26 July 2008 Imaging and Cardiology Jonathan Goldman ... - ICON plc

Vol. 14Winter Issue 2008Technology and Central LaboratoriesNews Flash: ICONBiotechnology:Acquires PrevalereDelivering onLife Sciences Inc.the PromiseSee page 8Product Development:ImagingWhich Wayand Cardiologyto Approval?Conventional SafetyMarkersICON Profileand PotentialFutureThomasDirectionsFrey, MD, MFPMPresident, ICONDevelopment SolutionsTechnological Advancesin Clinical TrialManagementDid you know?Fast facts about ICONICON Biotechnology ProfileJonathan Goldman, MDFACCChief Medical OfficerICON Medical ImagingDid you know?CONTACT US:U.S.:Erica HillTel: CONTACT +1 215 616 US: 3286E-mail: US:Erica.Hill@iconplc.comTel: +215 616 3286Europe: :Susan DempseyTel: Europe: +353 1 291 2057E-mail: SusanSusan.Dempsey@iconplc.comTel: +353 1 291 2057:Imaging and CardiologyJonathan Goldman, M.D., FACC l Chief Medical Officer, ICON Medical ImagingUnique characteristics of the heartThe heart serves the critical function of maintainingblood supply and is a vital organ for survival. Thelocation of the heart in the body has been studiedsince long before the advent of imaging. Over twothousand years ago, Aristotle in ancient Greecetheorized that since the heart was “central, mobile, andhot, and well supplied with structures which served tocommunicate between it and the rest of the body” itmust be a central and single structure. Of course, wenow know that as well as pumping and relaxationfunctions, the heart has its own electrical conductionsystem, and can even produce hormones. As theheart is a relatively superficial organ, it is amenable tophysical examination too. This is the attraction ofcardiology: the study of disease where a diagnosis canbe made by simple history, physical examination, ECGand non-invasive imaging tests. Although relatively fewdiseases affect the heart (such as coronary arterydisease), these are common and often fatal in latestages. There are many potential therapeutic targets,and enormous interest in developing new and betterways of diagnosing cardiac disease and assessingdisease severity. This underlines the value of cardiacimaging to assess efficacy and safety in clinical trials.Imaging tests in clinical trialsA variety of imaging techniques are used to image theheart. These use different characteristics of physics tocreate the image. Examples of different imagingmodalities include ultrasound (echocardiography,contrast echocardiography, carotid intima medialthickness, intravascular ultrasound), radioisotopeinjection (single photon electron computed tomography,positron emission tomography), computed tomography,magnetic resonance imaging, coronary angiography,and venography. Examples of some imagesacquired by these techniques are shown in Figures 1Figure 1: Cardiac CT image:coronary calcificationto 4. The unique challenge that all of these modalitiesface is the fact that the heart is a functional organwhich moves in multiple different directions, resultingin certain artifacts unless image acquisition is eithertruly “real-time” or is timed to “quiet periods” in thecardiac cycle by ECG gating. Table 1 describes thecommonly used imaging techniques in the clinical trialsetting, together with unique characteristics.These imaging techniques are used in many clinicaltrial settings. Cardiac imaging may be used to directlyassess a cardiac imaging agent or device, or a novelpharmacologic stress agent. Examples of thesestudies are shown in Table 2. Alternatively, imagingmay represent a biomarker of efficacy in studies ofdrugs or devices in the heart failure setting, wherefavorable effects suggest efficacy and guide laterstudies in which clinical outcome is an importantdeterminant of regulatory approval. Examples areshown in Table 3.continued on page 244021 US.indd 3 12/1/08 10:19:45 AM

Pg 02Table 1: Application of Imaging in Clinical TrialsImaging Modality Mode of Action Measurements Strengths ChallengesEchocardiographyUltrasound reflects offmyocardium. Can alsodetect microspheres formarkers of blood in cavitiesor in heart muscle(“perfusion”).Cardiac cavity size, function(especially left ventricularfunction), filling pressures(“diastolic function”), valvefunction, fluid around heart(“pericardial effusion”),pressure in the pulmonaryartery, resistance in thelungs, and cardiac output.Widely available, easy, nopost processing required.No radiation.Good screening test forabnormal function.Handheld transducer bytechnologist.Operator dependent.May be limited by patientfactors such as obesity,lung disease, and poorwindows.Need to control qualityat entry.SPECTIsotope taken up by heartcells, proportional to bloodflow. Gamma camera detectsemitted radioactivity.Heart perfusion at restand stress.Perfusion defects at stress,but not rest, imply significantcoronary