clinical research _monitoring

Monitoring guidelines : 

Monitoring guidelines Dr.Sarah

Organizing presentations : 

Organizing presentations Monitoring- a promising CR profesion Types of Monitoring visits Site pre-initiation visit Site initiation visit Site monitoring and SD verification Site close out visit

Statistics : 

Statistics 90% of CRO are building up only Monitoring capabilities 80% of clinical trial projects in India are for monitoring 70% of the Manpower in CR industry are monitors 60% of revenues come from monitoring

What to Monitor : 

What to Monitor Adherence to Protocol, GCP, SOP, regulatory Data cleanliness To ensure consistency To prevent fraud To troubleshoot To educate study staff on drug handling, protocol procedures and GCPs and safety reporting and ethical issues Maintain temporal sequence of event

MONITOR ALLOCATION : 

MONITOR ALLOCATION No. of Investigators/ sites in the study No. of locations/ sites where the sites of a study(including facilities) are present. Geographic distances and approachability to and from the sites. Type of product involved in a study (rug for human use, medicinal device)

MONITOR ALLOCATION : 

MONITOR ALLOCATION Complexity of the study No. of subjects planned Pace of recruitment at sites

Monitoring Guidelines : 

Monitoring Guidelines Indian GCPICMR Guidelines ICH-GCP Guidelines FDA Guidelines EU directives

MONITOR RESPONSIBLITIES : 

MONITOR RESPONSIBLITIES Messenger Overseer Negotiator Inspection Trouble shooter/ trainer Observer Trainer

MONITOR: Cognitive Skills : 

MONITOR: Cognitive Skills Demonstrated Knowledge and understanding of Study conduct Critical parameters of protocol -Enrollment and drop out rates -adverse events and reporting rates

MONITOR: Communication skills : 

MONITOR: Communication skills Good interpersonal skills with site team Assertive , diplomatic, professional Demonstrated ability to Clearly identify problems Communication with staff by asking relevant questions

MONITOR: Communication skills : 

MONITOR: Communication skills Demonstrated ability to Present information in pleasant, organized manner Participate in problem solving in a non-alarming manner with site staff Participate in team meetings-as a team player

SITE PRE-INITIATION VISIT : 

SITE PRE-INITIATION VISIT MEET PI/ Team :qualification Identify crc Assess site facility- project room Infrastructure (cupboard,refrigerators), communication facilities-telephone, fax, email. Investigators/ CRC willingness

SITE PRE-INITIATION VISIT : 

SITE PRE-INITIATION VISIT EC- function and procedures Local lab- capability/ suitability Investigational product storage Discuss the budget, reimbursement procedure. Verify a sample of source document.

SITE INITIATION VISIT : 

SITE INITIATION VISIT Confidentiality agreement Investigator’s agreement Regulatory approval: DCGI Signed EC approval Signed contract letter of agreement Current lab certification and noraml value/ reference ranges

SITE INITIATION VISIT : 

SITE INITIATION VISIT Current, signed, dated C.V. of site Current, signed, dated C.V. of lab staff Investigational product available at the site.

Initiation meeting activities : 

Initiation meeting activities Detailed discussion of the protocol, including -inclusion exclusion criteria -Study procedures -Adverse event and medical history reporting Randomization procedure(if applicable) Drug accountability (storage and dispensing record keeping procedures)

Initiation meeting activities : 

Initiation meeting activities Serious adverse event reporting( procedure, timelines) Case report form(dummy CRF filling how to avoid errors) Monitoring visits- how often, what should be covered, what will be ready Regulatory requirements

Initiation meeting activities : 

Initiation meeting activities GCP requirements EC reporting and interaction procedures. TMF maintenance and update Possible QA audits and Inspections Periodic reports of enrollment Reimbursement procedures Documentation of visit

SITE MONITORING VISIT : 

SITE MONITORING VISIT

SAMPLE CONDUCT OF MONITORING VISIT : 

SAMPLE CONDUCT OF MONITORING VISIT 1 day review of site specific in house file and data Monitoring plan, request made, dates finalized. Scope: What documents to review What % documents to review Which logs and forms to review

2 days at site : 

2 days at site Meet investigator Review TMF Visit Pharmacy/ laboratory Review completed CRF Review events (SAE reported) Review reimbursement Document visit

MONITORING PERSPECTIVE : 

MONITORING PERSPECTIVE Process Dates Logic Consistency Documentation Close communication loops/ trails

MONITORING TIPS : 

MONITORING TIPS Plan from beginning- have documented SDV Ensure consistency(between sites, files, subjects) Don’t expect perfection-proactively identify and document deviations and follow up with the site for not repeating the same.

