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Peer reviewed

Daniel Manak | Jae Chung, MBA, CPA | Sherry Reuter, BSN, MSHS

S o l u t i o n S - B a S e d

Study Startup 2.0

Reinventing How Clinical Trials Begin


nyonewhohaseverparticipatedinclinicalstudystartupfordrugs, devices,orbiologicsknowsthatitisatedious,labor-intensive,and frustratingprocessthatoftenfailstomeettimelines.1Methodsusedtocompletestartuptasksremainlargelypaper-basedandareofteninefficientand slow.2,3 Thisscenarioleavesmuchroomforimprovement,andthisarticleexplores state-of-the-art approaches to bringing about the desired goal of completingstartuptasksmoreefficiently,reducingthenumberofclinical trialsthatdonotcompleteontimeandwithinbudget.Specifically,thefocushereisonbestpracticesandnewtechnologiesforstreamliningstartup processes.Thetechnologiesarebasedoncloudcomputing,adynamically scalablemethodofprovidingsoftwaretotheend-userfromaweb-based servertodeliverapplicationsondemand. Utilizingsharedvirtualizedresources,theseuser-friendlyprogramscan simplifydocumentexchangeanddecreaserepetitivetaskswhileprovidingup-to-theminutetransparencytoallstakeholdersinvolvedinstartup. Sponsor-siterelationsimprove,leadingtogreaterbuy-inbysitesandcontractresearchorganizations(CROs)andgreatermotivationtoperform.The sponsorthatisfunctioninginafinanciallyandtime-squeezedenvironment may realize dramatic time and cost savings as tasks are completed and trackedinanorganizedandsimplifiedmanner,allowingstudiestoproceed onschedule.

t e c h n o l o g y

This article explores state-of-the-art approaches to bringing about the desired goal of completing startup tasks more efficiently, reducing the number of clinical trials that do not complete on time and within budget.

Startup 1.0: The Process


Clinicalstudystartupisthemultisteppracticeofselectingandpreparing investigativesitesforinitiation.Itisacollaborationofstakeholders:sponsor, CRO, site, institutional review board (IRB) or ethics committee (EC), andavarietyofoutsourcedproviders.Itconsistsofexchangingnumerous documents,communication,andbudgetandcontractnegotiations,which involve:
Distribution,collection,andevaluationofpretrialquestionnaire RegulatorydocumentcompletionandIRB/ECapproval Negotiationofcontractsandbudgets Schedulingandperformingsiteevaluationvisits Conductinginvestigatormeetings/sitetraining Provisionofsuppliesandtestarticle

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Theworkbeginswithsiteidentification, an increasingly global function, and continues until all selected sites are initiated. Eachcomponentofstartuphasseveralsteps,oftentrackedusingmultiple spreadsheetscreatedandaccessedby variouspartners.Generally,thesecreateinefficienciesbecausethemethods arenotstandardizedacrossfunctions orcentralizedforeasyaccess;sothey tendtobereinventedforeachstudy. AviewofstartupappearsinFigure1. The figure is not meant to be inclusive of all guidelines from the InternationalConferenceonHarmonization (ICH),butcanserveasaframeworkfor understandingstartupcomplexity. Giventhenatureofthestartupprocess,itisnotsurprisingthatthecurrentsystembreedsdelays.ALinkedIn study conducted in 2010 questioned 205 clinical trial professionals about theirviewsofthestartupprocess;341% respondedthatitwaslengthy,manual, and inefficient, while 30% reported thatitwasOK,butcoulduseimprovement.Ina2009CenterWatchsurvey ofinvestigativesites,startupactivities

factoredheavilyinstudydelays,with contractandbudgetnegotiationcited asthemostfrequentcauseat49%,followedbypatientrecruitmentandother routinetasks(seeFigure2).4Research suggests that sponsors stand to lose between$600,000and$8millioneach dayproductdevelopmentisstalled;5so startupprocessesthatdragoncutinto thebottomlineinaverydirectway. There is a lot at stake in startup, whichiswhycontinuingwiththestatus quo is not a sustainable business practice.Abetteroptionistoemploy standardsandprocesschangesforsite selection, complemented by technology to bring about startup improvementsthatwillextendintootherstages of development.6 Some technologies designed for startup use cloud computing,whichisdescribedinFigure3.