disease.Widely available, easy, hugeclinical experience.Can quantitate images withsemi-automated software.Images must be post processed.Substantial readervariability exists.High radiation dose.Cardiac cavity size, function(especially left ventricularfunction).Cardiac CT High resolution CT scan. Image coronary arterieswith high resolution.Cardiac cavity size, function.Quick to do. Potentiallya non-invasive test todetect CAD.Could replace highly riskyinvasive alternative.Cannot overcomecalcification. Motionartifacts troublesome.Cannot differentiatemoderate from severecoronary obstructions.High radiation dose.MRIMagnet assesses musclemotion, sometimes withcontrast agent.Cardiac cavity size, function(especially left ventricularfunction), filling pressures(“diastolic function”), valvefunction, fluid around heart(“pericardial effusion”),pressure in the pulmonaryartery, resistance in thelungs, cardiac output.High technology.Standard of truth for leftventricular size, functionand mass.Can detect perfusion.Very sensitive to smallinfarcts.Software settings at site.Specialized equipment.Not suitable as screeningtest.Contrast may be toxic tokidney.Coronary AngiographyInject dye directly intocoronary artery.Severity of coronarynarrowing.Assessment of patency ofcoronary stents.Widely available.Gold standard for presenceand severity of coronaryartery disease.Invasive.High morbidity fromvascular access andcardiac complications.Diagnostic procedure toplan for revascularization orsurgery.44021 US.indd 4 12/1/08 10:19:46 AM

Pg 03Table 2: Examples of Primary diagnostic studiesProduct Imaging Mode EndpointNew adenosinereceptor agonistNew CT Angiocontrast agentNew Ultrasoundcontrast agentRest/stress cardiacSPECTCT AngioX Ray AngioRest/stress perfusionEchoRest/stress SPECTX Ray AngioSensitivity and specificityof SPECT for CAD diagnosis,compared to existingstress method.Sensitivity and specificityof CTA for CAD diagnosis,compared to X Ray Angio.Equivalence of Echo andSPECT to diagnose CADcompared to X Ray angio.Figure 2: Cardiac SPECT and perfusionechocardiography imagesImaging has an increasing role in the evaluation of cardiac safetywhere it is used together with adverse events, ECG, and laboratorytests for cardiac enzymes to assess for cardiac toxicity. This ismost often found where animal studies suggest possible signal forsafety concern, or where cardiac toxicity is a known class effect fortoxicity. Some examples are shown in Table 4.Role of the Central Imaging Core LaboratoryImaging studies in some clinical trials are performed and interpretedat clinical sites according to standard of care. This is not idealin the clinical trial setting, since it introduces bias in the way thatimages may be acquired or interpreted, without the use of a singlemethodology or ability to query potentially erroneous findings (orbeneficial ones). In the worst case, false documentation of asafety concern could mean withholding of chemotherapy.Conversely, missed cardiac toxicity could lead to early mortalityinduced by an experimental drug. The role of a central lab is toprovide medical, technical, statistical, operational and regulatoryexpertise to the imaging study. Good standardization and trainingshould avoid such false signals and ensure high quality data.It is clearly essential that sites have adequate equipment to acquireand archive images, and have adequately qualified staff, who areprepared to be trained on the particular protocol. This can beproblematic, as in some studies the Imaging laboratory has onlylimited relation to the investigator. Good communication betweenthe clinical CRO, core laboratory, imaging laboratory and studycoordinator is key.It is very important for the core laboratory to consult with thesponsor in the objectives of the study so that the most suitableIt is clearly essential that sites have adequateequipment to acquire and archive images, andhave adequately qualified staff, who are preparedto be trained on the particular protocol.Table 3: Examples of use of Imaging as a biomarker of EfficacyProduct Indication ImagingModeIntracardiac deviceto exclude cardiacaneurysm from thecirculationHeart FailureEchoMRICTEndpointImprovement inventricular functionor cardiacoutput.Novel inotropes Heart Failure Echo Improvement inventricular functionor cardiacoutput.Novel gene therapy Heart Failure EchoMRICTSPECTPETPulmonaryvasodilatorLipid loweringtherapyPulmonaryhypertensionHyperlipidemiaEchoIntravascularultrasoundImprovement inventricular functionor cardiacoutput or perfusion,or viability.Effect on pulmonarypressure andresistance.Reduction inatheroscleroticplaque.continued on page 444021 US.indd 5 12/1/08 10:19:46 AM

