than say consumers.” Within its consumer division, GSK has made two key achievements: a 100 percent recycled plastic soft drinks bottle, and several of its consumer facilities achieving zero percent to landfi ll. “With the bottle,” says Rhodes, “we were using 20 percent recycled plastic and then we went to 30 percent, then 40. Each time we made a step change we had to do all the stability trials again. We had to look at the color of the bottles and we had to see whether anything was leeching out. And in the end they said, “Right, let’s go for 100 percent, and then we’re done. We’ll do the stability and then we’ll know. And if we can’t get enough we’ll go back to 90.” “It was great because it was iconic. It was a barrier, a bit like the solar panels on the roof. We just said, ‘Let’s do it, let’s go for it.’ And a lot of that is then having the drive and ambition. Wanting to be ambitious and take a lead as opposed to just being part of the pack. And it worked. And so they can say, ‘Great, we’ve done it now. We don’t have to worry about that any more.’ “The zero to landfi ll starts with somebody at the top saying, ‘We’re going to do this. And when we come to those difficult decisions, we’re going to fi nd an answer.’ You get strange things happening, like in the cafeteria we had a particular type of coffee machine that produced very nice coffee using these laminated pouches, but the pouches weren’t recyclable. “Suddenly we had a waste stream we couldn’t recycle, so we changed them. Then we get people ringing up and saying they don’t like the coffee, and we have to tell them they can’t have it any more, until they can come up with a recyclable pouch. So you do end up getting down to the minutia of trying to solve something.”

Greater awareness In terms of the future, Rhodes predicts that the big shift will be in transferring this awareness of sustainability from the consumer side, where the link with the brands already exists, into pharma. He allows that there will be hurdles, including the oft-mentioned regulatory aspects, but he counters that by pointing out that GSK has good engineers and good scientists. His feeling is that a lot of it comes down to just saying, ‘Th is is how we’re going to be.’ “There are some things that will help us along the way, and one of them is partnering,” says Rhodes. “Some of the key leverages are partnering with different suppliers and seeing how we can close the loop. Saying that if they provide this material, and we’ve got all these off-cuts, how can they take it back and use that somewhere in the process? Trying to push it and say that there has to be a solution. Chucking it in a landfi ll is just not sustainable. There’s got to be a better way out there. “It may mean we have to spend a bit of money on research; for example, we’re spending some money at the moment with someone who’s got some start up technology. If it works, then we’ve got an outlet for one of our waste streams that currently goes to landfi ll. “We’re also kicking off a trial in the US to look at recycling some of our medical devices back from the patient. We wouldn’t put them back into the medical devices, but if they end up as a car bumper, well that’s better than just fi lling a hole in the ground.” Regulatory hurdles are often cited as a barrier to increased environmental sustainability. While Rhodes concedes that there are hurdles, he believes there are not as many as some might suggest. “And whether the height of the hurdle is quite as high as we say it is is another question,” he says. “We tend to exaggerate. And sometimes we don’t ask the question, we just say that the regulations will never allow it, instead of going back and saying, ‘Actually are you sure that’s really what you want?’ “If you get it right in the R&D phase when you register it and you’ve got the design in there, then that shouldn’t be an issue later on. It’s addressing how many changes you make as a product comes up to patent loss in terms of processing, ingredients, packaging, because you realize it’s not going to be cost effective any longer. If you can do that when you’re worried about the patent hurdle, why not do it at the beginning?” „

“A project for the environment might have a payback of five to seven years. In the past, we wouldn’t have approved that. But now we’re saying actually, spend it now, because it will save you an awful lot of money later on”

Mark Rhodes is VP Sustainability Pharmaceutical and Consumer Healthcare, GlaxoSmithKline. 95

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The real value driver Patrick Lucy explains the benefits of protein expression and opportunity cost.


t the heart of most, if not all, biologic drug development programs is the ability to express human proteins in their proper three-dimensional state. Whether the protein is required for structural studies, analytical assessment, or per se is the therapeutic/vaccine candidate, it is imperative to rapidly produce high quality protein of interest in sufficient quantities for evaluation. The cost of delayed drug development is estimated at $1 million per day and the cost of each day of delay is the same, regardless of the source of the delay (due to inability to synthesize protein) during the drug development lifecycle.

“The cost of delayed drug development is estimated at $1 million per day” The traditional approach to protein expression is to seek a host perceived to be inexpensive, facile to use and accessible. Recent research suggests that this type of approach results in a 75 percent failure rate, with success being defined as high titers of soluble, active, high quality protein. Once the initial failure has occurred, most efforts will involve seeking alternative hosts in a linear, iterative and extremely costly process, until finding a solution, or in some cases, altogether abandoning efforts for expression and product development. Experience from a myriad of biotechnology companies suggests a recombinant protein host strain requires typically between six to 18 months of development time, to ultimately ar-


rive at a host that will meet near and long-term down selection is to test each antigen in vivo to needs. This development effort typically does not measure immunogenic performance. If a develoccur in one continuous effort, but rather during opment team approached this program in the periods of increased and intense product demand traditional linear and iterative fashion, it would during the development process. While this type of initially attempt the expression of each antigen approach is extremely common, it results in sigin E.coli. On average only two to three of the 10 nificant opportunity cost and manifests in delayed candidate antigens will be produced in soluble programs, inefficient use of resources, and overall active form. The remaining antigens require pipeline stagnation. screening in additional expression strains, at What if there was a single platform in larger scale, in alternative hosts or refolded, which one could screen hunwhich presents significant dreds to thousands of unique product quality/reproducibilhost strains using a high ity risks in addition to longthroughput, parallel approach, term cost of goods challenges. which demonstrated a success Alternatively, if the researcher rate of greater than 95 perexpressed the same set of 10 cent, and routinely delivered a antigens in the Pfēnex robust production strain capaExpression Technology, eight ble of producing high titers of to 10 soluble, active antigens soluble, active protein within would be available for evaluaeight weeks? This performance tion within five to eight weeks. would enable the drug developHence, as opposed to using er to express approximately the most efficient technology, three-to four-fold more prothe traditional E. coli apteins, and arrive at a producproach to protein expression Patrick Lucy is the Vice President of Business Development of tion strain in one-seventh the would incur significant opPfēnex Inc. He played a leadership time. The Pfēnex Expression portunity cost, at an extreme role on the original team that developed Pfēnex Expression Technology platform provides competitive disadvantage. Technology and subsequently led the successful commercial launch this type of success and speed Protein expression is at of the platform. Lucy is to drug developers. The platthe core of every pharmaceuexperienced in the areas of alliance management, licensing, form consists of a vast library of tical development effort, with intellectual property, biopharmaceutical operations and expression components inthe challenges experienced by biopharmaceutical facility design, cluding novel proprietary plasprotein expression scientists construction and validation. mids and host strains. These significant. Antiquated techcomponents combined with nologies with limited tools Pseudomonas fluorescens’ obligate aerobic nature simply cannot meet the challenges posed by and a robotic, parallel screening process results in today’s next generation drug development unprecedented protein expression speed and sucprograms. The Pfēnex Expression Technology cess rate. platform provides a robust solution to the As an example, consider a vaccine developchallenge of efficient, high quality protein exment program for which the innovator compapression, and enables drug development with ny has identified 10 putative antigens for a the avoidance of millions of dollars in opporvaccine formulation. The ideal approach to tunity cost. n

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Quality data Understanding the final FDA guidance for patient reported outcomes. By Scott Dixon


n December 2009 the Food and Drug Administration (FDA) released its final guidance for industry on patient-reported outcome measures to help the biopharmaceutical industry understand what the agency will be looking for when it reviews new drug applications that include patient reported outcome (PRO) data. Th is guidance has been under review for the last three years and has become increasingly anticipated with the rise in post-approval drug surveillance and the growing need for quality data gathered directly from patients across all phases of drug development. In the guidance, the FDA affirms that the federal code (21 CFR 312 Subpart D) outlining the general responsibilities of sponsors applies to PRO regardless of the technology (including paper) employed. Within these responsibilities are strict mandates for detailed record keeping and providing access to the FDA to conduct source verification on the data. This traceability requirement recognizes the limitations of paper-based data collection methods, particularly the lack of an audit trail. Further, the FDA wants to ensure that study participants are adhering to trial protocols, meaning if they are supposed to be completing a diary at specific intervals they are complying with that protocol rather than sporadically entering historical data. Again, this acknowledges the restrictions of paper, as there is no ability to track when and where a patient enters data. These assertions provide validity to electronic PRO (ePRO) as there is a time stamp, and hence an audit trail, when data is collected electronically. The experience of many providers has shown that the data collected by ePRO is more accurate, more timely and more comprehensive than traditional paper models. Along these lines, the guidance also provides direction for moving from various modalities and validating the modal change. An example would be moving from paper to electronic, be it web, personal digital assistant (PDA) or interactive voice response (IVR) systems. When the technology moves from paper to electronic there is a substantial change to the structure of the instrument and the FDA wants to ensure this technology shift does not impact the validity of the data entered. The closer the new mode can approximate the previous structure, the more easily the format’s adequacy can be confirmed.

With web-based ePRO, an entire form can be displayed, and font size, color schema and so on can more closely match the paper form than what is possible with a PDA or an IVR. A PDA device only allows for review of one or two questions at a time, resulting in context being lost, which could impact how a subject completes a form. Additionally with IVR, the technology itself can limit the type of answers a patient could provide. For example, with multiple choice questions, paper, web-based ePRO and PDAs allow more than one answer to be selected, giving a range of data. An IVR, however, is often limited to only accepting a single answer, affecting the scope and accu-

“The experience of many providers has shown that the data collected by ePRO is more accurate, more timely and more comprehensive than traditional paper models” racy of the data. The validation doesn’t simply go away when shift ing from a paper instrument to a web-based ePRO, but it can become more straightforward. The focus of this guidance, in essence, is the need for sponsors to follow accepted development models and good documentation practices and ensure adequate validation is in place, as well as to consider various patient-reported outcome options. It requires sponsors to be able to clearly demonstrate the documentation, validation and change control, and have adequate records of all the development testing and validation. All of this is consistent with and further re-emphasizes previous FDA guidance and regulations; including 21 CFR Part 11 and other guidance for computerized systems and clinical investigations. This guidance extends earlier instructions laid out by the FDA and conforms to the general regulatory framework it has established for collecting clinical trial data. „ Scott Dixon is Vice President of OutcomeLogix Group and Global CRO Partnerships. He has more than 18 years experience in the healthcare, life sciences and pharmaceutical industries. Prior to this role, he was Chief Operating and Strategy Officer at ePRO provider Maaguzi LLC, which was acquired by Phase Forward in July 2009.


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Celgene Corporation’s Kamal Shah looks at why most new drug compounds fail to progress beyond the clinical trial stage.


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espite all the scientific advances made over the past couple of decades, one of the main challenges in the pharmaceutical industry remains the failure of many drugs to reach successful registration and approval. According to Kamal Shah, Head of Global Trials Safety Surveillance for Celgene Corporation, the number of drugs that progress from discovery to approval hasn’t changed much, in terms of the failure rate still being very high. “The pharmaceutical industry needs to come to a consensus and perhaps learn from the past and figure out where the biggest failures are occurring,” Shah says. “There are usually ample warnings from discovery all the way to the registration and approval process, but somehow the people working on these projects are missing them. Th is could be because they are focused on their own career aspirations. “If you look at the development of a compound, most of the people who start working from phase I or earlier are in charge of that compound, and the failure of that compound could affect their career development. The f lipside of that is that they may hype up the compound rather than thinking more scientifically and perhaps more critically about its chances of success or failure. If the drug succeeds, of course, everybody working on it gets the rewards, so it’s a Catch 22 as to how to get away from that model. “I’m sure other scientific areas have the same problem, and they have found a way of lessening it. If there was an independent review in the middle of or at every stage of the trial, it might make this process more successful. We can’t eradicate the failure rate completely, of course, but if it could be reduced by only 10, 20 or 30 percent, that’s a huge amount of research money going somewhere else.” The other challenge Shah points to is that the US is paying for a lot of the innovation in research and discovery, which is not necessarily compensated when the resulting drugs move into other markets. “In poorer countries where government resources are stretched, this is understandable,” he says, “but for developed countries there is a need to share the burden of development rather than it being placed on only one or two countries. There are a lot of countries that can afford to pay, and they need to come together, just like the EMEA has become one body. I’m sure if the organizations like the FDA, the EMEA and the Department of Health worked together, they could come up with some formula of how to divide the expenses.”

Safety first Patient safety is obviously a critically important consideration in clinical trials, and awareness is certainly not a problem within the industry, as Shah points out: “It’s not a question of whether people are aware of safety in clinical trials, because if somebody’s living in today’s world, I’m sure they’re reading the paper, looking at the compound and probably most of them are involved in answering the questions from the regulatory agency about safety. “The challenge on the clinical trial side is that efficacy is the driving force. Safety brings bad news occasionally to the table, and that’s one of the reasons it has not been accepted as a member of the core team, maybe just by default. The bearer of bad news is never welcome anywhere, but the teams need to look at this and the critical approach of how can you ignore safety, because drugs are approved now based on the benefitrisk ratio rather than just efficacy. “In order to reach an acceptable level of safety, you have to make sure that safety is fully in tune and working right from phase I trials into human, all the way through. There are a lot of challenges involved in improving safety and listening to the dose selection as well as all the risk mitigation strategies that make a potential failure down the road less likely.” 101

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0 1 2 3 4 5 6 7 8 9 10 11 12



trial population, making it easier to get drugs accepted worldwide. However, he also points to the challenges that deProduct Sureillance Phace IV Introduction velop through the need to satisfy local agencies and regulations and practices, Registration which can occasionally throw a wrench 1 into proceedings. Despite this, Shah sees the interPhace III nationalization of clinical trials as a 2 Clinical Tests continuing trend within the industry. (Human) Phace II 2-5 “A lot of companies are trying it. It Development allows them to get good enrolment 5-10 Phace I from a lot of areas outside of traditional, research-based centers. They Preclinical Tests also get exposure to patients who are 10-20 (Animal) not controlled in the same fashion and Substances so might help indicate how the drug Basic 10,000-30,000 might react when it gets marketed, so Synthesis, Research Substances you have better population exposure.” Examination Another thing that Shah sees & Screen evolving in the next five or 10 years is the development of more collaborative It has become almost impossible to separate safety from efficacy in partnerships with local expertise, either internally or acquired through clinical trials, because regulatory agencies now ask for a benefit-risk aspartnerships with service providers. He predicts that service provider sessment as a combination. “The problem there is that the assessment of industries are going to continue to grow in terms of being the source of acceptable risk is never well defined,” says Shah. “For many major diseases doing a lot of trials. it’s not very difficult, but there is no consensus amongst different regula“The question is whether they will be able to maintain the talent tory agencies in North America, Europe and Asia, for example. pool, which keeps changing,” Shah says. “Quality of service is never “The regulatory agencies worldwide are attempting to come up with guaranteed for the duration of the trial, even with the best companies. a formula for assessing and giving a number to the benefit risk, but that’s “Personally, I also feel there is a strong need for collaboration beanother big challenge. You can put a number on efficacy, and if you reach tween academic centers and pharmaceutical companies, because most that, you succeed. With safety, things need to be considered on an inof the targets are being developed or invented or discovered at academic dividual basis: drugs have idiosyncratic centers, and then the development of the comreactions and some behave differently pound goes to the pharmaceutical industry. in, say, a patient who is compromised “There needs to be stronger, more collaborin liver function or renal function. ative efforts between the academic centers that Th is has to be individualized and acted can bring a lot more science to the table, rather upon. It will be very difficult to come than just a faster approach to the development up with a fi xed number where you say, process, and maybe can help in selecting the ‘Okay, this is the benefit-risk ratio, and best candidate, rather than just a candidate. if the number is one, then the drugs get There are academic centers that can bring more approved or not.’ It’s an evolving scipartnership to the table, even for conducting ence in terms of how to perfect it.” trials, which is right now one of the biggest reasons for failure. Trials could be conducted International outlook either in collaboration with or maybe even inAnother change in the clinical trial dependent of the pharma industry, which gives landscape has been the number of trials being conducted internationally. the potential for a better success rate. In Shah’s view, international trials are a very good way of making sure “The active involvement of large academic centers, the involvement the drug is exposed to varieties of populations and individual country of good research physicians and the people who are at the forefront on practices and habits as well as individual genetic considerations that may the treatment side of the disease, would bring a lot to the drug developbe brought in by different parts of the world. ment and clinical trial process.” „ He underlines the fact that the opening up of certain areas, such as Latin America and Southeast Asia, has brought more diversity to the Kamal Shah is Head of Global Trials Safety Surveillance at Celgene Corporation..

