Selecting Sites And Investigators
Selecting Sites and InvestigatorsAn Approach for Central and Eastern EuropeARTVILLE IMAGES, PHOTO COLLAGE KRIS TENCEJanos DemeterPoor selections can transform the life of a CRA into anightmare.When problems become serious, everybody involvedusually tries to find out who is responsible for the unsatisfactory conduct of the study. Then they have to takecorrective action, such as influence the investigator,recruit additional sites, close the problematic sites,and/or change the clinical research associate (CRA).Correcting errors once a study is running, however, canbe far more difficult and expensive than preventing problems by rethinking the selection procedure, or evenrebuilding it from scratch (see Rebuilding box). Involving local CROs or someone else with considerable localknowledge should be regarded as a necessary—if notalways sufficient—step toward optimizing the selectionprocedure.Our experience in managing clinical studies in Hungary and in the neighboring Central and Eastern European (CEE) countries has taught us the importance ofcapitalizing on “local knowledge.” Wehave evaluated more than a thousandIn many CEE nations,sites and conducted studies at several hundred. We believe that thesponsors mustqualitative and quantitative data wecontract withcollected enables us to draw somegeneral conclusions. Our perspectiveelecting investigators and sites isinstitutions ratheron the selection process is limited,an impor tant par t of a clinicalthan investigators,however, to that of a CRO operatingstudy. Both the quality of thein the eastern part of Europe. Hence,medical data to be collected andwhich makes thewe report here on problems withthe speed of its collection dependsystem an importantsites and investigators we find to beprimarily on who collects it and themost frequent and typical in Hungaryway they do it. Because sites andpart of the selectionand some other CEE countries.investigators are selected so early inequation.Our method is to first identify thethe clinical development process,dimensions that characterize theeven the smallest mistakes can evenselection process, then to analyze our findings, andtually become more important. Despite the importancefinally to seek the best practices to improve that process.of the selection process, many mistakes have beenThe large variety of data we have collected aimed to evallinked to it—mistakes that lead to a poor recruitmentuate site investigators, not to determine their relevancerate, lower quality data, and large numbers of queries.S56APPLIED CLINICAL TRIALSMarch 2002
to the selection process itself. One could argue, however, thatthe closer the rate of enrollment is to the predicted one, the better the investigator site. But I am cautious about drawing quantitative conclusions because of the complexity of factors thatinfluence the rate of enrollment. To find a quantitative relationship between the rating of the center based on the selection process and predictability of enrollment, then we have to take intoconsideration the ceteris paribus clause. That is, all other factorsbeing equal, what is the influence of site selection on subjectenrollment?One trivial example is an influenza study for which the precondition for starting the trial was the existence of a flu epidemic. But no such epidemic occurred in our countr y thatyear. Even if it had, the number of patients would had beendetermined primarily by the seriousness of the epidemic—which would have masked the predictive power of the selectionprocess.In other cases, studies were already running in a number ofcountries but the sponsors were dissatisfied with the speed ofenrollment. In those cases, the goal was to enroll as many subjects as possible before the end of the enrollment period—regardless of how many centers had to be opened and the costeffectiveness of that approach. In still other cases, a prolongedenrollment period made it difficult to define the denominator ofRebuilding ChecklistWith an understanding of the background presented in thearticle, you will be ready to rethink your selection procedure and, if necessary, rebuild it from scratch using thisstep-by-step checklist. Ask yourself about your long-term goals with the investigator site, and analyze whether your procedures fit thedeclared purposes. Avoid generic evaluation, becausewhat is valid for one study and one situation might notfit another one. Identify as early as possible the person(s) who will takethe final decision on the selection and discuss with thetargets with that person. Add value to the feasibility phase or preselection process. Sponsors should pay for this and CROs shouldtake it as seriously as the final site selection job. Atleast some of the potential sites should be visited andthe potential investigators should be motivated tospend time and maximum attention on the study evenat this stage. Using basic information about the study, design a studyspecific questionnaire, weight and score the answers. Evaluate the investigator, evaluate the staff, evaluatethe site, and evaluate the system as a whole. Design the right incentive system from the very beginning. Go even at the feasibility stage with estimatedinvestigator fee data and try to figure out how this sumwill be split between the institution, the investigator,and others. Reserve bonuses for high-speed, high-quality enrollment. At the end of the selection visits, don’t be shy aboutsuggesting sites different from those you suggestedafter a feasibility study or preselection activities.58the enrollment rate (number of patients included over a certaintime period). These