Drug Safety - ICON plc

DrugSafetyProviding strategies andsolutions to help sponsorsmaximize drug safety

Drug SafetyDrug SafetyThe challenge of safetyEvery day, around the globe, pharmaceutical researchersare working to develop safe, effective medicines to relievesuffering and promote health. Although there have been manysignificant accomplishments in the pharmaceutical industry,over the last 20 years, there have also been serious setbacks.Numerous, highly publicized instances of drug safety recallshave had lasting repercussions within the industry and haveled to an increased focus on issues related to drug safetyand surveillance.“The new safety regulationshave an appreciable impacton the industry as a whole”According to 77% of respondents surveyed in a recent research study *At ICON, we have the expertise that spans the entire lifecycle of drug development. Ourteam of global safety experts is ideally positioned to design and implement comprehensivedrug risk management programs and Phase IV safety surveillance programs.Drug Safety at ICONA global and growing problemAll drugs have inherent risks associated with them. In the U.S.alone, it is estimated that over 100,000 people die each yearfrom adverse drug reactions (ADRs) or medication mistakes(nearly double the rate of deaths reported just a decade ago).In Europe, an Impact Assessment carried out for the EUCommission estimated that ADRs kill over 197,000 per year inEuropean hospitals.Most side effects surface during the clinical trial phase andare addressed either by changing the drug’s formulation,adjusting the dosage, or identifying groups of patientswho should not use the drug. However, many side effects,including some that are serious or even life-threatening,only come to light after the drug has reached the generalpopulation and it may be many months, or even years, beforetheir dangers are revealed or fully understood.Safety today: Regulators are taking a closer lookAs more patients around the world take more medicationsand the incidence of adverse events keeps rising, regulatorybodies are increasingly scrutinizing the safety profiles ofboth new and established drugs. They are now requiringpharmaceutical companies to conduct more research andprovide more data related to the safety of their products.The FDA Amendments Act of 2007 was created primarilyto fund additional safety review resources within the FDA.Safety agencies in Europe are also engaged in strengtheningsafety regulations. The EU Clinical Trials Directive made thefailure to report adverse events from clinical trials a criminaloffence, while the Medicines and Healthcare ProductsRegulatory Agency has also begun to aggressively pressfor changes in EU and British law relating to drug safetyassessment and monitoring.Safety is also clearly identified as one of the four pillars of theEuropean Innovative Medicines Initiative that aims to improvethe predictivity of safety evaluation by addressing problemsand bottlenecks specifically related to safety evaluation andrisk-benefit analysis.Safety management: The importance of a global strategySafety management requires a strategic plan that anticipatesand addresses multiple scenarios, risks and contingencies. Asthe drug and device market becomes ever more multi-national,these strategic plans need a global focus. However, trackingproducts, compiling adverse event data and meeting theregulatory requirements of many different countries can be adaunting challenge.ICONDevelopment Solutions• Early Formulation Analyses• Drug Development Services• Clinical Pharmacology• Proof of Concept• Bioanalytical Services• Phase I Patient Studies• PK/PD Modelling andSimulationICONClinical Research• Risk Management Strategies• Medical Affairs• Drug Safety &Pharmacovigilance• Data Safety MonitoringBoards• Post-Marketing SafetySurveillance• Total Product Safety Center• Registries, ObservationalStudies and EpidemiologyICONMedical Imaging• Medical Imaging CoreLaboratory- Imaging endpoints forefficacy and safety• Full-Service Solution forDiagnostic Contrast Agent &Device Trials• Electronic Solutions forSafety, Endpoint andAdjudication Committees• Event Adjudication &DSMB SupportICONCentral Laboratories• Comprehensive test menuof over 400 assays for safetyand esoteric testing• Data Management• In-house R&D Laboratoryto evaluate new assays andassay transfer• Solution for managing LocalLaboratory Results (iRIS)• On-site Sample Managementand Storage*According to the findings of a research study “Safety First: The Impact on New Regulations on Clinical Development,” May 09, conducted by IMS/ICON plc. This study was based on a surveyof 140 industry safety specialists including Heads of Medical, Drug Safety, Pharmacovigilance, and Regulatory within large and mid-sized pharmaceutical companies and biotech firms.23