“Trials could be conducted either in collaboration with or maybe even independent of the pharma industry, which gives the potential for a better success rate”


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9/2/10 09:16:22


Effective site management Christene Leiper explains how identifying key challenges and improving site management can save time and reduce costs.

has been minimal and the evaluable number not reached, this has led to poor results and in some instances a failed study. While any one site might be performing well in a clinical trial, others may be falling behind in areas such as patient enrollment or data collection, or there may be other issues that prevent an individual site from performing well. It is in your interest to identify the issues quickly, before they become a significant block to trial results. A good project management team can help here and ensure your trial stays on track.

Key site management tips Identify, qualify and select the right sites Negotiate good site contracts and budgets Get supporting sites in local or central IRB/IEC submissions right


ny clinical trial is only as good as However, there is more to selecting a PI than its weakest component, and adjust these criteria. A PI must be the right one dressing this makes for a stronfor your trial. They need to have the right reger, more robust project. Poor sources available and must be ready when you site selection and poor site management can want to start the trial. be costly in terms of resource and time allocaSome PIs are so much in demand that tion, and also the clinical trial a clinical trial start date is budget. Any efficiencies that delayed. It then becomes a lead to quicker completion of trade-off: do you wait for the studies will provide an opporinvestigator or choose someone tunity to bring a drug to market who is less in demand? quicker, or at the very least make For day-to-day running of a decision on the suitability of a trial, sub-investigators play a a drug for market easier and major role, but it is the PI who reduce trial costs. Recognizing is the responsible leader of the this, pharmaceutical companies team. Once again, the chalare partnering with innovative lenge is to select the right site CROs to manage site selection and look at the whole team, not Professor Christene Leiper has and management. just the PI. over 25 years of experience in clinical research. She is For any study to succeed, Subject recruitment is President of Onorach Ltd., a CRO located in Scotland it is essential to choose the also crucial. There needs to with a global focus. The right investigator. A principal be a proper search of patient company philosophy is to engage with clients as a investigator (PI) should have a records to justify selecting clinical trial partner and it has experience in site selection formidable knowledge in the a site. In the past, sites have and management. Prof. Leiper therapeutic area of the trials and been selected that have said can be contacted at christene. also strong knowledge of how they have sufficient numbers clinical trials are conducted to for a study, when in reality the FDA requirements. It is critical that the PI’s subjects have not matched the criteria needed resumÊ is adequate for the trial undertaken. for inclusion. Where the subject population

Design/produce training materials to ICH-GCP standards Conduct site training on key aspects and on ICH-GCP requirements for the trial Establish toll-free help lines with 24/7 access Track/document project communications for Trial Master File compliance Provide sites with regular study updates

Clinical trial management by a CRO that understands the importance of good site selection can assist in the navigation of the clinical trial project, taking the burden off investigators so that they can focus on the patient, and ensuring that the study is conducted at the highest standards of quality, ethics and performance. Th is support ensures collection of the robust, high-quality study data necessary for regulatory and product approval submissions. By making the right choices in site selection and management, pharma companies can reduce risk, reduce cost and reduce the time taken to complete a clinical trial. „


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Streamlining data Amy Furlong explains why a centralized data system is more reliable.


ncreasing cardiac safety concerns have resulted in heightened regulatory scrutiny and the requirement for quality electrocardiogram (ECG) data to be provided in the early stages of drug development. Currently, a decentralized ECG study model is used in many clinical trials to monitor a new drug’s effect on the electrical functions of the heart. A decentralized system involves ECG studies being carried out across multiple investigator sites using local ECG machines. However, this approach has a number of limitations, including poor accuracy, consistency and efficiency of ECG data. A centralized approach has been found to overcome these shortcomings.

“Not only does centralization reduce inconsistencies that may occur from site to site, it alleviates sponsor/CRO and site burden” Centralizing the collection of quality ECG data, using digital ECG systems at a core laboratory, accelerates the analysis process. Using high resolution digital methodology allows for more dependable data to be generated, as transcription and misinterpretation errors associated with a decentralized approach are eliminated. The improved reliability of data collected using this approach leads to significant cost reduction and reduces the need for re-testing. Some digital ECG systems offer the additional benefit of automatically checking for missing visits or changes in demography. A qualified cardiologist at the core laboratory evaluates each ECG, which ensures maximum data quality and consistency. Not only does centralization reduce inconsistencies that may occur from site to site, it alleviates laboratory and site workloads.


Additionally, the centralization of ECG analysis Conventional ECG systems produce paper eliminates unnecessary over-read fees and reprintouts of key ECG data, which are transcribed duces site technical fee payments. Using centralin order for results to be analyzed. Transcription ized equipment is an integral feature of a core errors often occur, leading to inaccurate results laboratory, requiring no extra expenditure for and impacting the overall validity of trials. These machine rental. new modern instruments work by directly upTo enable trial sponsors to take full advanloading data onto the core laboratory computer tage of these centralized ECG model benefits, insystem, eliminating transcription errors and innovative new instruments are necessary to creasing data accuracy. provide improved accuracy, reliability, space effiAlthough not officially mandated in current ciency and cost effectiveness. Conventional ECG legislation, regulators often request that digital machines can weigh between seven and 10 lbs ECG data are submitted to a central digital sysand be of substantial size, tem, known as a data waremaking them expensive to house. All data stored on the transport and store, as well as system can then be accessed time consuming and difficult by regulators, facilitating and to prepare for use. Average accelerating inspections. The rental costs for such machines latest centralized digital ECG generally vary between $100 systems enable clinical trial and $150 per month. sponsors to easily comply Recent technological adwith this requirement as they vancements will see the introstore all data centrally and duction of highly compact simply transfer them to the ECG instrumentation, prodata warehouse. viding full ECG functionality Advanced software at a fraction of the size of traplatforms have also been deditional systems. veloped to enable seamless Amy Furlong is Executive Vice President of Cardiac Safety Revolutionary new instruintegration of new instruOperations for ERT. Furlong holds a ments that will substantially ments into existing computBachelor of Science degree in Biology and a Master of Science reduce the costs of centralizaer systems. This is degree in Quality Assurance and Regulatory Affairs from Temple tion are being developed. particularly beneficial in University’s School of Pharmacy. She These small hand-held determs of both staff time and has more than 10 years of clinical research experience, specializing in vices are easier to maneuver cost, especially to sponsors regulatory compliance and computer system validation. and significantly less expenand CROs where the invessive to ship and store, making tigator site is not familiar it easier for companies to adopt a centralized with ECG systems. New centralized digital ECG system. Integration of these new instruments solutions, which will feature the new instrumeninto computer systems will enable information tation, demonstrate clear benefits over tradito be automatically downloaded before a trial, tional decentralized methods, ensuring patient saving staff time and costs associated with prosafety and regulatory compliance while reducing gramming correct algorithms and patient desite burden and increasing accuracy, reliability mographics. Utilization of this advanced and usability. n instrumentation, with the process enhanceFor more information, please visit ments and reduced site and sponsor burden, will For further information, please contact Amy Furlong at ERT. Email: result in measurable cost savings.

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NGP talks to GSK’s Paul Matthews about the unique challenges posed by the marriage of imaging and drug development.


eing the Vice President for Imaging at GSK is not just a job for Paul Matthews. Speaking to him, it is immediately clear that he is passionate about the opportunity to bring chemical imaging to the heart of drug development. As he explains, this is not because it is just another test, but because it creates greater confidence in drug development, particularly at the early stage. He notes the current challenges of a high attrition rate in the industry – when attrition is late in the drug pipeline it’s both extremely expensive and time-consuming, and is not doing either the patients or the industry itself any good as a result. “We’d like to bring confidence in decision-making early and we can do this by trying to study pharmacology in humans in the same ways that we’ve become accustomed to and with the same detail of information we’ve been accustomed to getting in pre-clinical species. In order to do this, we need to have powerful non-invasive approaches to quantitative physiology and pharmacology. This is what imaging is really all about,” explains Matthews. “While I speak of imaging in the context of drug development, it’s not about developing pretty pictures, although that’s a side benefit. It’s

about providing quantitative information related to where a molecule might move in the body in a biodistribution study, molecular interactions of a putative drug with its target, or about physiological responses of the human tissue. This is what imaging can bring to us and its confidence in decision-making is the impact.” He describes the current relationship between drug development and imaging as an “interesting period of marriage”. Matthews adds that the technology connecting the two has been missing for some time, at least in principle, but what has really been missing is the connection of drug development in the hands of people who understand how to use the information that’s derived from investigation and those with an expertise in imaging. “Bringing imaging to drug development isn’t just about going down a checklist,” he says. “It’s about developing powerful questions and then finding the technology that answers those questions and not different ones. Previously, the limits placed on the ability of the imaging to have an impact on drug development happened through parties that were not engaged with the same agenda. A company would go to an academic site or an external CRO, who had a limited understanding either of the problems of drug development or the specific problems of a molecular series.


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“By communicating the results of trials and the rationale leading up to them in an open public forum, we can increase the quality of the science�

GSK Imaging Centre In partnership with Imperial College and the UK Medical Research Council, GSK has built a Clinical Imaging Centre (CIC) at Hammersmith Hospital in London, UK. The CIC houses leading imaging scientists and state-of-the-art PET and MRI equipment. The imaging center partnership is one of the largest industry-university collaborations.

The goals of the CIC include to: - Accelerate effective drug discovery and development in GSK - Establish a center of excellence with a critical mass of imaging expertise - Develop and utilize imaging methods for novel molecular targets from the GSK portfolio - Characterize the distribution and pharmacokinetics of novel drug candidates in man - Characterize key human diseases represented by the GSK portfolio - Develop and implement novel methodologies for the above 109

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“Here, what we’ve been able to do is actually merge clinical teams developing drugs with teams delivering this high-level pharmacological and physiological data, so the two have a common language. The questions can be translated across. The tools can be suited to the problem. And that’s what is beginning to make these studies impact rapidly. To give you a flavor for this, in the last seven months we’ve done as many studies with the opening of the imaging center and bringing it up to full speed, as GSK did in a similar area over the previous couple of years, and that’s because we can make things move much faster, do studies that count and bring value to the company and, ultimately, to patients.”

Communication R&D is one of the key functions in which science and the business of pharma are merged, and ensuring communication between the two is essential. However, this is no easy task. Matthews explains that communication is the number one challenge facing any large organization among the three issues that each organization must face. “One is communication across R&D itself to help this very broad organization learn to optimize its ability to work together, so that we don’t have individual drug units pursuing similar problems without knowing about each other. “The second area of communication is perhaps even more critical if we’re to transform the industry, and that’s to communicate the needs of late-phase development into early phase and to merge the problems that late phase will encounter in the clinic into the early development decisionmaking. And, in turn, to use the science from early development to translate out to late phase, to help define the populations that are targeted for a new treatment, the way studies are designed and also the way in which the potential benefits are communicated. “That leads to the third communication problem. Making drugs is fundamentally a very complex scientific effort. We need to get away from the notion that every drug hitting the same target is equivalent and communicate the potential differentiation of our molecules, which we’re working towards from the very beginning of discovery way out past the stage at which it’s marketed. “We need to help physicians and patients understand the differences between drugs within the pharmacopoeia, but also the differences between the way drugs may act in different kinds of people. This is a new type of agenda that we’re going to have to grasp. I’ve mentioned three: communicating with R&D, communicating between early and late-stage pipeline and communicating the science of drug development to the user population. But they’re all wrapped up together. It’s about making science the core of drug development and being transparent about how the information is used in the process,” he says. Matthews explains that actively promoting this course of communication throughout the organization is something that the senior executives within GSK’s R&D department are attempting to do. He notes that one key element that has been taken into account is to create working teams that are small enough to speak together, are co-located and have a limited agenda, which allows issues to be fully aired and done so openly amongst larger segments of the group. These groups have been named development performance units, or DPU. Matthews explains that the major drug development units, either the larger units or the former Centers for Excellence in Drug Discovery

(CEDDs), have been divided up into these DPUs. The size of each unit ranges between 40 and 70 people, all of whom are located on single sites, and this allows for face-to-face communication on a regular basis. However, although this brings many advantages to the communication process, by dividing up a big organization into smaller units the risk remains of failure to communicate between each DPU. “To some extent, this is helped by organizing clusters of DPUs together as CEDDs, or units as in oncology,” says Matthews. “For our pharmaceuticals, where the leadership regularly meets together with a leader of the CEDD or unit in order to develop coordinated strategies and provide a communication strategy that, again, is limited to a relatively manageable number of players who can meet regularly, face to face. “You can understand that I’m a great fan of trying to get human-tohuman contact to make those communications. Now, fi nally, what we’re trying to also do is create structures that move across DPUs and CEDDs and begin to share what is learned from one with the others. These take a variety of forms; they’re suited to the problems that they’re trying to address.”

