Trials in the Middle East and North Africa

V INSIDE o l u CROs m in Asia e 2 0 N u m b Volume 20, Number 4 April 2011 e r 4

YOUR PEER-REVIEWED GUIDE TO GLOBAL CLINICAL T RIALS M ANAGEMENT appliedclinicaltrialsonline.com

1992–2011 ➤ GLOBAL TRIALS ACT

Trials in the Middle East

2020 e Year c of Servi and North Africa G l o b al

T Historical Overview: r i al s United Kingdom Trials A PPL

I KKS Network Increases E D C Output in Germany L I N IC A L T R

IAL Also in this issue S ■ Presidential Panel Considers Tighter Rules ■ European Union Provides Guidance ■ Natural Language Processing ■ Reducing Costs Through Technology

Complete contents on pages 6 Ap ri l 2 0 1 1 PAREXEL International +1 781 487 9900 www.PAREXEL.com Right where you need us • Regulatory expertise across international boundaries PAREXEL knows scientific drug development from end to end. We complement your capabilities with • Phase I–IV clinical services for your indication, our strategic insight, deep scientific knowledge, and compound, and patient population tactical expertise—providing you support and guidance • Technology aligned to accelerate development to secure strategic advantage. and maximize ROI • Market access strategy and communications to reach With nearly 30 years of experience and 10,000 your markets and achieve peak revenue quickly professionals in more than 50 countries, we provide the precise fit of expertise when, where and how you need it.

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4 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 PRESENTS TWO MUST ATTEND EVENTS: THE ONLY EVENT THAT FOCUSES ON BUSINESS DEVELOPMENT’S ROLE IN THE OUTSOURCING PROCESS, FROM INITIAL PROSPECTING TO LONG-TERM 3rd Annual RELATIONSHIP MANAGEMENT EFFECTIVE BUSINESS NEW! DEVELOPMENT FOR 2011: OUTSOURCING  Full day seminar for new BD professionals  New half-day workshops on managing prospects through the buying cycle and RELATIONSHIPS transparency among partners OPTIMIZING COLLABORATION BETWEEN EXTERNAL SERVICE  Unique panel of providers who are not PROVIDER BD AND PHARMA/BIOTECH SPONSORS CROs, focused on their concerns and challenges JULY 19-21, 2011 | HYATT AT THE BELLEVUE | PHILADELPHIA, PA  How to implement metrics to manage KEYNOTE: JOHN HUBBARD, PhD, FCP, Senior Vice President & Worldwide Head, risk and drive quality in clinical trials Development Operations, PFIZER, INC.  Partners revealing the inner structures WALL STREET FORECAST: ERIC COLDWELL, Managing Director – Healthcare Equity of their strategic partnerships Research, Distributors, Technology & CROs, ROBERT W. BAIRD & CO., INC.  Moving the BD focus to EU/ROW to CONSULTANTS’ VIEW OF PARTNERSHIP TRENDS: jump start development projects MIKE DEAGLE, Partner, and JOHN M. EBEID, Principal, PRTM  Rising to the challenge of global EXCLUSIVE TOWN HALL MEETING: feasibility through medical informatics Your opportunity to learn from the outsourcing  How Sponsors and Providers should strategies of 8 different sponsors! prepare for bid-defenses

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Register Today and save 15% of the Conference Registration Rate! Simply enter EXLACT when registering for either event! SAVE THE DATE! 7th Latin America Rave Reviews from Previous Latin America Clinical Trials Events Clinical Trials Conference I loved this event! Complete agenda with sponsor, CRO, legal representative and Site perspective. Addressed the critical issues Conducting Fast, Efﬁ cient, and I cannot say how much I liked this! -Clinical Program Manager, P zer High Quality Trials in Latin America August 18-19, 2011 ~ Buenos Aires, Argentina It was a great day. It was really good to see how companies are working with methodologies and the results they are Why you can’t afford to miss this event; achieving. 1. A continued focus on regional regulatory timelines, protocol approvals -Senior Manager, Clinical Operations, Eli Lilly and special requirements 2. Driving good clinical quality standards in clinical trial activities CONFERENCE SPONSORS: 3. The legal / compliance aspects and managing risk of each department involved in the clinical trial 4. Due to a growing competitive landscape the sharp increase in clinical trial activity and patient recruitment For more information on sponsorships and exhibiting please contact: Jayson Mercado at 212-400-6236 or [email protected] 5. Controversial ethical issues when conducting trials in the region

For more information on these events and to Register please visit: www.exlpharma.com or call 866-207-6528 applied clinical Trials

Volume 20, Number 4

CoVer STory GLoBaL TriaLS

44 Clinical Research 36 mena: The Dawn of a new era in the UK Rani Abraham Kerry Dyson and Due to a variety of factors, the amount of trials conducted in the Middle East Davide Garrisi and North Africa has increased. A brief history of clinical trials in the region, as well as a look at the current landscape.

CommenTary CLiniCaL TriaLS 10 From the editor CommUniTy 20 years Partnering 14 news in Clinical Trials 56 Business and People Update Lisa Henderson 58 20 Calendar of events View from Washington 50 Academic Strength Clinical research ethics, in Germany oversight Draw Scrutiny markeTPLaCe Herbert Maier-Lenz Jill Wechsler 59 advertiser index 26 View from Brussels 60 Showcase The launch of the KKS Network has eU regulation: Help 61 helped Germany increase its clinical From a Guiding Hand marketplace trial output. Peter O’Donnell The KKS Network 30 Technology Viewpoint Kiel mining for Words: Lübeck

Hannover Berlin Münster The Case for nLP Witten-Herdecke Essen Halle Düsseldorf Wayne R. Kubick Leipzig Köln Dresden KKS Sites Marburg KKS Locations Mainz with Paediatric- 62 module a Closing Thought Heidelberg Associated Darwin at Work: Regensburg Members Network of Freiburg Surgical Centers Trial Technology München (CHIR Net) Garry D. Johnson

Our MiSSiOn

Applied Clinical Trials is the authoritative, peer-reviewed resource and thought leader for the global community that designs, initiates, manages, conducts, and monitors clinical trials. Industry professionals learn effective and efficient solutions to strategic and tactical challenges within the tightly regulated, highly competitive pharma ceutical environment.

6 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011

applied clinical Trials editorial advisory Board

Kiran Avancha, PhD, RPh Brian J. Koziol, PhD Clinical Research Pharmacist Director, Project Management University of Miami Hospital and & Strategic Operations Clinics/Sylvester Comprehensive Amgen Inc. Cancer Center Thousand Oaks, CA Miami, FL Patricia E. Koziol, PhD Over 18,250* BPA-quali ed Aaron F. Bartlone, MS President Vice President PEK Associates, Inc. & Head of Global Quality Holmdel, NJ UCB Brussels, Belgium Jeffrey S. Litwin, MD clinical trial professionals Executive Vice President Maarten Beekman, MD & Chief Medical Officer Vice President, Medical & ERT Regulatory Affairs Philadelphia, PA AstraZeneca around the globe are reading Zoetermeer, Netherlands Somesh Nigam, PhD Vice President Paul Bleicher, MD, PhD Healthcare Informatics Chief Medical Officer Medical Devices & Diagnostics Applied Clinical Trials… Humedica Johnson & Johnson Boston, MA New Brunswick, NJ Timothy Callahan, PhD VIcky Parikh, MD, MPH Chief Scientific Officer Executive Director Biomedical Systems Mid-Atlantic Medical Research WHY? Because ACT delivers over 18 years Saint Louis, MO Centers Hollywood, MD of editorial excellence with the current Jo Collier, MBChB, FFPM Medical Director Timothy Pratt, PhD, MBA and high-quality content that clinical trial Clinical Science and Principal Pharmacokinetics CRUCIAL professionals trust. By reading ACT, industry Quotient Clinical Clinical/Business Consultants professionals learn e ective and e cient Nottingham, UK Minneapolis, MN Anthony J. Costello Stanley C. Rogers solutions to strategic and tactical challenges Chief Operating Officer Executive Vice President Mytrus, Inc. SMHW Associates, LLC within the tightly regulated, highly San Francisco, CA Lawrenceville, NJ Francis P. Crawley Richard Rubin, MD competitive pharmaceutical environment. Executive Director Director Good Clinical Practice The Vermont Clinical Alliance–Europe Study Center Kessel-Lo, Belgium Burlington, VT Domenico Criscuolo, MD, PhD, FFPM Stephen Senn, PhD Chief Executive Officer Professor of Statistics Genovax Department of Statistics Colleretto Giacosa, Italy The University of Glasgow Glasgow, UK Edward Stewart Geary, MD Vice President Johanna Schenk, MD, FFPM & Global Safety Officer Senior Partner Eisai Co., Ltd. & Managing Director Tokyo, Japan PharmaProjekthaus GmbH & Co. KG Uwe Gudat, MD Frankfurt, Germany Medical Director Office of Chief Medical Officer Albert J. Siemens, PhD Merck Serono Chairman Geneva, Switzerland Novella Clinical Inc. Research Triangle Park, NC Felix Khin-Maung-Gyi PharmD, MBA, CIP Thomas Sudhop, MD Chief Executive Officer Director and Professor Chesapeake Research Review, Inc. Federal Institute for Drugs Columbia, MD and Medical Devices Bonn, Germany Michael R. Hamrell, PhD, RAC President John R. Vogel, PhD MORIAH Consultants Drug Development Consultant Yorba Linda, CA John R. Vogel Associates, Inc. Kihei, HI Erica J. Heath, CIP, MBA President Glen de Vries Ethical and Independent Review President Services, LLC Medidata Solutions Worldwide San Anselmo, CA New York, NY FREE PRINT AND ONLINE SUBSCRIPTIONS

The expertise of Editorial Advisory Board members is essential to the www.AppliedClinicalTrialsOnline.com credibility and integrity of Applied Clinical Trials. These clinical trials experts share with the editors the wisdom gained through their experience in many *BPA December 2009 areas of drug development. EAB members review manuscripts, suggest topics for coverage, and advise the editors on industry issues. All manuscripts must first be submitted to the Editor-in-Chief, Applied Clinical Trials, 485 Route 1 South, Building F, First Floor, Iselin, NJ 08830 USA.

8 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 You asked for it ... DataLabs EDC – designed for you!

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20 Years Partnering in Clinical Trials

Outsourcing in his April, both Applied Clinical Trials and IIR’s Partnerships in clinical trials must TClinical Trials conference share a big birthday—20 years. Already this year, the headlines indicate a very strong year for increased lead to positive alliances. From Merck’s deal with Parexel on biosimilar development, partnerships to to Takeda choosing Covance and Quintiles for its virtual outsourcing overcome age-old model, to Elan’s primary service provider choice of PPD—what had been M&A-induced clinical trial stress in pharma for the past two years struggles. is now somewhat of a boon for the CROs. Outsourcing in this industry invariably leads to partnerships. Sure the tactical functional service providers exist for a reason. But the more strategic variety of alliances mentioned above require a true partner in clinical development.

Age old struggles reduces time; 53% believe it either re- The Partnerships in Clinical Trials con- duces costs or has no impact on costs; ference was held in Phoenix, AZ at the and 77% believe it increases data quality. end of March. At the Plenary Session, From ISR’s standpoint, with the cur- The Avoca Group released its survey rent size, global scope, and clinical results on “The Sponsor Dilemma, trial complexity, oversight is its own Maintaining Efficiency while Ensur- justification. ing Proper CRO Oversight.” I spoke to Denise Calaprice-Witty, PhD, Executive Sponsor/CRO dialogue Director, Survey Research and Relation- The Partnerships conference delves ship Management Programs at The into more than survey findings by Avoca Group about the top-line results. providing actual dialogue between She said that the focus for sponsors the sponsors and CROs on their real-life past two years was on efficiency and how problems. Past conference panels have to design outsourcing to save time and aired the grievances on both sides of money. “This year, there is a swing in the fence without holding back. CEOs, the pendulum to concern about quality,” clin ops directors, investigators, CRAs, she said. Specifically, sponsors feel they and more have come forward with their aren’t getting it and CROs say they can opinions and experiences, with positive deliver it if the sponsors didn’t make cuts dialogue as a result. to budgets. And, says Calaprice-Whitty, The contract research organization micromanagement of CROs comes out of in regard to clinical trials—outsourcing a lack of quality metrics used upfront in as we know it—was established over 30 the planning stages. “What we’re seeing years ago. It was in the mid-1980s that is that more quality could be gotten out the FDA regulations first mentioned and of providers because the sponsors could defined CROs. manage it better,” said Calaprice-Whitty. In this time, the industry has evolved In this month’s news section, ISR Re- from what could be argued as a cottage Lisa Henderson ports offers its insight into this topic with industry to the sophisticated business it its Staff Quality and Models report. The is today. The changes within the space, Editor-in-Chief report found that CROs and sponsors the pharmaceutical industry, and the e-mail: [email protected] agree that oversight may be excessive regulatory authorities that CROs and www.appliedclinicaltrialsonline.com but there are benefits. Nearly half of the third-party vendors satellite around have sponsor respondents indicated oversight indeed changed the playing field.

10 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 appliedclinicaltrialsonline.com

ere are several tips that may be tution/investigator the anticipated useful in working successfully time frame for review. Understand noteworthy with an Academic Medical Cen- their historical enrollment numbers H Go to: ter (AMC) for clinical trials: and discuss barriers to recruitment Ensure that the protocol is a good and retention. appliedclinicaltrialsonline.com fit. Are they interested in the research Don’t be afraid to interview the site to read these exclusive stories being conducted? Are the inclusion/ staff before engaging them formally and other featured content. exclusion criteria a good match for in the study. Initiate contact with the their patient pool? Are there compet- AMC’s office of clinical research and ing trials that may siphon patients? go from there. Late Phase Research Ensure the investigators’ availabil- Consider outsourcing to organiza- A webcast sponsored by Oracle ity for the trial. Is the investigator on tions that are experienced working Health Sciences entitled “Using site and seeing subjects regularly? Or with AMCs, and can navigate time- Web-Based Capture in Late do they travel constantly and rarely consuming yet critical activities, such Phase Research and Patient see subjects? Is their study coordina- as: independent institutional review Registries” is now available on- tor able to run the trial effectively in board services, contract and budget demand at www.appliedclinical their absence? negotiations, and internal audits. trialsonline.com/webbased. If a CRO is being utilized, be sure that the team has experience with Kimberly Irvine is the EVP of Operations AMCs and can navigate the system at BRANY, www.brany.com. SDV Remains a Target effectively. Ask for case studies and Many articles in the past few request an experienced team. Editor’s Note: The full text of this months have focused on more Establish expectations that are article is available on the web in the realistic. Determine from the insti- Online Extras section. efficient use of source data veri- fication, away from the current 100 percent target. See www. How signicantly will biosimilar clinical development appliedclinicaltrialsonline.com/sdv. affect CROs in the next two years?

Blog Posts Not at all Go to our home page and 25% read our blogs. Latest install- 50% Signicantly ments cover Oncology and

25% Imaging; GCP Training in the EU; Collaborative Clinical Trials and

Somewhat IVR vs. IWR.

Source: appliedclinicaltrialsonline.com survey, 3/8/11-3/22/11 Phase News Biosimilar/Biologic Market Developments For the latest in clinical trials Since the new year, each month has brought a major news announcement regard- results, go to our home page ing biosimilar drug development. Merck’s choice of Parexel for its biosimilar under Phase News. This RSS feed development program; Quintiles’ stake in Samsung’s journey toward biologics; keeps viewers up to date on the and Amgen’s and Biogen’s hints it would develop biosimilar candidates. The latest in drug developments. biosimilar market is estimated to be $19 billion by 2014.

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TherapeuTic corner Alzheimer’s Advances Depend on Early Diagnosis

ccording to PhRMA’s “Medi- mend approval Acines in Development for of Amyvid Alzheimer’s Disease” report conditional on a Alzheimer's Drugs By Phase issued in 2010, there are currently reader training 60 five marketed drugs that temporar- program that ily reduce symptoms of Alzheimer’s. demonstrates 49 50 However, there are no vaccines to reader accuracy prevent the disease or medications and consistency that will delay its onset, severity, or through a re- 40 36 cure the disease. At the core of the dis- read of previ- ease is early diagnosis. It is important ously acquired 30 that Alzheimer’s be detected in the scans. The FDA predementia stage. Currently, when did take the 20 Alzheimer’s is detected, brain atrophy committee’s ad- has already begun and the prognosis vice and issued 9 10 is about nine years to death. In addi- Lilly a complete tion to the benefits on quality-of-life, response letter PhRMA notes that a treatment to delay addressing the 0 onset by five years would save the reader issue in Phase I Phase II Phase III healthcare system $447 billion. March. Source: Adapted from PhRMA’s Medicines in Development for Alzheimer’s Below are some highlights about Amyvid is Disease, 2010. It excludes medicines categorized as in clinical trials, Phase current medicines in development. a molecular 0, and for indications of cognitive disorders associated with schizophrenia or multiple sclerosis. In the vaccine area, AFFiRiS’s cur- imaging agent rently has three Alzheimer’s vaccine that is injected candidates that are designed to induce into the patient who then undergoes the International Genomics of antibodies targeting the beta-amyloid a PET scan to detect beta-amyloid Alzheimer’s Project, to discover and peptide that is believed to contribute plaque in the brain, which would be map the genes that contribute to to the pathology of Alzheimer’s. With an indicator of Alzheimer’s disease. Alzheimer’s disease. The collaboration Affitope AD03, the third of its candi- At issue is the ability to ensure the includes universities in Europe and dates, which is in Phase I, AFFiRiS readers of the scans are trained the United States. In the initial phase additionally targets modified beta- adequately for the needs of market of the work, more than 20,000 people amyloid peptides which are presumed implementation. with Alzheimer’s and about 20,000 to have different toxicity profiles in Lilly acquired Avid Radiophar- healthy elderly subjects will be com- humans. Its clinicaltrials.gov identifier maceuticals for $300 million in De- pared. As the study progresses, 10,000 is NCT01309763. Affitope AD02 is cur- cember 2010. Amyvid was the first additional people with Alzheimer’s and rently in Phase II to study safety and beta-amyloid imaging compound to the same number of healthy elderly tolerability of different doses for early enter multi-center, investigational new subjects will be added to the study. Alzheimer’s. Its clinicaltrials.gov iden- drug clinical studies in the United The subjects for these studies come tifier is NCT01117818. States. Prior to receiving the complete from different Alzheimer research In the area of disease diagnosis, the response letter, Eli Lilly CEO John project locations across Europe, the FDA’s Peripheral and Central Nervous Lechleiter said in interviews that the United Kingdom, the United States, System Drugs Advisory Committee company was confident it would work and Canada. recommended against approval of Eli with the FDA and get approval. Ceregene is developing a gene ther- Lilly’s Amyvid (florbetapir) in mid-Jan- In the area of genetics, the Alzheim- apy product in Phase II trials, however, uary based on the currently available er’s Association announced in Febru- its candidate for Parkinson’s is cur- data; but, voted unanimously to recom- ary, the launch of a collaboration of rently garnering more attention.