MONITORING TIPS : 

MONITORING TIPS Get it right the first time Keep the investigator informed Know protocol/ guidelines (GCP)

MONITORING PROCESS : 

MONITORING PROCESS PM SOP Protocol Agreement TOM Develop Monitoring plans training Site allocation Site initiation Identify monitor PI CONTACT Plan site visit Checklist SOP Site info recruitment Enrollment status CRF collected Deviation Deaths/withdrawn sae SDV CRF review TMF review Lab visit Safety monitoring Ctm monitoring Reg. Doc. review ICF review Status reporting

Monitoring process : 

Monitoring process Noncompliance findings Crf retrival Query resolutions Reconcile, Compensation, finance Non-critical critical Data clarification forms Report Status to manager Monitoring Visit report Inform PI Document with reason Waiver from sponsor Common tools used Crf retrieval log Crf correction log Data clarification form SAE tracking log Patient tracking log IP tracking log SDV checklist Protocol deviation log File notes Monitoring report Crf data managment

Slide 28: 

Subject tracking log Protocol no. center no. Protocol title PI

CRF CORRECTION NOTE FORM : 

CRF CORRECTION NOTE FORM

Slide 30: 

CRF TRANSMISSION LOG PRTOCOL NO PI SUB.ID CENTER NO DATE

: 

DATA CLARIFICATION FORM Protocol no center no Sub ID/ Initials PI Pi sign ________ date________________ Cra sign _______________ date_______________

Source data clarification list : 

Source data clarification list Patient no Initials Date of visit Phy.Exam ICF Date Randomization date Sub Characteristics

Source data clarification list : 

Source data clarification list Inclusion criteria Exclusion criteria Medical History Study treatment and dosing Conmed AE IP accoutablity review IP storage Hematology/ Lab test.

Slide 34: 

SAE LOG

Source data Verification : 

Source data Verification Dr. Sarah

What is Source data Verification : 

What is Source data Verification GCP definition: …..the data and reported results are credible And accurate and the rights, integrity and confidentiality of the trial subjects are protected.

Source data Verification : 

Source data Verification SDV is a process to evaluate the conformity of the data presented in CRF with the Source data and is conducted to ensure that the data collected are reliable and allow reconstruction and evaluation of the study

Frame work of SDV : 

Frame work of SDV SDV SDV PROTOCOL GCP SOP CONTRACT AGREEMENT SPONSOR -CRO -SMO ICH GCP CLINICL TRIALS SPONSOR/ CRO

Why Source data Verification : 

Why Source data Verification Evaluation- study and quality of data Demonstrate compliance Possibility of reconstruct

What is Source data : 

What is Source data Information Finding Observation Other activities in a Clinical trial

SOURCE DOCUMENTS : 

SOURCE DOCUMENTS Hospital and GP notes Recordings from automated instruments Lab reports and records Scan and Xrays films, reports Nurse records/ charts IP dispensing record Photographs/ Negatives Microfiches Pharmacy records

Who does Source data Verification : 

Who does Source data Verification Monitor Auditor Sponsor’s representative Regulatory auditors, inspectors Issues Involved:- Confidentiality Access to data

What are Verified : 

What are Verified CRF entry= Source data Accuracy Completeness Validity and Reliability Issues involved Confidentiality 100% SDV

CMAERecord of entry of subject in study. : 

CMAERecord of entry of subject in study. Record of subject entry in study Consent date and process Primary Efficacy criteria Entry Criteria MED. HISTORY AE CM KEY VERIFICATION POINTS Patient exists, entry documented ICF-sign, dates, process Primary & Secondary endpoints Inclusion & exclusion Disease profile & treatment AE, reporting procedures, timelines Concomitant medication/ procedures

Extent of SDV : 

Extent of SDV Experienced Investigator No of PATIENTS Recruitment SOP Protocol Phase of trial Data quantity

SDV METHODS : 

SDV METHODS Total SDV: 100 % verification Q- SDV : x % verification

Type of SDV errors : 

Type of SDV errors Simple errors-repetitive in nature Unintentional one- one time error Intentional errors- if critical, suspect fraud Deliberate violations- suspect fraud

Common SDV findings : 

Common SDV findings Corrections made- not signed and dated CRF not completely filled in Insignificant lab test missed Data directly entered onto CRF Virtual data source Dose calculations error Brief medical history Source document-CRF-entries do not match Inadequate source data.