Challenges Matthews provides an example of GSK’s peer review forum – a group of senior clinical scientists who meet on a weekly basis to review new protocols coming through drug discovery. The review is voluntary, although it is taken up by almost every unit moving protocols forward, and provides feedback on the science and attempts to help create the strongest protocols possible. In doing so, the hope is that expertise is brought across from one unit to bear on the problems of another. Another challenge that continues to increase is the identification of disease areas that are being pursued across DPUs or CEDDS. Matthews notes that discussion groups are coming together to look at the strategy for the company in terms of the science and the relatively autonomous units that lie beyond that. He also notes that there are a number of higher-level mechanisms that are set up to provide scientific feedback in the form of scientific advisory boards that sit above the CEDDS and DPUs, in which learnings are shared so the best science can be produced, as well as to allow a good accountability for safe clinical practice and trials. “It’s not a solved problem. It has to be addressed at multiple levels using different approaches. One of the things that we’re trying to grasp is making person-to-person contact the foundation of this, because that’s ultimately what’s so much more effective,” says Matthews. Internal communication is essential for better science and employs an equally critical role for the wider public – more information communicated on the same level of efficacy and depth of R&D has the potential to cut down on health scares. Matthews explains that some recent examples of this have been generated by the pharmaceutical industry itself which failed to communicate the science well to the news media, who misunderstand as a result. So how is this to be remedied? Matthews believes that it will be a slow process, but one in which GSK can be confident and successful. “First, we’ve got to create an open, transparent industry. We have to be able to communicate why we’re pursuing the areas that we are. We have to communicate the importance of science and objective thinking being at the


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basis of our decision-making. And, finally, we have to be able to commuthan being carried away by the need to move a molecule on to the next nicate this science, the results of clinical trials for example, in a fully open stage. Bringing together scientists from different backgrounds is vital and transparent fashion. so that they don’t carry the same biases to the problem. GSK’s aim is to “At the same time, we have to be willing to engage our scientific comcreate an independent development unit, contributing to drug efforts in munity and even the public in very open feedback. We have to get away multiple CEDDs, DPUs and units. from KOL meetings that are stacked with people who we think are going GSK’s overall strategy is divided into three priorities – to grow, to provide us the right answers. We have to go out and find the people deliver and simplify each specific role in each area of responsibility. who are going to be able to comment the most robustly and provide the Matthews explains the importance of simplicity: “When companies strongest opinions on what we’re trying to do. That’s GSK’s commitment grow, there is an effort to address many problems – communications, now. By having open science, by communicating the results of trials and governance, coordination – but what they inevitably do is create more the rationale leading up to them in an open public forum, we can increase and more rules, so it becomes increasingly byzantine. the quality of the science, because now it’s being tested against the best the “Our goal, as a group within GSK that is trying not just to conceive scientific community has to offer. clinical trials, but to execute them, and not just ordinary clinical trials, “We can also help the public have more confidence that decisions but trials that put a premium on speed and efficiency, our job is to try to aren’t being made behind the backs of everyone, that things aren’t being identify the hairballs that we can throw out of the mix to try to help us hidden. Finally, we have to continue to address the issues move more quickly. So simplification is something that of scientific ethics and business ethics throughout the becomes critical to our business case. process. We have to make sure that the motivations of “We depend on being able to move rapidly from the people we have involved, both within the company solutions to one problem to the challenge of solving anand outside, are transparent and appropriate. other. If we’re mired by bureaucracy and unnecessary “We have to appreciate the tremendous responsibilcomplexity, our mission is going to be severely limited. ity that has been vested in the pharmaceutical industry So simplification is something we’re taking to heart. to be the primary bringers of new therapies to the public. We’re continuously re-examining all of our processes We have to recognize that we have a pact with the public and the way we relate to our partners; we’re trying to who depend on our drugs, with the shareholders who bring out unnecessary elements to do all the simple are supporting the company, to be ethical in everything things like cutting meetings, making meetings more we do. If we begin to stray from that, we’re only going to focused, but also to try to make all of our processes as hurt ourselves. simple, transparent and needs based as possible.” Paul Matthews is Vice President for “GSK has taken these values very strongly to heart; Growing the company is also important – transImaging at GlaxoSmithKline and Head of the GSK Clinical Imaging they’re a core of what we’re all about. An example of lating value into growth is the company’s strategy. By Centre. this is our peer review group that vets every early stage growing in quality rather than quantity, GSK can bring protocol going through, trying to provide good scientific greater value to the market. Matthews explains that input. This group includes not just GSK staff but also external scientific the focus is on making more rational, early-phase decisions, which will advisers, who are independent of the drug pipeline of progression and drive better drugs for patients. who can openly look at our science and provide us with the clearest docuHe envisions delivery as having a sense of urgency, which permeates mented feedback that we can get from them,” he says. throughout the organization. Interactions between DPUs and CEDDs are fast-paced, making the drug development timeline significantly Technology shorter. “We’re trying to bring more patients into the organization in GSK has a track record of turning such fi ndings into powerful and regular discussions about what the patient needs, so that we can show marketable drugs; Matthews explains that drug development must not the bench scientists what it is like to have the disease that we’re trying only have strong communication to be successful but also be collabto work on. orative. “We’re in a very special place; we’re at the interface between “We’re also trying to bring an intelligent plan to drug development pre-clinical science and clinical science, trying to translate the fi ndings so that we don’t repeat things that don’t need to be repeated. So urgency, from our pre-clinical colleagues into pharmacology in humans to help and bringing science and a considered development approach to the provide confident decisions moving forward. problem, are how we’re trying to bring delivery. “We see that as our space. Again, we try to be fi rm, open scientific “Our belief is that with a rational development process, with a scicritics of the development program; we try to ensure that we’re asking ence-based development process and with a very open and transparent powerful questions that will either help a molecule move forward, if approach to that science, we’re going to ensure that the molecules that it’s appropriate, or kill a molecule if there is good reason to stop the we’re moving forward deserve to be moved forward, and that we addevelopment.” dress efficacy and safety issues that need to be highlighted at the earliest To take on this challenge, GSK has a range of scientists participatstages possible. Th is limits the amount of resources, ultimately, that we ing in development; this range is varied and they do not all share the may waste. And in the end, it is going to deliver products of real value same scientific agendas. Th is allows the project to be objective rather to the market.” „ 111

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How the integration of appropriate imaging modality increases the efficiency of clinical trials By Michael Morales and Bruce Hillman


he capabilities of imaging today possess far more extensive applications than existed 100 years ago. With conventional procedures being replaced or enhanced with more advanced novel imaging or nuclear modalities, researchers are gaining a wealth of resources for various functions. Thus, imaging plays a far more active role in the development process. Moreover, the integration of the appropriate imaging technique in a development program reduces necessary time and costs, thereby increasing its efficiency. In selecting the most appropriate modality, several considerations must be made. Each development program possesses distinct attributes and goals that must be addressed before imaging can be integrated. How will the imaging be utilized? Will the information serve as a biomarker, endpoint or marketing tool? In each of these situations, imaging operates in a different capacity. As a biomarker, imaging provides a more comprehensive analysis of therapeutic effects and pathways of action; in early phases, imaging can be incorporated to elucidate mechanisms, reveal drug activity and assess the value of a new medical device. As an endpoint, imaging shortens the time to reach conclusions. During certain situations, data may be collected that will not contribute to the regulatory application; this imaging is often useful in marketing functions after approval has been received. Thus, imaging plays a role in every step of the development process. If properly employed, imaging reduces time and cost expenditures primarily by lowering variability in decision making. With earlier results in safety and efficacy, researchers can make go/no-go decisions sooner without consuming unnecessary energies while

waiting. One application of this exists when contemporaneous, original and accurate, some changes in glucose uptake in cells over time method of archival must also be established. are critical to the recognition of drug activACR Image Metrix utilizes a proprietary ity; including a conventional PET scan using system, TRIAD OA, for the anonymization, F18-FDG eliminates the wait as FDG more re-identification, analysis and archival of quickly mimics the actions of image data. TRIAD represents glucose. Likewise, DCE-MRI the data management changes allows earlier estimates of that imaging has effected in drug efficacy by examining the the development program envascular changes in a tumor, vironment because it supports which begin more quickly than seamless, rapid management actual tumor shrinkage. of data through the use of the However, imaging soluweb. Where sharing images tions would lack relevance once involved multiple steps, without cohesive data managenow data can be uploaded Bruce Hillman, MD, is the Chief ment, which actively demands onto a secure site to promote Scientific Officer for ACR Image standardization in data acquiinstantaneous action. WithMetrix. He has been selected for Who’s Who in Medicine and sition, management, quality out delays in image transfer, Healthcare and Who’s Who in the World. Prior to his experience control, archival and analysis. the image can be QC’d by the with ACR Image Metrix, Hillman The first step in standardized imaging technologist for readwas the Chair and principal investigator of the American data acquisition is validation, ers to perform interpretation College of Radiology Imaging Network (ACRIN). which examines and qualifies and quantitative analysis more the utilized technology as a quickly, without information whole, including the computgetting lost between steps. ers and users. Because image Henceforth, imaging will acquisition involves an inhercontinue to play a larger role in ent risk for human error, users development programs, from must be trained in accordance start-up to post-marketing with SOPs and GCPs while activities. As this technology the technology is being tested continues to be refi ned, its role to create an environment of in clinical development will control. Image management only increase. Already, its must establish means of source benefits boast streamlining Michael Morales holds the documentation in accordance the decision making process position of General Manager with ACR Image Metrix. As such, with HIPPA regulations and and necessitating stronger Morales has responsibility for strategic, tactical and financial must ensure the integrity of operational data management operations. His accrual of over 30 the image collected during inprocesses. Clearly, imaging’s years of experience in organizing and coordinating large-scale terpretation and quantitative contributions to success jusclinical research to accelerate drug development programs analysis. Because source data tify its inclusion in your study involving imaging is critical to the must be attributable, legible, today. „ success of his position.


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The perfect storm

the current gold standard of care, cost-effectiveness, long-term risk management and satisfying reimbursement criteria. While elements of value creation, such as patient-reported outcomes (PROs) or quality-of-life measures, can be incorporated into phase II or III clinical trials, the real goal of these studies remains getting the drug licensed and it is imperative that this goal is not compromised by building in too many more objectives. Hence the need to have a longer term strategic clinical plan that includes post-marketing studies. These studies are concerned with what the product actually looks like in real life, rather than in the highly selective context of a mainstream clinical trial. For example, in a real-world setting patients may have several diseases and be taking several therapies at once. To pursue late-phase development effectively, though, requires specific expertise that goes beyond that employed in the traditional phase III setting. Expertise is required in areas such as PROs, health economics, statistics and outcomes research and, as with all forms of research, the key success factor is designing the studies correctly from the outset. Nurses and patients can also help to fill out a drug’s profile post-approval. Sponsored nurses not only play a crucial role in patient education and compliance with therapy, they can also collect outbiotechs remains under heavy pressure in a capcomes data from hospital databases under conital constrained environment. Pharmaceutical tract. Patients can also contribute through media companies need to re-examine the way they such as the iGuard online medical monitoring sermanage the lifecycle of their vice, which was launched in drugs, in particular the role of 2007 with start-up funding from late phase studies if they are to Quintiles. The service now has differentiate their products over two million users. and build a comprehensive Ultimately however what value proposition in an inis required is a major change in creasingly saturated and thinking to ensure there is a payer-dominated marketcontinuum of studies, which place. If they don’t take up this encompass both the more trachallenge, the payers themditional and the more innovaselves will be only too happy to tive approaches, which will step into the breach and, in the provide the right data at the end, it will largely come down right time to satisfy the needs of to price. the increasing stakeholder John Hall is Vice President, Global Ultimately it comes down groups. It is only by thinking Medical Affairs, Epidemiology and Outcomes Research for Quintiles. to real lifecycle development. strategically early on in the deA former practicing physician, The concept of value has velopment process that the bioHall brings over 25 years experience in development and widened to encompass not just pharma industry will be able to commercialization strategy, having served in medical affairs whether a drug is safe and continue to develop new and with Eli Lilly, Glaxo, Allen and ‘works’ but other key factors better medicines that deliver Hanburys and an independent consulting company. such as how it performs against real patient benefits. n

John Hall tells NGP about the burning issues in the biopharmaceutical industry.


here is a new health landscape in which the rules are changing on all fronts. Patients are taking more control over decision-making regarding their treatments, with access to a wealth of information available at their fingertips on the web. There is also a greater emphasis on safety on the part of both regulators and consumers. Furthermore, there is a greater value consciousness on the part of both patients and payers. This means that there is a heightened need for different types of data for the changing stakeholder groups that goes beyond the data traditionally gathered for the regulatory authorities. It is now vitally important to consider these needs and to do so early in the drug development process. These drivers have contributed to ‘the perfect storm’ for biopharma companies. Going forward, it is easy to envision how the impending ‘patent cliff’ that is unfolding will serve to heighten the pressure that the biopharma industry faces. Specifically, from 2009 through 2014, an estimated $128 billion of branded revenues will go generic. At the same time, funding for



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Turning pipelines into profits How drug discovery bottlenecks can be addressed, according to Grace.


ew people genuinely enjoy change, but the pressure is on for pharmaceutical companies to change the way they do R&D, to more efficiently produce new drugs in a post-blockbuster world. A visionary might approach bottlenecks in their process by developing a custom solution such as specialized software or equipment platforms. While the emphasis on new technologies and innovations is commendable, such custom solutions are often complex and risky, adding significant time and expense. Thankfully, ready-made commercial solutions, such as the Reveleris flash chromatography system, are available to address bottlenecks in the drug discovery and development process. As discussed in a recent Chemical and Engineering News article, the days of feeling flush with cash are over, and the pharmaceutical industry must begin making simpler, more effective changes. Recent attempts to reduce overall drug development costs have included drastic cost cutting and ‘merger mania’. However, the industry’s attention has now shifted to examining and im-

“The pitfalls of customized solutions can be avoided by implementing commercially available solutions” proving processes to shorten R&D time and fuel the pipeline. This is a critical time to consider the difference between customized and commercial solutions to productivity opportunities. The productivity of the pharmaceutical industry is often measured by the quality and quantity of new drugs in the development pipeline. Those companies that commit to effective transformation will reap the benefits of a rejuvenated pipeline both short and long term. There are many paths to strengthen a pipeline – diversifying with biologics, focusing on fewer disease targets, in-licensing more therapies


and adapting to offer other products (such as generics and other health products). However, pharmaceutical companies must focus on their core business – discovering and developing new molecular entities – to drive long-term, sustainable growth. In many cases, this requires an overhaul of their internal drug discovery processes. Good operations management addresses bottlenecks to improve overall performance, quality and throughput. This new emphasis on ‘process’ means drug discovery must be streamlined to quickly deliver high quality NMEs without sacrificing quality. To address attrition concerns, companies must have more confidence that NMEs will perform better with less risk of failing in phase II. Leads must be advanced quickly, or failed early. Adopting new technologies to achieve these process improvements is critical. For many years, the industry has chosen the path of customized solutions for these improvements, such as proprietary hardware or software developed internally or co-created in external collaborations. These projects may be born of an innovative spirit, but they can often fail. Large teams, typically including the scientists in the affected labs, are chartered to develop and implement the customized technology ‘efficiency project’. These projects take much of the scientists’ time in designing, planning and testing. The

result can be a negative effect on drug discovery output since the scientists’ time and energy, which should be focused on developing and testing NMEs, is instead focused on the efficiency project. The drive to continuously advance NMEs is diluted, and progress is slowed. Later, upon review of the new custom technology, the project may be deemed an expensive failure or abandoned due to a lack of measurable productivity improvement. The pitfalls of customized solutions can be avoided by implementing commercially available solutions without the distraction of lengthy, complicated projects. Such solutions, whether instrumentation, software or consumables, are developed with productivity in mind and can be implemented quickly and cost-effectively. As the world’s leading supplier of silica gel to the pharmaceutical industry, Grace recognizes the challenges of NME purification. The Reveleris flash chromatography system was designed to address one of the most common bottlenecks in drug discovery: purification. Along with our solutions in process media, packing systems and column packing services, Grace can help pharmaceutical companies improve productivity throughout the R&D process. n This article was written through the collaborative efforts of Grace’s Marketing, R&D and Six Sigma teams. Please see to read our editorial on the purification bottleneck.

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IN THE DRIVING SEAT In this excerpt from an interview with NGP’s sister media channel, MeettheBoss TV, Sanofi Pasteur’s Rene Labatut tells Victoria Newing the secrets to staying in control of your vaccine manufacturing processes. You have 22 years of experience in biotechnology across 9 variety of disciplines. How does this insight help you in your current role? Rene Labatut. My experience has helped me in two ways. First, to have the right level of humility – there are a lot of things you have to learn and you can be surprised every day; the biotech world is like that. And also to always be looking at the big picture; sometimes I need to go into very detailed things, but I must always have the ability to go back and forth between the different levels of vision, as well as to build a vision of what’s next based on experience and extrapolation between things. My key mission is to be the guardian of industrial knowledge for the company. To be a guardian is a dynamic thing and not a passive one; not keeping things as they are, but moving them into what they should be in the next 20 years. It’s transferring new products from R&D to manufacturing: taking them from phase II up to commercial launch.