they can be found, and what types ofsiteswillbeabletoaccess,recruit, andenrollthem.Anidealsiteprofile shouldbeusedinaccordancewiththe protocoltoguideeverystepofsiteselection;otherwise,sitesarelikelytobe chosenthatwillnotperformwell. Next,thesponsororCROcompiles a list of potential sites that meet the uniquecriteriadefinedintheidealsite profile,perhapsbeginningbyidentifyingsiteswithwhichtheyhavepreviousexperience.Othersourcesofsites include online directories, referrals fromtrustedsources,socialnetworkingsites,sitenetworks,sitemanagementorganizations,andphysicianlists (typically by specialty) from professionalmedicalassociations.Additional siteselectiontipsinclude:
developingacustomizedpretrial

Improving the Process


Acriticalelementofstartupissiteselection. Finding reliable, performing sites begins with sponsors and CROs developing a detailed plan to define the target patient population, where

questionnairebasedoncharacteristicsoftheidealsite; reviewingresponsestothequestionnaires;and performingsiteevaluationvisits, focusingontheprincipalinvestigators(PIs)interestinthe

Figure 1 The Complex Process of Clinical Study Startup


Initial contact by pharma, biotech, or device sponsor NO PI not interested YES Site review of pretrial questionnaire and protocol requirements NO PI not interested PI declines study Sponsor does not select PI/site YES Study offered to PI Accepted

Confidentiality agreement

Perform prestudy visit

Start regulatory document collection

Budget negotiations Contract negotiations

Budget and Contracts Final; may need final contracts to submit to IRB/EC Submit to IRB/EC: IRB/EC application CVs/Licenses of personnel Protocol Informed consent form with site information HIPAA authorization (U.S.) Final contracts (country dependent) Submit to regulatory agency(s) FDA Form 1572 Curriculum vitae, medical license of PI Financial disclosure (U.S. and EU if necessary) Approval

IRB/EC submission prep Regulatory documents complete Regulatory/Good Clinical Practices document prep

Site evaluation visit and/or investigator meeting

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Figure 2 Factors Most Often Causing Study Delays (n=950)


49% 41%

26%

26%

25%

it should focus on honest discussion aboutthetargetedpopulationandthe sitesabilitytorecruitandperformthe trialsuccessfully. Statisticsindicatethattheindustry continuestodoapoorjobwithrecruitment, as evidenced by these dismal facts:
70%ofinvestigativesitesare

Contract and budget negotiation and approval

Patient recruitment and enrollment

Protocol design and refinement

Legal review

IRB review and approval

Source: CenterWatch Survey of Investigative Sites in the U.S. (2009)

studyandrealisticassessment ofthesitesabilitytoconductit successfully. Unfortunately, all too often sites are chosen that lack the ability and/ ormotivationtoconductthetrialsuccessfully. This happens for several reasons.First,timelinesarealmostalwaysextremelyshort,sothereisrarely timetoproperlyidentifysitesbeyond acursoryreviewofthepretrialques-

tionnaire. When there is little scrutiny of what is written on the questionnaire,thephenomenonknownas Lasagnas Law comes into play; this lawcapturesthenotionthatinvestigativesitesfrequentlyoverestimatethe numberofsubjectstheywillbeable to enroll.7 Second, there is often inadequatecommunicationbetweenthe sponsorandthePIastothetypesof challengesheorsheforeseeswiththe protocol.Third,thesiteevaluationvis-