Drug SafetyDrug Safety“ the number of Phase IV trialsare expected to increase in thenext five years.”According to 80% of interviewees surveyed in a recent research study.*Getting a head start on safety in earlydevelopmentThe most successful development programs incorporate safetyconsiderations right at the outset of the process. At ICON,we assist sponsors in creating and executing comprehensivedevelopment plans that include processes and methodologiesfor identifying and addressing important safety issues. OurDevelopment Solutions division acts as an early “translationalmedicine” research resource for sponsors who are developingnew drugs and providing sponsors with critical insights on howa new compound is likely to behave under a variety of scenarios.Early FormulationICON can examine and analyze the chemical structure of theactive substance ingredient(s) and the initial formulation of anew product. Our analyses include time and cost-savingscreening procedures for the purpose of acquiring predictiveinformation with both safety and efficacy implications.Our services include:• Advice on quantification methodologies to provide keyinformation about the active and inactive ingredients ofthe compound• Advice on light, temperature and humidity sensitivitytesting requirements• Guidance to refine and further develop the formationand initial dosage forms for the productThe goal in all these procedures is to ensure that any newtherapeutic compound will be as safe and stable as possible.During this early formulation process, we can also help clientsto plan and execute non-clinical pharmacology and toxicologytesting, a critical regulatory requirement on the drugdevelopment pathway.Pharmacology and Toxicology TestingICON’s toxicology professionals have the expertise to review theinformation about your compound and provide advice on whetheryour development program should include sequential single andrepeat-dose (subchronic and chronic) studies in a variety of rodentand non-rodent species to examine the effects of the drug atdifferent dose levels and durations. The focus of these studies isto define target-organ toxicity following systemic exposure and toprovide data on the no observable effect level (NOEL) and the noobservable adverse effect level (NOAEL) - information critical tothe selection of an initial safe dose in man. ICON can also provideguidance on what other in vitro and in vivo safety studies shouldbe conducted including genotoxicity, reproductive, immunotoxicity,drug-drug interaction, local toxicity, and phototoxicity studies.ICON can also support nonclinical CV safety testing (ICH7SB) andthe in-vitro assessment of CYP450 pathways of metabolism.First-Time-in-ManOnce the pre-clinical package satisfies regulatory drugcharacterization and safety requirements, ICON can supportthe conduct of Phase I studies, within healthy human volunteersor patients who have a target disease. For these studies, ICONutilizes our specialized Phase I units in Texas, Nebraska, andManchester, UK. We have extensive experience in a rangeof studies including first-time-in-man, dose escalation, PK/PD, multiple dose drug interaction, Phase I patient and specialpopulation studies. ICON’s bioanalytical labs in Whitesboro, NYand Manchester, UK can assay both small and large molecule drugproducts and interface with our PK-PD modeling group to providePopulation PK analysis during the later development phases.Tracking safety across later development phasesAs potential new drugs move further through the developmentprocess, proactive monitoring, evaluation, and handling of safetyissues are essential for safeguarding patient safety.*According to the findings of a research study “Safety First: The Impact on New Regulations on Clinical Development,” May 09, conducted by IMS/ICON plc. This study was based on a surveyof 140 industry safety specialists including Heads of Medical, Drug Safety, Pharmacovigilance, and Regulatory within large and mid-sized pharmaceutical companies and biotech firms.Our full spectrum of services include:• Total Product Safety Center- Post-marketing Surveillance (Adverse EventCollection / handling)- Drug Information Services- Product Complaint Management• Fully validated, E2B compliant global safety database• Qualified Person for Pharmacovigilance (QPPV) in Europe• Signal detection activities / data mining• Global interaction with Competent Authorities• Aggregate