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GLoBaL neWS Researchers Tackle Problems in Bowel Disease

any promising compounds for disease, and it might be prudent to wait tive damage. He anticipates that future Minflammatory bowel disease longer to observe a clinical effect. work will involve the use of a new in- (IBD) are lost during the com- Better endpoints are also needed, he dex of digestive damage, and this may plex development process, and it is vital noted. In many IBD trials, the chosen help to provide clinicians with a clearer to find out why and discover some solu- endpoint is mucosal healing (the ab- definition of early Crohn’s disease. tions to prevent further leakage from sence of ulcers is used as a marker to This new index is known as the Lé- the clinical trials pipeline. Translating indicate healing). This simple endpoint mann Score. The score was developed basic science into clinical practice is easy to identify, especially in Crohn’s to understand cumulative bowel dam- is proving difficult in IBD, partly be- disease, and is a strong indication of a age and the impact of early interven- cause of the immunological problems drug’s effectiveness. However, it does tion, and it is based on a comprehensive suffered by trial subjects and partly have limitations, not least because there assessment of structural bowel dam- because no good experimental model is no full validation of what exactly an age. This score is based on damage, exists, particularly for Crohn’s disease. ulcer is. Colombel thinks qualitative not disease activity, and it will take into These are the views of Jean Frédéric studies of this aspect are necessary, and account damage location, extent, and Colombel, MD, Professor of Hepato- queries whether one small ulcer is evi- severity. The Lémann Score will allow gastroenterology at Centre Hospitalier dence of non-mucosal healing. physicians to assess the cumulative Régional Universitaire, Lille, France. The Crohn’s Disease Endoscopic In- and progressive damage and to study He gave the closing plenary lecture dex of Severity (CDEIS) may be a much the effects of early intervention on dam- at the 6th Congress of the European more sensitive score when assessing age progression. Crohn’s and Colitis Organization, held mucosal healing, even though many phy- When only looking at clinical dis- in Dublin in late February. sicians appear reluctant to use the index ease activity in patients, physicians “Keeping drugs in the clinical trials because they regard it as a complex tool. may miss the progressive accumula- pipeline is often a difficult challenge,” Using the CDEIS helps to define the end- tion of digestive damage. The current he said. “The placebo effect is a killer points, and therefore is a useful instru- endpoints of the clinical picture, histol- of drugs.” ment in IBD trials, he pointed out. When ogy, and endoscopy can no longer be To optimize the chances of success, considering that the gold standard of used to assess digestive damage and he recommends a reduction of concomi- healing in patients with IBD is “minor the impact of drugs on the long-term tant medication, selecting a robust iden- lesions,” the endpoint of definition of mu- natural history of IBD, he said. Follow- tifiable endpoint, only entering patients cosal healing on the CDEIS should be ing the path of rheumatologists when with active disease into clinical trials, six. If clinicians are looking for a more assessing endpoints, he supports using a short duration for induction studies, stringent endpoint of “no lesions,” then the “Sharp Index,” which is an index of and the minimization of clinic visits. Fo- the CDEIS should be three. bone destruction and is used in many cusing on patients with active disease is Currently physicians are assessing clinical trials as a primary endpoint. the most important of these factors, but the limitations of endpoints on very The challenge for future clinical another important issue is the length short-term periods, he stated. Short- trials in IBD is to look at large studies of the evaluation, noted Colombel, who term studies are “the black box of clini- with robust endpoints and to begin is a visiting professor at the Inflam- cal trials,” and therapeutic strategies thinking about non inferiority trials. matory Bowel Disease Center, Mount are of value for assessing a greater pro- Access to patients in the early stages Sinai School of Medicine, New York. portion of the patient’s life. Induction of the disease is vital when designing He argued that a longer evaluation time studies are currently being undertaken IBD trials, and also of interest are also raises the possibility of increasing up to a maximum of two years. Colom- long-term studies looking at disease the placebo effect. It is best to opt for an bel made a plea that during this time, modification with new endpoints, in- open point of six weeks clinical remis- physicians ought not to define patients’ novative strategies (tight control, dose sion in IBD trials, but this may be too lives in terms of flare-ups and remis- reduction, and discontinuation), and short a time, particularly for those sub- sions. New endpoints are needed in personalized medicine. jects who enter a trial with severe active IBD trials to accurately assess diges- — Edna Astbury-Ward, PhD

16 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011

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TechnoLoGY Diagnosis on the Run: There’s an App for That

nly two weeks before the FDA Mobile tech stats Oapproved a mobile medical im- on usage in healthcare aging application for the iPad include: 72% of US and iPhone, Colin Miller, PhD, Senior physicians use smart Vice President, Medical Affairs for Bio- phones, predicted to go Clinica, had his own first-hand imaging up to 81% by 2012; and app moment. His sons were snowboard- 22% of US physicians ing six hours from home, when the call use iPads. These statis- came that the youngest one was in the tics were gleaned from hospital with a fracture. Miller directed a blog writer reporting his eldest son to get the DICOM file of from HIMSS the week the clavicle fracture, decode it and e- of February 21. The mail it to a radiologist friend, who him- blogger noted that self was traveling. Within moments, the areas of growth his friend relayed the severity of the for mobile healthcare Source: Colin Miller included the Pharma/ fracture (not serious) after viewing the Miller was able to get a second opinion on his image on his iPhone. In the meantime, Clinical information son’s broken clavical remotely. Miller and his wife made the drive systems piece for phy- more relaxed knowing that their son’s sicians. These findings prognosis was good. In fact, the friend bear up Miller’s premise that the intu- app development for clinical trials. “The confirmed the diagnosis from his full- itiveness and ease of use of these tablets human data in clinical trials and the screen computer the next day. The break down any previous technological problems of encryption and safety and same findings as what he determined platform barriers, especially among the security is the next nut to crack.” from the iPhone-viewed scan. technology-averse healthcare practitio- Miller is confident these challenges Call it evolution and revolution, but ner group. However, there remains the will be sorted out, and has reason to there is a rapidity of events by which industry-specific barrier. believe they will, based on recent con- Miller discovered his son’s diagnosis; As is well-documented, and using versations with app developers. Here followed by the FDA’s approval of EDC as an example, the pharmaceutical are some real scenarios from John Mobile MIM for physicians to exam- industry is itself not a fast technology Rogue of New England Survey Sys- ine pictures from patient scans for adopter. Said Miller, “We drag along tems that could mean the difference computerized tomography, MRIs, and because of the regulatory requirements. to this space: time to create CRFs, one positron emission tomography scans; And we’re very poor on the technology day from two to three months; present followed by a call Miller received from uptake.” It was only in 2008 that more number of queries 13,000 down to 17. a company readying an app launch for than 50% of trials used EDC, but that has Explained Miller: “Of the top things the iPad and Android tablet systems been slow going for close to 20 years. that can really slow down a trial—pro- for an EDC piece in the clinical tri- But with the financial and develop- tocol development, CRFs, drug supply, als space. “It’s all happening so very ment pressure pharma is under, the site enrollment, and IRB approval—you quickly,” noted Miller. need to push to these technologies are only taking one item off the critical The FDA approved Mobile MIM for using wireless, broadband, and cloud path (using above scenarios). But if you a 510(k) clearance on February 4, the computing for efficiencies may foster take out one, down to one day, your fo- first FDA approved diagnostic radiol- faster adoption rates. cus becomes much clearer and maybe ogy application for mobile devices to “One of the historic challenges you can reduce the others by half.” allow physicians to view medical im- of data collection (using these tech- Miller outlines that many of these ages on the iPhone and iPad. It is avail- nologies) is how to be sure it can’t be critical path items could easily be able now through the US Apple App hacked into,” noted Miller when asked adapted for app use, to streamline the Store, according to the company. about the next set of challenges facing whole process. —Lisa Henderson

18 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011

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DaTa anaLYSiS

steps to increasing trial efficiency and Sponsor Oversight of CROs lowering industry clinical development he perennial sponsor complaint: From ISR’s perspective, the size, spending. Achieving the right oversight T“Outsourcing costs too much.” The global scope, and complexity of today’s balance can have profound effects on perennial CRO response: “If you clinical trials are justification enough for both individual development programs didn’t assign so much internal resource a degree of oversight. Pharma’s business and companies. to manage us, it would be cheaper.” challenge is identifying when enough —Industry Standard Research, Well, it’s true and both groups is enough; the point when investing in www.ISRreports.com acknowledge it. Over 90% of sponsor more oversight no and CRO respondents indicate that longer returns a

27% resources are assigned to oversee better clinical trial. Far too much 18% outsourced studies. While CROs and Service providers’

40% sponsors agree that oversight may be business challenge is Slightly more than is needed 34% excessive, they do not agree on the to better understand 0% Just the right amount consequences. In ISR’s Staff Quality why sponsors 32% and Models report, 78% of CROs believe insist on oversight, Service Providers (N=30) 27% Slightly less than is needed Sponsors (N=73) that oversight increases the amount of and then develop 11% time necessary to complete a clinical systems, training, 0% Far less than is needed trial compared to only 25% of sponsors. and people to arrive 4% Sponsors hold what may be considered at the right balance. 7% Don’t know contradictory beliefs regarding their This is an evolving 1% oversight of CROs. They believe their issue and having a 0% 20% 40% 60% 80% own oversight to be excessive; however better understanding Source: ISR Reports many believe there are benefits too. of development Nearly half of the sponsor respondents outsourcing models Sponsors were asked: “What level of management oversight do you think your organization uses indicated oversight reduces time; 53% as well as sponsor when managing a service provider?” cros were believe it either reduces costs or has and service provider asked: “What level of oversight do you think spon- oversight rationale no impact on costs; and 77% believe it sors use when managing a service provider?” increases data quality. are important first

April 2011 appliedclinicaltrialsonline.com Applied CliniCAl TriAlS 19 View from Washington

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standards and how they relate to international clinical trials. Clinical Research Ethics, Instead of producing a fat study that sits on the shelf, Eric Meslin, Professor and Director of the Indiana Oversight Draw Scrutiny University Center for Bioethics, en- couraged the panel to define a more coherent, unified, transparent US re- Presidential panel experts, is “probably not.” While search policy to replace today’s “leaky the Tuskegee syphilis study, which system.” Robert Califf, Vice Chancellor to examine need began in 1932, was infamous for for Clinical Research at Duke Univer- for tighter rules withholding treatment from some sity, advised the Commission to clearly syphilis patients, the Guatemalan define the important attributes of the governing US and study is even more shocking because research ecosystem and then identify foreign clinical trials. researchers intentionally infected ways to measure them. mental patients and prison inmates. ational and international Scientists and ethicists advising the Considering context authorities have been strug- commission at its first meeting on To start, commission investigators are gling for decades to ensure the subject last month said that rules examining documents and informa- the protection and appropri- and policies developed over the last tion on the Guatemalan study, which N 50 years would prevent the design ate care of patients participating in was uncovered by Wellesley College biomedical research studies. The task and conduct of such a study. But they Professor Susan Reverby as part of her has become even more challenging as admitted that no law actually blocks research on Tuskegee. The staff will more clinical trials take place outside such action by a privately funded report on what specifically happened the United States and Europe—not researcher who is not seeking regu- in Guatemala in the 1946-1948 trials only to reduce costs and access pa- latory approval for a new medical and to what extent the US government tients more readily, but for global product—a situation likely to gener- and medical establishment facilitated pharmaceutical companies to be able ate proposals for stricter standards these studies. It’s likely that other un- to develop products appropriate for for- and oversight. known research projects of a similar eign populations. The bioethics commission is sched- nature will be discovered. The lack of common international uled to report back to the White House The investigators acknowledge the standards and rules, however, gives by September, putting this review at importance of examining these events rise to perennial scandals and abuses. the top of its priority list. Commission in their historical context to assess Research sponsors struggle regu- Chair Amy Gutmann, President of the the extent the studies conformed with larly with concerns about adequate University of Pennsylvania, opened the or diverged from the relevant ethi- informed consent, patient selection, March 1, 2011 meeting by acknowledg- cal standards of the time. Back when study oversight, placebo controls, ac- ing that the Guatemalan prisoners and these studies occurred, explained cess to resulting therapies, and stan- patients in the study were treated un- biomedical historian Susan Lederer, dard of care for research participants. ethically. “A civilization can be judged University of Wisconsin School of These issues once again have come to by the way it treats its most vulnerable Medicine and Public Health, there the fore following revelations last fall individuals,” she observed, setting were few policies on the organiza- about highly unethical medical stud- the stage for a thorough examination tion of clinical trials or the roles of ies conducted in Guatemala 65 years of the adequacy of existing research researchers, participants, control ago supported by the US Public Health groups, and randomization. Medi- Service. President Barack Obama has cal Ethics Professor Dan Brock of asked the Presidential Commission for Harvard Medical School noted that in the Study of Bioethical Issues to exam- Jill Wechsler 1946 many ethical practices consid- ine what took place in Guatemala and is the Washington editor ered standard today were not yet on whether today’s standards are strong of Applied Clinical Trials, the table, although they were emerg- enough to prevent such practices from (301) 656-4634 ing following revelations about medi- recurring today. [email protected] cal experimentation in Nazi Germany. The short answer to the second Meanwhile, researchers studying the question, according to research spread of sexually transmitted infec-

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tious disease during World War II driving influences on research ethics in medical research from the United were anxious to document effective outside the United States and how best States, observed Califf, reflects the prevention and treatment strategies to address conflicts between US and desire of all countries to have clinical for clinicians. international policies. research done in the context of their Eric Meslin noted that not only populations due to genetic variation, Better today? has the volume of international stud- cultural perceptions, and differences In addition to delving into past prac- ies grown, but so has the number of in medical treatment. US studies not tices, the Commission is reviewing the countries that host studies and the only are very expensive, he noted, but current state of biomedical research diversity in funding sources, many also often yield poor data due to high and how well US regulations and inter- involving large collaborations and dropout rates.

The shift in medical research from the United States More investigations An important goal for this examina- reflects the desire of all countries to have clinical tion is to bolster public trust and con- research done in the context of their populations. fidence in the ability of the research community to protect patients enrolled national standards protect the health partnerships. There is more emphasis in clinical studies and to ensure that and wellbeing of patients participat- on community engagement in research resulting data is valid and impartial. ing in US-funded studies. A special plans and on determining an appro- Revelations about the Guatemala study panel on international research, which priate standard of care for research undermine this perception, as does a includes ethics and research experts participants, along with a proliferation steady stream of reports on unethical from the United States, Guatemala, of research guidelines and standards, research practices. India, China, Egypt, Africa, South and a deeper understanding of ethical A muckraking article in the Janu- America, and Europe, is assessing issues on all sides. The massive shift ary 2011 issue of Vanity Fair, for example, blasted the globalization of clinical research, citing deaths of hundreds of poor research partici- THE GEORGE WASHINGTON UNIVERSITY pants and the tendency of sponsors SCHOOL OF MEDICINE AND HEALTH SCIENCES to hide studies that produce nega- tive results. A study published last Accelerate Your Pathway … year in the journal Pediatrics cites an increase in pediatric studies being Career and Leadership Development in: For more conducted outside the United States information: • Clinical Research Administration – BSHS/MSHS as raising questions about whether www.gwumc.edu/healthsci • Clinical and Translational Research – MSHS the foreign data is meaningful for US [email protected] • Regulatory Affairs – MSHS 202.994.3564 patients, and whether study partici- • Innovative online programs • Dual degree programs pants can gain access to the medi- • Graduate certificate programs • Globally recognized cines under study. Pfizer continues to face litigation and criticism stemming School of Medicine and Health Sciences from a 1996 study of the effective- Come to an institution known for academic excellence ness of the experimental antibiotic offering degrees to clinical and regulatory researchers Trovan in treating Nigerian children and professionals for over ten years. with meningitis; several patients died, leading to lawsuits and allegations of unethical practices. Research globalization, moreover, is prompting the Justice Department to investigate whether pharmaceutical companies conducting overseas clinical trials may be violating the Foreign Corrupt Practices Act. Fees to foreign investigators, clinicians, www.gwu.edu G42046 THE GEORGE WASHINGTON UNIVERSITY IS AN EQUAL OPPORTUNITY/AFFIRMATIVE ACTION INSTITUTION CERTIFIED TO OPERATE IN VA BY SCHEV. or laboratory officials who work for