Th is also involves being in charge of continuous improvement for any manufacturing process, as well as technological innovation. That’s my primary responsibility. Besides that and within that, there is all the techno transfer between internal sites and also between Sanofi Pasteur and our partners. Sanofi Pasteur is the largest company in the world devoted entirely to human vaccines. How do manufacturing processes differ across the globe? RL. Sanofi Pasteur’s manufacturing processes use the same standards but have different processes for the same therapeutic queues. We have three Tetanus processes, for example: one in Canada, one in the US and one in France, and now because of the recent acquisition we have one in India too.


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The difference in these processes is historical: they come from the original companies. Now when we are developing a process, even if we have several manufacturing units, at the end it’s notably true in formulation. The processes are the same; the challenge in this field is to keep it the same because along the life of a process in a different unit, you always have circumstances where people make minor changes. So you have to be very strong on your change control policy. There is a system called a process book, which is an electronically organized reference where people fi nd the detailed description of what they have to do. It is web-based, so any information can be accessible in less than six minutes; and there is exactly the same reference for people who are running the same process in two locations.

Rene Labatut MeettheBoss TV

It’s anticipated that the demand for new and existing vaccines will double by the year 2012. What measures are you taking to ensure that Sanofi can deliver and meet market demands? RL. Four or five years ago we engaged in a strong investment policy. On a yearly basis we invest between €350 million to €400 million [US$480 million to $550 million], and have built a huge inactivated polio vaccine capacity in Lyon, France. We have more than doubled our flu capacity in the US for seasonal flu and the formulation/fi lling in the US has also been extended. We have invested close to $200 million in this unit and we have also invested very heavily in Normandy, France, to do formulation, as well as fi lling and packaging for distribution of vaccines on a worldwide basis. Now we are also leveraging all the capacity we have at the group level, notably in packaging because it’s less specific for vaccines. We have a plan to invest more than €250 million [US$34 million] to build a new dengue unit; and there is also an ongoing plan to develop new vaccines for diseases which are not yet covered by vaccination programs.

“We want to drive our processes instead of following them; when you drive you are in control” What new approaches are needed to drive manufacturing processes more efficiently and to overcome the complexities of new vaccines? RL. New vaccines for new diseases can be more complex to produce because they have processes that are more complicated, such as new conjugates or new formulation types, which are more difficult to manage. The other way around is to design your product approach – this can be more complex for something like the dengue vaccine, which is a vaccine for a

chimera,– but the management of the process itself is not so complex. The way you manage your cell and the interaction between the cell and the virus is difficult, but in comparison to a classical inactivated polio vaccine, the process itself is simpler because the complexity has moved into the product itself and the construct will simplify after the process. A vaccine is a preventative medicine; when you inject a vaccine into someone they are not sick yet, and the worst thing you can do is to make them sick using the vaccine. So the level of attention you must pay to safety is very high. Th is ties in with the trend of moving to a more preventative type of medicine from a curative one, and requires a different way of thinking. The only area where the risk/benefit ratio is very high is in therapeutic vaccines – but mostly these type of products are the last line of defense – or therapeutic use where the risk is death within six to nine months, so it’s a different story. You’re an advocate of the software solution process. Can you elaborate on the benefits that this can offer a company like Sanofi? RL. We want to drive our processes instead of following them; when you drive you are in control. When you are following, you are just reporting what’s happened, which is not really the mindset we should have. We want to go to a QBD-type approach and have a consistency of output of our process; consistency of results versus the classical consistency of settings. There is a lot of classical approach in secure process control. Following critical parameters step-by-step independently of each other assumes that if you take a given step the result of this step will not influence the step after. In our process there is a lot of difficulty, and it’s not mathematically accurate to say that the steps are independent. We have to consider the process as a rule, with interconnection between steps; and the result of what happened in step one will have an effect on what will happen in step six or eight and can be corrected by what will happen in step 10. But you need to have the overall behavior; and this type of soft ware is trying to address that, looking at the overall process and how it behaves and interlinks. And instead of having a critical parameter only on 119

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What drives the performance of the process, in terms of product and making yields? The huge leverage it yields. If you understand very well how your complex biological system is working, then you can apply a method or attune the way you drive your process to increase. Just by managing the biological organism we handle its physiology very closely and see how it behaves when it becomes invasive in the body, then use the defense mechanism as a leverage to obtain the product we want versus when it is in a comfortable situation doing regular things.

one step, you have a cluster that are on different steps. But it’s based on a mathematical model like genetic algorithm, which is a learning-type process. And the way we use it, notably on high frequency products, enables us to look at what happened in the early stages of the process for some parameters. We must then predict – based on all the models – where it will end if we don’t correct the settings and diagnose what will be the appropriate corrective setting we have to put in place before the end of the process. Then we can be sure that we are very close to the point where we want to end in terms of product quality and product yield. How does the manufacturing process help drive the need for innovation? RL. The innovation I’m focusing on centers on discovery work in vaccines. We now face the challenge of being able to do this in an economically viable way and also in a volume way, in terms of the number of doses produced at a reasonable cost. They must be affordable on a worldwide basis, which is not a niche market for most of these products. We need to innovate to make this possible, to extrapolate directly what’s done at the lab bench scale. We cannot do it at the large scale that we need, so there is some innovation there to be driven by us. We also need to improve processes and assure process performance. We need to think about doing it differently – changing and applying new technology or a new way of thinking, leading into new manufacturing technology even for existing products. The big drive behind that is that you can manufacture a certain way, and put the cost of goods at a value of 10. The number has no real value, it’s just to give an order of magnitude. If you want to sell that in Western Europe, that’s fi ne. But if you want to address it on a worldwide basis and encompass developing areas, you have to bring your 10 down to under one; and to do this you have to have a technology breakthrough. There are different ways to achieve this. First, you think of the classical approach of applying Lean to your manufacturing process or getting rid of things that don’t make sense or are just there because of history or habits. The second step is to maximize the value of what you get out of the things that it still makes sense to do.

How is innovation formalized and managed at Sanofi Pasteur? RL. In order to manage innovation, we have had to sort out what the fields of innovation are. We are looking at what we have in the pot from discovery down to commercial. What is the overall portfolio of products in the company, the ones that are at the early stages, as well as the ones we are manufacturing? We’re working on the type of processes and the technology we are using from the early microorganism down to the final box – looking at where the needs for technology are in the company and also in terms of order of magnitude in the market. First, we are looking at needs we have not covered by existing technology: where we have developed something, where it applies and what is the value for the company according to the span, focus or depth into a certain product. That’s the needs part. We are also scanning what’s going on in different areas of the industry, not only in pharma, but also food and microelectronics. We are scanning what’s going on in universities and at the very early stages, looking at where it can apply and where it can make a difference; in doing so, we want to develop technology. Our technical teams are evaluating continuously with biotech teams or with universities, several of which we have contracts with. What role do issues such as the relationship between development costs and drug prices play in the transfer from R&D to operations? RL. If you take too long in transferring from R&D to operations costs will increase: any time you take will be costly and this will have an impact on the cost of the goods. If you find ways to speed up this transition or transfer, normally you will reduce the cost at the end and you have more leverage to be able to negotiate or provide the services with a better price. That said, to be able to transfer quickly from R&D to operations, you need to have a very specific approach on the R&D development level because things that are a little bit fuzzy or not totally developed will induce a lot of rework during the transfer or just after the transfer, and that doesn’t help to keep costs at an optimized level. Sanofi ensures that we’re optimizing that process by mostly imposing a quality by design mindset, starting in phase I. The pharmaceutical development of new products is jointly managed by the VP of R&D and myself, and to ensure the team diagnoses in phase I or phase II the critical quality attribute of any product, the critical process barometer associated with the system. Then there is also preparing the scale-up algorithm: starting to optimize upfront as much as we can yield reliability and the capability of processes to eliminate what can be damaging for the operation afterwards; and also to help minimize the investment needed. „ Rene Labatut is Vice President of Global Manufacturing Technology at Sanofi Pasteur.


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Achieving sustainable performance Debra Shumar explains the importance of knowing where and how to use Lean and Six Sigma.


ach year, companies set out to align their organization with its strategic plan. Nonetheless, the execution of the plan is, far too often, misaligned or out of sync with the company’s overall values, mission and vision. Consequently, the leadership of the company, including the board of directors, must possess and share a singular vision that not only allows them to create expectations but also to hold everyone to them. Since managing a company without risk is impossible, the next best thing is to manage a company with controllable minimal risk. This can be accomplished by setting up a comprehensive system called problem detection and performance review. In this regard, pharmaceutical companies present a unique set of circumstances. They have the ability to research and to develop drugs that enhance the lives of people, but they must do so in a cost-effective, efficient manner so that the drugs being developed can be sold to the consumer at a reasonable cost. This is where goals and objectives that incorporate Lean and Six Sigma thinking are most effective. The drive to succeed is both a company and an individual goal. Therefore, the company must have a mindset that insures that the company’s processes both facilitate and foster an atmosphere in which the newest technician in research believes that his/her thoughts and suggestions are valued just as much as those of the CEO. Problem detection and performance review processes can help guide where Lean and Six Sigma projects may be best suited to achieve sustainable growth for the company. But serious questions remain: does this company have a process in place for sharing failures and successes among departments when developing a drug? Does this company communicate (through the written word and the use of metrics) what has fostered an efficient, cost-effective method for conceiving new drugs? Since the primary concern for the management team is how to deal with mounting pressure to reduce the costs associated with the development of new drugs, making certain that the requisite skills are in place becomes paramount. For example, a study was conducted to understand the strategic control approaches used by major cancer centers in the country and to relate these practices to financial performance. According to the Journal of Healthcare Management, “The results suggested that high performing cancer centers use more sophisticated analytical tools and approaches, and invest greater financial resources in

performance analysis and performance reviews than low performing organizations”. Consequently, if (and it’s a big ‘if’) corporate goals establish the need to reduce costs, to eliminate waste and to encourage individuals to take ownership of their work, the company will then be well along on its way to sustainable growth. Vital to this transformation is making sure that Lean and Six Sigma objectives, goals and metrics are aligned from the top to the bottom to demonstrate consistency of purpose. This translates into sustainable performance across departments, functions, regions, divisions and corporate boards. In his book People and Performance, Peter Drucker states, “Any business enterprise must build a true team and weld individual efforts into a common effort. Each member of the enterprise contributes something different but they must all contribute toward a common goal.” Transforming the way companies work requires the creation and appreciation of a kind of workforce that (to a single person) understands their contribution to the company as a whole. Managing Lean and Six Sigma projects in support of these objectives requires them to become embedded into the overall business system so that the necessary behaviors are second nature – no one even thinks about ‘achieving objectives’ anymore. Or, as Peter Drucker concludes, “Business performance therefore requires that each job be directed to the objective of the whole business.” This, then, is the vanguard to the success of any company because it is real and it is sustainable. „

“Problem detection and performance review processes can help guide where Lean and Six Sigma projects may be best suited to achieve sustainable growth for the company”

Debra Shumar is President and Founder of 3P Partners, a DL Shumar & Associates Co. LLC. 3P Partners provides innovative approaches, services and software solutions in quality, cultural transformation, Lean and Six Sigma management, and supply chain risk management for improving business, operational and workplace performance.


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Predictive analytics Alfred Sherk discusses new developments that can help enhance Lean capabilities.


he application of predictive analytics to extend the use of the Lean pull process into complex manufacturing processes offers great potential for improving the responsiveness and efficiency of global pharmaceutical manufacturing chain operations. Predictive analytics are substituted for the Kanban method used in assembly operations to provide the demand signal for the pull process. Predictive analytics is the application of statistical data analysis to capture relationships used to predict future trends and behaviors. Credit card companies use predictive analytics in sophisticated fraud detection systems and leading retailers and e-tailers use predictive analytics to suggest additional items that may be of interest to the customer based on past behaviors and demographics. In process manufacturing, Rockwell Automation uses predictive control models that enable process systems to adjust more quickly and accurately than with actual measurements. Applying these predictive control techniques significantly improves performance. The Lean pull process dramatically improved Toyota and Dell’s assembly operations by eliminating dependence on inaccurate forecasts. The Lean pull process uses firm orders as a demand signal and propagates it along the production chain. However, manufacturers with high


structural complexity require reasonably long production runs to achieve acceptable production economics. Accordingly, production-scheduling decisions need to be made before a complete demand signal from customers is available. In such environments, it had been assumed that the Lean pull process could not be used. SherTrack’s research on demand patterns has enabled the successful application of predictive analytics to the order-to-fulfillment process. SherTrack’s predictive analytics algorithms provide an accurate, synthetic customer order signal in the operational time horizon of the next two to three production cycles, enabling application of the very efficient Lean pull process in operations where it was thought too complex to use. The traditional approach to coping with poor demand visibility is to forecast demand, set inventory targets that incorporate safety stocks then optimize the production response. Unfortunately, forecast error renders this process incapable of handling the structural and dynamic complexity of multi-product facilities. Across all industries, best-in-class forecast error (such as demand variation) exceeds 40 percent mean absolute deviation, which means that while forecasts are appropriate for tactical planning issues, they really can’t be effectively used in execution. Most advanced planning and scheduling (APS) solu-

tions were developed to meet the needs of the production planning process with finite scheduling capabilities added later. However, the needs for very efficient execution level order fulfillment processes are markedly different than those required for tactical planning. In complex production processes, the most difficult constraints to resolve are the needs of competing products for the same production resource. The dynamic fluctuations in demand for individual products stress forecast-based processes beyond their capability limits. The most common operational response to complexity is to carry more inventories and to require extended lead times. Long end-to-end throughput times and operational complexity are critical barriers to operational excellence. The combination of predictive analytics with innovative probabilistic inventory and scheduling solvers provide effective control of complex manufacturing, enabling performance close to the physical process limits. New predictive modeling capabilities use proven data based decision support methods to quantify process capabilities and identify improvement opportunities critical for attaining operational excellence. This approach also provides the ability to balance customer service, inventory levels and production costs to enhance operational excellence, and reduces operational risk. Today, innovations in predictive analytics and probabilistic inventory and scheduling solvers provide practical tools for the deployment of the Lean pull order-to-fulfillment process in the pharmaceutical industry. In industries with similar characteristics, innovative manufacturers have recently leveraged the new hybrid of Lean pull and probabilistic algorithms to help transform their business processes and gain competitive advantage. n Alfred Sherk is the founder and CEO of SherTrack, provider of innovative, predictive analytic solutions for synchronizing supply with demand. He is a past member of the Technical Advisory Board for Michigan State University’s Graduate School of Business and is a limited partner in North Coast Technology Investors LP.