morethanonemonthbehind inenrollment,andonly7%of sitesreportmeetingenrollment timelines.4 Amajorpharmaceuticalcompanyreportedthatbetween2000 and2006,26%ofsitesrecruited 80%ofparticipants;11%ofsites recruitedonesubject;andfor oncologystudies,37%ofsites recruitednosubjects.8 Recentresearchhighlightsthesavingsthatcanberealizedbyplanning andimplementingimprovedprocesses for this basic clinical trial activity.9 The research makes the assumption that if 65,000 investigator sites are initiatedannually,andthecostofinitiatingeachonewere$20,000,evena 1%reductioninnonperformingsites wouldsavetheindustry$13million. By identifying nonperforming sites, fewersiteswouldbeneeded,andmore subjectswouldbeenrolledateachof theremainingsites. A few words about metrics are in order.SponsorsandCROschargedwith siteselectionshouldkeepmetricssuch asthefollowingonsiteperformance, becausetheycanofferanindicationof sitepotential:
Timetoscreeningoffirstsubject Numberofsubjectsenrolled

Figure 3 What is Cloud Computing? Cloud computing refers to a web-based method of providing software to the end-user, similar to the way consumers access applications or apps on their BlackBerries, iPhones, or Droids. Desired applications are delivered on demand from a web-based server with shared virtualized resources. With this format, cloud computing enables the ramping up or scaling down of computing resources as workload dictates. Importantly, with cloud computing, there is no need for local software installation by either the client or end-user. The only requirement is a device with a web browser and an Internet connection, meaning that the desired software can be used from virtually anywhere. This setup provides an important cost-saving advantage, because with technology changing at warp speed, users can immediately access the latest functionality without purchasing additional hardware or having to update older software applications. Neither is there a need for onsite training for users or support. Support is provided by the software provider, and user interfaces are intuitive. Technical support is provided by the software provider, but typically tips and tricks, wizards, and training videos are embedded within the software itself.
Source: Whatis.com

comparedtothenumberthesite forecasted Numberofsubjectscompleted Reasonsforsubjectswithdrawing fromthestudy Numberofprotocoldeviationsor violations Accuratedocumentturnaround times

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Timetocompletionofcasereport

forms(CRFs) Numberofdataqueries TheevaluationofsponsorandCRO performanceinstartupisasimportant as the evaluation of site metrics. For example,asiteisnotresponsiblefora delaycausedbytheturnaroundtimea sponsortakeswithdocumentssuchas contractsorbudgets.

widelybeingadoptedbysponsorsand CROsforotheraspectsofclinicaltrial managementdonotnecessarilyfocus on startup, either. A broad review of marketsolutionsisbeyondthescope ofthisarticle,butacloudcomputing platformisdiscussedasacompelling alternative.

on a permissioned basis, providing a visible measure of performance. Thisinformationenablestheteamto quicklyidentifysourcesofslowdowns orotherissuesneedingattention. The cloud-based startup functions include:
streamliningthestartupwork-

Applying the Cloud to Startup


Successful startup relies on highly organized project management processes and the ability to quickly exchange documents among stakeholders.Acloud-basedsystemenables fast and secure document exchange

flowtosavetimeandmoney;
collaboratingwithinternaland

Technology and Startup


Bringing new technology to startup can be an important complement to improvingthecurrentwaystartupis

The evaluation of sponsor and CRO performance in startup is as important as the evaluation of site metrics.
conducted. As electronic data capture(EDC)andclinicaltrialmanagementsystem(CTMS)products,which manage operational and administrativeclinicaltrialactivities,havebeen adopted, new technological options areneededtooptimizestartupoperations.Continuingtoclingtopaperor spreadsheets is not likely to achieve thekindsofimprovementsneededto conform to increasingly compressed timelinesorfacilitatetheexchangeof documents. TheLinkedInsurveyreferredtoearlier revealed that more than 53% of respondents were using Excel spreadsheets to track their startup progress, and6%wereusingpaper(seeFigure4).3 Spreadsheets may be standalone or part of a patchwork solution with a database, reporting software, and possibly a webportal platform. These homegrowneffortsoftenrequirealevelofinformationtechnologysupport that is beyond the capacity of many in-houseresources.Asaresult,companies may struggle to keep up with thelatestupdates,andmaybeunable toestablishandstaffaHelpDesk.Additionally,thesesystemsrarelyaddress the specific needs of startup. Similarly, off-the-shelf solutions that are andgeneratesanaudittrail.Thesystemcanbeconfiguredtogeneraterealtimereportsandstatusalertsandbring them to the attention of the correct teammembersregardingthenextstep intheprocess.Thereisalsoalevelof transparencyinthecloudthatcannot berealizedotherwise;thatis,throughoutthestartupprocess,allmembersof thestudyteamcantrackandevaluate processes and tasks instantaneously,