Pg 04Table 4: Example of use of Imaging as marker of SafetyProduct Indication Imaging Mode EndpointNovel Growth FactorinhibitorSerotonin receptoragonistCancer therapy Echo Screen patients foreligibility at baseline.Identify cardiactoxicity (ventriculardysfunction).Obesity Echo Identify drug inducedvalve toxicity.Figure 3: X Ray coronary angiogramimages are acquired and measured, and to try to reduce thetemptation of some sponsors to measure every possibleparameter. Optimal design would then lead to the creation of anImaging charter, appropriate statistical endpoints, an image acquisitionmanual, system release specification and design and validationof the electronic case report form. ICON Medical Imaging (IMI) hasdeveloped a proprietary online platform, MIRA, for image viewingand measurement that can apply to multiple modes. Alternatively,for some imaging modalities such as quantitative coronaryangiography, 3rd party software may be incorporated with MIRAand linked to an eCRF.Regulatory aspects are very important, as all aspects of imagehandling are potentially open to audit by the sponsor or FDA.Ultimately, all cardiac imaging studies will succeed or fail based upon theimage interpretation. Sometimes a software-only interpretation may beused, but due to artifacts this is rarely used for any primary analysis incardiac studies. Thus, image interpretation generally involves preliminaryquantitation by a technologist, or a cardiologist over-read, or both. Theexperience and attention to detail of the reader is critical, but so is thetraining of the reader on sample cases and feedback if errors are made.Variability is assessed by inter and intra-reader variability testing for keyparameters.The majority of pharmaceutical and biotechnology industry sponsoredclinical trials requiring cardiac imaging have used core laboratories fromthe academic sector. ICON Medical Imaging can offer a unique combinationof academic experience and superior technology to address all ofthe requirements of a clinical trial requiring imaging.Figure 4: Quantitative 2 Dimensional Echocardiography44021 US.indd 6 12/1/08 10:19:48 AM

Pg 05Conventional Safety Markers and Potential Future DirectionsJoseph Schappert, MD l Medical Director, ICON Central LaboratoriesIntroductionPatient safety is a major issue in clinical practice, as it is in clinicaltrials. The laboratory contributes to assuring patient safetythrough the provision of accurate results and reports, timely resultreporting, reporting of alert or ‘panic’ values to the clinical staff,etc. 1 But since the utilization of ‘ … quantitative measures ofbiologic effects that provide information links between mechanismof action and clinical effectiveness … (and) predict effectivenessare needed to guide drug development’, 2 this article will focus onproper utilization of laboratory tests and their limitations forassuring the safety of subjects in clinical trials.Since drug related toxicity is often reversible, particularly when it isdetected early, the availability of markers, which accurately assessacute injury to vital organs is an important goal. Biomarkers withpoor predictive value for the detection of toxicity provide littleconfidence in decision making and may produce false reassurancesand/or unwarranted concerns. Better biomarkers shouldassist in identifying signs of toxicity earlier in the product life-cycle.Since the development and further assessment of many agents forwhich ambiguous signs of toxicity are observed are dropped fromthe development pipeline, even though they often have shownpromising results in subjects without these, better delineation oftheir toxicity with biomarkers may result in patients who needthese agents and who would not exhibit toxicity having access toan important therapeutic option. But since clinicians exhibitreluctance to including novel biomarkers into protocols, preferringto rely on more traditional and better known assays, biomarkeradoption may not be facile.This overview addresses conventional safety markers and potentialfuture directions for the laboratory assessment of cardiotoxicity,nephrotoxicity and hepatotoxicity.CardiotoxicitySince 9% of withdrawals of prescription drugs from worldwidepharmaceutical markets are due to cardiotoxicity, 3 and approximately17% of pharmaceuticals in clinical trials produce cardiovasculartoxicity, cardiovascular toxicity is a major safety concern. 4Cardiotoxicity is also a limiting factor in the utilization of a widevariety of therapeutically important agents (e.g., oncology,anti-retroviral therapy, etc.)Cardiac troponin (cTn) is currently the most effective biomarker ofmyocardial injury. 5 Troponin is a globular protein, with three forms,I (cTnI), T (cTnT), and C (TnC), which regulates actin-myosininteractions in the myocardium. 