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Breaking flow cytometric paradigms Grant Howes explains why a multi-faceted single instrument is most efficient for researchers.


oday’s life science researchers utilize technologies from many disciplines. Purchasing then mastering varied instruments and technologies devours time and monetary resources. Often a technique may be needed in only a single experimental phase, leading to infrequently used instruments cluttering valuable bench space. The ideal solution is an instrument that can perform a myriad of multi-parametric applications. A flow cytometer fits that description but, to date, flow cytometry has not enjoyed mainstream acceptance primarily due to the cost, size and complexity of existing instruments. As with so many technologies, manufacturers have added a seemingly endless series of bells and whistles to mature platforms over time, rendering them increasingly unwieldy. Conventional flow cytometers are expensive, large, high-maintenance instruments that require extensive training to use correctly. The Accuri C6 Flow Cytometer System breaks the flow cytometry paradigm. With a footprint, weight and price similar to a realtime qPCR system or microplate reader, the C6 puts an essential cell analysis tool into the hands of more biologists than ever before. The instrument offers all the performance features of larger, complex flow cytometers and does not require expert operators or dedicated staff, making flow cytometry equally available to both novices and experts. Researchers have used flow cytometry for an expanding application set for decades. Th is quantitative, analytical technology is often used to study cellular phenomena that might also be investigated by microscopy, microplate reading, qPCR or Western blots. Beyond classical immunophenotyping, such experiments include cell cycle analysis, apoptosis, cell proliferation and viability as

well as assessment of transfection efficiency very small areas of data display make the C6 and molecular-level changes in phosphoryeasy to use for both novices and experienced lation and methylation states, cellular and users. The C6 allows the separation of data molecular profi ling and rare cell screening. acquisition and data analysis by obviating the Current choices in kits, buffers, antibodyneed for setting voltages. Th is advance allows fluorochrome conjugates and protocols make novices to be able to collect high-quality data designing and implementing multicolor with minimal direction or supervision and to assays easier than ever. The proliferation of set gating strategies and fluorescence commultiplex bead-based assays has allowed flow pensation values during, or after, data colleccytometers to replace time-consuming, comtion. Data collected on a C6 is always retained monplace assays such as ELISAs, and opened and can be re-analyzed, at any time, if gating the door for flow cytometry to be used much or compensation errors are discovered, or in more widely in the fields of gene and protein light of new research fi ndings. microarray analysis. The Accuri C6 Flow Cytometer offers Due to the wide variations in fluoresunique advantages over more traditional cence and light scatter sigmethods by enabling multinals produced by different parametric, individual types of cells and particles, cell analysis. With a linear flow cytometrists often dynamic range over six despend significant time and cades, the C6 quantitatively valuable sample, optimizcaptures the entire scope of ing amplifier gains and/or biological variations in a PMT voltage settings. These single run without the need settings cannot be changed for data acquisition optimipost-analysis if signals were zation or tuning. The C6 can improperly amplified, realso quantitatively measure sulting in the irretrievable the concentration of cells loss of data. or particles in samples and The Accuri C6 Flow correlate this with the speCytometer is equipped with cific known volumes being Grant Howes is Marketing Director at Accuri Cytometers, Inc. An industry pre-optimized detectors, sampled. Multi-parametric veteran, Howes has worked in cell calibrated to operate within flow cytometric analysis analysis for over 30 years and has close to 25 years of flow cytometry their linear range, so it can can now replace other less experience in both the research and clinical marketplaces. be used to analyze a wide accurate techniques and variety of samples, ranging be accomplished as needs from dim, barely-fluoresdictate. By designing a twocent, micron-sized platelets through large, laser, six-detector, affordable flow cytometer, >30 micron, highly-fluorescent cell lines. The Accuri has successfully addressed the maincombination of high-resolution digital-signal stream cell biology applications with a single processing (24-bit DSP), resulting in an explatform and freed up valuable resources. „ pansive dynamic range on all detectors, and For more information please visit www. the CFlow soft ware capability to ‘zoom’ in on


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Following in the footsteps of many other industries, in the past few years the pharmaceutical industry has begun to embrace the concepts of Lean and Six Sigma in its manufacturing operations. Here, Carmen Doran, Global Operational Excellence Champion, and Domingo Traver, Head of Supply Chain Excellence and IQP for Novartis Pharma Technical Operations, tell us about their company’s progress in implementing these processes. 128

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Carmen Doran of Novartis Pharma Technical Operations explains how the unique combination of Lean and Six Sigma is bringing about significant performance improvements through the work of the company’s global and local IQP Champions.


s Global Operational Excellence Champion, Carmen Doran supports all 23 sites for Novartis Pharma’s Technical Operations, as well as the global support functions, by providing a systematic training and certification program across the organization. Th is aims to foster a culture of operational excellence (internally referred to as IQP: Innovation, Quality and Productivity). She comments that operational excellence in Novartis Pharma covers a wide range of topics, tools and techniques, which allow flexibility in identifying the best approach for a specific problem or opportunity. “The philosophies of Lean and Six Sigma represent a way of thinking and looking at a problem, in order to understand the root cause(s) and then solve the problem in a sustainable manner,” she explains. “Th is approach is different to the traditional management styles focusing on short-term ‘quick fi x’ solutions rather than on identifying the problem correctly and ensuring the solution is effective and sustainable longterm. We try to use this approach across all areas of the business.” Initially set out as two different methods, Lean and Six Sigma are very much interlinked and constantly evolving, a development that Doran notes to be present in Novartis Pharma Technical Operations. She explains how previously, projects would solely use Lean and focus on reducing waste, or would apply a Six Sigma approach to reducing variability. “The Lean philosophy is to have flow through the process and to do this, you need to have processes you can rely on. A stable and reliable process is then the foundation for continuous improvement. So Lean and Six Sigma go hand in hand to achieve operational excellence. “We look at the flow of value all the way through our processes down to the customer, whoever the customer may be; in our case, this is ultimately the patient. If we look at some of the supporting functions like Human Resources, we’ve been applying the Lean and Six Sigma way of thinking to these processes, going through the steps of identifying

“We have a very clear strategic direction for operational excellence, which allows all of the sites to move in the same direction” the problem, understanding the customer needs and root causes of the problem and then fi nding the solution that matches to those. By doing so, we are for instance ensuring the improvement and sustainability for recruitment processes where the benefiting customers are actually both the employee and the business. “We apply the same approach in non-manufacturing environments as we do in production. It’s a natural progression that we need support functions aligned to the new way of working and thinking in manufacturing. Like a lot of companies, Novartis started to apply these method-

Carmen Doran is Global Operational Excellence Champion for Novartis Pharma Technical Operations.

ologies and philosophies in the manufacturing area fi rst, and now the ideas are spreading to the rest of the business. In manufacturing it’s very easy to see the processes and to work on the processes because that’s what is right in front of your eyes. In other business areas, some of the work we do focuses on simply making the process transparent,” explains Doran. As a Global IQP Champion at Novartis, Doran explains that she has a number of requests to provide Lean support; these come from people who have heard about Lean through their colleagues or through seeing the benefits themselves. In order to accommodate what Doran explains as a “pull system” for IQP support, Novartis has its IQP Champions across the world, operating different skills in different areas and matching the business needs with the company’s resources. “We often use an external pair of eyes on a process. That external view may come from another internal function, another manufacturing site or a global function. Novartis has a strong network of people across the globe, all with different backgrounds, but all working on Lean and Six Sigma in a rather unified manner. They are capable of implementing various problem-solving tools and methodologies in projects and of linking them together to create a culture leading towards operational excellence,” she explains. 129

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Pharma Technical Operations has successfully handled some natural resistance to change and to the use of these new processes thanks to strong leadership endorsement, although Doran admits that there are still some people who are coming round to the idea. Enthusiasm for a new project, she points out, is often created upon seeing the results. If a person working on a project has enjoyed it and demonstrated good results, then others can judge for themselves.

Expansion As a global company, Novartis Pharma Technical Operations has sites located across the US, Europe, the Middle East, Latin America and Asia. Prior to taking up her current role, Doran worked in the company’s recently opened Pharmaceutical Operations site in Singapore. She explains that there are variarions in the take-up of Lean Six Sigma across different locations, but not always in the way you might think. “The difference for us in terms of adoption is not necessarily the culture but the maturity of the site. When you have a site that has been around for 50

Domingo Traver of Novartis Pharma Technical Operations talks about the satisfaction he derives from the successful implementation of Lean and Six Sigma in the pharmaceutical supply chain.


years where you have people with a lot of history at that site, then it takes a different approach for them to change their way of thinking than if you have a brand new site like Singapore. For them, everything is new. “We can show them results from other sites, and there isn’t that resistance to change because they understand how it works together in the overall business model. So rather than people’s cultural differences, adoption depends on the life cycle of the site,” says Doran. In order to meet the challenges that often accompany such implementations, she calls upon the company’s network of IQP Champions: each site has a single point of contact for all best practice sharing. “If I have a site in China that needs some input from a site in the US, they can directly contact the local IQP Champion and ask about the results and learnings.” Communication between the multiple sites is essential. Doran places most emphasis on the power of speech and interactions between people, and explains that although Novartis publishes its IQP project results on the internal website and in newsletters, most results are seen from the effects of a strong network. Monthly teleconferences with IQP

units together. IQP is the internal name: innovation, quality and productivity for the operational excellence or continuous processing program.” In his role at Novartis Pharma, Traver looks after logistics and IQP, as well as leading the multimarket network for supply chain. He points to the fact that the current level of regulation and quality control within the pharmaceutical industry has a direct impact on the development and implementation of new efficiency processes. While regulation is necessary to ensure the safety of the end products, Lean and Six Sigma can additionally help to support the overall processes. “For example,” Traver points out, “existing procedures may show that a particular process takes eight hours. By understanding your internal processes and applying Lean techniques, you will be able to demonstrate improvements and hence reduce the time required. Lean, therefore, challenges your current processes and technologies while at the same time making them more efficient.” Another challenge can lie in implementing such changes across an entire organization, which is why the Technical Operations unit at Novartis Pharma started with several pilot programs. After the successful implementation of these pilots, the initiative has now been rolled out across global functions, such as supply chain.

ealthcare markets around the world are rapidly evolving and pharmaceutical companies need to be prepared to address these changes; for example, regulators and payers are becoming more challenging while patients are taking a more active role in their disease management. All of this affects the pharmaceutical business, where increasing efficiencies can support future growth. As Domingo Traver explains that rather than reinventing the wheel, it makes sense for pharmaceutical companies to draw lessons from what their counterparts in other industries have already done. He describes how the processes of Lean and Six Sigma – pioneered by Toyota and Motorola respectively – have taken hold within the Technical Operations organization at Novartis Pharma, where he is Creating change Head of Supply Chain Excellence and IQP. Prior to taking up his current position, Traver Domingo Traver is Head of Supply Chain “The idea was fi rst that we implement was Functional Champion IQP for Novartis PharExcellence and IQP for Technical Operations at Novartis Pharma AG. Lean to reduce waste in our processes, and mOps Spain, where he was principally in charge of then apply Six Sigma to reduce variability; it’s deploying IQP and aligning IQP efforts with the a two-step process,” he explains. “We have implemented the Lean global Technical Operations vision and strategy. He was leader of the phase, and in certain areas, such as quality assurance, we have also Lean – POO (Process Oriented Organization) project that ended with begun to apply Six Sigma. For example, Lean has been implemented the implementation of the new organizational structure in Barbera in in the different operational units; it is now time to link all of these May, 2007.


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Champion networks, ad hoc teleconferences and regular meetings focus on the challenges facing the site, the successes, their goals and what’s in store for the future. “Although the sites are on the same journey, they’re all at different stages, but they’re all looking for alignment through our Operational Excellence Scorecard. We have a very clear strategic direction for operational excellence in Novartis Pharma Technical Operations, which allows all of the sites to move in the same direction. That's one of the reasons we’ve been successfully able to turn those challenges along the journey at a site into something that has been enjoyable and rewarding.” Novartis Pharma is certainly not alone in facing these challenges. The pharmaceutical industry has been dogged by pressures to reduce costs in light of the recent economic crisis. “We could focus on cost, but the better way is to focus on the speed and the agility of the processes,” explains Doran. “One of the biggest concerns for all pharmaceutical companies is the speed at which they are able to adapt to change. A lot of our processes

can be improved, and maybe we haven’t had the challenge that some of the faster-moving consumer industries have had in terms of reaction to market requirements. Those companies who can respond quickly to the market needs by being flexible and reducing their cycle times, both in manufacturing and in development, will be the ones who can overcome these challenges.” Added pressures come from the highly regulated nature of the industry. “None of us would want to take medicine if it wasn't highly regulated,” says Doran. However, she notes that the pharma industry must also recognize that it is not alone in terms of the level of regulation it must undergo, pointing to the aerospace industry as facing similar challenges. “At the end of the day, what I feel has made the Lean and Six Sigma thinking successful for us is the combination of the technical process improvements, cultural aspects and a clear strategic direction that fosters, for all involved, a passion to strive for operational excellence,” she concludes. „

“It was a very interesting project, because it included two elements,” he recalls. “One was the pure implementation of Lean Six Sigma – hence, applying the techniques and helping the teams understand what these techniques mean and how to use them. The other element was about POO, which was aimed at changing the organization’s culture and mindset in regard to how people approach business operations. Among others, this included a change in management tools as well as business understanding. “We used the Kotter model, starting with the ‘burning platform’. Th is allowed us to see how people behaved differently after POO had been initiated a number of weeks previously. Th is was really exciting to me, as you could see how the organization as a whole had improved. “You have different people behaving in different ways; for example, some may be afraid of change. Generally, there will always be 10 percent of people who are quite change resistant. However, you can manage these 10 percent by demonstrating how the other 90 percent benefited from

“I was very happy that despite the challenges we managed the turnaround”

The Kotter model

new processes and a new culture. I was very happy that despite the challenges we managed the turnaround.” Traver feels that Lean and Six Sigma have a strong future within the pharmaceutical industry, as well as in other industries. He points out that there are many areas in which these concepts are yet to be introduced. “Lean Six Sigma helps us to improve our processes and to reduce variability. It is really helpful in many industries, and yet there are parts of the world that still have not taken advantage of it. So I would say overall that there is a lot of future in this yet.”

In 1995, Harvard Business School professor and change management guru John Kotter published a book entitled Leading Change, within which he outlined his now well-known eight-step change process:

3. Create a vision

5. Remove obstacles

7. Build on change

Help people see for themselves what you’re trying to achieve

Check continually for barriers to change

Keep looking for improvements

2. Form a guiding coalition

4. Communicate the vision

6. Create short-term wins

8. Anchor change in your culture

Set up strong leadership by gaining support from key people

Talk often about and apply your vision as much as possible

Give your people an early taste of victory

Make sure change is embedded in every aspect of your organization

1. Create a sense of urgency Open an honest dialogue about what’s happening in the marketplace 131

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The potential of continuous processing in secondary manufacturing.


harmaceutical secondary manufacturing has long stood in stark contrast to the drug discovery end of the business, as well as to other sectors, when it comes to innovation such as continuous manufacturing. Is that about to change? Siemens’ Rebecca Vangenechten and Ivo Backx argue that the coming decade could see secondary manufacturing not just catch up but leapfrog other sectors and that mindset will be a crucial factor. Some of the reasons that explain the relatively slow pace of secondary manufacturing change also explain why the sector is likely to see a transformation. Few other industries would survive if they presided over utilization rates around 30 or 40 percent and took as long as a month or even two months to manufacture a product that could be made in two days. Large inefficient batch manufacturing would have been consigned to the dustbin. In pharma, however, the profits that have come from the traditional blockbuster drug discovery model have masked manufacturing inefficiency and regulation has inhibited change. Now, however, the traditional business model is breaking down with consequent pressures on all parts of the pharma value chain. Manufacturing’s contribution to improving yield, reducing time, cost and waste is increasingly critical. Regulation that previously had insisted on


batch testing is now moving to be much more supportive of real-time product release and process analysis, heralding a future where the validation and establishment of continuous manufacturing will be easier. A small number of companies are taking extremely innovative steps. At Siemens we are working with leading players to develop a continuous secondary manufacturing process. Such a move seeks to achieve significant business benefits. Even a one percent yield improvement translates into hundreds of millions of savings. Small, fully enclosed processes, with a high level of automation and reduced manual intervention, will enable companies to reduce variability, deliver high yields, increase profitability and lower operating, inventory and capital costs. It is an attractive future but the barriers remain significant. However, achievability is not one of them. Continuous processing with realtime release and full understanding and control of each step of the process is well established in other sectors, such as chemicals and food and beverages. What has been different in pharma is the regulatory context but, with this changing, the bigger barriers are inside companies and, in some respects, inside mindsets. Integration of each process stage is crucial for continuous manufacturing. However, pharma

companies tend to work with ‘islands of automation’ where every unit of operation is more or less independent from an integration point of view. Changing to an integrated approach, which is standard in many other industries, is a big step for pharma companies. At Siemens, we have wide experience of continuous manufacturing, as well as an understanding of pharma’s needs, and can partner companies to make it a reality. We find that companies are excited once they succeed with integration but find it difficult to be convinced beforehand simply because it is outside of their experience. Another key barrier is that these changes require companies to work in a more multi-disciplinary way, crossing system worlds. For the first time, if you are in analytics you have to speak to people in process control and so on. Multi-disciplinary teams are an absolute must but not everyone is ready for that. The relatively slow uptake of process analytical technology (PAT), crucial for continuous manufacturing, following the FDA’s 2004 PAT initiative, highlights the challenge facing companies. Mindset changes and internal culture changes will be key to the successful introduction of PAT as a first step towards continuous manufacturing. The companies that are first to overcome the barriers will not just reap the reward of increased competitiveness. Because of the stage of its introduction, they have the opportunity to implement the technology to a higher level than in industries where it is already established. From being a laggard, secondary manufacturing has the potential to become a trendsetter. n

Rebecca Vangenechten is a Life Sciences Industry Consultant with Siemens. She is responsible for business development life sciences US and focuses on innovative technologies, including process analytic technology (PAT).