externalpartnersfromasingle dashboard; optimizingtheorganizationand exchangeofdocumentswith security; maintainingversioncontrolof documents; providingreal-timeandtransparentstartupstatustotheentire studyteam; beingauditready;and utilizingvaluablemetricsgatheredforpost-studyanalysisand futureplanning. Theimportanceofthistechnology extendsbeyonditsabilitytoimprove andaccelerateasingletrial.Investing inorganization andimprovedmethodology can have a positive impact on current as well as future trial operations, and this benefit can extend

Figure 4 Managing Startup Activities (n=205)


53.2%

15.6% 11.2%

13.6% 6.3%

Excel

Sharepoint

Internal homegrown software

Third-party solution

Paper-based

Source: LinkedIn Survey 2010

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acrossmultipleproductandtherapeuticlines. Ultimately, a well-designed cloudbased system will wield a so-called network effecta term borrowed from adoption of the telephone and, more recently, from social networking.Anetworkeffectreferstothefact thatatechnologicaltoolbecomesmore valuable as more people use it.10 For example,smartphonesareincreasingly valued as more people use them and rely on them for an ever-expanding rangeoffunctionality.Ifoneconsiders wherethecellphonewas20yearsago and where the smartphone is today, thetechnologyhasadvancedbeyond makingphonecalls.Varioususesare widespread,includingtexting,online banking, travel planning, shopping, e-mailing, and, in the near future, clinicaltrialmanagement.Thisrange of functionality establishes a virtual community. Applying this methodology to startup, as more stakeholders adopt cloud-based technology, will inch it toward becoming the norm, creatinganevenlargerbaseofusers astheyjointhebandwagon.

table 1 Sampling of Electronic Submissions FDA Electronic Common Technical Document (eCTD) PIM Labeling Standard 1/1/2008 all electronic submissions to Center for Drug Evaluation and Research (CDER) must use eCTD N/A EMA 1/1/2010 all electronic submissions must use eCTD for Centralized Procedure Timeline for going live for Centralized Procedure to be determined; PIM is in pilot mode N/A

Structured Product Labeling (SPL)


Source: FDA, EMA

10/31/2005 all labeling submission must be in SPL format

A cloud-based system enables fast and secure document exchange and generates an audit trail.
Drivers Toward the Cloud
Forstakeholdersstilluncertainabout takingthatfirststeptowardthecloud, there are several key drivers pushing themarketinthatdirection.First,regulatoryagencies,suchastheU.S.Food andDrugAdministration(FDA)andthe European Medicines Agency (EMA), havestartedrequiringelectronicsubmissionsusinghighlystructuredformats,sotheycanbetransmittedover the Internet and read electronically. Thegoaloftheseinitiativesistoreduce paper,improvedataquality,cutcosts, andspeedreviewofinformation.

As shown in Table 1, some of the submissionsleaningtowardorrequiring electronic formatting include the electronic common technical document,11,12theStructuredProductLabelingstandardintheU.S.,13andtheProduct Information Management (PIM) labeling standard in pilot-mode in Europe.14,15Also,in2006,FDAopened the Electronic Submissions Gateway (ESG),acentraltransmissionpointfor sending information electronically to itsfinaldestinationwithintheagency. Currently,ESGismigratingtoanew datacenter.16 Aseconddrivertowardthecloudis thefactthatsolutionscanbedesigned

tocomplywithFDA-based21Code of Federal Regulations(CFR)Part11,the Electronic Records; Electronic Signaturesrule.17Accordingtotherule, electronic records and electronic signaturescan,underspecifiedconditions, beacceptedastheirpaperequivalent. Electronicrecordscanbecreatedin closedoropensystems.Asdefined in the rule, a closed system refers to an environment in which systems access is controlled by persons who areresponsibleforthecontentofelectronicrecordsonthesystem.Anopen system refers to an environment in whichsystemaccessisnot controlled by persons who are responsible for