6 Since 2000, cTn has beenrecommended by the American College of Cardiology and theEuropean Society of Cardiology as the preferred biomarker foracute myocardial injury. It has high sensitivity, good specificity, andplays an important role in risk stratification. Since elevations introponin, which may be within the reference range, occur beforechanges in left ventricular ejection fraction, its utilization has alsobeen extended to the assessment of a number of pathologies,including drug related cardiotoxicity, renal disease, unstableangina, etc. 7Brain natriuretic peptide (BNP) is a neurohormone, which iselevated in response to volume overload. BNP is widely utilized asa biomarker of congestive heart failure (CHF) but elevations arealso associated with impairment of left ventricular function. 8 Dueto their lack of tissue sensitivity and specificity, particularly in thepresence of skeletal muscle injury, classical markers of cardiotoxicity(lactate dehyrogenase [LDH], creatine kinase [CK] and itsisoenzymes and myoglobin) have been superceded by cTn, and44021 US.indd 7 12/1/08 10:19:54 AM

Pg 06Patient safety is amajor issue in clinicalpractice, as it is inclinical trials.to a lesser degree by BNP. A translational biomarker of potentialinterest is fatty acid binding protein 3 (FABP3), which has anintracellular transport function for long chain fatty acids. Sincetroponin is bound to a structural component of the myocardium,the location of FABP3 in the cytosol results in higher concentrationsof FABP3 earlier than troponin, and greater sensitivity toacute myocardial injury. The major issue with FABP3 as abiomarker for cardiotoxicity is its lack of specificity in the presenceof muscle injury or renal failure.NephrotoxicityThe accurate and timely assessment of renal function is essentialto assuring the safety of subjects enrolled in clinical trials. While‘acute renal failure’ (ARF) has traditionally been utilized to describeacute renal dysfunctions, ranging from mild prerenal azotemia tosevere oliguria associated with acute tubular necrosis, the term‘acute kidney injury’ (AKI) has recently been adopted. ARF isreserved for patients who have AKI and who require renal replacementtherapy (dialysis or renal transplantation).AKI has been variably defined as an increase in serum creatininevalues of 100%, of 50% and of 0.3 mg/dL over differing timeintervals. Conventional serum renal function tests (serum creatinineand urea nitrogen) are late markers of nephrotoxicity. Theirelevations are associated with relatively advanced and severedamage to the proximal tubule on histopathologic examination.Due to their lack of sensitivity and their failure to accurately reflectrapid changes in renal function, the utilization of conventionalmarkers can result in delays in therapeutic decision making, witha potential impact on outcomes. Conventional markers also lackspecificity. For example, creatinine values vary with changes inmuscle mass and tubular secretion, have a wide reference interval,and are impacted by nonrenal factors (e.g. body weight, race, age,sex, total body volume, drugs, muscle metabolism and proteinintake; prerenal factors; and, postrenal factors).The lack of sensitive and specific renal biomarkers may haveimpaired progress in this field, with mortality rates for severe acutekidney disease stable over the past 50 years. It has also had adetrimental effect on the design and the assessment of outcomesof clinical trials. To address this, the design of panels consisting ofbiomarkers, intended to increase sensitivity and specificity and topermit the identification of AKI subtypes, are currently in thediscovery, development, translational and/or validation phase.These biomarkers include neutophil gelatinase-associatedlipocalcin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18(IL-18), and cystatin C. 9NGAL is a growth and differentiation factor found in the tubularcells of the kidney. 10 It is involved in the intracellular transport oflow molecular weight molecules and is a sensitive, specific andpredictive early marker of AKI. Following ischemic or nephrotoxicAKI, NGAP is upregulated, with serum levels increasing 10 foldand urine levels increasing 100 fold in 2-6 hours. NGAL has beenshown to be an independent predictor of clinical outcomes andduration of AKI. Cystatin C, a member of the cystatin ‘superfamily’of protease inhibitors, is freely filtered by the glomerulus. Unlikecreatinine, it is not affected by age, gender, race or muscle mass.44021 US.indd 8 12/1/08 10:19:56 AM