examples prevent drawing quantitative conclusions based on the retrospective data.Nevertheless, it is possible to draw qualitative conclusionsbased upon the key factors that link the selection process to theperformance of the centers. We plan to design a questionnairedesigned to reveal the way information collected during theselection process is correlated with the performance of thesites.Problem areasThe problem areas that we found to influence the performanceof sites investigators are goal setting, partner identification, anddecision-making. All the pitfalls we encounter appear to be theconsequence of errors in one of those areas.Goal-setting. Goal setting involves the whole set of problemsassociated with one deceptively simple question: What does agood center or investigator look like? First, it is necessary todefine good. We may all agree that a selection is successful if thesite and the investigator selected do good work. There are, however, no good or bad sites per se. They can be assessed onlytogether with the project’s targets. So it is first necessary todetermine what are—and what should be—the goals. Otherquestions one has to think about before beginning the selectionprocess are: Who sets the goals? What are acceptable compromises? Surprisingly, one soon discovers that the answers are notat all obvious.Partner identification. A clinical trial involves many stakeholders, including a sponsor, an investigator, often a CRO. Althoughthe sponsor is a single legal entity, real-life sponsors are madeup of different departments and individuals, including externalspecialists, safety committees, scientific boards, and other service providers. CROs act on behalf of sponsors, and ofteninclude departments similar to those of sponsor companies.Finally, equally important contributors to the big picture includethe investigator and site staff, the hospital as a legal entity, thelaboratory. During the selection process a CRA represents thesponsor (perhaps through a CRO) and interacts with an investigator. One might ask whether the CRA and investigator can represent the interests of all the stakeholders in a nondistorted way.Decision making. Given the stakes for all involved, it seemsobvious that it is important who is involved in the investigatorsite selection process and who takes the final decisions. Mostproblems arise from the fact that the “goal-setters,” the “executors,” and the “decision-makers” rarely try to reach consensus.Many times, the CRO doing a feasibility study doesn’t knowwho the sponsor is. It is only when a selection is made that ithas an opportunity to consult with the sponsor’s representative.That is too late, and below I demonstrate what leads me to thatconclusion.Selection processGoal-setting. As in the case of other basic notions in a clinicalstudy, the fundamentals of the investigator site selection shouldbe derived from the “constitution of clinical studies,” that is, theInternational Conference on Harmonisation Guideline for GoodClinical Practice.1 The GCP guideline is very general on investigator selection: “The sponsor is responsible for selecting theAPPLIED CLINICAL TRIALSMarch 2002
TABLE 1 Analysis of Six Selection SOPsCounterpartIdentificationDecision maker(based on)Initial interest, patient population, competingstudies, staff, technical equipment, securityand storage, working space for monitorInvestigatorProject Leader(personal visit)Qualifications, patient population, time,facilities, staff, interestInvestigatorStudy project manager(PM) or experiencedmonitor. If no previousexperience with theinvestigator, PM decides(by phone if previousexperience within 12months)Interest and abilities, experience, previousinspections, budget, anticipated workload,and conflicting studiesInvestigatorPM or designee(not mentioned)4 Selecting a center and sponsorQualifications and previous experience,population of potential subjects, time availablefor the study, well-qualified staff, interest,understands the importance of timelines;facilities and equipment, storage and security,working space for monitorInvestigatorTrial SiteMonitor reports to PM,sponsor takes finaldecision(not mentioned)5 Define the procedure for site visitsAdequacyPatient populationStorage/preparation facilitiesEC/IRBNoneEmployee or designeeDescribes the (Not mentioned)administrationprocedureof the visit(selection,monitoring, andclose-out alltogether) itself.Qualified by training and experiencePotential to recruitHas timeNo potential conflict from other studiesFacilitiesTrial SiteInvestigatorsPurpose1 Identifying potential InvestigatorsDetermining their suitability to conductstudies according to the ICH guideline2 Identifying potential investigatorsAscertaining whether the investigator andcenter are suitable for the purpose ofconducting the clinical trial3 Identifying physicians who are interestedin conducting clinical trialsTo evaluate a site6 Selection of new investigatorsEstablishing suitability of investigatorand of site to conduct a clinical trialSelection Criteriainvestigator(s)/institution(s). Each investigator should be qualified by training and experience and should have adequateresources (see 4.1, 4.2) to properly conduct the trial for whichthe investigator is selected” (5.6.1).Section 4 of the guideline, under Investigator’s Qualificationsand Agreements and Adequate Resources, we find somewhatmore detailed descriptions:The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial, shouldmeet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence of such qualifications through upto-date curriculum vitae and/or other relevant documentation requestedby