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government health systems could America would involve more inexpe- proportion of foreign sites (see Applied be considered payments to foreign rienced investigators and weak regu- Clinical Trials, “View from Washing- officials, and the feds are looking latory oversight, making it difficult ton,” August 2010). at whether such sponsor payments to assure adequate protection of hu- Proposals for FDA to expand its influence the reliability of data from man subjects. oversight of clinical studies ignore foreign clinical trials. In a June 2010 report, the OIG the agency’s limited resources to do This federal probe reflects reports urged FDA to look more closely at so. The administration’s budget plan from the Health and Human Ser- the results from trials not conducted for 2012, which requests a little additional funding for FDA, is not likely to Proposals for FDA to expand its oversight of survive the budget-cutting campaign on Capitol Hill. Most of the extra clinical studies ignore the agency’s limited money would come from higher user resources to do so. fees on pharmaceutical and biotech companies, and is targeted to support vices Office of the Inspector General under an investigational new drug ap- special projects, such as development (OIG) documenting inadequate plication and to expand its volume of of biosimilars and medical counter- FDA oversight of a growing volume overseas inspections. The analysts cal- measures, import monitoring, and of foreign clinical data in new drug culated that in 2008, up to 65 percent efforts to ensure the safety of high- applications. A 2001 OIG analysis of clinical trials supporting registra- risk therapies. Everyone wants FDA reported a rise in recorded foreign tion of products in the United States to conduct more inspections of food clinical investigators from only 271 were conducted outside the country. processors and foreign drug manu- in 1990 to almost 4,500 by 1999. The And while FDA inspected nearly 2 facturers, as well as research sites, OIG warned that more clinical re- percent of domestic clinical trials sites but there’s scant funding to support search in Eastern Europe and Latin in 2008, it visited less than half that those efforts. ❏

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a standard disclaimer for all EU guidance, that “the views expressed in this EU Regulation: Help questions and answers document are not legally binding. Ultimately, only the European Court of Justice can give From a Guiding Hand an authoritative interpretation of community law.” But it provides some helpful indications of some of the basics March marked a busy the case, sometimes with the medical and some of the complications in the devices supplied directly by the spon- everyday decisions about trial design month for the EU with sor), the clinical trials rules apply to and execution. guidance updates the medicine, and the medical devices The questions range from the broad have to comply with the EU rules for (e.g., “What is a ‘clinical trial?’” or and the launch of new placing on the market and putting into “How is ‘sponsor’ defined?”), to the medicine research. service of medical devices. highly specific (e.g., “A study might If the study is comparing a medicine involve the administration of a me- dvances in technology drive against a device for the same indication dicinal product, while the object of the advances in regulation—but (for example, a comparison of a warm- investigation is not the administered Aoften not fast enough for the ing medicinal product applied topically medicinal product, but exclusively the fastest movers. The conse- with a warming medical device applied physiology of the body. Are these stud- quence, in the field of clinical trials, on the skin), the 2001 rules apply to the ies ‘clinical trials?’” or “Can the dates is that sponsors with innovative ap- part of the study assessing the medi- of the annual safety reports be aligned proaches are sometimes obliged to op- cine, but not to the device. with other periodic reporting require- erate without clarity or certainty about ments?”). They also extend to the pro- what rules apply. Update cedural (e.g., “After the receipt of the As a matter of routine, the European The guidance comes in the latest opinion of the Ethics Committee, is the Union therefore tries to help out with update, published on March 18, to a applicant allowed to appeal against the updates wherever it can. It has just, for document that perhaps deserves wider opinion?” or “If a site does not start the instance, provided guidance on what attention than it receives: the Euro- trial, but was listed on the application the 2001 clinical trials rules mean for pean Commission’s “Questions and form when the trial got authorization, studies that involve a medical device. Answers,” which is part of Eudralex, what should the sponsor do?”). Its answer makes a distinction ac- the EU’s compendium of legislation on cording to the role of the device. If it pharmaceuticals. The Q&A guidance Women and clinical trials can be regarded as a single integral is an annex to Volume 10 of Eudralex— March was remarkable not only for the product, combining a device and the chapter dealing with clinical trials. update to the guidance on EU rules for a medicine product, and the study This latest version of the Q&A is the clinical trials. It was also the month concerns the medicine, then the 2001 eighth to date. The content is regularly that marked the 100th anniversary of rules apply. At its simplest, the guid- discussed within the commission’s International Women’s Day, and the ance indicates this would be the case ad hoc group for the development of European and Developing Countries of a prefilled syringe, which would implementing guidelines for the 2001 Clinical Trials Partnership (EDCTP) be regarded as an integral delivery rules, which is chaired by the commis- celebrated this anniversary by honor- product. Similarly, combined advanced sion and includes representatives of all ing the contribution of women, in all therapy medicinal products as defined EU member states. It makes clear, in capacities, in the fight against HIV/ under the EU’s 2007 rules would also AIDS, tuberculosis, and malaria. be covered. In addition, an interven- This worthy partnership, on which tional study would be a clinical trial, Peter O’Donnell this column has commented in the and would thus fall under the 2001 is a freelance journalist past, aims to accelerate the develop- regulatory framework. But if the object who specializes in ment of new or improved drugs, vac- of the study is the device, then the European health affairs cines, and microbicides against HIV/ and is based in Brussels, clinical trials rules do not apply. AIDS, malaria, and tuberculosis. It was Belgium. If the object of the study is a medici- created in 2003 as a European response nal product and medical devices are to the global health crisis caused by used during the trial (as is frequently these three main poverty-related

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diseases, and now brings between 14 feed. From June 2005 to August 2008, EU medicines research funding European Union member states plus 882 women were enrolled, 824 of whom Also in March, and closer to home, Norway and Switzerland together with gave birth to 805 live born infants. The the European Union announced that 47 sub-Saharan African countries. results show that providing a combina- eight new research projects worth Many projects funded by EDCTP tion of a triple antiretroviral combina- €172 million would be launched are of immediate relevance to the tion to pregnant and breastfeeding over the coming weeks under the struggle for equal opportunities for mothers is a safe and effective way to so-called Innovative Medicines Ini- women and to the improvement of the reduce HIV transmission to infants. tiative. The focus will be on cancer, health of women and children. Women The findings have influenced the re- rheumatoid arthritis, infectious disorders, and e-health. EDCTP highlighted some of the scientific and One of the projects, known as BTCure, will focus on development medical work of women in the projects it funds of curative treatments for early inter- in honor of International Women’s Day. vention against rheumatoid arthritis. The aim is to develop an understand- play crucial roles in all EDCTP activi- vised World Health Organization guide- ing of the early process in arthritis ties as policy makers, scientific project lines on prevention of mother-to-child subsets that will allow precise and managers, research scientists, health- transmission of HIV and infant feeding. eventually curative treatments to be care professionals, field workers, pa- Another project, led by Professor used before irreversible destruction tients, and healthy volunteers. Clara Menéndez, aims at developing and loss of joint function and mobility This year’s observance of Interna- new clinical interventions to fight ma- have occurred in patients. Another, tional Women’s Day focused on equal laria by the evaluation of different anti- known as PREDECT, is developing access to education, training, and malarial drug alternatives as intermit- new models for novel treatments of science and technology, and EDCTP tent preventive treatment in pregnancy breast, prostate, and lung cancer. It highlighted some of the scientific and in the context of insecticide treated nets. says it will permit the emergence of medical work of women in the projects It will compare the safety and efficacy faithful models for target validation it funds. In total, 43 out of 160 EDCTP- of the currently recommended drug and beyond, as a response to the poor funded projects are led by female with those of mefloquine. The study predictability of drug efficacy in tra- scientists as project coordinators: this includes HIV-infected pregnant women ditional preclinical discovery meth- total comprises 15 integrated clinical to provide a better understanding of the ods, particularly for target validation. trial projects, seven career develop- interactions between antimalarial and It will focus on complex but transfer- ment and senior fellowship projects, HIV treatments. Another EDCTP proj- able next generation in vitro and in five directly funded PhD and MSc ect aims to optimize the existing dose vivo models for breast, prostate, and training awards, nine projects to estab- and regimen of intermittent preventive lung cancers. lish or enhance the capacity to conduct treatment in pregnant women with Innovative Medicines Initiative medical research in conformity to pro- sulfadoxine-pyrimethamine. (IMI) claims that the first wave of fessional ethical standards, one project And an EDCTP-funded project lead its projects, now up and running for furthering collaboration in regional by Kishor Mandaliya, MD, is sampling around a year, are already providing networks of excellence, and six net- a variety of study populations in four tangible benefits, ranging from the working grants. EDCTP says that gen- African settings in a bid to refine both biggest database ever compiled on der balance is one of the concerns in clinical and laboratory methods and schizophrenia to an international con- evaluating applications for the funding findings in search of more reliable sensus statement on the classification of projects, and projects often provide safety biomarkers for the development of patients with severe asthma and for extensive professional training for of microbiocides for intra-vaginal ap- international agreement on the strat- women healthcare workers. plication to prevent infection with HIV egy to be followed to qualify biomark- and possibly other sexually transmit- ers for drug safety in clinical trials. EDCTP studies ted infections. Recent research with Further upcoming IMI projects, likely One of the EDCTP studies—Kesho anti-retroviral based microbiocides to be launched in 2012, will cover the Bora, which means “a better future” in has shown promise in offering women development of treatments for autism, Swahili—offers new hope for prevent- protection against HIV, but, as EDCTP tuberculosis, and diabetes, and the ing HIV infection and death among points out, there is still a need to in- safety of drugs and vaccines. infants in low-resource settings where crease knowledge on reliable biomark- Altogether—in terms of medicines, many mothers with the virus breast- ers during Phase I and II trials. at least—not a bad month. ❏

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less read). Much of this is health related—an estimated 10 billion patient Mining for Words: The records have already been created— and some of that might even be crucial to health decisions, if only it was avail- Case for NLP able when needed. In the particular case of pharmacovigilance, currently only an esti- Natural language the electronic form. Since a comment mated 10 percent of all drug related can contain literally anything, these adverse events are actively reported processing could still need to be closely reviewed—just as cases to manufacturers or regula- change the way we in case they involve a significant find- tors. What about the others? Are ing or inference. FDA reviewers have there possibly patient notes in health interpret documents also expressed their intense interest records that never get transcribed and data. in gaining access to other possible into a MedWatch form? Are patients safety-relevant information that may discussing their side effects in public n the world of clinical trials, we be lurking in electronic health records web forums, blogs, specialty sites like spend a great deal of time design- (EHRs) but never made it to the CRF, patientslikeme.com, or even tweets? ing case report forms (CRFs) to though we still have many technologi- How would we know? And if we did Irecord the specific data points we cal, legal, and political barriers inhibit- know, should manufacturers have to want to collect for a protocol. It’s im- ing that. Much of the data in EHRs is collect, report, and process these like portant to design CRFs with the goal of currently recorded as free-form text other case reports? If so, how will populating a database that will need to in the form of notes jotted down by they keep up? be analyzed, so CRF designers try to a physician (sometimes on scanned Michael Ibara, a fellow evangelist collect categorical data values through paper)—not as structured data that for integrating EHRs with clinical re- value lists, Boolean responses, or would easily fit into a relational data- search and safety, has predicted that numeric measurements as much as base for systematic analysis. the cost of acquiring digital safety in- possible. As a general rule we eschew free-form text responses to questions, because these can’t be automatically Currently only an estimated 10 percent of all drug analyzed—you need a human being related adverse events are actively reported as with some domain experience to read, interpret, and decide what to do with cases to manufacturers or regulators. such responses. In cases when we do allow free text—as in the verbatim There’s quite a lot of free text infor- formation will drop significantly as the description of an adverse event (AE)— mation floating around these days — industry catches up with technology, we subsequently code this text with IDC has estimated that more than which follows the evolutionary trend of dictionary-derived standard values 1,000 exabytes of digital data are being information from atoms into bits that that can be systematically analyzed in produced around the globe each year. Nicholas Negroponte described in Be- the database. (For those of you who care about such ing Digital. Moreover, as cost drops, Now in the paper CRF world, it’s things, 1,000 exabytes = 1 zettabyte = typically volume increases. It’s been possible for an investigator to scribble 1021 bytes—or far more than myriad said that FDA is already anticipating additional free-text anywhere on a human minds can ever imagine, much that they’ll have to begin to monitor page, and many FDA reviewers would such websites for potential safety in- scour CRFs for evidence of notes hid- formation in the future. Yet they are den in the margins that might contain already stretched, processing over one insight—or even infer an adverse event Wayne R. Kubick million AE reports each year—how that never was never directly described is Senior Director, Life would they cope if millions more were on the AE page. EDC limits this ability Sciences Product Strategy suddenly beginning to appear? at Oracle Health Sciences. to ad lib—but most systems still allow He can be reached at the use of comments so an investigator [email protected]. Natural language processing can record information that doesn’t Which is why the topic of Natural quite fit into the pre-defined slots on Language Processing (NLP) comes

30 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 4.45pm Tianjin, China.

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Laboratory Technician, Laila, prepares samples for a Phase II study assessing the feasibility and safety of a new drug in subjects with heart failure. Technology Viewpoint

to mind. NLP is loosely defined as diagnoses, and adverse events to sup- Other uses for NLP computer understanding, analysis, port safety surveillance. There are many other relevant life manipulation, or even generation of A separate lecture by University of sciences applications for NLP beyond natural language communication. Illinois Professor Catherine Blake de- safety. For example, while we are Many of us saw IBM’s Watson star scribed a method using semantic web- finally getting closer to creating a on Jeopardy recently, when he (or at like triplet structures to perform meta- standard for structured protocols, our least his NLP male voice) adequately analysis by extracting product claims past and current clinical trial proto- bested two breathing humans by from published literature, including cols are simply free-text documents. understanding, interpreting, and the proper handling of modifiers (so NLP could be used to extract struc- responding to the Jeopardy answers as to differentiate, for example, differ- tured data elements from published with dazzling speed. NLP is Hal, or ences in claims for studies performed protocol documents—to support meta your cell phone’s voice command fea- on rats vs. humans). analysis and provide context for the ture, and a major piece of search en- Another example was a paper clinical data that could be further gines like Google which often have an presented by Martijn J. Schuemie explored retrospectively (as with the uncanny ability to understand what at last year’s ISPE conference titled FDA’s current comparative effective- you really meant—even if that wasn’t “Automated Classification of Free ness project using a new clinical data exactly what you typed. Text Electronic Health Records for repository). Stanford University, whose NLP group has been leading researchers for years, developed its NLP can be used in life sciences research to help protocol disambiguator tool to look for us master hoards of scanned paper or electronic inconsistencies between narratives free text to find out specific useful information. and structure using NLP. Of course, interpreting the mean- ing of language by computer is still We have many needs to better ap- Epidemiological Studies,” an EU- somewhat of an art as well as sci- ply NLP in life sciences research to ADR funded project that used text ence—see, for instance, the amus- help us master hoards of scanned data mining of narratives to extract ing but unprintable website devoted paper or electronic free text to find diagnoses and adverse events from to archiving classic missteps of the out specific useful information, such medical records. iPhone autocorrect text feature. as adverse events, symptoms, diag- Some of my CDISC friends have Computers can’t always tell when noses, and drugs taken in observa- been involved in the Strategic Health they interpret something that doesn’t tional data, or medical history, which IT Advanced Research Projects Area make sense—or even might cause is generally unstructured even in program (SHARPn, which is funded by offense. But the research has shown clinical trials. ONC) to develop tools to influence and accuracy of up to 90 percent in some Fortunately, there has been a great extend secondary uses of healthcare cases—possibly as good or better deal of academic research on how to do data. Among other things, SHARPn than tired, overworked humans. De- this. Even with traditional electronic has created an NLP annotation tool spite a couple of embarrassing goofs, case reports, crucial information may called cTAKES. cTAKES is already Watson comported himself pretty be lurking in the narrative which may adept at identifying drug utilization in- well on Jeopardy too. not be correctly represented in the formation in text and is currently being NLP is not a new concept. Indeed, structured data elements of the case evaluated to discern smoking status it dates back to Alan Turing and his report. It would be helpful to use NLP and side effects. Some of the available famous test in 1950. There have been to extract and compare such informa- NLP tools used by some of the re- many funded research efforts in the tion to help validate the consistency searchers I’ve mentioned include ME- decades since. But there’s a time to and completeness of a report. TIS, Anni 2.0, and MedLEE , among move beyond research and begin to many others. incorporate such science into applied NLP research In addition, commercial solutions are use in the real world. In life sciences, I recently attended a lecture at FDA by also becoming available. Along with we have many cases where we could Professor Carol Friedman of Columbia the usual big players are intriguing employ NLP to help us interpret University, whose research uses NLP new companies like First Life Research mountains of documents and extract to review published literature, clinical which has developed technology to structured information to increase study reports, and EHR text to identify understand patient language and trans- our range of knowledge. It’s about possible contraindications, symptoms, form it into actionable content. time we did so. ❏

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Phase I-IV Bioanalytical Bioequivalence Consulting Staffing CROsC ini iAs a CROs in Asia IntroductIon

Recent survey shows the motivation for conducting clinical trials in Asia varies according to the country. Unique Challenges in Asia-Pac Applied Clinical Trials’ Editors

recent survey was conducted by endpoint leaves the standard of care for PRTM, a management consultancy that country open to interpretation; regula- A with locations in Asia, Europe, and tory concern; and data distortion, should the United States, titled “Trends in Asia it trend in an opposite direction from the Clinical Outsourcing.” The survey featured rest of the data. an analysis of Asian trials by country from Data issues separate from endpoint cri- 2003 to 2008, which similarly reflects the teria is also a concern. The overall qual- increase in trials mentioned by the phar- ity of trial data in Asia—outside of India, maceutical executives. Japan, and South Korea—is perceived to Benefits for conducting trials in emerging be inferior to the West according to PRTM. regions include speed of recruitment, ac- This is especially true of China and Taiwan. cess to naïve therapeutically-treated sub- There are approximately 138 CROs jects, and reduced costs per participant. in China, according to a Chinese-based According to the PRTM survey, low cost consultancy. for trials was not the dominating factor for The PRTM survey noted that “although conducting a clinical trial in Asia. Their multinational CROs continue to grow in survey of pharmaceutical companies and size and influence, major pharmas are CROs in the United States, the European working hard to blend the best of both Union, and Asia showed those reasons worlds—seeking ways to link the opera- varied according to the country. tions of local Asian CROs with those of However, the reciprocal challenges in- their global CROs in the region.” CROs clude timing of regulatory hurdles, great themselves also are actively seeking out variability of CRO expertise, price quotes those local CROs to gain expertise on the for work in those regions, and questions landscape. According to its survey, the surrounding data quality. multinational pharma sponsors operating Pharmaceutical sponsors have reported outside of Japan use a combination of difficulty in finding a CRO that is truly local and global CROs for varying out- global, with equal capabilities in each of sourced functions. the major regions. Additionally, there are vastly different levels of experience among Full-service outsourcing in Asia the CROs and their employees, and a lack According to the PTRM survey, the vast of a globally consistent approach. majority of multinational sponsors take Sponsors also note that specific to Asia advantage of full-service outsourcing on a Pacific, not including India, the CROs were protocol-by-protocol basis. In this context struggling with the experience issue as full service includes site-related activities, well as employee retention. data management, clinical supplies, regu- Sponsors also note that data collected latory support, and pharmacovigilance. from Asia-Pac needs to have a hard clini- Some sponsors outsource a broader cal endpoint—not subjective. A subjective scope of activities—for example, by de-