Pg 07Hepatotoxicity is the single most frequent cause of new drug application (NDA) disapprovals, limitations onutilization, and withdrawals of approval submissions by the FDA.A 50% increase over a 12 hour period is predictive of AKI. Itsmajor disadvantages are great intraindividual (‘biologic’) variationand lack of specificity (elevations observed in malignancy, HIVinfection, glucocorticoid therapy, etc). But in association with otherbiomarkers and in the proper clinical setting, cystatin C may beanticipated to play an important role in the identification of acutekidney injury. Il-18 is a proinflammatory cytokine, which is cleavedin the proximal tubule and released into the urine in response toAKI. It has demonstrated effectiveness as an early marker of AKIand in the differential diagnosis of acute tubular necrosis. KIM-1 isan immunoglobulin superfamily cell surface protein, whichrecognizes apoptotic cell-specific surface proteins. 11 It is notexpressed on myeloid cells. During ischemic or toxic AKI, KIM-1 ismarkedly induced in the proximal tubules, and differentiates AKIfrom prerenal azotemia, chronic renal disease and urinary tractinfection. At 12 hours, it is a predictive biomarker for clinical12, 13outcomes, including dialysis and death.By identifying the primary location of injury (proximal tubule, distaltubule, interstitium, or vasculature) and the duration, course andpathogenesis of AKI (see Table 1), the differential expression ofbiomarkers, such as these, may be anticipated to assist in theearly identification and classification of AKI, to provide riskstratification and prognostic information, and to expedite the drugdevelopment process.HepatotoxicityOver the past 50 years, hepatotoxicity is the single most frequentcause of new drug application (NDA) disapprovals, limitations onutilization, and withdrawals of approval submissions by the FDA.Unpredictable hepatotoxic reactions are unrelated to dose, occurwithout warning, and have latency periods of days to 12 months.Drug-induced liver injury (DILI), particularly idiosyncratic toxicities,is observed with low frequencies (

Pg 08may vary greatly, from spectrophotometry (cardiac) to multiplexedELISA assays (renal) or genomic signatures (liver). But based onthe rapid growth of our knowledge in genomics, transcriptomics,proteomics, and metabolomics and the ensuing growth in thediscovery and development of novel biomarkers, it should beanticipated that the clinical laboratory will assume an even greaterrole in the provision of safety testing in the future.Resources1Handler S, Altman R, Perera S, et al. A systematic review of theperformance characteristics of clinical event monitor signals used to detectadverse drug events in the hospital setting. J Am Med Inform Assoc2007;14:451-458.2Challenge and Opportunity on the Critical Path to New Medical Products.http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html. Accessed 17Aug 2008.3Fung M, Thornton A, Mybeck K, et al. Evaluation of the characteristics ofsafety withdrawal of prescription drugs from worldwide pharmaceuticalmarkets: 1960 to 1999. Drug Info J 2001;35:293-317.4Olson H, Betton G, Robinson D, et al. Concordance of the toxicity ofpharmaceuticals in humans and in animals. Regul Toxicol Pharmacol2000;32:56-67.5O’Brien P. Cardiac Troponin is the most effective translational safetybiomarker for myocardial injury in cardiotoxicity. Tocicology 2008;245:206-2186Metzger J, Westfall M. Covalent and noncovalent modification of thinfilament action. The essential role of troponins in cardiac muscle regulation.Circ Res 2004; 94:146-158.7Waxman D, Hecht S, Schappert J, Husk G. A model for troponin I as aquantitative predictor of in-house mortality. JACC 2006;48:1755-17628Suter T, Meier B. Detection of anthracycline-induced cardiotoxicity; is therelight at the end of the tunnel (Editorial). Ann Oncology 2002;13:647-649.9Devarajan P, Williams L. Proteomics for biomarker discovery in acutekidney injury. Semin Nephrol 2007;27:637-651.10Schmidt-Ott K, Mori K, Li J, et al. Dual action of neutrophil gelatinaseassociatedlipocalin. J Am Soc Nephrol 2007;18:407-413.11Ichimura T, Asseldonk J, Humphreys B, et al. Kidney injury molecule-1 isa phosphtidylserine receptor that confers phagocytic phenotype onepithelial cells. J Clin Invest 2008;118:1657-1668.12Parikh C, Devarajan P. New biomarkers of acute kidney injury. Crit CareMed 2008;36:S159-S165.13Bagshaw S, Langenberg C, Haase M, Wun L, May C, Bellomo R.Urinary biomarkers in septic acute kidney injury. Intensive Care Med 2007;33:1285-1296.14Navarro V, Senior J. Drug-Related Hepatotoxicity. NEJM 2006; 354:731-9.15Guidance for Industry: Drug Induced Liver Injury: Premarketing ClinicalEvaluation. http://www.fda.gov/cder/guidance/index.htm. Accessed 17Aug 2007ICON Acquires Prevalere Life Sciences Inc.ICON has expanded its bioanalytical and immunoassay servicesinto the United States through the acquisition of Prevalere LifeSciences Inc., a wholly owned subsidiary of ORS Labs Inc.Prevalere is one of the leading providers of bioanalytical andimmunoassay laboratory services to the biotechnology andpharmaceutical industries and operates from a 49,000 