the sponsor, the IRB/IEC, and/or the regulatory authority(ies). (4.1.1)The guideline describes adequate resources in the same section: “The Investigator should be able to demonstrate (e.g.,based on retrospective data) a potential for recruiting therequired number of suitable subjects within the agreed recruitment period” (4.2.1). “The investigator should have sufficienttime to properly conduct and complete the trial within theagreed trial period” (4.2.2). “The investigator should have available an adequate number of qualified staff and adequate facili60Monitor(No visit if previousexperience within thepast 6 monthsNew investigator: initialphone, then prestudyvisit)ties for the foreseen duration of the trial to conduct the trialproperly and safely” (4.2.3).The ICH definitions give sponsors and CROs sufficient roomto apply their subsets of criteria in the selection process. Theircriteria are more or less projected in the standard operating procedures (SOPs) of the company that performs the investigatorsite selection. Table 1 presents examples of selection guidelinesfrom six different SOP systems—each from a different manufacturer or CRO (including ours). It is intended to illustrate thedimensions of the selection process: The overall focus of the SOP and its declared purpose The selection criteria that the author of the SOP considereddecisive for selecting a site or an investigator The basis for the selections of the decision makers.A new approachCareful reading of the goals reveals that most of the companies consider the selection process as being unidirectional(we select them). Contrar y to this view, nowadays theburning question is “Who selects whom?” We read about2 andobser ve more and more cases in which the investigatorAPPLIED CLINICAL TRIALSMarch 2002
Figure 1. Events in a typical selection process.reports having other proposals for competing studies and needing some time to decide which sponsor to select! Only the firstand third SOPs appear to grasp that very important aspect, thecommitment of the investigator. We should ask ourselveswhether an otherwise perfect investigator really wants to workwith us on a specific study. The time available for the study—pointed out as a selection criterion by almost everyone—is secondary to the commitment. If the investigator shows initial interest or if we can design an incentive that triggers interest, then aninvestigator will find time for the study, even at the expense ofgiving up something else (leisure, time with family, otherresearch). We have time for what we want to have!Looking at the goals also reveals that, although all of theSOPs describe basic “inclusion criteria” for investigators, noneof them contain “exclusion criteria”—that is, factors that are thebasis for deciding not to select a site. We suggest lookingbeyond the descriptions in the GCP guideline and the SOP forsite selection. Instead, seek a real partnership with the investigator and the study team.Inclusion/exclusion criteria. First, set clear inclusion/exclusioncriteria describing what the ideal investigator should look likeand the trade-offs you could live with. At the same time, be prepared to sell yourselves, to sell the sponsor, and to sell the study.Find out what expectations the investigator has, and decidewhether it is possible to meet them.Questionnaire. Next, design a questionnaire, fine-tune it on thebasis of the discussion with the decision-maker of the sponsor62company, and, finally, assign possible scores and weights to thequestions. Working space for the monitor may be important forexample, but it is far less important than the experience of theinvestigator! A carefully worked-out scoring system permits youto deliver a final score for each site based on weighted scores forthe individual criteria. Comprehensive questionnaires arewidely used,3 yet few of them deliver a final quantitative measureof the suitability of the site. Questionnaires should be study-specific, otherwise it is not possible to evaluate what is perhaps themost important element—the initial interest of the investigator.Partner identification. Table 1 shows that most companies—perhaps driven by what is described in the ICH guideline for GCP—focus on investigator selection. Few companies see selection assimply an administrative process. While the GCP guidelinedoes, indeed, consider the selection process primarily an investigator selection process, it describes the suitability of a trial siteonly from the point of view of facilities, equipment, storage conditions, laboratory facilities, and the monitor’s workspace. Theinvestigator’s knowledge and expertise is the factor of primaryimportance, followed closely by the quality of the site staff andits infrastructure. This concept comes from Western Europeancountries, primarily from companies based in the United States.The contracts those companies propose are contracts betweenthe sponsor company and an individual investigator. But suchcontracts don’t work in many CEE countries.In many CEE countries, the institution or hospital is the legalentity with the exclusive right to sign contracts with sponsors.Investigators are simply employees of the institution. The institution assigns investigators to research activities in addition totheir regular jobs and will award them some extra money for theextra work. Theoretically, the institution has the right to appointthe investigator, to withdraw that appointment, to appoint thestudy staff, and to decide on the way the investigator fee is split.This status quo was inherited from the former social systemof our countries, where the whole health care