2 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 velopment program or even by country. These are usually contracted to global Contents CROs through strategic partnerships. While local sponsors also rely heavily on 2 Introduction: Unique full-service outsourcing, their scope is lim- Challenges in Asia-Pac ited to whole development programs for early-stage development. Applied Clinical Trials’ Editors regulatory landscape 4 Demystifying Asian Trials Of the largest Asia-Pacific regulatory au- Jessica Lui, MD thorities, both India’s Central Drugs Stan- dard Control Organization under the Direc- 6 Imaging CROs in Asia torate General of Health Services, Ministry Richard Taranto and Richard Walovitch of Health and Family Welfare, and Japan’s Pharmaceutical and Food Safety Bureau 8 Sponsor Index under its Ministry of Health, Labor, and Welfare have established regulatory processes in place. South Korea has been increasingly growing its clinical trials market, Applied CliniCAl TriAls ArTiCles which grew 150 percent between 2006 and relATed To AsiA: 2009. Its regulatory authority, also known as the Food and Drug Administration, has a robust function and established policies Today’s Global Site Landscape, for drug research, safety, and evaluation. June 2010, http://appliedclinicaltrial- China reorganized its drug regulatory sonline.com/sitelandscape systems under the State Food and Drug Administration (SFDA) in 1998, with many The China Experience, June 2010, regulations emerging post 2004. The regu- http://appliedclinicaltrialsonline.com/ latory time frame in China is still on the China long side, roughly eight to 12 months to get approval for a clinical trial. However, Conducting Clinical Trials Beyond according to reports, the SFDA is very open to addressing this and shortening Europe, October 2010, http://applied- those time lines. clinicaltrialsonline.com/Europe The SFDA in China, also reportedly wants to have greater understanding New Era of R&D Laws in India, Janu- of the various therapeutic areas for the ary 2009, http://appliedclinicaltrialson- drugs in development, and would like to line.com/newera see accredited research sites developed outside of the existing popular locations The Spotlight Falls on India, for clinical trials in China, such as Beijing September 2009, http://appliedclini- and Shanghai. caltrialsonline.com/India In the immediate future, the large global CROs will continue to stake their ground in EDC Acceptance in Japan, Asia, and China is the last frontier. Com- petition to ally or acquire local CROs, as November 2009, http://appliedclinical- well as competition with other CROs to trialsonline.com/EDCJapan gain the outsourced trials in China from the sponsor community will continue.

April 2011 appliedclinicaltrialsonline.com Applied CliniCAl TriAlS 3 CROs in Asia:Asia Crisis or Opportunity

Conducting clinical research in the East brings a new group of challenges to sponsors. Demystifying Asian Trials

Jessica Liu, MD

ith every aspect of drug develop- sponsors may want to consider enrolling ment moving east, there are only patients in highly populous countries like Wtwo kinds of clinical trial sponsors: India, China, Indonesia, Japan, the Philip- those running sites in Asia, and those pines, Thailand, and Malaysia. However, thinking about running sites in Asia. sponsors must be aware that competition For the latter, Asia appears from afar an for participants in countries like China is impenetrable black box. While that box is increasing. A country like South Korea may rumored to hold significant cost savings and be less populous than China, but it still access to the fastest-growing healthcare boasts roughly 50 million people and, as market in the world, tapping into it means an emerging region for clinical research, navigating regulatory and operational chal- may offer less competition for enrollment. lenges compounded by language barriers. The incidence of the target disease in Even for drug and device developers each country’s population may also play a with established clinical trial sites in Asia, role in trial site planning. Asia offers rela- expanding from one country to the next tively more patients for first-line and sec- can pose challenges. Each country has ond-line cancer drug evaluation than the its own distinct cost structure, population West, where such patient stores have been base, medical practice standards, infra- largely exhausted. Highly developed Asian structure, government policies, and cul- countries have a higher incidence of dis- tural differences. eases common in the West, like obesity and diabetes, while diseases like tubercu- Cost considerations losis are more common in Southeast Asia. Most drug developers are aware that con- Some countries, like India, have diverse pa- ducting preclinical research in Asia is far tient populations afflicted with diseases of more cost-efficient than conducting the both the developing and developed world. same research in America or Western Eu- There are certain diseases for which the rope. Many drug developers are rapidly dis- standard-of-care in Asia is similar to that covering the same is true with clinical trials. in the western world, including breast can- Running trial sites in China, Thailand, the cer, lung cancer, and diabetes. Sponsors Philippines, or Malaysia can save a sponsor of clinical trials in these indications can 60 percent. Most countries in Asia are at feel relatively comfortable establishing trial least 20 percent to 30 percent more cost- sites in any Asian country. But for many efficient than their western counterparts, indications, medical practice standards but there are exceptions to every rule. differ both from East to West and between the different Asian regions. Numbers game With more than 4 billion people, Asia of- Getting the job done fers sponsors a deep pool from which Principal investigators in the United States to draw trial participants. In particular, and Western Europe have been running

4 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 clinical trials for 40-plus years—their coun- business strategy, not as an afterthought. terparts in Asia are lucky to have half as It’s a process that needs to be started much experience. Sponsors should be pre- early, yet it is dynamic and should be re- pared that Asian trial sites—even those that visited often. have adapted Western-style medical practices—may need more assistance when it Cultural considerations comes to following protocol and differenti- Language barriers can be easily overcome ating between medical practice and clinical by CRO partners with offices across Asia, research. Sponsors should not assume that and sponsors are often pleased to learn all potential Asian trial sites will have the that investigators in most Asian countries infrastructure—even fax machines or freez- are eager to participate in clinical research. ers—needed for a clinical trial. Fortunately, It is viewed as a way to advance their qual- vendors of clinical trial services from data ity of care and position themselves on the storage to cold-chain supply are following cutting edge of scientific innovation. Regu- the Eastern migration of research and mak- latory reviewers, too, are often eager to ing everyone’s job easier. help, if a sponsor knows what questions to ask and how to ask them. Political factors Yet there are certain cultural consider- Each Asian country’s policies on protocol ations that sponsors need to address up- approvals, insurance regulations, import front. For example, some Asian research- licenses, and myriad other factors can af- ers may believe that their participation in fect a sponsor’s ability to establish and run a trial gives them the right to publish data a site. Ironically, countries like China and on their findings, while sponsors require at Thailand, which have historically been con- least some degree of control over the pub- sidered “easy” targets for clinical trials, are lication of trial data. now increasing their regulations and making the trial review and approval process more Question of ethics formal, demanding, and time-consuming. As the fastest-growing pharmaceutical China in particular is associated with a rela- market in the world, China is a major con- tively long lead time for getting protocols sideration in the marketing plans of most approved and trials operational. Meanwhile drug developers. Biotechnology and phar- South Korea and Taiwan are starting to maceutical companies are often interested realize that participation in global clinical in establishing trial sites in China as part trials is critical to advancing their medical of a plan to support eventual approval in practice standards, and are working to ease Chinese markets, and the same is true regulations and facilitate protocol reviews. of Japan. In addition, there are certain diseases that present a serious unmet Rules and regulations medical need specifically within Asian The regulatory bodies in South Korea and populations, such as foot-and-mouth Taiwan, as well as in Singapore, have ad- disease. Such indications obviously lend opted an FDA flavor to their practices, so themselves to Asian clinical trials. Yet if a sponsors may not feel as much culture sponsor has no plans to launch a drug in shock when dealing with them. Yet each certain Asian countries, then conducting Asian country has its own regulatory id- clinical research in those countries may iosyncrasies. No matter how harmonized present ethical challenges. Asia may appear, the cookie-cutter approach simply doesn’t work. Clinical trial Jessica Liu, MD, Senior Director of Clinical sponsors must consider their regulatory Operations, Head of Asia-Pacific, Global Operations, strategy in Asia as part of their overall INC Research.

April 2011 appliedclinicaltrialsonline.com Applied CliniCAl TriAlS 5 CROs in Asia

Improvements in image acquisition and read quality: a look at the value of standardization in oncology trials. Imaging CROs in Asia Richard Taranto and Richard Walovitch

ith access to a large and geneti- standardize image acquisition protocols, cally diverse patient population, manage the collection and QC of imaging Wlower overall costs, and relatively data sets, and coordinate the central review fewer trials than in the United States or of images by a panel of trained radiologists. Europe, Asia has become an increasingly Standardization of image acquisition re- attractive market for conducting clinical quires the collection of information about trials. Oncology trials in particular are ex- the equipment (both hardware and software) periencing major growth in the region, and that a potential site has available to scan the trend is likely to continue in parallel participating study subjects. With varieties with improving infrastructure for hospitals in vendor and software platforms across a and other clinical facilities. For pharma- multi-center study, it is critical to confirm ceutical companies looking to conduct acceptability and compliance ahead of first trials in Asia, this means a number of new patient first visit. This is where an imaging opportunities and challenges to consider. CRO’s expertise can be instrumental. Pro- One such area relates to the use of viding a standard image acquisition proto- medical imaging, which has become a col to sites in advance and confirming that vital component in oncology trials. Imag- the sites can acquire scans following these ing biomarkers are increasingly accepted procedures is essential to establishing a as surrogate endpoints in oncology trials, harmonized imaging data set across sites making the need for improvements in im- and timepoints in a longitudinal study and is age acquisition and read quality more ap- where an imaging CRO can play a key role parent. This includes a greater emphasis in reducing a study’s size and duration. on reader training and testing. Improving By centrally collecting all imaging vis- the quality of reads can help better stratify its, a sponsor can verify that consistent patients for treatment, evaluate safety, im- techniques were followed in scan acquisi- prove dose selection, and even provide tion and establish a library of complete early prognostic information to assess the images. It is also important to confirm that effectiveness of a particular treatment. imaging visits occur within the protocol defined study window. Proactive notification Standardizing image acquisition to sites, reminding coordinators that imag- As growth in clinical trials in Asia explodes ing visits are due for a particular subject is in parallel with improving infrastructure for helpful to improve compliance. Any issues imaging facilities, the need for standardizing identified should be followed to resolution image acquisition and image review is in- to improve the quality of the imaging visits creasing. Pharmaceutical companies con- and accuracy of independent assessments. ducting oncology clinical trials exclusively within the Asia-Pacific region, or as part of Minimizing bias a global study, benefit from identifying a In addition, imaging CROs can assist in partner that can qualify imaging facilities, incorporating certain design features into

6 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 an oncology trial to minimize bias and in- CROs, should establish proper procedures crease precision and accuracy of poten- to adequately monitor reader performance tially subjective observer-dependent as- during the course of the trial and assess sessments. By paying special attention overall reader variability at the end of the to blinding of patient data and the use of trial. The testing methodology should in- central (external) review committees, spon- clude guidelines for the identification of sors can increase the uniformity of efficacy test cases, assessment by blinded read- endpoints based on tumor assessments. ers, and regular analysis and review of Without independent central review, bias reader performance results. stemming from the sponsor or study moni- Many different methods can be applied tor’s familiarity with particular patients may to assess reader performance and improve influence endpoint assessments. If strin- the precision and accuracy of the data gent processes are put in place to reduce set. Working with statisticians that under- the potential for bias at the onset, the va- stand imaging data is critical to employ- lidity of the conclusions drawn are less ing the right test and to interpret results likely to be questioned. appropriately. If the sponsor and CRO are To minimize bias in review and ultimately equipped with a valid measure of reader in the analysis of study outcome, identifying variability, they can investigate the causes an independent review committee com- of low-reader reproducibility and proac- posed of radiologists with clinical expertise tively identify potential problem areas. Fac- in oncology is paramount to study success. tors such as poor image quality, insuffi- Thorough training and testing procedures cient reader training, unclear read criteria, should be followed to qualify the reading and low individual reader performance are team prior to initiating on study reads. In common causes, but the efficient use of many studies, it is also beneficial to have statistics allows both parties to take the subject eligibility confirmed by the inde- appropriate remediation steps to increase pendent reading panel to ensure the right the trial’s chances of success. patients are included in the study, avoiding With oncology trial growth in Asia ex- costly delays in recruitment and time wasted pected to continue, standardization of im- following patients that are inappropriately age acquisition and reader variability train- included in the intent to treat population. ing and testing will become increasingly When defining the image review pro- important. To fully maximize the value of the cess during imaging charter development, imaging used in these trials, increased pre- sponsors should determine the most ap- cision and accuracy of readers is necessary propriate reading paradigm relevant to the for achieving reproducibility in performance disease process and phase of research. and reducing variability that adversely af- For example, most Phase III oncology fects sample size of trials. By employing an studies require a double-read with adjudi- imaging CRO with expertise in reader vari- cation model if using progression-free sur- ability testing and training to carefully man- vival as the primary endpoint. By selecting age read quality, sponsors can reduce vari- a read process, and by having an under- ability using imaging assessments, increase standing of the inherent variability in reads, the ability to discern differences in treatment a sponsor can identify the best ways to groups, and thus provide greater potential monitor variability over time. for demonstrating a drug’s efficacy.

Methodology Richard Taranto, Executive Vice President, and Reader testing methodology should also Richard Walovitch, PhD, President, WorldCare be defined during imaging charter devel- Clinical, LLC, 7 Bulfinch Place, PO Box 8908, opment. Sponsors, together with imaging Boston, MA, www.wcclinical.com.

April 2011 appliedclinicaltrialsonline.com Applied CliniCAl TriAlS 7 CROs in Asia SponSor Index

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Vladimir maraVic/Getty imaGes

the MENA region is thought to be on the edge The Middle East and North Africa of a cardiovascular disease epidemic. Turkey, Saudi Arabia, and Egypt are considered the big- region has seen a recent increase in gest recipients of Foreign Direct Investment (FDI) with investments ranging from $2 billion clinical trials research. to $2.7 billion in order to address this issue. The governments of various countries in the MENA region are currently focusing on boosting linical trials have had such foreign investment. a great impact on the global In order to boost FDI, hundreds of scientific community that in- “free zones” have been introduced in the Cterest in clinical research has PEER MENA region, which allow full foreign transcended into regions that ownership of businesses. The incentives are relatively naive to conducting trials. REVIEWED of free zones, besides allowing complete Over the past few years the Middle East foreign ownership, are greatly simplified and North Africa (MENA) region has witnessed administrative and registration procedures for the dawn of a new era in clinical research. registration of new businesses. Some countries Though these changes have, by and large, not in the MENA region also offer complete exemp- reached the entire scientific community, they tion from private and corporate income taxes. have made a significant impact. Investigators are Many countries in the MENA region are also now beginning to appreciate the significance of seeking to strengthen their trade partnerships conducting local trials. with Europe through the Euro-Med trade agree- The MENA region is considered one of the ments. Trade is also being promoted through fastest growing economies in the world, with the the Pan-Arab Free Trade Area and the Gulf Co- key drivers being oil, gas, and petrochemicals. operation Council (GCC)—these entities are in As a result, there has been significant invest- the process of seeking membership in the World ment in healthcare and modern hospitals incor- Trade Organization (WTO). In May 2003, the porating state of the art equipment—now avail- Middle East Free Trade Area (MEFTA) initia- able for the conduct of clinical trials. However, tive was proposed by the United States with the this economic growth has also brought about purpose of creating a United States/Middle East marked changes in lifestyles of the local popula- free trade area by 2013. The changes to busi- tion. Sedentary lifestyle, low physical activity, ness and trade processes in MENA countries smoking, and an increasingly unhealthy diet are expected to facilitate the growth of clinical have become a part of this society. Consequently, research conducted in the region.

36 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 DEMYSTIFYING THE INTRICACIES OF ASIA

TRUSTED RESULTS: ASIA PACIFIC

There is a big difference between a global footprint and true global operations when it comes to managing global clinical trials.