table 2 Challenges of Cloud Computing for Sites Challenge Provide reliable service Sites using cloud computing cannot afford to have interruptions in their serviceever Mitigation Strategy Design for reliability and build in backup Systems must either be up or covered by backup systems at all times (industry standard = 99.9% uptime) Ensure automatic nightly backups that are encrypted Redundant power systems for backup power supply Utilize equipment and systems designed for maximum security Secure data centers with 24-hour manned security, video surveillance, and buildings engineered for local seismic, storm, and flood risks Interoperability is possible through file format, data sharing, and data integration File format for study startup data should be formatted in XML, which can be generated from any number of source applications and received and processed by CTMS and EDC products

Security Sites have zero tolerance for unauthorized access of user data; data must be safe, backed up, and recoverable at all times Interoperability with other systems It is common for sites to have multiple systems to run an entire process; data must be able to be easily shared across multiple systems

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the content of electronic records on thesystem.Inthisinstance,document encryptionanduseofappropriatedigitalsignaturestandardsarerequiredto ensure record authenticity, integrity, andconfidentiality.Bothsystemsmust haveappropriatebackup,validationof systems to ensure accuracy and reliability,aswellasothercontrols.The ability to use electronic records and signaturesincompliancewith21CFR Part11isessentialtospuracceptance ofcloud-basedsystems. Sitesimplementingcloudcomputingwillfacechallengestypicalofany technologyadoption,suchasconnectivityissuesacrosstheglobe,firewalls, andtraining.Table2describessomeof the challenges unique to cloud computing,withspecialemphasisonsite concerns.

Acknowledgment
TheauthorswishtoacknowledgeAnn NeuerofMedicaldeScriptions,GenLi, PhD,MBA,andPeterDiBiaso,MHSA, forprovidingassistanceineditingthe manuscript, and Lata Gupta for contributingtotheresearch.

References
1.Panzitta D. 2010. Avoiding the five common mistakes at study startup. Applied Clinical Trials July 27; availableathttp:// appliedclinicaltrialsonline.findpharma.com /appliedclinicaltrials/Articles/Avoiding-the -5-Common-Mistakes-at-Study-Startup /ArticleStandard/Article/detail/680437?ref =25,accessedFebruary16,2011. 2.FarfelG,NeuerA.2009.FasterStudyStart-Up andReducedCoststhroughtheUseofClinicalDocumentExchangePortals.WhitePaper, available at www.pharmaceutical-business -review.com/content/files/whitepaper.ashx?id =2025&code=qosnVwdwCOn91B96tym3OA4 8Hps%253d,accessedFebruary16,2011. 3.LinkedInonlineresearchstudy.July10,2010. ContactDanManakatdmanak@gobalto.com formoreinformation. 4.CenterWatchSurveyofInvestigativeSitesin theU.S.,2009. 5.CuttingEdgeInformation.2004.Accelerating clinical trials: budgets, patient recruitment, andproductivity.Proprietaryreport,available at http://connect.cuttingedgeinfo.com/news /news_0337.htm,accessedMarch7,2011. 6.FeeR.2007.Thecostofclinicaltrials.Drug Discovery & DevelopmentMarch1(10):32. 7. SpilkerB,CramerJA.1992.Patient Recruitment in Clinical Trials.NewYork:RavenPress. 8. GidronM.2007.CultivatingclinicalinvestigatorsachallengeforPfizer.Clinical Trials Advisor 12: 3-4; available at www.fdanews.com /ext/files/CTA.pdf,accessedFebruary15,2011. 9.LiG.2008.Siteactivation:thekeytomore efficient clinical trials. PharmaExec.com, December12;availableathttp://pharmexec .findpharma.com/pharmexec/article/article Detail.jsp?id=571374&pageID=3, accessed January11,2011. 10. CoxR,LarsenPT.2010.Facebookspower,and itsweakness.The New York Times,May27; available at www.nytimes.com/2010/05/27 /business/27views.html,accessedFebruary15, 2011. 11. U.S. Food and Drug Administration. 2009. eCTDSubmissionWaivers,June18;available atwww.fda.gov/Drugs/DevelopmentApproval Process/FormsSubmissionRequirements/ ElectronicSubmissions/ucm163186.htm, accessedFebruary16,2011.