Ivo Backx is working at present as Senior Consultant for drug manufacturing at the Vertical Market Management Pharma department for Industrial Automation and Drives Technology at Siemens.


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Paul Dupont explains how growing trends in the consumer healthcare industry signal promising market opportunities for leading nutraceutical and pharmaceutical companies.

The rise of



hile originally regarded strictly as a specialty market, probiotic supplements are now mainstream. According to LexisNexis, 231 probiotic products were launched in 2008, compared with 34 just three years prior; 75 percent of women report being interested in a digestive system ‘makeover’. Distinguished medical journals confirm the industry’s credibility by publishing an increasing number of clinical trials with the popularity of probiotics being measured by the $43 million drugstore sales in 2008. Notably, probiotics are characterized as “the vital healthcare concept of the 21st century,” in Probiotics – A Global Update of Market Trends & Opportunities. Reputation and R&D are key to the competitive advantage. The elements that bring success to leading nutraceutical and pharmaceutical companies – global reputations, sophisticated research and development, and savvy marketing – position them to excel in the consumer healthcare industry and awareness of probiotics has grown exponentially in the past decade. Some estimates indicate, for example, that nearly half of Americans know


of probiotics. Yet a significantly smaller percentage understands their benefits. This disparity between awareness and understanding gives the top nutraceutical and pharmaceutical companies an advantage – consumers associate perceived benefits with the companies whose name they recognize and reputation they trust. Users of probiotics demand the proven clinical research that an established nutraceutical or pharmaceutical company can provide. This clinical substantiation influences their purchase preference and in the process creates a valued customer because probiotics consumers are loyal brand users. According to the Natural Marketing Institute, nearly half of probiotics users report that even in a sluggish economy they will pay a premium for what they perceive to be high-quality supplements. The pharmaceutical and nutraceutical industries’s well-established research and development operations position them to identify and introduce new consumer healthcare products beyond digestive health predominantly addressed by the probiotics market. Ropack is uniquely positioned to manufacture and package probiotics. For the

nutraceutical and pharmaceutical industries, a pivotal step in the decision to enter the consumer healthcare market is the creation of a strategy for outsourcing the manufacturing and packaging of these sensitive products. Since 2004, Ropack has worked with biopharmaceutical and world-class probiotic organizations. Our low relative humidity packaging is between 20 percent and 50 percent RH yearround, and the excursion period out of cold storage is tracked in the batch dossier. Once packaged, products are returned to the cold chamber until they are released and shipments are prepared. Cold room temperatures are maintained at 4-5° C and are temperature mapped and under alarm in the unlikely event that the temperature should drop below 1.5° C or rise above 8.5° C. Our common current probiotics packaging includes sachets, Alu tubes, CSP flip-top vials, cold form blister and blister with individual desiccant. At Ropack, we use our expertise and experience to meet your needs with creativity and agility. It is our dedication to client satisfaction that is your best guarantee of a lasting and trustworthy relationship. We welcome your next packaging challenge. Ropack offers turnkey primary and secondary pharmaceutical packaging services of solid oral dosages, tablets, powder and encapsulation into blisters, pouches, bottles and carded blisters in facilities that are cGMP compliant and FDA certified. We are competitive, flexible and agile, supporting clinical trials, short-run startups, commercial production and warehousing and distribution services for more than 90 US, Canadian and European pharmaceutical and nutraceutical customers. Our proven track record in new product launches will help support and accelerate your goto-market timeline. At Ropack, we value our culture of innovation and continuous improvement and are uniquely qualified to support and fast track product launches of consumer health, OT and Rx products for global pharmaceutical companies. n

Paul Dupont is Director of Business Development North America for Ropack. He has over 20 years of experience launching new business development initiatives in the food, pharmaceutical and nutraceutical industries, and expanding market presence to new geographic territories.

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Streamlining regulatory submissions Ethan smith explains how life sciences organizations can automate regulatory submission processes to gain strategic advantage.


ecause regulatory agencies make decisions, recommendations and, ultimately, grant approvals based on the content of regulatory submission documents, the submission document process is one of the most – if not the most – critical documentation process for every life sciences organization. While this point is widely accepted, the processes by which these documents are produced, reviewed and approved before submission are often not well understood or documented and frequently depend on heavy manual intervention and heroics to meet submission deadlines, despite the fact that these deadlines are typically planned for many months – sometimes years – in advance. Automating submission document processes with business process management (BPM) soft ware can alleviate these burdens by significantly reducing end-to-end process cycle times and enforcing adherence to submission deadlines. The key business processes required for success are the planning, writing, scientific review, quality assurance, approval and issuing processes for all submission documents, including the clinical study report. With BPM, life sciences organizations can web-enable process work-steps, capture critical content and process data, and create useful information for resource planning, performance metrics, and, ultimately, process improvement. Other strategic benefits include rapid access to and incorporation of clinical data, shortened review cycles, improved global resource management and productivity, and significant transaction cost savings – all of which drive competitive advantage.

Working together A common misconception among life sciences organizations is that BPM and content management are competing disciplines, which is absolutely false. Content management is a competency and set of technologies that are complemented and extended through the employment of a BPM solution. With respect to

submission document processes, the content management solution remains the secure, validated repository for controlled documents and associated content. The business processes for creating and processing said content and documents are what BPM handles – essentially providing a process wrapper around the validated content management repository. Furthermore, extracting the business processes from the actual content artifacts increases process agility, and also provides the business greater control without the risks and costs associated with custom changes to validated enterprise content management applications. Once the business processes have been defi ned, the BPM application can access controlled documents via hyperlinks to the content management repository – ensuring the version control features are maintained while seamlessly providing business users immediate access to the working documents associated with a specific process. Taking advantage of the strengths of both technologies, this approach empowers the business to better manage and control its business processes and activities, and also simplifies the maintenance and management of the validated content management system for IT.

“A common misconception is that BPM and content management are competing disciplines, which is absolutely false”

while simultaneously improving turnaround times for submission documents. The automated processes are accessible online and work items can be handled by any resource from any location – and management is still provided with complete visibility into every transaction. Not only does this allow companies to more effectively leverage offshore resources, but it also enables work items to ‘follow the sun’ and be worked on across multiple time zones – maximizing the available working hours in a 24-hour period. Delivering the means to effectively create more hours in the work day is a dream come true for managers when regulatory submission deadlines are rapidly approaching. Increasing productivity With growing disease inThese and other advanEthan Smith leads the life sciences cidence globally and increased tages provided by a BPM industry vertical for Metastorm access to care in emerging solution make processes globally. He has over 10 years of experience consulting to the markets, globalization repreboth faster and cheaper, industry and solving processrelated problems to create tangible sents a key growth segment for while at the same time probusiness value for life sciences life sciences companies. At the viding management with organizations. same, rising cost pressures are complete transparency forcing life sciences companies into where each document to look for ways to globalize their operations for resides at any point in time, and giving them the sustainable operational cost savings. Another ability to reprioritize and reassign work with advantage to automating submission document ease. BPM makes all of this possible, while still processes through BPM is that it offers a unique maintaining the content in the same validated approach to utilizing lower offshore resources, repository where it has always been.


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9/2/10 09:15:17

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PUTTING PEOPLE FIRST Nycomed’s Charles Depasse tells NGP about the challenges of recruiting in the pharmaceutical industry and why training is important for personal and career development.


n 2007, the then relatively small Nycomed acquired the much larger Altana Pharma, causing some challenges in integration that were not always easy to handle for its HR team. Charles Depasse, Nycomed’s Executive Vice President of Human Resources, talks of the uncertainty that a merger creates and the importance of communication in asserting Nycomed’s company values and in supporting both those employees who left and those who stayed. “It’s not easy to stay in a company when you see some of your colleagues leave, and also when you get more work and maybe more expectations than you had before. And those were the key challenges that we had to work with,” says Depasse. “We tried to overcome those by sharing our values and our approach, trying to be as open as we could about the changes and keeping our employees aware at least of the timelines. We identified what we thought would be a fair way to treat those who had to leave with the necessary support and showing that it would be a fair process in the selection, as well as to create a new company culture from the two companies.” Depasse is used to dealing with challenges, many of which result from the pharmaceutical industry’s specific recruitment needs. He points to specialized areas such as market access or R&D, for which it can often be hard to find the best candidates. He adds that this situation could be ameliorated by the fact that in recent years large pharma companies have been cutting back on their R&D departments – both AstraZeneca and GlaxoSmithKline have recently announced reductions in the thousands. “I expect we’ll see a lot of very good people on the market as a result,” Depasse says. “It will help alleviate the skill shortage, but we need to look in more detail to see if it will resolve the entire problem. We are also seeing some of those who have left large companies looking forward to working for a midsize company, where their breadth of responsibility can be increased – where they get to understand the whole picture and have more room for maneuver than they would have in a very large corporation.


“That’s at least how we see it. And Nycomed being based in Switzerland, we have people coming from the large companies in Switzerland who are happy to join us. In a mid-size company like ours, you have more of an opportunity to have an influence, your individualism can be recognized and appreciated more, and that certainly is something that we also try to stress. The culture of the company is something that we like to cherish. Having an international approach and giving everyone the impression of working in a small company, even though we’re growing to become a bigger one, is part of what we keep close to our hearts.”

People development Ensuring new graduates are also able to enter the industry and fill the need for certain skills is important. Depasse cites the benefits of the compa-

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ny’s R&D centre in Constance, Germany, to the city’s university: “Building links with universities by participating in common R&D projects, and in general being seen as a participant in the scientific community, is very important.” Establishing links with young graduates in order to bring them into the company as trainees and participate in training programs is also part of Nycomed’s approach. Depasse adds that being known as a company that has links with academia is also good for the commercial side. The trend towards developing employees to take on new roles rather than hiring externally is one that is being see in many different industries, including the pharmaceutical sector. Nycomed has embraced this approach, taking the view that people development is key to keeping people motivated and allowing everyone in the company to develop as individuals, as Depasse explains.

“Motivating, training and developing our people is important for us on all levels, and we focus on internal programs where possible. This is valuable for our culture, and the professional networking and synergetic sharing of best practices. We like to give everyone the option and the opportunity to develop in an area that’s appropriate for them. Our internal development center, the Nycomed Academy, offers a broad range of workshops, classroom training and online learning, covering the key areas for Nycomed’s future. “We have also developed an internal program for young leaders where we ask our top executives to present the company and themselves, and have our employees work on business-relevant projects, where they can see the benefit of the application. Not all of the projects, of course, will materialize, but quite a few will. We believe that creates as good a dynamic as an external program”, says Depasse. 139

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Charles Depasse

“Building links with universities by participating in common R&D projects is very important” Nycomed is currently focusing on the sales and marketing area within its internal training, developed in conjunction with regional managers, and market access is one topic that the company has developed. Depasse explains that this involves training on key account management, as well as general training in project management and value training, whereby the focus is on ensuring that every new employee understands clearly Nycomed’s values in an attempt to build empathy and trust. “We want to be sure that everyone understands what’s behind those words,” he says. “What does it mean in the day-to-day behavior, what do we expect from our leaders, and what can employees expect from their leaders, so that we align expectations on both sides.”

World view With most large and mid-sized pharmaceutical companies operating internationally, they are bound to face unique challenges in various parts of the world. Depasse says that in recruitment at least, areas such as Europe and North America are not as different as they once were. One of the main difficulties in recruiting across Europe has historically been language, with the US obviously having the advantage of a common mother tongue. Depasse points out that this problem is gradually being eroded due to the dramatic improvement of the level of English in Europe. “The situation has reversed itself somewhat,” he says. “Now the fact that in Europe you bring in people from different backgrounds and cultures can be an advantage because it adds diversity.” He adds that Americans were once more willing than Europeans to relocate to take up a new job, but now there is more mobility within Europe, with the added bonus of the distances being shorter.


He describes the challenges as no longer being so distinct between the two regions; instead, he believes the biggest challenge facing pharmaceutical recruitment lies in the developing world. “The challenge is in developing countries, whether it’s China, Mexico, Saudi Arabia or Russia/CIS. Finding the best talent there is certainly an even greater challenge than in the US or Europe, because the war for talent is more aggressive there. “We also see that attracting talent from Europe to those countries using generous expat packages has become a thing of the past. We have budget restrictions, and also the expectation is that you will be able to hire locally. On the other hand, the good thing is that we also see a number of people from developing countries who are highly qualified, highly trained, and more flexible about going abroad, and sometimes returning to their home country in a more senior position as a result. So that’s been a very positive development.” When asked what the future holds for the pharmaceutical industry, Depasse reiterates that the industry as a whole is maturing, and HR departments will find themselves having to adapt to the new challenges and opportunities that this brings. He cites the recent mergers among the industry’s top players as one example: “These mergers will result in a number of highly qualified professionals being made available on the market, and so perhaps the classic model of having difficulties in finding R&D or sales and marketing executives will be eased somewhat. “Otherwise, the difficulty of bringing new products to the market is continuing. It’s relentless; it’s even maybe tougher than before. So specialized fields, in particular market access, will remain an area where the whole industry is looking for the best talent. Those are the trends that I see going forward,” he concludes. n Charles Depasse is Executive Vice President of Human Resources at Nycomed.

Commitment to professional education The Nycomed Academy, a combination of online learning and classroom instruction, offers a range of courses: from developing leadership and improving team dynamics to global marketing courses and building relations with key customers. Local and regional courses complement the offering at the global level. Personal development tools are being designed to identify key competencies for motivational leadership based on the company’s values, results from surveys and competency models. The Nycomed Academy’s motto ‘Educate, Motivate, Achieve’ underscores the company’s commitment to becoming a learning organization.


9/2/10 09:21:27


Empowering the workforce NGP asked Bruce Jones to answer one company’s questions about developing a leadership culture.


t’s great that this company is working so hard to create a culture that builds loyalty and empowers employees. Empowering employees is a key lesson in ‘Disney’s Approach to Leadership Excellence’ – one of five core programs we offer at Disney Institute. The opportunity for this company and its managers is to examine how to truly empower employees for long-term effectiveness. The answer may surprise them, as it lies in their hands. Disney has always trained well and, as recently as the 1990s, many leaders thought that hiring great people and training them was sufficient. Employees would do as they were told and guest service would be seamless. Disney employees, or cast members, as we call them, take great pride in their work and want to do more, but we had created an environment where the expectation was to simply collect a paycheck. We were not effective at connecting the cast with their jobs and the guests they were serving, and we were missing a vast opportunity.