square footfacility in Whitesboro, New York. Prevalere will complement ICON’sexisting European-based bioanalytical lab capabilities, where ICONDevelopment Solutions recently moved to a new, purpose-builtbioanalytical and immunoassay laboratory in Manchester, England.Commenting on the acquisition, Peter Gray, CEO, ICON plc, said,“The acquisition of Prevalere gives ICON much greater scale in therapidly growing market for bioanalytical and immunoassaylaboratory services and adds value to our service offering in earlyphase clinical development. Prevalere brings to ICON a highlyexperienced team, an excellent lab facility in the United States anda strong market reputation amongst top-tier pharmaceutical andbiotechnology companies.”More information about Prevalere can be foundat www.prevalere.com.44021 US.indd 10 12/1/08 10:19:59 AM

Pg 09Technological advances in clinical trial managementKris Gustafson l Sr. Vice President & Global Head, Interactive Technologies and Lifecycle Sciences GroupICON Clinical ResearchTwenty years ago, pharmaceutical researchers looked forward tothe day when advances in technology would reduce or eveneliminate the truckload of paperwork required for a typical NDAsubmission. Many in the industry visualized an all-electronicclinical trial, and sophisticated software that could track patients,analyze data, resolve queries, prepare reports, create models,send alerts and even project outcomes, based on biochemicaland genetic data.That day is here. Today, every clinical trial in the world relies onelectronic tools for data management and communications.Researchers use an array of tools that didn’t even exist 20 yearsago. From laptops and Blackberries, from electronic CRFs to IVRphone systems, the clinical trial of 2008 is critically dependent onthe silicon chip. And as studies become larger, more globalized,and more logistically complex, technology will play an evenbigger role.A profound shiftIn 2004, an article in Applied Clinical Trials noted that:“The use of paper in offices, from the printing of emails and Webpages, is growing at 6-8% per year, with the average employeeprinting 33 Internet pages per day. Paper usage doubled from1981 (the introduction of the PC) to 1995. We still print out ourdocuments to read and review, keep paper to-do lists, and getour industry news in printed magazines.” 1It is an indication of how fast things change today that thesewords, written just four years ago, already feel out-of-date. Forone thing, an increasing number of people – including clinicalresearch and pharmaceutical professionals – are more comfortablethan ever communicating, learning and archiving informationin an online-only environment.Trend analysts and learning experts agree that the shift to avirtually paper-free world is gaining speed. As this happens, it isprofoundly changing the way human beings process information.Even highly educated people today have noticed a difference inthe way they read and absorb information. Many are finding itharder to focus on information presented in long-format text,preferring spreadsheets, graphics and short paragraphs –formats that are ideally suited for the electronic environment.As technology grows more powerful and pervasive,we will see significant changes in the way clinical trialinformation is gathered, organized and presented.Technology trends in clinical trialsOver the last decade, pharmaceutical, biotech companies andCROs have been implementing an increasing array of technologicalresources. Over this period we have watched as cutting-edgetrends have become established industry practices. Here are themost popular clinical trials technologies – and a few trends towatch.EDC (Electronic Data Capture)After an uncertain start in the 1990s, electronic data capture ishere to stay. Many of the initial drawbacks (including high softwarelicensing fees) have been addressed successfully, and there is anincreasing comfort level among sponsors and sites.There are many advantages to EDC beyond the reduction ofpaperwork. Real-time data checking can reduce queries andprevent costly errors from compounding. Regulatory submissionsare simplified. But perhaps even more significantly in today’s costandsafety-conscious environment, EDC can be used to conductprospective clinical trials on experimental compounds. The datafrom these prospective trials can help identify “winners” and“losers” before millions of dollars in research and developmentcosts are invested.IVRS (Interactive Voice Response Systems)Interactive Voice Response Systems are used extensively today astools for clinical trial management. These systems use telephonesto collect study data. While not as leading-edge as other technologies,IVRS has been successful precisely because it employs atechnology that is familiar everywhere. It has become particularlyuseful in emerging nations, where land-based telephone systemsmay be lacking and where cell phones are used by the majority ofthe population.44021 US.indd 11 12/1/08 10:20:02 AM

