Facilitating the FDA Bioresearch Monitoring Inspection for ...

1 A report by Promedica InternationalThe US Food and Drug Administration s (FDA) Bioresearch Monitoring (BIMO) programme is acomprehensive arrangement of on-site inspectionsand data audits designed to monitor all aspects of theconduct and reporting of FDA-regulated was established to assure the quality andintegrity of data submitted to the FDA in support ofnew product approvals and to provide for protectionof the rights and welfare of human subjectsparticipating in FDA regulated research. It hasbecome the cornerstone of the FDA s pre-approvalprocess for the introduction of new medical devicesinto the US research involves several entities the sponsor, study monitors, study investigator(s),study subjects and Institutional Review Boards(IRB). These entities must work together closely toaccomplish an appropriate scientific evaluation ofinvestigational devices for their targeted CFR Part definitions for eachentity, which are generalised as follows.

2 A sponsor is a person or an organisation thatinitiates, but does not actually conduct, the studyof an investigational device. A monitor is an individual designated by a sponsorto oversee the progress of an investigation. An investigator is an individual who actuallyconducts a clinical investigation. The investigatorprovides immediate direction with respect to testdevice administration or dispensation to studysubject(s). In the event an investigation isconducted by a team of individuals, theinvestigator is the responsible leader of that team. A subject is a human being who participates in aninvestigation. A subject may be healthy or mayhave a medical condition or disease. An IRB is any board, committee, or other groupformally designated to review biomedical researchinvolving subjects. The IRB must be established,operated and functioning in conformance with 21 CFR Part 56 (Institutional Review Boards).2 BIMO s programme is implemented in the US andinternationally via compliance programmes applyingto non-clinical testing labs (GLP), clinicalinvestigators, sponsor/monitors and article focuses exclusively on steps that can betaken to facilitate an efficient sponsor/monitorcompliance ObligationsThe FDA has defined the following specificobligations for clinical study sponsors:3 obtain FDA approval, where necessary, prior tostudy initiation; manufacture and label investigational productsappropriately; initiate, withhold or discontinue clinical trials as required; refrain from commercialisation of investigationalproducts; control the distribution and return ofinvestigational products; select qualified investigators to conduct studies; disseminate appropriate information to investigators; select qualified persons to monitor study conduct; monitor clinical investigations adequately.

3 Evaluate and report adverse experiences; Facilitating the FDA Bioresearch Monitoring Inspection forSponsor/monitorsBUSINESS BRIEFING: MEDICAL DEVICE MANUFACTURING & TECHNOLOGY 20051 Technology & Services1. 21 CFR Part 812: Investigational Device Exemptions2. 21 CFR Part 56: Institutional Review Boards3. FDA Compliance Program Guidance Manual: CP maintain adequate study records; and submit study progress reports and final the time of a BIMO Inspection , documentationon-hand should reflect the sponsor s conformancewith these obligations. In the sections that follow,suggestions are provided for the development andorganisation of documentation that will provideevidence regarding compliance with the FDA srequirements. Ideally, these steps should be taken before the study is initiated and internal auditsof the programme maintenance should be performed Organisation and Personnel AssessmentOne of the first priorities for BIMO inspectors is todetermine how the clinical programme is organisedand how responsibilities were assigned.

4 To facilitatean efficient assessment, it is recommended thatsponsors do the following. Establish and maintain a written summary of keystudy activities and associated responsibility should be assigned to thesponsor or other contract responsibilities are expected; however, thesummary should clearly indicate who isresponsible for approval of protocols, plans, etc. If a contract research organisation (CRO), centrallaboratory/reading centre, or other contractresources are used to support study-relatedactivities, document their study responsibilities viaa written agreement. Maintain copies of theseagreement(s) and any amendments that occurduring the project. Develop and maintain organisation chart(s) for theclinical research department, which includes theteam(s) for the project under Inspection . Theduration of many device trials can be lengthy andpersonnel changes within the team are minimise confusion regarding responsibilitiesthroughout the project, organisation charts shouldclearly reflect changes in team membership andthe dates on which changes were effective.