It would have been easy to dismiss this child a new one at no cost to the parent. The as a cast member problem and send them to cast member can do this without checking with another round of training. But astute senior his or her leader, as long as he or she records leaders saw an opportunity to make bigger the transaction. This record creates opportunichanges that would positively influence our ties for coaching and ongoing collaboration company for years to come. They started by between cast members and leaders. These efforts unleashed the hidden value asking cast members what would help them from within the organization and have alfeel connected to their jobs. The answers lowed Disney to become world-renowned were startlingly simple. For example, cast for employee engagement and loyalty. And it members wanted the freedom to help guests doesn’t have anything to do with castles and immediately when problems occurred, princesses (well, maybe a little bit). Workand they wanted to do so without fear of ing in the happiest place on earth certainly retribution. In other words, they wanted has its benefits, but I doubt we would be the to be treated with the same respect we happiest place on earth if we didn’t treat our give our guests. cast members with respect. Guests come As a result, Disney embarked on back to our parks again and again because a journey focused on developing a culour cast members listen and act when they ture of great leadership rather than top-down make suggestions on ways to management. Leaders now improve the experience. The must demonstrate effective thousands of positive letters, empowerment, along with emails and phone calls we coaching and cast member receive from guests every development, to be sucyear almost always have one cessful in their jobs; in fact, thing in common – they rave leaders’ annual reviews about our cast members. are tied directly to the cast The biggest challenge members they oversee. If a for any company wishing cast member is not achievto implement changes, ones ing his or her goals, then that will result in increased neither is the leader. This reBruce Jones is Programming Director employee engagement and quires leaders to constantly for Disney Institute. In this role, Jones loyalty, is to develop a culinteract with and seek input oversees the team that develops engaging content built around the ture of trust. If employees from cast members, which five topics that Disney is best known for – leadership excellence, people feel they are heard, and that in turn fosters better service management, quality service, brand their ideas and suggestions at all levels of our company loyalty and inspiring creativity. He also ensures the content is suitable are taken seriously, they’ll (fellow cast members can be for presentation across a variety of formats, including webcasts, keynote respond in a positive way. A guests, too). presentations and multi-day courses. company that is successful Tools have been develin introducing this type of oped as part of this process culture will see a positive impact that goes to empower immediate service recovery. If a beyond employee satisfaction, all the way to child drops her ice cream cone for example, the bottom line. „ the cast member is empowered to offer the


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18/2/10 13:58:55


Utilizing social media Chuck Russo examines the FDA’s online balancing act between consumers and the healthcare industry.


ast November’s FDA public hearings on promotional use of the internet and social media in Washington, DC, was quite an event. Although the FDA allowed 350 attendees, the 60 plus speakers stole the show over the two long days. Speakers presented a variety of issues and concerns focused around questions posed by the FDA. Many of the speakers were very credible and, at the hearings’ conclusion, one could be considered conversant on issues surrounding the use of the internet and social media for healthcare purposes. The FDA called the hearing to address a number of pertinent communication challenges and gain industry insights from a variety of audience participants. The key area of focus for the hearing revolved around the accountability of pharmaceutical and medical device manufacturers in providing adequate disclosure for fair balance in limited online formats, such as paid search ads and tweets, and other online formats that healthcare companies use across the web. What are the responsibilities for follow-up and posting of corrective information on sites controlled by third parties? These hearings, presentations and brief discussions represent only the beginning of the debate of what should be acceptable use of social media. Unfortunately, this debate could drag on for some time; from these hearings, it was obvious we must move on these issues now. Social media is a two-way communication process supporting industry needs to safely utilize the media for communications while the public engages the industry in an effort to get the support and information they seek. Adverse reporting and the posting of side effect information were the two hottest issues presented. It was clear that guidelines do need to be established, and many speakers detailed reasons why they were looking to the FDA to lead this action and demonstrate a true understanding of the issues. Also driving the hearings was the recent FDA action in sending warning letters to pharmaceutical companies regarding the use of internet promotion that resulted in a dramatic reduction in the use of online channels by the industry. Combined with the lack of guidelines, this action has reduced the vital connection between the industry and the general public, thus increasing the chances that patients and their families will seek information from sources that are often unregulated and do not preserve the integrity of the information exchanged.

By defining guidelines the FDA will instantly establish the validity of social media as a viable communication channel, reinforcing patient beliefs that communication standards must be met by the industry. These standards must be created to protect the public interest and instill the confidence to freely exchange information with the healthcare industry. Over the past few years, pharmaceutical and medical device companies have experienced unprecedented negative public perception, and these guidelines could help the industry engage both its customers and its critics. A major part of the industry – healthcare providers – was noticeably missing at the meeting. Where were the voices of physicians and nurses? There were a few exceptions, including representatives from Sermo, a physician social website who discussed online social media that serves the physicians’ need for peer-to-peer interactions. Besides the FDA, providers had the most to learn from these hearings, considering their relationship and regular dialogue with patients. Th is venue could have reinforced their concerns for patient safety and established a perspective for how patients will seek future health information. Also missing was the American Medical Association, which could have taken a leadership position and expressed a strong point of view on behalf of its physician members and the managed care organizations that play a critical role in patient/physician communication and management. With the growth of social media and the increased use of the internet, all representatives of the healthcare industry will need to collectively strike a harmonious balance. The growth of social media is not slowing down and will continue to impact how patients, families, industry and healthcare providers will interact with each other. „

“Unfortunately, this debate could drag on for some time; from these hearings, it was obvious we must move on these issues now”

Chuck Russo is EVP, Chief Innovation and Customer Experience Officer of Corbett Accel Healthcare Group (CAHG). Russo leads and oversees the advancement of CAHG’s interactive and technology based businesses and functional departments, including Kinect Interactive Digital Communications, a full-service strategic interactive agency and LinQ, a studio-inspired technology services company.


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9/2/10 09:10:31


Feel the force With patent expiries and generic competition on the rise, the pharmaceutical industry is being scrutinized like never before. As a result, sales force effectiveness is taking top priority. By Matt Buttell “There is no such thing as a no-sale call. A sale is made on every call you make. Either you sell the client some stock or he sells you a reason he can’t buy. Either way, a sale is made; the only question is: Who is going to close? You or him?” These are the words of Ben Affleck’s character Jim Young in the 2000 movie Boiler Room – a dark and intense drama depicting the perils of working on a highly pressured, highlypaid sales floor at a suburban investment fi rm. While the movie is a dramatization of what life is like as a cold-call salesman, the ‘boiler room’ concept that goes hand-in-hand with sales is nothing new to the pitching floor: especially as far as Hollywood is concerned. Th ink Oliver Stone’s 1987 classic Wall Street, where Michael Douglas’ depiction of ruthless stockbroker Gordon Gekko earned him an Oscar win: “Greed is good”, Gekko warned us some 13 years ago. Or Alec Baldwin’s Blake in the 1992 movie Glengarry Glen Ross, where he defi nes the ABC of sales as “Always Be Closing.” Of course, outside the realms of the movies, while the reality for the sales force may not be half as ruthless, it is just as dramatic. And not least for the pharmaceutical industry. That’s because the industry is currently at a crossroads, facing the very real problem of patent expiries and the rise of generic substitutions – and the pharmaceutical sales force is top of the critical agenda. The challenges facing the pharmaceutical industry in 2010 are multi-faceted and have already been well publicized. For one, a slowdown of growth levels within mature markets is leading to a refocusing for the industry – in particular, Big Pharma – that sees future profits lying in emerging markets such as China and India: markets that have been dubbed by the media as ‘pharmerging’.


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As such, the pressures on the sales forces’ of pharmaceutical companies are great, not least as many of pharma’s biggest markets are now saturated with sales representatives. A direct result of this sees the industry’s selling techniques becoming increasingly ineffective and the industry is now being forced to embrace the reality that this model guarantees neither growth nor future profitability. Instead is the argument that there is a new opportunity presenting itself to the industry: the realization of moving beyond sales force growth and mass promotion and into a new era of sales force effectiveness.

Denied access According to the Pharmaceutical Sales Force Effectiveness Strategies report published by Business Insights last year, the social, demographic and economic context in which the pharmaceutical industry operates is changing dramatically, with huge implications for the industry as a whole. Dr. Ksenija Jakovcic, a Business Development Manager at SanMed and author of the report, notes how these challenges will have major ramifications for the way in which pharmaceutical companies market and sell the medicines they develop over the coming years. The study aims to highlight how the pressures associated with these challenges impact market efficiencies and discusses the idea that, currently, no aspect of pharma operations is under as much scrutiny as the sales and marketing function. It is an interesting point, given how pharmaceutical sales representatives are currently facing tight restrictions regarding access to physicians, not to mention – highlighted by President Obama’s ongoing healthcare reform debate – something of a negative public opinion right now. In fact, in reference to a lack of access, Jakovcic writes that about “one in four US physicians work in practices that refuses to see pharma reps. “And of the doctors who do see reps, about 40 percent will meet with them only with scheduled appointments,” she adds. What’s more, fi ndings reveal that the ‘by-appointment-only’ figure jumped by 23 percent during the last six months of 2008, a year before the report was published.

given at the Next Generation Pharmaceutical summit last year, Followwill commented, “I began my career in the Silicon Valley, the center of change and speed, so I was very much used to things happening quickly, Th is is a vastly different world from the pharmaceutical industry, where things move much more slowly.” Followwill went on to use the analogy that, over the last 30 or 40 years, the pharmaceutical industry has operated more like the automotive industry, something he defi ned as an “interesting cross-industry comparison”, given the significant meltdown the US automotive industry experienced last year. “Obviously the pharmaceutical industry doesn’t want to see itself at that point, so there is a lot of angst and worry currently circulating in the pharmaceutical world,” he added. “Nonetheless, the industry remains incredibly slow to change.” In fact, warns Followwill, until pharmaceutical companies shift their focus, change for the industry is unlikely to happen at all. “The industry is largely geared ruthlessly toward Wall Street and shareholder values, which have to be driven on a quarterly basis, Meeting analyst expectations on Wall Street remains the number one metric for a pharma CEO, and as long as that remains the case, there won’t be a gigantic amount of change. The pharma industry is probably not going to look that different in 10 years’ time.”

“Meeting analyst expectations on Wall Street remains the number one metric for a pharma CEO, and as long as that remains the case, there won’t be a gigantic amount of change” Dorman Followwill

Arms race One of the biggest issues facing the pharmaceutical sales force is the fact that while the perceived benefits of high return on investment have, in the past, been a key driver for companies to increase numbers, the reality has meant a surplus in the number of reps. That, alongside a raft of new pressures – including busier physicians, the proliferation of new drugs, greater competition among companies that produce and market drugs and evolving customer dynamics – has seen the ROI on detailing decline. What’s more, the pharmaceutical industry remains somewhat cautious about the concept of change, a fact underlined by Dorman Followwill, Vice President of Healthcare EIA at Frost & Sullivan. In an interview

New ideas Jakovcic, meanwhile, only echoes Followwill’s thoughts, explaining that while caution certainly does remain, the industry is slowly beginning to explore new ideas and innovative sales models. “Although only seven percent of surveyed respondents believe that new sales models will be rolled out in the next two years, the majority of interviewees expect that focused pilot projects will indeed gradually pave the way to new business models,” she writes. She believes that the most successful future pharmaceutical sales organizations will include a significant variable component and will be engineered for agility and for greater cost effectiveness. “A solution for the future is to establish a smaller internal sales organization composed of the highest performing sales reps. To build in flexibility, this fi xed resource would be supplemented by variable resources provided by controlled sales organizations (CSOs), whose expertise is in the rapid deployment and redeployment of custom profi le sales teams.” What’s more, the pharmaceutical industry, which has long been described as counter-recessionary – a fact largely based on the assumption that people will always need drugs regardless of the state of the economy – has shown signs of being far from invincible. According to analysts, whilst the recession-proof theory might be true at a surface level, a more granular analysis reveals dissimilarities between different segments of the industry. For instance, the providers of branded drugs, blockbusters and the newest treatments tend to make long-term investments in R&D, and have 147

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About 40% of doctors will meet reps only with an appointment

high sales and marketing costs as a result, while those manufacturers of off-patent, older drugs – usually manufactured at a much lower cost than the branded molecular rivals – typically operate off a lower R&D cost base, with smaller sales, marketing and budgets in tow. Th is issue has only been exacerbated by the ongoing recession and global economic crisis. As such, companies are asking themselves if this is the time to be investing in pharma sales or not as the industry refocuses its ideas on the way to approach the sales floor. However, the industry’s bottom line (profit) remains the bottom line, and it is clear that Big Pharma is going to have to change its sales model – though whether this will come about as a want or a desire to change, rather than a necessity, remains to be seen. In the end, the pressures the industry is facing – such as saturated markets, declining margins, increased pressure from generic competition and fewer blockbusters – mean that cost cuts are inevitable, and eventually that has to include cuts within the sales force. Thankfully though, as change does slowly begin to envelop the pharma industry, the Hollywood mentality of sales force effectiveness, at least, seems to be disappearing. As such, Michael Douglas’ egotistical Gekko, or even Alec Baldwin’s belligerent Blake, seemingly no longer have a home in pharmaceutical sales. Instead, the general consensus is that success lies in striking a balance between soft skills and hard skills

and analysts say that Emotional Intelligence – which includes attributes such as listening skills and dressing and behaving in a professional manner – are required just as much as Consultative Selling Skills (CSS), which include knowledge about the product, the medical condition it treats, and – in the end – the skill to close the deal. So, maybe Ben Affleck’s speech as Jim Young in Boiler Room shows some truth after all, but for Blake’s “Always Be Closing” mantra of years gone by, it seems the number’s up. And in its place, perhaps the usually static pharmaceutical industry will adopt a new ABC of sales: “Always Be Changing”. „

Side effects Researched and organized by eyeforpharma, a division of a private company headquartered in London, UK, the Sales Force Effectiveness Summits for 2010 go a long way to highlight the importance this topic is bringing to the industry. The first summit will be held in Barcelona in April and aims to give attendees a real insight into how change is impacting the industry. Keynote speakers will share knowledge designed to transform the pharmaceutical business model from product focused to customer-facing. A second summit will be held in New Jersey in May, tackling similar issues for the US market.


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9/2/10 09:05:34


Understanding the new prescribing influences Tom Haskell and John Moran of IMS’ Innovation Lab discuss how to evaluate new factors driving prescribing decisions.

What new factors are affecting prescribers’ medication choices? Tom Haskell. The list is growing exponentially, but we can classify them into three general categories: those that are managed-care driven, patient-driven and technology-driven. The influence of managed care extends beyond the use of generics to include the impact of tier position in drug choice and of noncompliance caused by prior authorization requirements. A more educated patient population has a strong voice in therapy and medication decisions. And physicians are relying more heavily on the internet through electronic medical journals, e-detailing and physician networking sites. These new influences will differ in the degree and duration of their impact and sorting the high-value activities from the ‘trendy’ ideas is the challenge.

How have these new channels complicated things for manufacturers? John Moran. Companies are increasingly moving to regional commercial models and figuring out how best to use traditional channels differentially across regions, which is complex enough. If not done well, adding new channels to the mix could make the process unmanageable for a regional business unit. Also, these various influences do not impact healthcare practitioners uniformly. Figuring out the rate and pace of impact regionally and by specialty poses an opportunity to maximize brand performance in the near and long term. What is the role of headquarters versus each region in adopting these channels? TH. It is up to the headquarters’ commercial analytics and market research functions to vet

new influence sources, qualitatively and quantitatively, and then to give specific deployment recommendations to regional units – and even the national franchise. Of course, recommendations should be made in conjunction with the regional business unit’s strategy and operating approach. For example, a region focused on obtaining preferred status for second-line therapy will benefit most from deploying channels that educate healthcare practitioners and payers on patient flows and treatment patterns. Determining how much to invest in which channels involves asking, ‘Which influences act where, what level of support should be reallocated from traditional channel and how should investment performance be measured’? These types of questions are strategic, rather than quantitative, and can only be answered with customer insights.