Pg 10IVRS systems have been used successfully to speed data capture,randomize study subjects, manage and track clinical supplies andissue reminders and alerts.ePRO (Electronic Patient-Reported Outcomes)Many clinical studies today rely on some form of patient diaries tocollect patient reported outcomes (PRO). PRO can provide vitalendpoint data and are therefore critical components of many trials.Traditionally, these diaries were paper documents – forms thatstudy subjects would fill in manually. However, paper-basedsystems have serious drawbacks:• Labor intensive: Study personnel must collect diaries, processinformation and perform quality checks• Costs of printing and distribution• Patients can lose diaries• Because diaries remain in patients’ hands, errors and omissionsmay not come to light until the end of a studyIn comparison with paper-based PRO, ePRO, which uses Internettechnology for patient data collection and communication, hasseveral advantages.RFID tag. RFID stands for “radio frequencyidentification device.” It’s the same technologythat’s used in credit cards, where a small striprecords unique identification about how you useyour card. Similarly, the eCap can record when amedicine container is opened, thus helping keepa record of patient compliance. RFID technologycan also be used on blister-packs, to recordwhen the seal is broken and a pill is removed.Data WarehousingIntegration of various systems within clinical trials has becomemore common than ever before. EDC systems often requireenrollment data from the IVRS. The IVRS requires site data fromthe CTMS. Each integration is often built on a study specific basisfor each technology vendor. The possibility of errors and datainconsistencies is enormous and the data flow diagrams look like apile of spaghetti. A central data repository, based on CDISC,would allow each vendor to build a reusable data integrationmodule. The data warehouse would allow consistent reportingacross multiple studies. In addition we would be able to reducethe time required to setup these systems in the beginning.http://ecap.biz eCapAdvantages of ePRO• Eliminates problems associated with paper diaries• Greatly increases patient compliance 2• Reminds patients of important study activities (site visits, dosechanges, etc.) with pre-programmed alarms, voice mailmessages or e-mails• Monitors data entry compliance in real time and issuesreminders, thus preventing missed entriesRegulatory agencies today look favorably on ePRO data as itprovides an excellent record of patient activity, and in most casesis more complete and accurate than paper diaries. Indeed, thenumber of clinical trials using ePRO continues to increase, fromapproximately 5% in 2002 to 15% in 2007. 3ePRO as a feasibility toolDropping non-compliant patients from a study is costly – but whatif you could predict in advance which patients would be non-compliantand correct the problem before the study started? Somesponsors are running pre-studies using placebos to learn whatfactors lead to non-compliance. Armed with this information, theycan design appropriate patient education materials, or refineprotocols to weed out subjects likely to be non-compliant. ePROtechnology can be invaluable in speeding up this process.eCapsOne novel use of technology that has recently appeared on thescene is the eCap. An eCap is a medicine bottle cap with a built-inPractical considerationsWhat does all this mean for clinical research professionals? Astechnology grows more powerful and pervasive, we will seesignificant changes in the way clinical trial information is gathered,organized and presented. Regulatory agencies are likely to changetheir requirements to favor new forms and formats for electronicallypresented data. Clinical professionals who can work comfortablyand creatively with technology will have the edge in the industry,making it even more critical to select and implement the mostefficient e-tools.Notes1Paul Bleicher, “The Fully Electronic Office (or Clinical Trial) Myth,”Applied Clinical Trials, October, 20042Stone AA, Shiffman S, Schwartz JE, Broderick JE, Hufford MR.“Patient non-compliance with paper diaries.” Br Med J2002;324:1193-1194.A National Cancer Institute (NCI) study reported that patientcompliance levels for electronic diaries were higher than for paperdiaries. The study also showed a large discrepancy betweencompliance levels reported by patients with paper diaries (90%reported) and their actual levels of compliance (11% actual). Incontrast, actual compliance with electronic diaries was 94%.3Gustafson, Kris, “ePRO – maximizing the benefit and minimizingthe pain,” World Pharmaceutical, April 17, 200844021 US.indd 12 12/1/08 10:20:03 AM