Common SDV findings : 

Common SDV findings Ineligible handwriting Several copies of source documents Missing reports Communication not filed properly Expectation from monitors Poor IP accountability Less time and involvement of PI

Common SDV findings : 

Common SDV findings AE not entered SAE reporting timelines not maintained Forms and logs not maintained

Why errors : 

Why errors Lack of source data Conflicting information Less time devoted Incorrect methodology Lack of training Carelessness Poor design(crf, protocol)

Acceptable standard for data accuracy : 

Acceptable standard for data accuracy Zero errors:- critical data (safety , ethics) < 0.5%: non critical data

Monitors Objective during SDV are : 

Monitors Objective during SDV are Records provided are accurate and complete. Subject existence and eligibility for participation. Availability of safety and efficacy information. Accuracy of transcription into CRF. Validity of procedures. Validity of signatures. Protocol compliance. No additional data have been excluded. No contradiction between data in source and in crf Without initialed corrections and explanations.

Some Handling tips : 

Some Handling tips Be honest, frank, assertive Always discuss SDV plan with PI at first meet Conduct SDV at early stages of the trial T-SDV (100%) should be done at first few subjects Source data can be original certified copies Trust PI but use your own judgment

Some Handling tips : 

Some Handling tips Do not panic behave professionally even if you find gross errors/ deviations the site, report politely, to the PI and if no corrective actions taken, report to Project Manager with facts and documents

Some Handling tips : 

Some Handling tips Be honest in SDV, cutting corners does not help Identify a place for SDV Do not miss out what will affect the outcome of the study Be friendly without compromising work SDV is monotonous, innovate methods to Enjoy it Get it right the first time Make a template/ plan

For SDV the Monitors Objectives are : 

For SDV the Monitors Objectives are Subject existence and eligibility for participation. Availability of safety/ efficacy information. Accuracy of transcription. Validity of procedures. Validity of signatures. Protocol compliance. No additional data has been excluded. There is no contradiction between SD and CRF.

Corrective Measures : 

Corrective Measures Document errors, don’t hide Ensure corrective measures, don’t repeat mistakes Inform sponsor, seek waiver Conduct additional SDV, QA/ Third party audts Inform Regulatory authorities if safety and ethics violated( DCGI, EC)

Monitoring during the Trial : 

Monitoring during the Trial Check protocol compliance(scheduling of subjects) Drug accountability, storage, access Safety and efficacy data. Maintenance of TMF CRF filling/ SDV Are all IB, SUSAR, Protocol amendments, etc submitted to EC

SITE CLOSE-OUT VISIT. : 

SITE CLOSE-OUT VISIT. Plan the visit. Ascertain the DCF’s are resolved Review TMF for completeness SAE report resolved Ensure return of unused drugs CRF completion, duly signed. Transfer of biological samples.

SITE CLOSE-OUT VISIT. : 

SITE CLOSE-OUT VISIT. Transfer of biological samples if applicable. Remind Investigator of retention policy. Remind Investigator of SAE follow-up procedures. Final reporting to EC and DCGI Complete close out report and follow up letter .

Planning a Monitoring Visit : 

Planning a Monitoring Visit Telephonic Confirmation for availability of PI/ staff/ Availability of access to records Inform PM Send Official letter before each visit stating date, time of visit, records you would need access to, no. of days visit is planned. Document to be filed in communication

During the Visit : 

During the Visit Ensure discipline. Work systematically Close out visit with PI to inform of findings and shortcomings, any corrective actions needed.Sign necessary documents and try to resolve as many shortcomings as possible during the visit. Send a monitoring report accurately documenting the results.

Monitoring reports, follow up letter : 

Monitoring reports, follow up letter Following issues are covered- Recruitment status. ICF document. SDV SAE reporting Subject compliance Missing or nonexisting source documents. Retrieval of CRFs

Monitoring reports, follow up letter : 

Monitoring reports, follow up letter IP accountability and storage Regulatory documentation status Staff and facility changes Administrative issues/ Logistics Request corrections and follow up actions.

Frequency of monitoring visit : 

Frequency of monitoring visit After first subject enrolled. After that depending on enrollment, SOP of sponsor, data collected, PI experience.