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Therapeutic areas of interest Diabetes in the MENA region is of Cardiovascular disease, diabetes, cancer, and chronic respiratory illness are widely prevalent in the MENA region. interest to companies investigating Obesity is also extremely prevalent in the region due to the effect of antidiabetic drugs in significant changes in lifestyle. Indeed, the World Health patients during Ramadan fasting. Organization (WHO) states that “increased consumption of more energy-dense, nutrient-poor foods with high levels of Obesity. The increased prevalence of obesity in the sugar and saturated fats, combined with reduced physical MENA region has become a major problem and is an estab- activity, have led to obesity rates that have risen three-fold lished risk factor for other diseases. or more since 1980 in some areas of North America, the Profound changes in society due to rapid modernization United Kingdom, Eastern Europe, the Middle East, the Pa- and changes in behavioral patterns are the major causes cific Islands, Australasia, and China.”1 of this epidemic. Obesity has increased across all ethnic Cardiovascular disease. There has been a considerable groups residing in the UAE, which is the fifth most obese rise in the prevalence of hypertension, hypercholester- nation worldwide, closely following Egypt, which is con- olaemia, and cardiac disease in the MENA region. Some sidered the fourth most obese nation globally. Sedentary pharma companies have undertaken a great commitment lifestyle and unhealthy eating habits have also increased the to help patients suffering with cardiovascular disease and prevalence of childhood obesity. In Qatar, 43% of children have conducted clinical trials and epidemiological surveys are overweight—a statistic that has prompted the Supreme to increase knowledge and progress the treatment of these Education Council of Qatar to initiate health awareness pro- diseases in the MENA region. grams in schools to address the problem. Diabetes. Diabetes is currently the fastest growing de- Cancer. The overall burden of cancer in the MENA bilitating disease worldwide. Moreover, in the United Arab region is rising. Current research is seeking to identify Emirates (UAE), diabetes is the second most prevalent in cancer trends which can provide an evidence base for gov- the world, affecting approximately 20% of people aged 20 ernments to initiate health policy planning. Moreover, sev- to 79, with a similar proportion of the population at risk of eral collaborative cancer research programs are currently developing the disease.2 Diabetes treatment currently con- ongoing in the MENA region to enable the development sumes an estimated 40% of the national health care budget. of cancer control strategies. In addition, palliative care In addition, heart disease related to diabetes was respon- programs are planned or have already been implemented sible for 31% of deaths in 2008. in some countries. A further five countries—Bahrain, Egypt, Kuwait, Metabolic disorders. Metabolic disorders such as hemo- Oman, and Saudi Arabia—are among the 10 highest for dia- globinopathies, glucose-6-phosphate dehydrogenase defi- betes prevalence worldwide. Over 26 million people in the ciency, and congenital malformations caused by recessive MENA region have diabetes, which is the expected cause genetic diseases are common in the MENA region. The of approximately 290,000 deaths; as such, satisfactory epi- Catalogue for Transmission Genetics in Arabs (CTGA) demiological diabetes studies are warranted. lists the genetic disorders occurring in the Arab world.3 The impact of diabetes in the MENA region is of great in- The orphan-designated Gaucher’s disease—(glucocer- terest to pharma companies, many of whom are currently in- ebrosidase deficiency) which results in fatty substance vestigating the effect of antidiabetic drugs in patients during accumulation in the spleen, liver, bone marrow, and central Ramadan fasting. Fasting during Ramadan is an obligatory nervous system—has been reported in the MENA region. duty for all healthy adult Muslims and, although the sick are Research is ongoing in patients with Gaucher’s disease to exempt, most Muslims insist on fasting. It is important for promote medical research and enable the patients to have diabetics who wish to fast during Ramadan to undergo prior access to investigational medications. In the UAE alone, as medical assessment and educational counseling. Clinical of October 2006, the CTGA database indicates the presence trials conducted in these patients will provide valuable data of 228 disease entries.4 Prevalence of this disorder and other on dose requirements of antidiabetic drugs and the use of genetic diseases in the MENA region is associated with sustained release formulations. Since these patients are re- consanguineous marriages. The tradition of consanguinity quired to eat their main meal after sunset and before dawn, is mainly due to socio-cultural factors. In countries such dosing has to be considered accordingly in order to maintain as the UAE, Yemen, and Qatar there has been a rise in con- adequate glycemic control. It is also important to understand sanguinity leading to an increase in recessive genetic disor- that for the person undergoing the fasting during Ramadan, ders, congenital malformations, and postnatal mortality. any oral or intravenous medications taken during the fasting Thalassaemia. There is a high prevalence of thalassaemia, period is considered as breaking the fast, regardless if it is in a hereditary form of anemia, in the MENA region due to response to a medical condition. the high prevalence of consanguinity.5 Initiatives have been

38 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011

Global Trials

undertaken by several government bodies to keep a check the complex requirements of the ethics committees (EC) on thalassaemia by offering premarital screening and ser- and regulatory authorities (RA) in the different MENA vices to those already affected. regions it is recommended that the advice of local regula- Many people with thalassaemia require frequent blood tory experts be sought to minimize delays during the start transfusions to restore red blood cell levels, which can lead up activities. to an iron accumulation requiring chelation to eliminate Clinical trial applications in the MENA region are re- the excess from the body. Patients with thalassaemia have viewed by the relevant country’s EC(s) who provide a no inherent mechanism to remove the excess iron, which, written notification of their approval or rejection. Some if untreated, can lead to significant morbidity and mortal- countries operate with a central EC which issue a single ity. Advances in the management of thalassaemia and the opinion; however a majority of countries in this region have introduction of patient-friendly medications have increased local ECs. Most of the countries in the MENA region have treatment compliance of thalassaemia sufferers. Ongoing a regulatory body that provides clinical trial oversight. thalassaemia clinical trials in the MENA region are seek- Recently established regulatory bodies include the Saudi ing to improve patient satisfaction and compliance with FDA in the Kingdom of Saudi Arabia and the Jordan FDA iron chelation therapy. in Jordan. In other countries the Ministry of Health (MoH) Sickle cell disease. Sickle cell disease (SCD) is widely acts as the regulatory body. The ECs and RAs operate in prevalent in Bahrain and the Eastern province of Saudi accordance with ICH-GCP guidelines and local regula- Arabia. Several studies have been published that evaluate tions. The RAs of most MENA countries have websites in the hematological findings and ascertain the nature of SCD English which lists the procedure and documents to be in Bahraini patients.6 Within these regions, SCD is present submitted for clinical trial applications. Although parallel with special features being hematological and clinically submission of clinical trial applications can be made to the mild, with low mortality rate in adults and children. ECs and RAs in a few countries, most countries allow only The high prevalence of SCD in Bahrain and the eastern sequential submission (i.e., the clinical trial application province of Bahrain is due to the malaria endemic which can be sent for RA review only after EC approval has been lasted until 1970. During this time hemoglobin in the lo- obtained). There is also a need for adaptation of clinical cal population underwent mutation to impair growth and trial documentation, including the informed consent form, development of malaria within the body. People, particu- to local requirements. All countries in the Middle East re- larly children, are more likely to survive malaria infection quire patient-facing documents to be translated into Arabic, if they have the sickle cell trait. The responsible mutated whereas North African countries may also require French gene is inherited by the next generation, thus conferring a translations. Investigational Medical Product (IMP) import survival advantage. procedures vary between MENA countries. In addition, Date palm pollen and sandstorm dust. Dates are commer- some countries require approval from other authorities for cial crops widely cultivated in the Middle East. The pollen the export of biological samples and IMP back to the origi- production of the date palm is highly prolific and is widely nator (if necessary). dispersed into the atmosphere; this is a common cause for Lebanon is a country of interest as it requires only the asthma and seasonal allergic rhinitis,7 which are common ethics committee approval and does not require regulatory conditions in these regions. In addition, sandstorms regu- authority authorization. Therefore the time required to larly occur in summer and sandstorm dust is a known trig- start a clinical trial in Lebanon is typically shorter than that ger for allergic and non-allergic respiratory ailments.8 in the other MENA countries. Egypt is another attractive market for clinical trials Clinical trial approvals in the MENA region due to relatively smaller costs and a large treatment-naive There has been an increase in clinical trials conducted in population. As such, there has been a steady influx of the MENA region in recent years, largely due to the preva- foreign companies into the country. Egypt has a par- lence of the conditions described above. Consequently, ticularly high hepatitis C prevalence, thought to be linked there is a growing need for support and training in order to the mass treatment campaigns for schistosomiasis, to conduct studies in these countries. Clinical trial approv- which used inadequately sterilized needles resulting in als in MENA region countries can be complex and time widespread transmission of the disease. Hepatitis C is consuming. Sound local knowledge is of paramount impor- a primary cause of liver cancer and incidence rates in tance and can expedite approval timelines. Therefore it is Egyptians are five to seven times as high compared to imperative that pharma companies and clinical research the general population. organizations (CROs) have a clear understanding of the Saudi Arabia is currently leading amongst the GCC regulatory requirements in the MENA region in order countries for clinical trials. Hospitals in Saudi Arabia gen- to obtain timely approvals and fast study start-up. Due to erally have a good infrastructure with well-qualified inves-

40 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 011010010100011100111100110110101101111011100000100010010110110011011011001001010100100100 1 000110010110110111000011101101111000010101001011010010100011100111100110110101101111011 0001000100101101100110110110010010101001001001 00011001011011011100001110110111100001010100 101101001010001110011110011011010110111101110000010001001011011001101101100100101010010010 0 0 00011001011011011100001110110111100001010100101101001010001110011110011011010110111101 000001000100101101100110110110010010101001001001 00011001011011011100001110110111100001010 100101101001010001110011110011011010110111101110000010001001011011001101101EnhancingEnhancing ClinicalClinical 100100101010010 01001 00011001011011011100001110110111100001010100101101001010001110011110011011010110111 1000001000100101101100110110110010010101001001001OperationsOperations withwith 0011001011011011100001110110111100001010 100101101001010001110011110011011010110111101110000010001001011011001101101100100101010010 01001 00011001011011011100001110110111100001010100101101001010001110011110011011010110111DigitalDigital SignaturesSignatures 1000001000100101101100110110110010010101001001001 0001100101101101110000111011011110000101 010010110100101000111001111001101101011011110111000001000100101101100110110110010010101001 001001 000110010110110111000011101101111000010101001011010010100011100111100110110101101 0111000001000100101101100110110110010010101001001001LIVE WEBCAST: Wednesday, April 13, 2011 at 8:00 AM PDT; 00011001011011011100001110110111 11:00 AM EDT; 15:00 GMT 100001 010100101101001010001110011110011011010110111101110000010001001011011001101101Register Free at http://appliedclinicaltrialsonline.com/signatures 100100101010 01001001 000110010110110111000011101101111000010101001011010010100011100111100110110101101 10111000001000100101101100110110110010010101001001001EVENT OVERVIEW: 000110010110110111000011101101111000 01010100101In101001010001110011110011011010110111101110000010001001011011001101101 this session, attendees will learn how digital signatures PRESENTER: 1001001010 10010010010001can be10010110110111000011101101111000010101001011010010100011100111100110110101 applied in clinical operations to speed study and Rodd Schlerf 110111000001000100101101100110110110010010101001001001site initiation, automate site monitoring reporting, enhance FDA00011001011011011100001110110111 and USDA 001010100101investigator101001010001110011110011011010110111101110000010001001011011001101101 portals, and support regulatory compliance. We Markets Manager 100100101 01001001001will 0001 also100101101101110000111011011110000101010010110100101000111001111001101 discuss how digital signatures enable secure docu- ARX 10101 011110111000001000100101101100110110110010010101001001001ment exchange and electronic submissions. 000110010110110111000011101101

KEY LEARNING OBJECTIVES MODERATOR: Lisa Henderson ■ Learn how clinical site initiation can be expedited by Editor-in-Chief using digital signatures for signing regulatory packet Applied Clinical Trials (eTMF) documents

■ Learn how to cut costs and ensure timely reporting by CRAs with digital signatures

■ Learn how digital signatures ensure document security and compliance, and e ciently support FDA audits Presented by

WHO SHOULD ATTEND

■ Clinical Operations Management Sponsored by ■ Clinical Research Associates

■ QA

■ Compliance O cers

■ IT professionals

For questions contact Jamie Carpenter at [email protected] Global Trials

tigators experienced in global clinical trial participation. The Middle East and North Africa The Saudi Arabian pharmaceutical market is one of the largest in the Middle East and represents 65%, or $1.7 bil- region is of great importance in lion, of the pharmaceutical market in GCC countries, which clinical research and has yet to is currently valued at $2.7 billion per year. In December reach its full potential. 2005, Saudi Arabia became a member of the WTO and currently its trade-related aspects of intellectual property clinical trials. Some CROs operating in the MENA region rights are compliant with liberalized foreign investment in have embarked on a mission to highlight the importance of all economic sectors. There is however a list of excluded education and training, many of whom are now providing activities that is not open for foreign investment that is held comprehensive training courses covering all facets of clini- by the Supreme Economic Council. cal research to address this need. Of late, the UAE has also opened up to clinical research and has hospitals with state-of-the-art infrastructure and Conclusion Joint Commission International Accreditation. A consider- The MENA region is of great importance in clinical re- able number of clinical trials are currently ongoing in the search and has yet to reach its full potential; the number UAE and it is expected that this will increase. of trials conducted there continues to increase. The rise in Since the MENA countries are still in the emerging clinical research in the MENA region is the result of a co- phase as far as clinical research is concerned, the costs operative, multidisciplinary effort of the regulatory authori- for conducting clinical trials are not as high as in the ties, ethics committees, investigators, pharma companies, United States and Europe. This is an advantage as most and CROs. Continuing this cooperation is key to the further global companies are currently seeking to curtail costs development and establishment of the MENA region in the and ensure economical conduct of clinical trials. Previously global marketplace for clinical research. the MENA region was not very open to conducting clinical trials and hence very few trials have been conducted. References However, in recent years there has been a remarkable dif- 1. World Health Organization “Noncommunicable Disease Pre- ference—as noted on clinicaltrials.gov—there has been vention and Health Promotion, Fact Sheet—Obesity and Over- a steady increase in the number of clinical trials in the weight,” http://www.who.int/hpr/NPH/docs/gs_obesity.pdf. MENA region. Expediting regulatory reforms, improve- 2. Dina El Shammaa, “Diabetes is a Growing Problem in UAE— ments in training, and growing experience are the main Experts,” Gulf News, (February 11, 2008), http://gulfnews.com/ reasons for this increase in clinical research conducted in news/gulf/uae/health/diabetes-is-a-growing-problem-in-uae- the region. There are 31,309 clinical trials worldwide, of experts-1.84110. which the United States accounts for 52% of them, whereas 3. Center for Arab Genomic Studies, online database, http://www. the MENA region accounts for 5.5%. The increase in the cags.org.ae/index.html. number of clinical trials reported on clinicaltrials.gov and 4. G. O. Tadmouri, S. Al-Haj Ali, P. Nair, and A. Fareed, “Genetic the increase in the number of FDA inspections in these Disorders in the United Arab Emirates: A 2006 Update,” http:// regions indicates that there is a substantial growth in the www.cags.org.ae/cb24c1.pdf. region as far as clinical trials are concerned. 5. L. I. Al-Gazali, R. Alwash, and Y. M. Abdulrazzaq, “United Arab Emirates: Communities and Community Genetics,” Community Need for clinical research training Genet, 8 (3) 186-96 (2005). The increasing number of clinical trials conducted in 6. S. S. Al Arrayed and N. Haites, “Features of Sickle-Cell Dis- the MENA region mandates that all involved personnel ease in Bahrain,” Eastern Mediterranean Health Journal, (1) undergo the necessary training to work on increasingly 112-119 (1995). complex studies. The importance of training is to ensure 7. A. A. A. Kwaasi, “Date Palm and Sand Borne Allergens,” Clin adequate quality in clinical trials and adherence to inter- Exp Allergy, (33) 419-426 (2003). national guidelines. Clinical research trainers can educate 8. A. A. Kwaasi, R. S. Parhar, F. A. al-Mohanna, H. A. Harfi, K. S, Col- and mentor those new to clinical research to meet the chal- lison, and S. T. al-Sedairy, “Aeroallergans and Viable Microbes in lenges of conducting trials in such emerging markets. Edu- Sandstorm Dust: Potential Triggers of Allergic and Nonallergic cation on quality assurance, regulatory affairs, and moni- Respiratory Ailments,” Allergy, 53 (3) 255-265 (1998). toring provides new clinical research staff with the basic training required to work on trials. For experienced clinical Rani Abraham is Associate Director, Regulatory Affairs research personnel, this training provides an opportunity and Operations, Middle East and North Africa, at ClinTec to refresh current understanding and keep abreast of International, AP 26, 506, Fifth Floor, Dubai Health Care regulatory changes that can severely impact the running of City, Dubai, UAE. e-mail: [email protected].