Get Ready for Startup 2.0


Sitemanagersandstudycoordinators are on the front lines in the ongoing struggle to develop important newtherapiesinthesafestandmost efficient manner possible. Traditional startup tools have proven to beinadequateinthisquestasstudiesincreaseinsize,complexity,and scale across the globe. What are needed are cutting-edge solutions thatwillenableend-userstoperform thearrayofstartuptasksquicklyand accurately. Withthehelpofprocesseslinkedto improvedsiteselection,theavailability of cloud-based technology, and theresultingnetworkeffect,thereis the potential to dramatically affect thecostandtimelinesforclinicaltrial conduct. As the next generation of tech-savvy workers enters the clinicaltrialsworkforce,theywillexpect automationoftasks,similartowhat hasbecomestandardpracticeinother industries. With the right tools, the clinicalresearchindustryispoisedto reapthesamebenefitsotherindustries have realized from optimizing their processes.

12. EuropeanMedicinesAgency.December2008. EMEAimplementationofelectronic-onlysubmissionsandmandatoryeCTDsubmissionsin theCentralisedProcedure:StatementofIntent. Availableatwww.emea.europa.eu/docs/en_GB /document_library/Regulatory_and_procedural _guideline/2009/10/WC500004098.pdf, accessedFebruary16,2011. 13. Draft Guidance for Industry and Reviewers onStructuredProductLabelingStandardfor ContentofLabelingTechnicalQuestionsand Answers,Revision;Availability.Federal Register,October28,2009.Availableatwww.federal register.gov/articles/2009/10/28/E9-25940 /draft-guidance-for-industry-and-reviewers -on-structured-product-labeling-standard -for-content-of,accessedFebruary16,2011. 14. European Medicines Agency. 2010. Update reportontheAgencysimplementationofEU Telematicsstrategy.ManagementBoardMeeting, 16 December 2010. Available at www .ema.europa.eu/docs/en_GB/document _library/Report/2010/12/WC500100176.pdf, accessedFebruary16,2011. 15. EUTelematics.PIM.GeneralFrequentlyAsked Questions.Availableathttp://pim.ema.europa .eu/faq.htm#faq9,accessedFebruary16,2011. 16.U.S.FoodandDrugAdministration.Electronic Submissions Gateway, February 2, 2011.Availableatwww.fda.gov/ForIndustry /ElectronicSubmissionsGateway/default.htm, accessedFebruary16,2011. 17.U.S.FoodandDrugAdministration.21Code of Federal Regulations Part11,availableat www.accessdata.fda.gov/scripts/cdrh/cfdocs /cfcfr/cfrsearch.cfm?cfrpart=11,accessedFebruary16,2011.

Daniel Manak is senior director of business development at goBalto. He has worked in pharmaceuticals, healthcare, and clinical research for more than 20 years. For this article, he provided oversight of collaborators, as well as substantial contributions to research, design, and drafting and revising text, and gave final approval of the version to be published. He can be reached at dmanak@gobalto.com. Jae Chung, MBA, CPA, is the founder and CeO of goBalto. Previously, he cofounded Celltrion, a leading biopharmaceutical supplier. For this article, he provided substantial contributions to concept development, contributed to the drafting and revision of the text, and gave final approval of the version to be published. He can be reached at jchung@gobalto.com. Sherry Reuter, BSN, MSHS, has more than 17 years of diverse experience in the clinical research industry, having held positions in pharmaceutical and biotechnology firms, CrOs, and academia. She now is president of Sherry reuter & Associates, LLC, a consulting company in the pharmaceutical arena. For this article, she provided substantial contributions to research, design, and drafting and revising the text, and gave final approval of the version to be published. She can be reached at sreuter@gwu.edu.

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