Pg 11ICON Profile: Jonathan Goldman, MD FACCTitle: Chief Medical OfficerICON Medical ImagingRole at ICON:I joined ICON Medical Imaging (formerly Beacon Bioscience) inNovember 2007 after 7 years as chief medical officer of acardiovascular biotechnology company. I am also a cardiologist,trained in the UK and US with a subspecialty interest incardiac imaging. I maintain clinical appointments at theUniversity of California, San Francisco, and at the John RadcliffeHospital in Oxford, UK. I am extremely pleased to join the ICONteam, and to have a role in developing ICON services in theareas of cardiovascular clinical trials, cardiovascular imaging,cardiac safety and cardiac adjudication.Background:I grew up in North London and completed my high schooleducation at Westminster School London in 1982. I attendedSt Bartholomews’ Hospital Medical College, University ofLondon and completed my MBBS Medical Degree withDistinction in 1989. I also completed a BSc in Immunology atSt. Marys’ Hospital Medical School (1986), and during mycardiology training was awarded an MD Degree from theUniversity of London following research at St. George’s HospitalMedical School, London. I later moved to the University of SanFrancisco, California where I completed level 3 training inEchocardiography.Career challengesMedicine has always been a competitive field, and this isparticularly true of cardiology. Moving to the US carriedadditional challenges, including all steps of the US MedicalLicensing Exams, as well obtaining state licensure and hospitalprivileges. Additional bureaucratic challenges included thespecific obstacles to green card for physicians who come tothe US in certain visa categories. I am pleased these are allbehind me now.Career highlightsInternal Medicine (University of London), 1992; Cardiology(University of London, 1999). I was Chief Medical Officer atPOINT Biomedical from 2000 to 2007 where we developed amicrosphere technology from Phase 1 through NDA. The primaryapplication of the technology was cardiovascular. Beacon Bioscience(now ICON Medical Imaging) was our Imaging Vendor.Working at ICON:I really like the team approach at ICON. My position allows forfrequent interaction with other divisions including ICON ClinicalResearch and ICON Development Solutions. Ultimately I aminterested in developing clinical trial offerings that will be good forpatients by developing more effective and safer therapeuticoptions. ICON is uniquely placed to achieve this by a combinationof integration, project management and application of technology.On your own time:I live in Mill Valley, California with my wife, Georgina and sonsMax (age 4) and Oliver (age 2). In my spare time I enjoy spendingtime with the family, and participating in the sport of rowing.I represent Marin Rowing Association in the Masters Division.“I really like the team approach at ICON. Myposition allows for frequent interaction withother divisions including ICON ClinicalResearch and ICON Development Solutions.”44021 US.indd 13 12/1/08 10:20:04 AM

First ClassPresortedU.S. PostagePAIDWarminster, PAPermit No. 225RETURN SERVICE REQUESTEDDid you know?• ICON Medical Imaging was the first commercial imaging labto offer quantitative coronary angiographic analysis withintegrated eCRF• ICON Medical Imaging offers an electronic adjudication solutionfor clinical event committees (CEC) or data safety monitoringboards (DSMBs)• ICON’s Interactive Technologies Group has implemented over850 trials worldwide, have managed over 50,000 sites, more than25,000,000 patient transactions, and have supported over65 languages in more than 85 countries• ICON Central Laboratories is a global provider of central laboratoryservices located in New York, Dublin, Ireland, Asia-Pacific and India• ICON Central Laboratories has over 550 active studies and18 years experience in over 70 countries in support of 34,000 sitesworldwide• ICON Clinical Research has conducted over 4,700 clinicalstudies involving more than 1 million patients in 83,000 centersthroughout the world.ICON Insight ©2008.To contact our newsletter staff, e-mailErica Hill at Erica.Hill@iconplc.comWeb: www.iconplc.comPhone: U.S. +1 215-616-3000 • Europe +353 1 291 2057ICON is a global provider of outsourced development services to the pharmaceutical, biotechnologyand medical device industries. We specialize in the strategic development, management and analysisof programs that support clinical development–from compound selection to Phase I-IV clinical studies.ICON currently has over 6,500 employees, operating from 72 locations in 38 countries.Further information is available at www.iconplc.com44021 US.indd 2 12/1/08 10:19:39 AM