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Kerry Dyson and Davide Garrisi Research in the United Kingdom

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(PICTF) in 1999. The PICTF committee exam- The current initiatives and a ined threats to competitiveness for clinical trials in the United Kingdom under headings such as historical overview of the clinical Start-up Time, Recruitment, and Research Qual- ity and Research Costs, and in its final report trial landscape. published in 2001 made many key recommendations to address the issues.1 Shortly afterward, the Association he United Kingdom has a of the British Pharmaceutical Industry long history of involvement in noted that: clinical trials and has enjoyed In recent years, the performance of UK sites Ta position of strength within involved in these international clinical trials biopharmaceutical research PEER has declined in terms of the speed of trial site and development. There is widespread REVIEWED initiation, patient recruitment, and quality of agreement across industry and govern- data generated, while trial costs have, in gen- ment that this position is under threat, eral, risen faster than in comparable countries. and has been for some time. This has led to a With increasing competition from research sites in number of initiatives within the United King- the developing world and states in Eastern Europe, it dom aimed at streamlining regulations and fa- has become more difficult for pharmaceutical compa- cilitating performance in clinical trials. The nies to justify the inclusion of UK sites. Unless their purpose of this article is to briefly chart the his- performance improves, the extent of UK participa- tory of these initiatives, and provide the reader tion in international trials will continue to decline, with a summary of the landscape for Phase II with possible adverse consequences for the UK phar- and Phase III clinical trials in the United King- maceutical industry more generally, as well as the dom at present. status of the UK as a center of medical and research excellence.2 Historical perspectives Immediately after the PICTF report was Concern in the late 1990s that the United King- published in 2001, the Ministerial Industry dom was losing its “market share” to other Strategy Group, which is described by the countries in Europe and other regions of the Department of Health as “a high-level group world led to the formation of a joint industry bringing together government and pharmaceu- and governmental advisory body, the Pharma- tical industry representatives” was formed and ceutical Industry Competitiveness Task Force continues to meet twice each year with the aim

44 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 to drive forward the implementation of the PICTF report A number of initiatives in the recommendations. In 2003, the Academy of Medical Sciences (a non- United Kingdom have focused on governmental group of UK-leading medical scientists) increasing the attractiveness of published a report entitled “Strengthening Clinical Re- the location for clinical trials. search”3 which also identified the decline in clinical research activity in the United Kingdom and made several recommendations focused on increasing the perceived hospitals are judged will include the number of patients value of clinical research within the healthcare system in their hospitals who participate in clinical trials. This of the United Kingdom. These recommendations were will hopefully increase the extent of high-level managerial not aimed specifically at distinct areas, such as set-up, commitment in NHS hospitals to drive forward the adop- regulation, cost, recruitment, etc., but rather at more tion and success of clinical trials. wide-reaching strategic approaches to encouraging In the last 10 years, therefore, there has been a num- clinical research in the United Kingdom. These recom- ber of government and industry initiatives in the United mendations included the creation of a national, govern- Kingdom focused on increasing the attractiveness of ment funded body (the National Network for Clinical the United Kingdom as a location for clinical trials. The Research) tasked with facilitation of clinical research next questions are: what have these initiatives delivered at every level, and incentivizing doctors within the Na- to date, and what is the current landscape for set-up and tional Health Service (NHS) to become involved in clini- delivery of clinical trials in the United Kingdom? In ex- cal research. ploring the answer to these questions, the authors will The 2006 publication “Government Strategy—Best focus on multi-center clinical trials conducted in second- Research for Best Health”4 acknowledged that industrial ary care within NHS hospitals. The landscape for clinical and academic research and development was a crucial trials in primary care is largely the same, although there factor in ensuring UK patients benefitted for innovative are some subtle differences which are beyond the scope new treatments. The strategy also acknowledged the of this article. challenges facing clinical trials in the United Kingdom and set out a five-year plan to address them. As a result Study set-up in the United Kingdom of this report, the National Institute of Health Research Importantly, in the United Kingdom all set-up processes (NIHR) was established in England in April 2006 in order can now be conducted in parallel, which in theory means to carry forward the vision, mission, and goals of best that all approvals can be gained within approximately 35 research for best health, including facilitating conduct days of the first submission. of industry-sponsored clinical trials within the NHS. As part of the implementation of these plans, and perhaps in Regulatory approval reference to the suggestions of the Academy of Medical Since the United Kingdom implemented the EU Direc- Sciences, a national network for clinical trials was indeed tive on Clinical Trials on May 1, 2004, the regulatory established (the NIHR Comprehensive Clinical Research agency in the United Kingdom (Medicines and Health- Network—CCRN). care Regulatory Agency—MHRA) reviews and approves In 2009, the UK government launched the Office of clinical trials according to the same regulations as every Life Sciences (OLS), dedicated to improving the operat- other EU member state. However, in reviewing valid ap- ing environment for the pharmaceutical, medical biotech, plications within 30 days of receipt it is one of the fastest and medical devices sectors. In December 2009 the OLS regulatory agencies in Europe. The applicant should re- published its Life Sciences Blueprint5 including the im- ceive a letter communicating the outcome of the review portant statement: within 35 days of submission. If approval is not imme- The Government will reinforce the need for greater emphasis on diately granted and further information is requested by research and clinical trials in the next NHS operating framework, the MHRA this must be provided within 14 days and the building on the existing commitment to include numbers of pa- MHRA must provide the final decision within 60 days of tients in clinical research in the metrics which trusts report in their the original application. Timelines can be extended in quality accounts. certain circumstances (e.g., applications involving gene This statement is very important; at present there is lit- therapy) to 90 days. Applications for studies recruiting tle incentive in the United Kingdom for doctors, patients, only healthy volunteers are generally considered within or managers to engage seriously in clinical trials. With 14 days, which again compares very favorably with other this latest initiative, for the first time the key performance countries in Europe and is indeed shorter than most indicators by which the success of chief executives of NHS countries in the world.

April 2011 appliedclinicaltrialsonline.com Applied CliniCAl TriAlS 45 Global Trials

Information Sheet/Informed Con- Review Intervals sent (PISIC), questionnaires, advertisements, etc. The EU Directive stipulates timelines for REC review, and the final decision of the REC 35 Patient Studies must be provided within 60 days of Healthy Volunteer Studies the initial application. In reality, how- 30 ever, the decision of the REC is usually received much sooner than 60 25 days—approximately 21 days is the norm for the initial response (which

20 typically includes a requirement for modifications to some aspect of trial documentation—usually the Patient 15

Review Interval (days) Information Sheet/Informed Con- sent form) and confirms that the 10 committee delegates authority to the chairman to issue final approval 5 if these concerns are adequately met. The sponsor can usually ad-

0 dress these issues by letter within Jul-08 Aug-08 Sep-08 Oct-08 Nov-08 Dec-08 Jan-09 Feb-09 Mar-09 Apr-09 May-09 Jun-09 Jul-09 approximately a week, and final ap- Month proval is typically granted within 35 to 40 days of the initial application. Source: www.mhra.gov.uk It should also be noted that there are a number of fully regulated, in- Figure 1. The interval review time in days in the UK for patient and dependent ethics committees which healthy volunteer studies. are typically accessed by commercial clinical pharmacology units and Between July 2008 and July 2009, a total of 674 applica- whose timelines are considerably shorter than main- tions were received by the MHRA for studies involving pa- stream NHS RECs. tient populations, which were reviewed in an average of 27 There are approximately 100 NHS RECs in the United days (Figure 1). In the same time period there were 253 ap- Kingdom, and the REC to whom the application is sent plications for healthy volunteer studies that were reviewed is chosen by the sponsor/investigator. Meeting dates, in an average of 13 days. submission deadlines, and contact details for all RECs With respect to timelines, therefore, the United King- are published on the National Research Ethics Service dom retains a position of parity at least with other regions (NRES) website (http://www.nres.npsa.nhs.uk/). When in the world for regulatory approval of Phase II/III studies, the preferred meeting of the nominated REC is already and retains a position of strength regarding timelines for full, it is possible for the study to be reviewed by any of the approval of Phase I studies. appropriate RECs wherever their geographic location in With respect to fees for regulatory submissions to the the United Kingdom. MHRA, these are comparatively modest, as shown in Table Recent developments in the UK REC service have fo- 1. Additionally, the level of information required is compa- cused on ease of use and clarity of the review process. rable to that in other regions, and is generally similar to an Detailed information regarding requirements for ethics FDA IND submission. committee submission and documentation (including advice on acceptable construction of the PISIC for example) Ethical approval is published on the National Research Ethics Service Consistent with the EU Directive on Clinical Trials, website. All letters conveying an opinion from a REC now there is a now a single opinion for ethical review in the contain a clear listing of the title, date, and version number United Kingdom. This means that the sponsor or inves- of all reviewed documents. In addition, a list of the com- tigator applies to a main Research Ethics Committee mittee members is also provided alongside a statement (REC) that reviews the ethical aspects of the protocol confirming that the REC operates to relevant UK SOPs and other documents to be used in the study—Patient and regulations.

46 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 parallel with the regulatory and main MHRA Rates REC applications. Fee payable from Site-specific approval is not a Type of trial Supporting data April 1, 2010 second ethical review, but acts as a check on the local suitability of the Cover letter, application form, IMP Phase I healthy £2,255 trial documentation, investigator dossier, protocol, and investigator’s volunteer trial ($3,572) qualifications, and site suitability. brochure This approval is issued by research and development departments for Phase I, Phase II, or Cover letter, application form, NHS research sites and confirms that Phase III patient trial IMP dossier containing relevant £4,244 the supporting facilities in the hos- with an unknown supporting information, protocol, ($6,814) pital (e.g., laboratories, pharmacy, product and investigator’s brochure etc.) are aware of the study and will- ing to participate. In addition, this lo- Phase I, Phase II, or Cover letter, application form, cal approval at NHS sites is released IMP dossier containing relevant £3,448 Phase III patient trial once contracts are agreed, which is a supporting information, protocol, ($5,536) with an known product and investigator’s brochure further check to ensure that the management of the hospital site accept the fee structure proposed. Cover letter, application form, £265 Phase IV trial SmPC (in English), and protocol ($425) In order to apply for site-specific approval, a site-specific information Source: www.mhra.gov.uk form is completed, signed either electronically or by hand by all relevant Table 1. Current fee structure and documentations for submission of parties, and all the required localized clinical trials to the MHRA. documents submitted (e.g., PISIC on local headed paper). The submission to the ethics committee is not complex, Local approval by NHS R&D departments is currently and can be performed by sponsor, CRO, or chief inves- the only aspect of clinical trial set-up in the United King- tigator (the chief investigator is required to sign the ap- dom with timelines, which are unregulated and some- plication whoever makes the submission). Encouragingly, what variable. Whilst the documentation itself is clear, ethics committees are now open to contact from either in- the collection of approval signatures on the submission vestigator or the sponsor/CRO and both parties are invited document and finalization of the contract, for example, to attend the review meeting. Sponsors and investigators can hamper the approval timelines and are often outside should attend the REC whenever possible in order that the control of the investigator themselves. Approval sig- clarifications can be provided where necessary to the com- natures on the submission document may include, for ex- mittee directly during the meeting. ample, the hospital data protection manager, the head of research and development, the heads of biochemistry and Fees for ethical review hematology laboratories, the head of radiology, and the At present, there are no fees levied by NHS research ethics head of pharmacy where the support of these services committees. Therefore, the ethical approval process in the is required. There is often no incentive for these busy United Kingdom is now clear and cost effective with time- individuals to review the protocol and budget in a timely lines that are competitive, adhered to, and regulated. fashion and apply their signatures to the form. For this reason, local knowledge is helpful regarding which UK Local approvals sites tend to have speedy local approval processes, and Until 2009, NHS hospital sites were obliged to receive lo- which do not. Additionally, the familiarity of the investi- cal approval from both their local ethics committee and gator and sponsor representatives with the local approval their research and development department. However, in process, and their willingness to drive this process re- 2009 this system was streamlined to introduce a single main critical. local approval process. In multicenter trials, each investigator site applies for “site specific approval” from their Key developments research and development department (in the case of integrated research Application System (irAS). NHS sites) or their local ethics committee (in the case of In the past, sponsors and investigators had to complete independent clinical research sites). This process runs in many separate forms when applying to regulatory and

April 2011 appliedclinicaltrialsonline.com Applied CliniCAl TriAlS 47 Global Trials

Recruitment Performance • Ministry of Justice (MoJ) • National Health Service (NHS)/ Health and Social Care (HSC) • NHS/HSC Research Ethics Com- Over 200% recruitment mittees • National Information Governance Board for Health and Social Care (NIGB) • Social Care Research Ethics Com- mittees The IRAS website can be freely accessed (https://www.myresearch- project.org.uk/) and also contains a

0% 200% detailed online training module and Recruited support documents. to target The niH Crn. The National In- stitute of Health Research Clinical Research Network is now fully operational in England, and links into similar networks within Scotland, Wales, and Northern Ireland. The aims of the NIH CRN include:6 • To improve the quality, speed, and

Under coordination of clinical research by recruitment 0% removing the barriers to research within the NHS Closed early Extended recruitment window Ran to agreed timelines • To streamline and performance manage NHS support for clinical Source: nIh CRn Coordinating Centre studies to ensure that the costs of research are met in a timely and ef- Figure 2. A visual summary of the recruitment performance of all NIHR ficient manner CRN studies to the end of 2009. • To unify and streamline administrative procedures associated with regu- governance bodies, and there was a large degree of dupli- lation, governance, reporting, and approvals cation of information between forms completed. The IRAS In order for clinical trials to benefit fully from the sup- website, however, allows both regulatory (MHRA), ethics port of the CRN, the study must be “adopted” by the CRN. committee, and all related applications to be completed Application for adoption is very straightforward, and pro- simultaneously. This application involves creation of one vides the sponsor with important feasibility information data set, from which forms required for various approval within 10 days of the application. If this stage is positive, a functions can be created. In addition, the forms can be more intensive review occurs, providing the sponsor with shared electronically with others to allow, for example, detailed information about the sites that are interested in review by sites when the sponsor/CRO is collating and participating, and their potential for recruitment. Impor- submitting the ethics committee application. Where ad- tantly as well, site budgets are created and reviewed at this ditional forms are required (e.g., gene therapy trials, for early stage. those involving radiation), these can be created from The NIH CRN is committed to working with sites to within the system. ensure that set-up is streamlined, recruitment is to target, The full list of organizations, each with their own sub- and quality is high. The opportunity for sponsors to work mission form, supported by the IRAS system include: with a single, government funded organization to address • Administration of Radioactive Substances Advisory Com- feasibility and deliver their studies across NHS sites is mittee (ARSAC) truly valuable and can only be positive, a view backed by • Gene Therapy Advisory Committee (GTAC) recent publications.7 • Medicines and Healthcare products Regulatory The magnitude of the impact of the NIHR CRN is, how- Agency (MHRA) ever, questionable at present. Figure 2 summarizes the re-

48 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 cruitment performance of all NIHR CRN studies to the end It will be interesting to note of 2009. Only a small number of studies fall in the bottom right quadrant of the figure, which indicates the worst of whether these developments can all outcomes (i.e., failing to recruit to target despite an ex- reverse the decline in share of the tended recruitment period). There are, however, a number UK’s global trial market. of studies that lie on the line to indicate poor recruitment when recruitment closed on time. Additionally, studies in the bottom left quadrant indicate under-recruitment, how- NHS Trusts and Clinical Research Departments in the Pharmaceu- ever with the explanation that the recruitment period was tical Industry (2003). shorter than planned. 3. Academy of Medical Sciences, Strengthening Clinical Research, Model agreements. Model clinical trial agreements A report from the Academy of Medical Sciences (Academy of Medi- now exist which provide a contract template for clinical tri- cal Sciences, London, 2003), www.acmedsci.ac.uk/p_scr.pdf. als performed within NHS hospitals. These include agree- 4. Department of Health, Best Research for Best Health: A New ments both for direct sponsor-site agreements, and where National Health Research Strategy, (January 25, 2006), http:// a CRO is also involved. The existence of these model www.dh.gov.uk/en/Publicationsandstatistics/Publications/ contract agreements ensures that sponsors and sites no PublicationsPolicyAndGuidance/DH_4127127. longer need extended contract review periods, since the 5. HM Government, Life Sciences Blueprint. A Statement from the contract template itself is the same between sites and even Office for Life Sciences, (2009), http://www.bis.gov.uk/assets/ between studies. biscore/corporate/docs/l/life-sciences-blueprint.pdf. Budget forecasting. The NIH CRN also makes avail- 6. National Institute for Health Research, website, http://www. able a standard budget template (the industry costing tem- ukcrn.org.uk/index/networks/comprehensive.html. plate), which provides a transparent process for sponsors to 7. S. M. Ng and A. M. Weindling, “The Impact of Networks on accurately predict and propose detailed site budgets to UK Clinical Trials in the United Kingdom,” Trials, (10) 100 (2009). NHS sites inclusive of institutional overheads and other additional costs. This simple spreadsheet saves considerable Kerry Dyson,* PhD, is Head of UK Operations, Suite 11, time; costs at each NHS hospital site can be forecast in this Sabrina House, Longden Coleham, Shrewsbury, SY3 7BF, manner. The costs for common procedures (x-rays, blood United Kingdom, e-mail: [email protected], and tests, etc.) are included in the template, as is the per hour Davide Garrisi is Head of Project Management Unit, both at cost of the investigator, research nurse, and administrator. CROM Group. The template also includes a market forces multiplication factor (ranging from 1.0 to 1.25) which adjusts the created budgets for the additional costs expected at those sites *To whom all correspondence should be addressed. which are in high demand and have additional price expectations (such as hospitals located within Inner London).

Summary Over the last 10 to 15 years there have been a number of key reports detailing recommendations aimed at facilitating the conduct of clinical trials in the United Kingdom. In response to these recommendations, there have been a number of important developments that are now changing the landscape of clinical trials in the United Kingdom in terms of set-up and delivery. It will be interesting to note whether these developments are sufficient to reverse the decline in share of the global clinical trial market that the United Kingdom has experienced.