5 Theorganisation charts should be supported by easilyaccessible team member r sum s and summariesof relevant training. Again, due to the lengthyduration of many device trials, it is recommendedthat a programme be implemented to update teammember r sum s annually. Develop and maintain a list of all studyinvestigators with whom investigatoragreements were executed. To facilitate theefficient comparison of subject records, it ishelpful to supplement this list with studyenrollment numbers by investigator. The listshould reflect the date of exit/entry for all Investigator Selection and MonitoringThe inspector will be interested to reviewdocumentation regarding study investigators theirqualifications, investigator agreement, relevantinformation provided by the sponsor to support theirdecision to participate in the study, and compliancewith FDA review can be streamlined via the developmentand maintenance of an organised filing system foreach study investigator.

6 It is recommended that filesbe subdivided into logical subsections whereinformation such as the following could be filed. Protocol original protocol and amendments,along with the associated fully-executedsignature page(s). Report of prior investigations (if applicable) original report and updates, along with signaturepage(s) reflecting investigator receipt. IRB approvals IRB membership list(s) ormultiple assurance number and documentation ofapproval of investigator(s), protocol(s) andconsent document(s). If applicable, subjectrecruitment or information materials anddeclarations of translation may also be included. IRB correspondence periodic progress reportssubmitted, notification of adverse events (AE) andmiscellaneous correspondence. Investigator agreements - original fully-executednon-disclosure and investigator agreement(s),along with the investigator s financial disclosure,curriculum vitaeand medical license.

7 Anyamendments to the original agreements shouldalso be included. Monitoring documentation of each monitoringvisit using an easy to view log, and associated sitevisit reports. Product accountability documentationreflecting investigational product shipment,receipt, use or return. Study management logs signature authorisationlogs identify each study staff member and their responsibilities; screening/enrollment logs2 Technology & ServicesBUSINESS BRIEFING: MEDICAL DEVICE MANUFACTURING & TECHNOLOGY 2005 Facilitating the FDA Bioresearch Monitoring Inspection for Sponsor/monitorsidentify sequentially each person screened for thestudy, their enrollment status and reason(s) forexclusion, if applicable; calibration logs providedocumentation of calibration or service for key instruments/equipment used for study-related measurements. Memos to file. Sponsor-investigator correspondence between thesponsor or its representative and the investigator.

8 Adverse event correspondence. Internal correspondence among the sponsor orsponsor-representatives related to the , investigator agreements are executedwith investigators who are not formally activated forstudy participation. It is recommended that studyfiles be maintained for these investigators as Procedures andActivities AssessmentReview of study Monitoring procedures andactivities is likely to be one of the most time-consuming activities conducted by the inspector. Atthis stage of the Inspection , the sponsor should beprepared for a detailed review of inspector-designated Monitoring reports and subject records,as well as all unanticipated adverse device effects orserious adverse events. In preparation for thisreview, the following steps should be implemented. Prepare and maintain written study monitoringprocedures and plans. These documents shouldbe subject to change controls. The studymonitoring plan may include, at minimum,information regarding clinical monitor trainingand responsibilities, Monitoring procedures tobe used and checklists or logs to confirmprocedural compliance, study definitions, andguidelines for reporting protocol deviations andadverse events, etc.

9 Subject data line listings should be prepared toprovide efficient comparison with related casereport forms (CRF). A line listing physicallyresembling the CRF promotes uniformity in thereview process and, because not every subject sdata is likely to be reviewed, data line listingsshould be segregated by subject. Some amount of the subject data received onCRFs is subject to further clarification andpossible change after the data has been reviewedby the sponsor. These questions and theirresponses should be documented, chronologicallyordered and readily available with the CRFs tosupport differences between line listings and theassociated CRFs. It is also suggested that a log bedeveloped to track queries generated and theirresolution to confirm that all questions asked weresatisfactorily answered. Develop and maintain a log of unanticipatedadverse device effects and serious adverse eventsreported by study sites.

10 The log might also containthe following important milestones date eachevent was reported by the site, date of IRBnotification, date of FDA reporting, and date ofnotification of other investigators (if applicable). Develop and maintain a log of protocoldeviations. This enables a quick assessment ofprotocol non-compliance by Collection and Handling AssessmentThe BIMO inspector will need to substantiate theintegrity of the sponsor s data collection,management and analysis activities in support of thePMA submission. This process can be facilitated viathe following steps. Develop and maintain a list of all clinical studiesincluded in the PMA submitted. If there werestudies done with the device that were notreported in the PMA, be prepared to address theseand indicate the reason why. Prepare and maintain written plans describingdata management systems and procedures, aswell as for the statistical analysis.