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

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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
Page 1 and 2: Vol. 14Winter Issue 2008Technology
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Page 7 and 8: Pg 07Hepatotoxicity is the single m
Page 9 and 10: Pg 09Technological advances in clin
Page 11 and 12: Pg 11ICON Profile: Jonathan Goldman

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

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