system—hospitals, outpatient facilities, and GP practices—was state-owned.Even today, when privatization in these countries is almost complete, most of the health care system remains state-owned. In arecent study, for example, less than 10% of the sites (cardiologyoutpatient facilities) were privately owned by the investigator.CEE site selectionBecause of the health care system, in CEE countries we selecttrial sites rather than investigators. Obviously, we select thosethat employ the investigators with whom we would like to work.While admitting that the key player in a study is the investigator—because the investigator’s knowledge and experience areof paramount importance in the treatment of the subjects—aprocess that considers only investigator selection is too individualistic an approach. This is true regardless of the ownership ofthe facilities.The hospitals are not simply backgrounds—at least, theyshould not be—they represent a whole system. The quality ofthe pharmacy, the laboratory, the radiology department, and theICU is important. Just as important, however, is the way they arefunctioning as a whole. Administrative, hierarchical, and personal relations among the functional units are very important.For example, we once lost a center where the investigator, theAPPLIED CLINICAL TRIALSMarch 2002
TABLE 2 Short-term and long-term interests of parties involved in the selection processShort-term interestsSponsorTo have the clinical trials performed asMarketing quickly as possible (time to market!). TheDepartment medication will be introduced /prescribedvia the opinion leaders, so they should beinvolved in the study.SponsorTo set a budget that would be approvedClinicaland to remain within it. At this stage theyDepartment would not like to spend money on aCRO’s fight for the project.They wouldrather let the CROs compete for theproject.CROCROs wish to use the least possible timeand effort for the feasibility study, whichtypically is unpaid. They avoid travel andpersonal visits, and generally prefer simplephone/fax interviews. The more optimisticthe feasibility report they deliver, the morelikely that they will get the job.Investigators During the feasibility phase they have noreason to refuse a study (unless it isprofessionally or ethically unacceptable).They don’t want to spend (at no cost) toomuch time on the decision. Their beststrategy is to appear enthusiastic and togive answers like "yes I can, yes I want to,yes, it’s possible.”Long-term interestsCommentsTo have a high-quality product on themarket with unique features that allowsthe sponsor to correctly position it vs.the competitors.At the end of the day, they want tohave turnover when the trial and thedrug registration process is over. Theyare not interested in evaluating theforeseeable performance of the site/investigator in the study.To have high-quality centers with highquality personnel who deliver high-qualitydata. They would like to remain withinthe inclus
site selection. Table 1 presents examples of selection guidelines from six different SOP systems—each from a different manu-facturer or CRO (including ours). It is intended to illustrate the dimensions of the selection process: The overall focus of the SOP and its declared purpose The s
retention—more than 50% investigators never conduct 2 nd trial High quality investigators in developing markets Facts CTMS Implication Identify valuable investigators and keep them by: Know your investigators Focus on high-value investigators - Leverage analytics tools - Grease the "squeaky wheels" only when necessary
1. Cover Sheet – form 3514 2. Name and Address of the Sponsor 3. Report of Prior Investigations 4. Investigational Plan 5. Manufacturing Information 6. Investigators Agreement 7. Investigators Certification 8. IRB Information 9. Name and Address of Investigators Institution 10. Financia
racial/ethnic minority investigators and research participants. The presence of more minority group investigators would encourage more racial/ethnic minority individuals to participate in research. Moreover, both empirical and anecdotal evidence reveals that racial/ethnic minority investigators often have a particular commitment to research
Statement by Individual Leaders and Investigators Involved in . records, insurance claims, financial records, location records, or genomic data. Prior to sharing research data, investigators may need to remove or alter data elements that . for analysis as lon
Internal Investigators . PDF file, and have the new Supervising PI sign it, and then uploaded here. Once you have executed instructions in slides 12-16, return to this slide. Adding New Internal Investigators . To add more staff, repeat the instructions in
Investigators represent the names responsible for leadership and infrastructure. Site Investigators represent the names of individuals at each recruiting site. All papers, including methodological papers, should have an acknowledgement list that consists of Infrastructure Investigators plus the FULL list. I. ADNI I, GO, II and III
What Investigators Need to Know About the Use of Animals Susan Brust Silk, Lori L. Hampton, and Patricia A. Brown Abstract. Investigators conducting research with animal subjects have an ethical and legal responsibility to ensure they are treated . There are three types of Assurances: domestic, interinstitu .
Report of the Investigators of Surgical and Pathology Issues at Three Essex County Hospitals, July 2010 The Investigators established a Pathology Review Team led by Dr. John Srigley and made up of 14 pathologists working in five large community hospitals in Ontario.