References 1. Department of Health, Pharmaceutical Industry Competitiveness Task Force: Final Report, (March 28, 2001), http://www.dh.gov. uk/ab/Archive/PICTF/index.htm. 2. The Association of the British Pharmaceutical Industry (ABPI), Model Clinical Trials Guidance, Guidance for R&D Managers in

April 2011 appliedclinicaltrialsonline.com Applied CliniCAl TriAlS 49 Global Trials

Herbert Maier-Lenz, MD

Kiel Lübeck

Berlin Hannover Academic Münster Essen Witten- Halle Herdecke Dresden Düsseldorf Leipzig Köln Marburg University sites with CTCs Mainz CTC Sites Strength in Heidelberg CTC Locations with Regensburg Paediatric Module (PAED-Net) München Network of regional Freiburg surgical Study Centres: (CHIR-Net; Partnership with KKSN) Germany

KKS NetworK

3% of the 637 published randomized clinical tri- The founding of the KKSN has als coming from this country. In contrast, 38% of these studies came from the United States and helped Germany increase its 14% from Great Britain.1 The above-mentioned shortcomings not only clinical trial output. influenced patient-oriented industrial clinical research but also academic patient-oriented clinical research. Clinical research going beyond indus- or a long time, Germany fell be- try-sponsored studies is vital from a pa- hind other countries in the area tient and general healthcare perspective: of clinical research. On the one The emphasis of investigator-initiated tri- Fhand, this was because it was als (IITs) is on the improvement and fur- only after the reform of the ther development of existing therapies. German Medicines Act (Arzneimittelge- PEER Academic clinical trials are therefore of setz—AMG) of 1976 (effective as of 1978) REVIEWED crucial importance for healthcare provi- that detailed regulations regarding clini- sion, as they answer questions which are cal trials were stipulated. On the other of secondary interest, or no interest at hand, infrastructure dedicated to patient-ori- all, to the pharmaceutical industry. Such trials, ented clinical research was lacking at universities for instance, prove the “true value” of a therapy and university hospitals and clinical research was after it is introduced into everyday clinical prac- conducted only as “after-work research.” German tice, including—and especially—in comparison universities had no facilities, which were solely to other, existing therapeutic measures (com- dedicated to the professional implementation of parative effectiveness research). This applies to clinical trials until the late 1990s. Furthermore, drug mono-therapies as well as to more complex, clinical researchers were not as highly esteemed multi-modular combination therapies and for the as researchers in fundamental science. It should areas of non-drug therapy and diagnostics. therefore be no surprise that there were notable Because of the acknowledged importance of shortcomings in the quality of clinical trials in clinical research for public health, the situation Germany when measured against international described above was highly criticized by public standards. Until the late 1990s, globally acknowl- bodies—particularly the German Council of Sci- edged trials, which produced lasting and signifi- ence and Humanities (Wissenschaftsrat) and the cant results, remained the exception in Germany. German Research Foundation (Deutsche Forsc- In terms of published trials in internationally hungsgemeinschaft—DFG).2 The criticism led acclaimed journals (Lancet, NJM), Germany re- to the establishment of a new funding program mained a nonstarter from 1993 to 1997 with only within the Federal Ministry of Education and

50 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 Between August 2004 and Decem- KKS Network Continuously Grows ber 2008, the Federal Institute for 500 Drugs and Medical Devices (BfArM) 493 received a total of 5,000 applications EMPLOYEES 400 for clinical trial authorizations. The 404 PEI processed about 800 applications 370 EMPLOYEES 300 EMPLOYEES during this period. Germany belongs 299 310 EMPLOYEES among the leading countries in the EMPLOYEES 200 European Union with these numbers. 202 The percentage of applications sub- EMPLOYEES 100 mitted for investigator-initiated trials 87 in comparison to industrial research EMPLOYEES 0 has been between 16% and 20% (2004 was an exception: 7.5%)—this is com- 2000 2002 2005 2006 2007 2008 2009 parable to figures prior to the 12th Source: KKS Network amendment.3 The competent authority specifically attests the high profession- Figure 1. The number of employees in the CTC network, KKS alism and quality of the IIT applica- Network, has increased more than five times in less than a decade. tions compiled with CTCs support.

Research (Bundesministerium für Bildung und Forschung). Founding the CTCs and KKS Network About 12 years ago, so-called Coordinating Centers for Clini- The realization of IITs requires a high level of medical, cal Trials—CTC, Koordinierungszentren für Klinische Stu- scientific, and methodical competence as well as special- dien (KKS)—were established as infrastructural means to ized expertise; it was mandatory to release them from their strengthen academic clinical research. The aim was to pro- niche position as “sideline activity” of physicians whose mote patient-oriented clinical research directly at the sites main job was to provide medical care to patients. Since where academic and scientific training, as well as research 1995 the federal government has continually enhanced and healthcare provision, take place pursuant to Anglo- its funding in the area of clinical research: The first infra- Saxon models. As institutions of universities/medical facul- structural measure specially tailored to this end was the ties, the Coordinating Centers for Clinical Trials were meant establishment of CTCs at 12 universities since 1998. Ap- to establish and develop awareness for internationally com- proximately 35 million Euros in funding were made avail- petitive clinical research and to facilitate the planning and able for this purpose. The objective of the CTC is to achieve conduct of such clinical trials for scientists, physicians, and lasting improvement of patient-oriented clinical research clinicians by providing professional trial support services. in Germany, to carry out academic (non-commercial) and The investment paid off: During the subsequent years, industrial clinical trials in collaboration with healthcare Germany caught up and the quality of academic clinical re- institutions, and, where appropriate, to develop the neces- search has since continuously improved. The infrastructure sary procedures for these objectives.4 In order to achieve measures have, for instance, helped research facilities cope standardized and comprehensive quality assurance, the with the regulatory changes following the establishment of centers were connected to one another, first as a working the 12th Amendment of the German Medicines Act (AMG) group, then as a consortium—the KKS Network (KKSN), in August 2004, which transferred the European Directive Network of the Coordinating Centers for Clinical Trials. 2001/20/EG into German law. Until then, the requirements Today the KKS Network comprises 16 institutions engag- for conducting non-commercial trials (IITs—investigator- ing nearly 500 employees nationwide—and it continues to initiated trials) were not fully comparable to those for clini- grow (Figure 1). cal trials carried out during the course of industrial drug On the basis of the CTC funding scheme, the Federal development. The stricter requirements have led to the ex- Ministry of Education and Research (Bundesministerium pectation for a sharp decline in academic clinical research. für Bildung und Forschung—BMBF) started to fund the Thanks to the dedicated structures, universities and uni- development of an additional six Clinical Trial Centers versity clinics were able to take on the additional responsi- (CTC) at German medical faculties/university hospitals bilities as sponsor of a clinical trial pursuant to the amend- with a budget of 24 million Euros in 2007. The prerequi- ment and to carry out their role in supervising, monitoring, site for this funding was an existing infrastructure for the and auditing the conduct of the clinical trial in accordance implementation of clinical trials at the medical faculty/uni- with GCP requirements. versity hospital. The focus of the new funding scheme was

April 2011 appliedclinicaltrialsonline.com Applied CliniCAl TriAlS 51 Global Trials

either fully or partially responsible for Sponsors in Supported Trials the individual trial elements. The areas covered usually encompass the Total Sponsors in trials where CTC study plan; the authorization and ap- assumes central responsibilities proval procedure at ethics committees; the Federal Institute for Drugs and 43% Medical Devices (Bundesinstitut für 20% Arzneimittel und Medizinprodukte— BfArM) or the Federal Agency for Sera and Vaccines (Paul-Ehrlich-Insti- 9% 8% tut—PEI); trial project management; quality assurance; trial monitoring; data management; and evaluation—all 72% the way through to publication. 48% The supervised IITs often assess very complex therapy procedures, which not only administer drugs but also apply procedures such as surgery, Industrial sponsors Non-commercial sponsors Other radiation treatment, and treatment Source: KKS Network with medical products. These trials require as much intensive support as Figure 2. Non-commercial sponsorship holds a slight edge over industrial. conventional clinical trials to gain marketing authorization (Figure 3). slightly different to the initial funding of the CTCs: fund- IITs can get off to a good start with the help of timely ing is for the infrastructure of the clinical centers of the support regarding the procurement of third-party funding university hospitals (resources for the conduct of clinical (e.g., within the scope of funding programs or from indus- trials—study nurses—or the promotion of young clinical trial sources) and through advice regarding the proper researchers). The funding shall enable the clinical centers submission of trial applications. The fact that the experts at to fully utilize the recruitment potential of the university the individual CTC manage to create an interface between hospital. All six centers funded by the BMBF through this methodical and clinical domains has a particularly positive program now belong to the KKSN. effect on IIT realization. Chronically under financed IITs cannot solicit these services from any other source at com- KKSN: responsibilities and work areas parable conditions. The KKSN offers a broad range of scientific services. What almost all of these projects have in common is that Partners from industry and academia gain access to first they are virtually solely “investigator driven” (i.e., initiated rate infrastructure with adjacent hospitals, medical prac- and motivated by a medical and scientific need to improve tice networks, and trial personnel (experienced investiga- therapy provision). These trials hardly encounter any com- tors, biometricians, study nurses, project managers, trial mercial interest and receive very little financial support. This monitors, etc.). The members of the KKSN supervise trials is true despite the fact that these and further examples from investigating almost all indications and collaborate with oncology, neurology, psychiatry, surgical specialties, and medical associations, study groups, and other—including pediatrics all demonstrate the importance of such trials as European—federations. KKSN is currently supporting tri- the respective illnesses are often life-threatening. Moreover, als in 20 countries. there is only a limited amount of treatment options in each According to KKSN’s 2009 statistics, in 43% of cases, case. The participating clinicians attest the CTC has a high CTC-supported trials are sponsored by industrial partners level of competence. Almost all of the trials mentioned were and 48% are covered by non-industrial sponsors—9% other.5 made possible through the participation of CTC institutions. In clinical trials where a CTC assumes central respon- Another important fact can be regarded as a direct posi- sibilities, the percentage of non-commercial sponsors is tive result of the existence of CTCs: the 12th German Med- even higher, 72% (Figure 2). This demonstrates the strong icines Act amendment did not lead to a significant decline demand for trial support for IITs. The KKSN offers special- in IITs. The new requirements were taught to clinicians by ized consulting services for IITs within this remit. means of topic-focused German Medicines Act amendment CTCs often support their customers from the first proj- modules and integrated into the KKSN standard curricu- ect plan draft all the way through to publication—and are lum for advanced chief investigator training. Today, many

52 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 hospitals stipulate a CTC pre-consultation as soon as a • Standard operating procedures (SOPs) faculty accepts sponsorship for a clinical trial. CTC is fully • SAS macros for standardized evaluation and report gen- integrated into the sponsor’s quality assurance process eration and the scientific and methodological advice supports the • Pharmacovigilance manual which specifies all aspects of investigator to fulfill the increased requirements according pharmacovigilance obligations during clinical trials to the German Medicines Act. • Innovative software solutions (MedDRA coding tool) for platform, version, and study independent application. Institutionalized partnerships The KKSN is an These products are developed according to international institutionalized partner of medical competence networks. standards, provide guidance to meet GCP-requirements, For instance, in 2003 the HIV Network assigned to CTC and help to save time and costs. Cologne (ZKS Köln - previously KKS Köln) with the task The question of how costs for IITs can be minimized of developing and maintaining a database of the hitherto without having to make concessions in quality assurance largest HIV patient cohort in Germany. This database is of constitutes the principle question of the ADAMON Proj- significant interest for industrial partners as well. ect—which is funded by the BMBF. As the sponsor deter- The development of a comprehensive biomaterials bank mines how much monitoring is required, the project aims as core project of the Heart Failure Competence Network to ascertain how the costly and labor-intensive monitoring (Kompetenznetz Herzinsuffizienz—KNHI) constitutes an- procedure can best be designed so as to achieve an ade- other prime example. The administration of all information quate balance between requirements and costs. The project takes place via a central, Internet-based biomaterials data- was initiated by the KKSN and is supported by the Federal base, which was established in the CTC Leipzig (Figure 4). Institute for Drugs and Medical Devices (BfArM). Twelve multi-center trials in 100 centers encompassing over 3,200 KKSN knowledge products patients will compare “full” monitoring to an adapted, risk- Several products have been developed with the expertise of graded monitoring procedure with regard to the effect on KKSN employees, such as: the quality of trial implementation.

April 2011 appliedclinicaltrialsonline.com Applied CliniCAl TriAlS 53 Global Trials

work will have on IIT implementation Apportionment of Trials and lobbies the legislator for adequate framework conditions. For example,

TOTAL 33 10 10 10 8 8 8 4 3 3 3 3 2 2 26 % the KKSN is represented within a con- 35 sultation group for X-ray and radiation protection and within a work group for subject insurance in non-commer- 30 cial clinical trials. It also participates in hearings regarding law amend- ments—such as those concerning the 25 AMG. Furthermore, the KKSN has taken on an active role as national part- TOTAL ner in the establishment of a European 20 research network called European Clinical Research Infrastructures Net- work (ECRIN). Cooperations, for ex- 15 ample with the Swiss Clinical Trial Or- ganization (SCTO), help to strengthen pan-European interests. In addition, 10 the KKSN is highly involved in an in- IIT ternational working group, initiated by the Federal Ministry of Education and 5 Research (BMBF). Within the frame of the Global Science Forum of the Or- ganization for Economic Cooperations 0 and Development (OECD), the group THEREOF 55 41 43 25 60 69 46 40 79 66 14 58 36 54 51 % aims to foster IITs at a global level. Members of the KKSN promote the

Other implementation of new regulations for Surgery non-commercial sponsors by arrang- Oncology Psychiatry Neurology Paediatrics Cardiology Infectology

Anaesthesia ing briefing events and further educa- Gynaecology Dermatology ENT medicine (incl. Neonatology) Haematology/ Endocrinology

Ophthalmology tion courses. Standardized basic and

Gastroenterology advanced education programs in the Source: KKS Network clinical field and at partner associa- *other: Nephrology, orthopedics, rare diseases, rheumatology, urology, pneumology, radiation tions convey and continuously enhance therapy, traumatology and others. the necessary know how. In collabora- **Multiple entries possible. tion with the Vienna School of Clinical Research, the KKSN developed an on- Figure 3. The hematology/oncology category had the highest line course on good clinical practice, apportionment. which is held in English.

Adequate framework conditions Public and alternative funding KKSN campaigns on a national and international level for One of the most pressing issues is to reimburse faculties the promotion of investigator initiated clinical trials. The for the significantly increased costs for clinical trials German Clinical Trials Register, for example, (Deutsches due to the AMG amendment. Public funds are manda- Register Klinischer Studien—DRKS, http://www.ger- tory for this purpose. The Federal Ministry of Education manctr.de) is a WHO-acknowledged trials register, which and Research (BMBF) started initiating tenders to this has been integrated into the so-called primary register end as of 2005—and the German Research Foundation within the WHO platform since October 2008. The DRKS (DFG) has participated in this scheme. The program, was developed by the CTC Freiburg (Studienzentrum which has a budget of about 20 million Euros per call Freiburg) and the German Cochrane Center. and will continue until 2012, is an important step in the Moreover, the KKSN also assesses and comments on right direction. However, the current funds of the BMBF the effect that planned revisions of the regulatory frame- and DFG for clinical research are not sufficient enough

54 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 5. Netzwerk der Koordinierungszen- The Matrix tren für Klinische Studien (Hrg.): Das KKS-Netzwerk im Überblick, 10 Jahre University/Medical Faculty/University Hospital Koordinie-rungszentren für Klinische Teaching Hospital Stydygroups Clinic/Hospital Studien, 2009 (KKS Network (ed.): The KKS Network at a glance, 10 years of Legal Department Ethics Committee CTCs). CHIR-Net KKS Research KKS Network Pharmacy Department 6. Helga Blasius, “Rechtliche und prak- tische Rahmenbedingungen für nicht- Central Laboratory Pharmacology PAED-Net Competence Networks kommerzielle klinische Studien,“ in Medicine Phase-I-Unit Biostatistics Pathology Deutsche Zeitschrift für Klinische Forsc- hung, 28-35 (2007), (Legal and practical

Network of framework conditions for non-commer- Medical Societies Industry CROs Physicians cial clinical trials).

Source: KKS Network Herbert Maier-Lenz, MD, Associated Figure 4. A working context of a coordination center for clinical trials. Member of the Executive Board, KKS Network, former Director of the Clinical Trials Centre Freiburg, to achieve evidence-based regular healthcare provision. Schauinslandstr 85 Germany, 79100 Freiburg, e-mail: Compared to the public funding in other countries, the [email protected]. IITs in Germany are notably (and chronically) under financed. The available funds for similar projects in the Editor’s Note: Additional figures are available in the online United States, for example, are often five to 15 times as version of the article at appliedclinicaltrialsonline.com. much as in Germany.6 The savings potential for sponsors or the public health sector through results from patient-oriented clinical research should constitute a crucial incentive for the design of new financing models. There is a need to establish CBI’s Pharma/Bio Boot Camp on financing models for the future which include all the affected stakeholders from the healthcare system, industry, and public finance. A possible solution could be to establish a research fund comprised of an adequate allocation of contributions from care providers, industry, statutory, and private health insurers as well as tax funds. This area could also be improved through regulatory provisions, which imbed real-practice clinical trials in current research practice.

References Design and Implement an eTMF to 1. M. Rothmund, “An International Comparison of the Position of Ensure Compliant Management of Clinical Research in Germany,” Dtsch. Med. Wochenschr, 122 (44) Essential Trial Documentation 1358-1362 (1997). 2. Deutsche Forschungsgemeinschaft, “Klinische Forschung,“ MAY 19-20, 2011 Denkschrift, Bonn 1999 (Clinical Research, Memorandum). CROWNE PLAZA DOWNTOWN • PHILADELPHIA, PA 3. Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), Sponsors: Statistik (website), accessed February 2, 2009. 4. C. M. Seiler, I. Bruns, S. Wolff, W. Lehmacher, M.Löffler, and H. Maier-Lenz, “Das Netzwerk der Koordinierungszentren für Organized by: Outstanding Support Provided by: Klinische Studien,“ (The Network of Coordination Centers for Clinical Trials) Lehrbuch Evidenz-basierte Medizin in Klinik und Praxis, (Evidence-based Medicine—Manual) Deutscher Ärzte-Ver- TO REGISTER, CALL 800-817-8601 OR VISIT WWW.CBINET.COM/ETMF lag (2007).