periodic reporting (PSURs / Annual Safety Reports)• Registry / Post-marketing authorization study design andimplementation• Specialized Safety ConsultingICON’s experienced medical and regulatory staff comprised ofhealthcare professionals, including physicians, nurses, and otherallied health professionals can provide a roadmap to navigate throughregulatory “grey areas” and ensure risk minimization activities areimplemented effectively and swiftly.Drug Safety and Pharmacovigilance services are centralized at sixglobal safety hubs located in the United States, United Kingdom,Germany, India, Argentina, Singapore and supported by 4 additionalMedical and Safety Centers in Mexico, Brazil, Latvia and Poland.This global reach places us in a strategic position to offer expert drugsafety and pharmacovigilance services with a high degree of oversight,consistency, and reliability.ICON Global Medical & Safety CentersKeySafety hubsSafety CentersMexico CityMexicoBuenos AiresArgentinaPhiladelphiaUnited StatesSouthamptonUKSao PauloBrazilFrankfurtGermanyRegistries, Observational Studies andEpidemiology - An evolving requirementICON has extensive experience designing and coordinatingprospective and retrospective safety studies for our clients.These studies, which include patient registries and observationalstudies, have been designed to meet a wide range of objectives,from fulfilling a post-marketing regulatory commitment to assessingthe comparative safety associated with the treatments for a specificdisease. Programs have ranged from a single center to over 2,000centers with patient populations ranging from 20 to over two millionacross all major therapeutic areas.The range of our specialties, combined with our technical expertise,allows ICON to support the scientific research needs of our clientsthrough multiple publications and presentations of research findings.Additionally, ICON has a scientific core team of epidemiologistsexperienced in cohort analyses, conducting retrospectivehealthcare-related database analyses, and safety registries.These individuals average 10 years of government, academic,industry, clinical, and consulting experience in epidemiology.RigaLatviaWarsawPolandChennaiIndiaSingaporeSingaporeFor more info about ICON’s Medical & Safety Services visit www.safetyiconplc.com or email safety@iconplc.com45

Drug SafetyDrug SafetyData Safety Monitoring BoardsData Safety Monitoring Boards (DSMBs) and Clinical EventCommittees (CEC) are becoming a more prominent elementof clinical research trials. They are comprised of physicianswith expertise in the relevant therapeutic area or clinicalspecialty that review all relevant study data to provide anindependent determination of trial endpoints or events.DSMBs, also known as Data Monitoring Committees (DMCs)or Independent Data Monitoring Committees (IDMCs) haveresponsibility for regularly reviewing all interim safety datacollected during the clinical trial process. Following thesereviews, DSMBs advise sponsors, investigators and institutionson issues related to subject safety as well as the continuingvalidity and scientific merit of the clinical trial under scrutiny.ICON has experienced professionals who can assist sponsorsin establishing and managing a DSMB in compliance withrelevant regulatory guidelines. Since 2002, we have incorporatedDSMBs into more than 100 studies across all major therapeuticareas. ICON’s unique cross-functional team approach allowsall members of the study team, including the DSMB, to interacteasily, for maximal customer service and benefit.Imaging, event adjudication and DSMB supportICON’s Medical Imaging division provides core laboratoryimaging services and customized medical informatics solutions.Their market leading experience and expertise has resultedin unique technology solutions for assessment of efficacyand safety in drug development. The technology used byICON Medical Imaging (IMI) for image and non-image basedassessment is based on proprietary technology called MIRA(Medical Image Review and Analysis System).This technology can be coupled with ICON’s clinical expertise inClinical Endpoint Committee (CEC) and DSMB to create a uniqueintegrated service for sponsors.MIRA enables clinical data and related images to be postedonline and viewed by CEC or DSMB members. For CEC, data is“cleaned” prior to posting and quality controlled for completenessby adjudication monitors in our Medical Safety & Servicesgroup. Entries are made in an eCRF integrated in the system.DSMB multipart tables and listings can be displayed, filtered andsearched remotely, which facilitates safety review.Imaging