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Do these new channels represent any opportunity for manufacturers? TH. Most defi nitely. To the extent that companies can select and deploy local activities in these channels, they can drive stronger customer relationships, optimize their P&L through more efficient brand spending and improve brand usage. Companies that understand the rate and pace of a channel’s impact regionally and by specialty can maximize brand performance in the near and long term.

JM. Traditional metrics such as brand share and volume can be applied to some, but not all, new influences. Others require new performance metrics such as penetration, treatment rates, disease intervention rates and patient compliance/adherence. We’re testing research questions now, but have identified some ‘givens’, such as brands operating under new commercial models must have a way to regularly assess the strength of the prescriber’s relationship to the brand and the corresponding value it delivers. Also, the believability of the brand’s message should be measured in light of other influences that either support or contradict the brand’s value proposition. Particularly in today’s highly connected environment, companies must be attuned to how an influence supports or undermines corporate communication and education efforts. Finally, measures should address the dual drivers of cost containment and comparative effectiveness. While measuring the impact of a pharmaceutical brand on patient outcomes and cost is still in its infancy as a commercial business practice, new metrics of cost and value are taking shape.

TH. Often models produce results that aren’t intuitive. In one study of coupon usage among patients in a specialty-focused disease area, IMS found that certain coupon types and offers significantly influenced the follow-on adherence of patients. It was reasonable to assume that couponing would have an impact on new patient share, but an impact on patient adherence was a surprise. This fi nding has significant by accounting for the ‘lifetime value’ of the patient brought into the franchise.

How can companies assess the impact of What must companies do to adopt approthese new channels? priate, new performance metrics? JM. In general, there are three types of TH. First and foremost, they need to develop measurement methods that can be used, a richer dialog with their customers through although there isn’t one right way to assess a combination of primary research and rep the impact of an influence channel. Often, interactions. Fortunately, they can fund such multiple models are required to best explain research by migrating other, more traditional the impact on prescribing. First, there are primary research activities, such as awareanalyses at the healthcare practitioner level ness, trial and usage studies, to secondary that compare the prescribing behavior of test data sources. A good starting point for using and control groups. This is only possible, of new metrics is to apply them initially only to course, if you can identify through secondnew influences. Eventually, they can then be ary or primary research which practitioners extended to traditional promotion and educahave been exposed to the new influence. tion activities. The second type is regional-level modeling, which includes a strategic framework What other tips do you have for companies for understanding the future impact of Can you give an example of a measureas they focus on new influence factors? influences that are working together. This ment of a new influence that produced JM. The fi rst step is to expand or redeploy research activities so that companies can meaentails modeling the influence’s contribution surprising results? sure the extent of practitioners’ to sales, gathering sentiments exposure to new influences and from participants, obtaining the resulting behavioral change. a perspective from the field, Brand managers should then and then deploying the activlook for gaps between the reity selectively and tracking its search fi ndings and their brand actual impact. The third type plan. Each year, they should is channel-level assessment. incorporate a few promotional With this, primary research is ‘R&D’ elements into the brand integrated with new-to-brand plan so that they can keep on prescribing metrics and value top of new channels. Once influassessments to identify how the ences are identified, prioritized influence affects HCP satisfacand included in the brand plan, tion, loyalty and prescribing. tracking and assessment can The results are used to prioritize begin. The organization will program efforts or to implement have to add a few key perforregion-specific programs that John Moran leads the US Innovation Tom Haskell is Director, US Innovation mance indicators, such as brand increase customer value in lagLabs for IMS. He serves as an advisor to Labs for IMS Health. In this role, he pharmaceutical clients across a range of directs the development of new, penetration, productivity and ging geographies. commercial disciplines, designing and creative solutions for pharmaceutical structuring solutions to meet clients’ and biotechnology clients in the R&D, adherence, to the brand dashkey commercial challenges. He holds a clinical and commercial spaces. Haskell board to monitor the spread of What specific metrics can be BS in Chemistry from Carnegie-Mellon is a graduate of Harvard University, University and an MBA from the majoring in Applied Mathematics and an influence and to track how derived from these research University of Pittsburgh. Computer Science. the brand is responding. „ methods? 151

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Choosing a hi-tech venue Eric Opron explains what businesses should expect from their communications technology when planning their next off-site event.


s technology continues to develop and the need for data to be shared quickly and securely grows, it has become essential for businesses to be able to seamlessly transition from inside the office to outside of it. Off-site conferences and meetings are vital events that bring people and ideas together. Today, present day cutting-edge network technology makes it not only possible, but expected that your convention space will be able to function as office space as well. The primary focus of any meeting should be the successful dissemination of information. The most stateof-the-art conferences need to stream live video, share Hidefinition images and support thousands of users (both wired and wirelessly) simultaneously. Whether it is for an interactive visual presentation or to provide attendees the ability to conduct business away from the office, the network demands for an off-site conference are great. Too often, organisers take for granted the stress these demands can place upon a venue’s network. There are three primary areas you should concern yourself with when evaluating a venue’s communication technology – scalability, security and prioritization. Many hotels and conference centers are ill prepared when it comes to large-scale data delivery. In today’s world, you must ensure your venue has a suitable data pipe to the internet, as well as the ability to transmit your data to any and all locations you desire, whether wired or wireless. While you may have months to rehearse and fi ne-tune your message within the comfortable confi nes of your corporate offices, any multi-media technology you require within a meeting space must be built in days, not months. Understanding a venue’s network capabilities can ensure your message delivery goes smoothly. The often sensitive nature of the information being shared at these conferences makes security paramount. When delivering essential content to your staff and attendees in a time-sensitive and mission-critical environment, one must ensure the local network is capable of segmenting your data (and message) so that it reaches the intended audience exclusively. The greatest risk for any company within a meeting space is the loss of confidential and possibly proprietary information.

In addition to delivering the data to where it needs to go securely and quickly, determining who needs it fi rst, especially at large conferences and meetings, is an important consideration. Communications have many layers when it comes to essential delivery. Those who need it fi rst, should get it fi rst. Most venues typically operate their networks as one flat LAN, thereby losing the ability to provide preference. If a certain segment of your meeting needs content fi rst, make sure your venue has the ability to provide it in the timely manner required. To determine if your conference venue is able to meet the communication technology needs and expectations required for your next off-site event, I recommend you ask three questions that will reveal key insights about your potential partner. Do you have a full-time communications staff on property? A network problem does not occur on a schedule, you need to have on-site access to a qualified technician that can be available when issues arise. Can we test drive before we buy? Hold a pre-event planning and consultation meeting with the communications staff at the venue in advance of your meeting date. By working with the communications staff ahead of time you will be comfortable with their capabilities and confident that your event will go smoothly. Have you done this before? If the staff has successfully met the needs of similar hi-tech meetings there is little reason to doubt they will be able to do the same for you. Ask for real world case studies to determine if their capabilities match your needs. „

“Many hotels and conference centers are ill prepared when it comes to large-scale data delivery”

Eric Opron is the Director of Sales and Marketing for the 2265-room Walt Disney World Swan and Dolphin Resort. With more than 20 years in the hospitality industry, he is responsible for the numerous groups that host events in the resort’s 329,000 sq. ft of meeting space.


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United Kingdom With pharmaceuticals h ti l b being i ah huge share of the country’s exports, the UK is a major industry player.


he chemical and pharmaceutical industry is strong in the UK, with two of the world’s largest pharmaceutical fi rms, GlaxoSmithKline and AstraZeneca, being based there. Along with other key technical industries, the UK is a world leader in the industry, with pharmaceuticals dominating the export part of the country’s economy. UK companies account for 40 percent of biotechnology products in the pipeline by European public companies and with R&D investment of over £3.3 billion ($5.2 billion) in 2005, it ranks with the US and Japan as one of the top three centers for pharmaceutical research. Moreover, 45 percent of new biotechnology drugs in late-stage clinical trials (phase III) in Europe are from the UK.

Healthcare The public system, the National Health Service (NHS), is one of the largest cohesive organizations in the world, employing over 1.3 million people. The government’s budget portioned the Department of Health £98.6 billion ($154 billion) for the fi scal year 2008-09, with the majority of that being spent on the NHS. Private healthcare operates on a parallel level to the NHS and is paid for by private insurance, which currently is used by less than eight percent of the population.

Angel of the North

Pharmaceutical companies GlaxoSmithKline: a pharmaceutical, biological and healthcare company, GSK is the world’s second largest pharmaceutical company. It is research-based with a wide portfolio of pharmaceutical products covering anti-infectives, central nervous system, respiratory, gastrointestinal/metabolic, oncology and vaccine products.


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Edinburgh military tattoo

AstraZeneca: a British-Swedish company that was formed in 1999 as the result of a merger between Astra AS and Zeneca Group plc. AstraZeneca develops, manufactures and sells pharmaceuticals to treat disorders in the gastrointestinal, cardiac and vascular, neurological and psychiatric, infection, respiratory, pathological inflammation and oncology areas. Astex Therapeutics: a biotechnology company focused on the discovery and development of drugs in oncology and other areas. The company’s research efforts focus on utilization of a proprietary ‘drug discovery engine’ dubbed Pyramid.

2012 London Olymic Stadium

Travel focus The city of London attracts millions of tourists into its metropolis each year. It is due to host the Summer Olympics in 2012 and the capital is gearing up to accommodate the many more millions of tourists the event will bring. With its own mayor and assembly, London is a prominent city and one of the world’s largest financial districts; central London incorporates more than half of the UK’s top 100 grossing UK companies. It also holds Europe’s longest shopping street, Oxford Street, which stretches a mile long. Queen Elizabeth’s home, Buckingham Palace, is situated in central London. The city is teeming with historical buildings. Westminster Abbey, the Tower of London and the Palace of Westminster were all built to accommodate the Royal Family.


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A roundup of upcoming conferences and events across the globe.



The American Pharmacists Association Annual Meeting and Exposition (APhA2010) March 12 – 15, 2010 The Walter E. Washington Convention Center Washington, DC

Future Directions in Pharmacy Education March 24, 2010 University of Reading Reading, UK t/events-and-courses.asp


Next Generation Pharmaceutical Summit Europe March 29 – 31, 2010

11th European Symposium on Controlled Drug Delivery April 7 – 9, 2010

Hotel CampoReal Golf Resort and Spa Oeste Region, Portugal

Hotel Zuiderduin Egmond aan Zee, The Netherlands

Sixth Health Asia 2010 International Exhibition and Conference April 2 – 4, 2020

ADMET Europe April 8 – 9, 2010

Karachi Expo Center Karachi, Pakistan

Holiday Inn, Munich City Centre Munich, Germany nces/ADMET2010

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Las Vegas

St. Petersberg


Global Healthcare & Medical Tourism Conference 2010 April 13 – 16, 2010

Strategies Against Counterfeit Medicines April 26 – 28, 2010

Coex Intercontinental Seoul Seoul, South Korea dex.php

Maritim Hotel Wurzburg Wurzburg, Germany

Boston Park Plaza Hotel and Towers Boston, MA NAiWC2010

Armada Speciality Pharmacy Summit May 4 – 7, 2010

Russian Pharmaceutical Forum May 19 – 21, 2010

The Wynn Hotel Las Vegas, NV

Corinthian Nevsky Palace St. Petersburg, Russia

Next Generation Pharmaceutical Summit The Boulders Resort Scottsdale, Arizona April 26 – 28, 2010

RNAi & miRNA World Congress May 5 – 7, 2010,

SNAPSHOT 158 Emergency workers evacuate an unconscious girl in Port-au-Prince, Haiti, following the magnitude 7.0 earthquake that hit the country.


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9/2/10 09:16:35


The benefits of going outside What’s behind the trend in increased outsourcing of biopharmaceutical development? By Byron Hill


arket trends and ABC Laboratories’ current experience indicate a healthy and sustainable growth in the outsourcing of major portions of protein pharmaceutical product development. According to a recent industry report, more than 75 percent of analytical development and testing for large molecules is outsourced, a figure that is expected to grow with the number of new large molecule candidates. What are the factors behind these decisions to outsource more and how does the contract pharmaceutical provider assure meeting client expectations? Time is money. Reduction in time to market is paramount in the pharmaceutical industry and is a universal consideration for all companies regardless of size and number of products in the pipeline. Large companies can leverage the contract laboratory in support of both primary and secondary drug candidates. Smaller R&D focused developers can utilize the contract laboratory now instead of waiting until their internal laboratories can eventually support their sample loads. Extending product lifecycle because of patent protection, generic or biosimilars and intense competition cannot generally reverse any loss of sales resulting from delay in development and licensure. Therefore, contract development organizations provide a mechanism to extend and enhance internal capacity as a means for meeting commercialization targets sooner rather than later. As a heavily regulated industry, pharmaceutical development and testing is governed by current good manufacturing practices (cGMP) that dictate extensive, highly structured quality systems. Setting up these systems and operating under them is expensive, requires substantial dedicated senior management oversight, and is training and documentation intense. The cost of providing such fully compliant cGMP organizations is many fold that of working in a typical R&D organization. Therefore, R&D focused companies choose to outsource work that is destined for regulatory agency scrutiny to avoid the cost and personnel required for these operations.

Contract laboratory personnel, rather than spending an entire career on a single or a few drug candidates, are constantly working with a challenging array of molecules and thus have vast experience in technical problem solving. Most pharmaceutical companies recognize this experience as another valuable extension of internal assets. The contract developer has the benefit of exposure to many clients, their interaction with regulatory agencies, and direct contact with regulators at a much higher frequency than typically experienced by a single company with a few products. As such, the contract organization typically has a broad base for identifying trends in regulatory agency expectations. Advice provided to the client based on these recent regulatory encounters reduces the risk of regulatory rejection of development strategy, providing a benefit recognized and sought after by drug developers. The typical pharmaceutical contract development organization is subject to constant inspections/audits by government agencies and by its clients. Major contract laboratories, for example, host several formal audits per week and constantly improve their quality systems and operations as a result of critical evaluation. In our experience, the standard for contract lab compliance is often much higher than the auditor imposes on his own quality organization. Th is benefits the pharmaceutical industry in assuring that work performed and destined for regulatory submission will be able to withstand agency scrutiny. In summary, contract pharmaceutical development organizations are cost-effective, highly skilled resources that operate under strict compliance to regulations. The ability to reduce risk and reach market sooner builds on and extends existing internal resources. These factors, as expressed by our current client base, are the underpinning of ABC Laboratories’ recent expansion of our pharmaceutical macromolecule services, staff and facilities. „

“Reduction in time to market is paramount in the pharmaceutical industry”

Specialization Much of the chemical and biological characterization of new pharmaceutical entities, especially macromolecules such as protein products, requires highly specialized instruments and expertise to operate them. Unless a company has an extensive pipeline of drug candidates to support, purchase of such equipment and expertise is not cost-effective.

Byron Hill is President and CEO of ABC Laboratories and has 40 years of experience in finance and general management, with an emphasis on technology-related industries. His expertise includes mergers and acquisitions, managing financial turnarounds, SEC reporting, ERP system implementations, management reporting, treasury and risk management. Hill earned his undergraduate degree from Southern Illinois University and is a certified public accountant.


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NGP US 18  

Next Generation Pharma US magazine. Issue 18. February 2010. Out from the shadows - Why the rapid rise of emerging markets will change the p...