April 2011 appliedclinicaltrialsonline.com Applied CliniCAl TriAlS 55 Community

BuSINESS AND PEOPLE uPDATE

People ◗ With over 20 years experience in computer compliance, business development, and consulting within the pharmaceutical industry, Colin Goddard has been appointed General Manager at the newly opened Plexys facility in Amsterdam, The Netherlands. Colin Goddard David Gill Jeffrey Freitag, MD Bruce Wakeman ◗ INC Research (Raleigh, NC) has made several new appointments including Patrick Melvin as Executive experience, Quanticate and Chief Executive Officer. Implementation at Mil- Director of Oncology, and People (London, UK) has Chairman and CEO Can- lenium, as the company’s Bruce Wakeman as Vice appointed Richard Ellis as dace Kendle, will continue Vice President, Clinical Re- President of Alliance Devel- General Manager. to serve as Chairman. In search Services. opment. David Gill, formerly ◗ The European Federation addition, Jamie Macdonald of Transenterix, has also of the Pharmaceutical Indus- will take on the position of Alliances joined the company’s execu- tries and Associations (Brus- Senior Vice President and •Elan (Dublin, Ireland) and tive team. sels, Belgium) has selected Chief Operating Officer. PPD (Wilmington, NC) have ◗ Jeffrey Freitag, MD, Senior Richard Bergström as its new ◗ Accelovance (Rockville, formed a global business Vice President, PharmaNet Director General. MD) has made two addi- collaboration focused on the Consulting, will expand his ◗ Ockham (Cary, NC) has tions to its senior manage- advancement, progression, role to become Chief Medi- promoted Michael Enright ment team including Joseph and execution of Elan’s de- cal Officer of PharmaNet from Chief Financial Officer W. Angle, Jr. as Chief Finan- velopment portfolio. Development Group (Princ- to President of its Ockham- cial Officer and Lisa Beth •Samsung Group (Seoul, eton, NJ) where he will be CROTM division where he Ferstenberg, MD, as Chief South Korea) has formed a the senior medical repre- will provide senior-level Medical Officer. $266 million venture with sentative for the company leadership and perspective ◗ Robert DiLaura, PhD, Eliot Quintiles Transnational (Dur- and provide guidance to to pharmaceutical, biotech- Siegel, MD, and Kiyoteru ham, NC) to make biologic physicians who are involved nology, and medical device Takenouchi, PhD, have been drugs as it seeks new busi- in designing and monitoring clients for the company’s appointed Board of Directors nesses to drive growth. Phase I through Phase III Phase I-IV clinical opera- for CDISC (Round Rock, TX), •Ricerca Biosciences (Con- clinical trials. tions globally. each for a three-year term. cord, OH) and Fulcrum ◗ CTI Clinical Trial and Con- ◗ Dmytro Razborov has been ◗ ClinTec International Pharma (Morrisville, NC) sulting Services (Cincin- appointed Regional Director (Glasgow, UK) has promoted have entered into a collabo- nati, OH) has promoted of Synexus’ (Manchester, Stuart Grant, PhD, into the ration to provide value-added Catherine Close to Director, UK) Ukraine with respon- newly created role of Associ- capabilities to biophar- Business Development and sibility for operations and ate Director of Regulatory maceutical companies by Client Management and has business development. Affairs and Medical Writing. creating a streamlined and promoted Meredith Boley to ◗ Kendle (Cincinnati, ◗ Cytel (Cambridge, MA), efficient process to move a Regulatory Specialist I. Da- OH) has announced that a provider of clinical trial candidate from development vid Flick has also joined as beginning May 1, Senior design and implementation to clinical evaluation. an Information Technology Vice President and Chief services and software, has •Medidata Solutions (New Support Specialist. Operating Officer Stephen announced the addition of York, NY) and ViroPharma ◗ Bringing with him over Cutler, PhD, will become the Jim Baker, formerly Senior (Exton, PA) have extended 10 years of recruitment company’s next President Director at Study Standards their agreement to use the

56 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 Medidata Rave electronic ees to accommodate an ex- data capture and clinical data panding portfolio of clients management platform for an- and projects. other multi-year period. •Marken (London, UK) has opened a directly owned Awards clinical trial supply depot in •Quintiles (Research Tri- Singapore. angle Park, NC) has been •ACM Global Central recognized as one of the top Laboratory’s (Rochester, organizations in the world NY) specimen processing for workforce training and department at its US site development excellence with has moved into a new 7,200 its inclusion in Training Mag- square feet facility. azine’s “Training Top 125” for the third year in a row. Products •The staffs of Chiltern Inter- •Phlexglobal (Buckingham- Federal Minister Dirk Niebel (second from left) during his tour national (Wilmington, NC) through the Ravensburg Vetter South manufacturing facility. udo shire, UK) has announced and Spectratox (Dundee, J. Vetter, partner and chairman of Vetter’s advisory board (far the launch of PhlexEview UK) celebrated the 25-year left) describes the aseptic filling process. version 3, the third genera- mark of working together tion of its electronic Trial using a validated and regula- Master File solution. The tory accepted in vivo human •Almac’s (Craigavon, North- NC) has established a team new version features an en- study method for the assess- ern Ireland) Diagnostics of experts specialized in hanced client-interface plat- ment of drug phototoxicity. business unit today an- carrying out rare disease form, system integration, •Eight organizations have nounced the launch of its trials in response to spon- and the option of a “software been awarded full accredita- Bioinformatics Consultancy sor demand. as a service” model. tion from the Association for service that will support dis- •Celerion (Lincoln, NE) has •Comprehend Clinical (San the Accreditation of Human covery and development of completed a clean room and Francisco, CA) released ver- Research Protection Pro- biomarkers as well as enable pharmacist certification to sion 1.0 of its first product grams including Central Ar- an in-depth understanding comply with USP 797 guide- Comprehend Clinical, a new kansas Veterans Healthcare of biology by partnering lines that enables in-house enterprise reporting and System (Little Rock, AR), with customers in the phar- preparation for microtracer visualization software pack- Children’s National Medical maceutical, biotech, and studies providing an alterna- age specifically for clinical Center (Washington, DC), diagnostics setting from the tive to the requirement for trials that runs against Guthrie Healthcare System initial study design through GMP manufacturing of the multiple databases in real (Sayre, PA), Mayo Clinic to the interpretation of data IV solution. time, while leaving the data (Rochester, MN), Minneapo- results. The company has •Association for Assess- in place. lis Medical Research Founda- also added two fully auto- ment and Accreditation of •Oracle (Redwood Shores, tion (Minneapolis, MN), The mated inline wallet press Laboratory Animal Care has CA) has announced the Rockefeller university (New machines to its Craigavon awarded full accreditation availability of Oracle Health York, NY), Wake Forest and Pennsylvania locations to Covance’s (Princeton, NJ) Sciences Central Coding university Health Sciences to reduce the timelines asso- early development research Release 3.0. The third gen- (Winston-Salem, NC), and ciated with the use of blister facility in Shanghai, China. eration of the web-based William Beaumont Hospital card packaging. clinical trial data coding and (Royal Oak, MI). •Health Decisions (Durham, New Facilities dictionary management ap- NC) has received Safe Har- •INTERLAB (Munich, Ger- plication includes expanded Company News bor Certification that recog- many) is opening a new lab query management and au- •German Federal Minister nizes that Health Decisions facility in Shanghai, China, tomated workflows that help of Economic Cooperation meets or exceeds directives mid 2011. clinical trial sponsors and and Development toured of the European Union for •ClinPharm Consulting has contract research organiza- Vetter’s (Ravensburg, Ger- data privacy and protection. moved into new offices in tions improve the efficiency many) South facility during •Max Neeman International Research Triangle Park, NC and consistency of the cod- a regional tour. (Research Triangle Park, and is hiring more employing process.

April 2011 appliedclinicaltrialsonline.com Applied CliniCAl TriAlS 57 Calendar of Events

>> For a comprehensive calendar of events see appliedclinicaltrialsonline.com To have your event considered, contact Kayda Norman at [email protected] or (732) 346-3035.

9-10: The EU Clinical Trial Pharmaceutical Scientists, (703) ICSRs in the EEA, London, UK. May Directive, Berlin, Germany. 243-2800, www.aapspharma- Contact: DIA Contact: CfPIE ceutica.com 2-3: Writing Effective Standard 23-25: ADME, PK/TK, and Drug Operating Procedures and 10: EudraVigilance Infor- 18-19: 2nd Annual Project Metabolism in Drug Discovery Other Process Documents, Los mation Day, London, UK. Management for Bio/Pharma- and Development, Los Angeles, Angeles, CA. Contact: CfPIE Contact: DIA ceutical Clinical Operations, CA. Contact: CfPIE Chicago, IL. Contact: CBI 2-4: Biomarker World 10-11: 5th Annual Conference 25-26: Project Management Congress, Philadelphia, PA. in Japan for Asian New Drug 18-20: EudraVigilance Train- for the Phase III and LCM (Life Contact: CHI Development, Tokyo, Japan. ing—Electronic Reporting of Cycle Management) of the ICSRs in the EEA, London, UK. Drug Development Process, 2-4: Global Pharmacovigilance Contact: DIA Contact: DIA Berlin, Germany. Contact: CfPIE Training Course, Arlington, VA. 10-11: GLP for Study Directors, Contact: PERI Principal Investigators, Study 19-20: DEVICE Research— Regulations and Guidelines June 2-4: Cancer: Pathophysiology, Staff, and Management: Scien- tists and Managers, Cambridge, for DEVICE Clinical Research, Current Therapies, Clinical 1-2: FDA Inspections of Clinical UK. Contact: BARQA Las Vegas, NV. Contact: SoCRA Trials, and Drug Development, Data Systems, Dublin, Ireland. Washington, DC. Contact: PERI 11: Managing Multi-site Good 19-20: 3rd Annual Summit Contact: CfPIE Laboratory Practice Studies, on Clinical Trial Investigator 2-4: cGMP Quality Principles 2-3: Practical Methods for Cambridge, UK. Contact: BARQA Portals, TBD. Contact: CBI for Pharmaceuticals, Biophar- Project Management, King of maceuticals, Biologics, and 11-12: Medical Devices: EU 19-20: Clinical Document Prussia, PA. Contact: CfPIE Medical Devices, Los Angeles, Directives, Guidance, CE Management—A Trial-by-Trial 3-7: 2011 American Society CA. Contact: CfPIE Marking and ISO Standard Approach to Compliance, Berlin, Germany. Contact: CfPIE of Clinical Oncology Annual 4-5: FDA Clinical Trial Require- Certifications, Berlin, Germany. Meeting, Chicago, IL. ments Regulations, Compli- Contact: CfPIE 23-24: Pharmacokinetic Contact: ASCO Concepts in Drug Develop- ance, and GCP Conference, 12-13: Practical Methods for ment, Arlington, VA. 6-8: Drug Development Denver, CO. Contact: SoCRA Project Management, Berlin, Decisions: The NDA Simula- Contact: PERI 4-5: Writing in the Regulated Germany. Contact: CfPIE tion Workshop, Arlington, VA. 23-24: Project Management Contact: PERI Environment When English Is 16-18: Biologics Drug Develop- Your Second Language, Los for Phase I and II Clinical ment: An Integrated Overview 6 -8: Good Clinical Practices Angeles, CA. Contact: CfPIE Trials, Berlin, Germany. of Manufacturing, Non-Clinical, (GCP), Los Angeles, CA. Contact: CfPIE 5-6: Coordinating a Clini- and Regulatory Requirements, Contact: CfPIE cal Trial, Coral Springs, FL. Arlington, VA. Contact: PERI 23-24: Clinical Trial Design 6-9: 2011 ISPE Washington Contact: Medical Research for Medical Devices , Berlin, 16-19: 2011 AAPS National Conference, Washington, DC. Management, (877) 633-3322, Germany. Contact: CfPIE Biotechnology Conference, Contact: International Society of www.cra-training.com San Francisco, CA. Contact: 23-25: EudraVigilance Train- Pharmaceutical Engineering, (813) 5-6: Effective Laboratory American Association of ing—Electronic Reporting of 960-2105, www.ispe.org Safety Management, King of Prussia, PA. Contact: CfPIE ACDM: Association for CBI: Center for Business DIA: Drug Information Clinical Data Management, Intelligence, (781) 939-2400, Association, (215) 442-6100, 5-6: European Filing & Regis- +44 1727 896080 www.cbinet.com www.diahome.org tration Procedures, Berlin, ASCO: American Society of PERI: Pharmaceutical Educa- Germany. Contact: CfPIE CfPIE: Center for Professional Clinical Oncology, tion and Research Institute, Innovation and Education, (571) 483-1300, www.asco.org (703) 276-0178, www.peri.org 5-6: Pharmaceutical and (610) 688-1708, www.cfpie.com Biopharmaceutical Quality Control Laboratories—A BARQA: British Association SoCRA: Society of Clinical Regulatory Compliance of Research Quality CHI: Cambridge Health Research Associates, (800) Assurance, +44 1473 221411, Institute, (781) 972-5400, SoCRA92 or (215) 822-8644, Primer, Los Angeles, CA. www.barqa.com www.healthtech.com www.socra.org Contact: CfPIE

58 Applied CliniCAl TriAlS appliedclinicaltrialsonline.com April 2011 8: Effective EDC Training Strat- Practices for Clinical Research cal Trials, Los Angeles, CA. Management, Cambridge, UK. egies Webinar, 12:00 p.m.-1:30 Programs, Chicago, IL. Contact: CfPIE Contact: BARQA p.m. Contact: ACDM Contact: SoCRA 21-22: Level One Certificate 30-July 1: Good Clinical 8-10: EudraVigilance Train- 16-17: Clinical Research in CDM-Part 1 of 8, 12:00 Practice Regulatory Inspec- ing—Electronic Reporting of Monitoring and GCP Workshop p.m.-1:30 p.m. Contact: ACDM tions, Cambridge, UK. ICSRs in the EEA, London, UK. for Monitors, Site Coordina- Contact: BARQA 21-23: Regulatory Strat- Contact: DIA tors, and Auditors, New Orleans, egy for Established Active LA. Contact: SoCRA 9-10: Standard Operating Substances, Amsterdam, The July Procedures (SOPs) Develop- 19-23: 47th DIA Annual Meeting, Netherlands. Contact: The 1-2: Partnerships in Clini- ment and Implementation, Chicago, IL. Contact: DIA Organization for Professionals Halifax, Canada. Contact: SoCRA in Regulatory Affairs, +44 (0) 20 cal Trials Latin America, São 20-21: Oncologic Develop- 7510 2560, www.topra.org Paulo, Brazil. Contact: Institute 9-10: Adverse Drug Events— ment Strategies: Protocol for International Research, (888) Understanding and Reporting Development, Arlington, VA. 22-23: Biomarker Applications 670-8200, www.iirusa.com Requirements, Los Angeles, CA. Contact: PERI on Drug Development, Arling- Contact: CfPIE ton, VA. Contact: PERI 1-2: International Clinical 20-21: Preparation of FDA Trials Workshop, Luj-Napoca, 13-14: Pediatric Pharmaceuti- Submissions and Communicat- 22-24: The Drug Development Romania. Contact: ASCO cal Development, Arlington, ing with the FDA (INDs, NDAs, Process—From Discovery to VA. Contact: PERI BLAs, ANDAs, Post-Approval Commercialization, King of 1-2: Advanced Cancer Course: International Clinical Trials Supplements), Los Angeles, CA. Prussia, PA. Contact: CfPIE 15-16: Medical Devices: EU Workshop (Romanian Society Contact: CfPIE Directives, Guidance, CE 23-24: Latin America—Under- for Radiotherapy and Medical Marking and ISO Standard 20-22: EudraVigilance Train- standing Regulatory Compli- Oncology, Cluj-Napoca, Certifications, King of Prussia, ing—Electronic Reporting of ance Requirements, King of Romania. Contact: ASCO PA. Contact: CfPIE ICSRs in the EEA, London, UK. Prussia, PA. Contact: CfPIE 6-8: EudraVigilance Train- Contact: DIA 16-17: Advanced Site Manage- 28-29: Good Clinical Practices ing—Electronic Reporting of ment: Finance and Produc- 21-22: Project Management for Study Directors, Principal ICSRs in the EEA, London, UK. tivity Enhanced Business for Phase I and II Clini- Investigators, Study Staff, and Contact: DIA

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April 2011 appliedclinicaltrialsonline.com APPLIED CLINICAL TRIALS 61 A Closing Thought

To see more A Closing Thought articles, visit appliedclinicaltrialsonline.com Darwin at Work: Trial Technology

he challenges facing the pharmaceutical industry have never been greater: patent expiries, increased government regulation, industry Tconsolidation, declining drug discovery success rates, the impact of generics, the escalating cost of conducting clinical trials, non-performing sites, patient recruitment, etc. In this environment, clinical trial sponsors and researchers are being asked to demonstrate better returns on investment while maximizing efficiencies across the clinical trial process.

While there is no “silver-bullet,” tech- a greater sense of urgency around this, nology, and technology-enabled solutions, especially given the unrelenting pressure play an increasingly important role in re- pharma faces today—pressure to bring ducing cost-drivers while simultaneously drugs to market faster, while controlling improving decision making and results. costs. Some of these options have been Let’s look at two examples: electronic around nearly 20 years—folks, that’s a Better access to data capture (EDC) and interactive web couple of “technology millennia.” Yet, response (IWR) technologies. There was based on personal experience, pharma information vastly a time when clinical trial data collection, seems to spend more on sales force auto- improves the reporting, query resolution, and ran- mation (customer relationship manage- decision-making domization were largely paper-based; at ment) than it does managing this critical process. best, “spreadsheet-based.” Today, using business component. EDC and IWR, these tasks can be fully Garry D. Johnson automated resulting in greater speed Survival of the fittest Senior Vice President & for study set-up, elimination of “double- So how does “Darwin” fit into this? It’s Chief Technology Officer, BioClinica, Inc. data entry,” improved accuracy (fewer pretty simple really. Darwin said, “in the errors), online data clarification forms struggle for survival, the fittest win out at processing, and electronic case report the expense of their rivals because they forms that can be automatically tracked succeed in adapting themselves best to and stored, as well as faster data lock. their environment.” To which I say: “It’s In addition, better access to information time to adapt.” vastly improves the decision-making pro- Technology certainly isn’t the only an- cess allowing action to be taken earlier swer to solve today’s business challenges on issues ranging from compliance to (in pharma or otherwise), but it is an im- site enrollment. With proactive, full-ser- portant part of the solution. At the same vice data management, the availability of time, providers of clinical technology “clean data” is significantly enhanced. solutions need to do a much better job So, the question is, with the increased of making these systems more intuitive focus on return-on-investment, efficiency, and easier to use. Partnership, instead of and effectiveness, why is it that only 40 today’s arm’s length supplier model, will percent to 50 percent (depending on the help speed the adoption of the new tech- source) of clinical trials employ these nologies required to meet the challenges proven technology solutions? I’ve spoken to come. with industry leaders about this, some re- In conclusion, (and with apologies ally smart people, and heard things like: to Alice Kahn), I offer the following “Pharma is very conservative, so we’re thought: “For a list of all the ways tech- slow to adopt new technology.” Maybe so, nology has failed to improve the quality but it seems to me that there needs to be of clinical trials, please press three.”

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