as a Biomarker for cardiac safetyICON Medical Imaging also provides expertise in the design,toxicity thresholds, site training, centralized collection, masking,technologist quantitation, reader training and cardiologistover-read of all major cardiac imaging modalities. Each imagingmodality can be used to assess for a possible toxic effect of adrug on cardiac or vascular function. Our academic links, wideexperience in prior studies and regulatory background in cardiacimaging is unique amongst commercial core imaging laboratories.Our Services include:• Chief Medical Officer is a practicing Cardiologist, certified inmultiple modalities• Imaging specialists are registered cardiac technologists• Quantitative measurement of left ventricular function byechocardiography, MUGA (Multiple Gated Acquisition Scan),coronary angiography, cardiac MRI (Magnetic ResonanceImaging), SPECT, CT angiography• Measurement of myocardial perfusion by SPECT, MRI• MIRA system allows on-line review of echocardiographyimages for rapid reportingOur academic links, wideexperience in prior studiesand regulatory background incardiac imaging is unique in thecommercial core imaging sector.Central Laboratory testing - Ensuring clinicallyrelevant safeguardsLaboratory test results often provide the first indication that apotential safety issue may exist, either in an individual studysubject or in the study population as a whole. As a global centrallaboratory, dedicated exclusively to clinical trials, ICON CentralLaboratories works closely with sponsors from the time a clinicalprotocol is in development until study closeout to ensure clinicallyrelevant safeguards for subject safety.Due to the ever-changing scope and complexity of availablelaboratory testing, we recommend pre-study collaboration todetermine appropriate marker selection and to help ensure thatthe required specificity is available to monitor study subjects andmake certain that clinical endpoints are met.Rapid test result turnaround is critical and our scientific affairsand global logistics staff help expedite this process. Front-endstudy planning and consultation services help sponsors evaluaterequired assays against sample transit times from geographicallydiverse sites. This ensures timely availability of subjects’ testresults for appropriate medical management.We work closely with sponsors and sites to provide robust toolsto detect and respond to clinical issues that may arise, usingcapabilities such as study-specific alert ranges, delta flags andtoxicity grading, to offer maximum protection to study subjects.And we continue to look for new ways to support safety reportingactivities. For example, we utilized an on-demand languageinterpretation service via telephone for use when site servicesstaff must communicate panic values and urgent alerts to siteswith limited English-speaking ability.To drive efficiencies ICOLabs, a secure, web-based remotedata access tool gives medical and safety monitors the abilityto review laboratory results against specified criteria or acrossresult histories for one subject, the entire study population or auser-defined sub-population. This tool improves the quality ofthe pharmacovigilance process and increases the efficiency ofpersonnel responsible for monitoring subject safety.ICON sets the standardThe safety of marketed drugs as well as those in developmenthas never been such a priority. Today, safety managementrequires a strategic plan that anticipates and addressesmultiple scenarios, risks and contingencies. Clinical researchorganizations must demonstrate that they can ensure that safetyprograms are conducted according to the highest scientificstandards. ICON understands the safety lifecycle –from product inception through commercialization. Our teamof global safety experts is ideally positioned to design andimplement comprehensive drug risk management programsand Phase IV safety surveillance programs.67

Corporate Headquarters:South County Business ParkLeopardstown, Dublin 18, IrelandT: +353 1 291 2000F: +353 1 291 2700W: www.iconplc.comICON Central Laboratories:123 Smith Street, FarmingdaleNew York 11735T: +1 631 777 8833F: +1 631 777 3904E: labinfo@iconplc.comICON Medical Imaging:2800 Kelly RoadWarrington, PA 18976T: +1 267 482 6300F: +1 267 482 6301E: imaging@iconplc.comICON Clinical Research US:212 Church RoadNorth Wales, PA 19454T: +1 215 616 3000F: +1 215 699 6288E: info-clinical@iconplc.comICON Development Solutions:6031 University BoulevardSuite 300, Ellicott City, MD 21043T: +1 (410) 696 3000F: +1 (410) 480 0776E: IDSinfo@iconplc.comwww.iconplc.com Version 1 / 2009