Clinical trial monitoring

Clinical Trial Monitoring as per ICH-GCP E6 R2

1. MONITORING IN CLINICAL TRIALS Prepared By : Mukesh Kumar Saroj Edited By: Dr. Ashish Singh parihar

2. MONITORING 2 The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted , recorded and reported in accordance with the protocol , SOPs , GCP , and any regulatory requirements”. ICH GCP Section 5.18

3. Purpose of Monitoring 3 Protection of rights and wellbeing of human participants Ensure consent in place for record access. Trial data are accurate, complete and verifiable from source documents. Conduct of trial is in compliance with the currently approved protocol, GCP, and all applicable regulatory requirements. ICH GCP Section 5.18.1

4. Qualities of a goog Monitor 4 Appropriately trained. Adequate scientific and/or clinical knowledge. - Documented with training logs and CVs. Thoroughly familiar with: - IMP - Protocol - Consent form - Sponsor & trial SOPs - GCP Knowledge of local laws, regulations, customs & local language. ICH GCP Section 5.18.2

5. Extent & nature of Monitoring 5 Monitoring should be proportionate to: - Objective - Purpose - Design - Blinding - Size and complexity - Outcome measures - Risks ICH GCP Section 5.18.3

6. Types of Monitoring 6 1) Central monitoring. - Determination of key eligibility criteria through collection of: - Consent forms - Scans - Pathology reports - Statistics - Unusual patterns of data. ICH GCP 5.18.3

7. Types of Monitoring 7 2) Risk Based monitoring . ICH GCP 5.18.3 Limited resources should be used to where it is really necessary. High risk part . - For subject protection - For reliability of trial results - For protection of future patients Risk-based approach ! (6 Rs ) 1- Risk Identification 2- Risk Evaluation 3- Risk Control 4- Risk Communication 5- Risk Review 6- Risk Reporting ICH GCP Sections 2.13, 5.0 (, 5.20.1)

8. Types of Monitoring Cont.. 8 3) On site Monitoring. - Staff training - Access to necessary documents - Confirm pharmacy and lab resources in place * Count study drugs - Adherence to protocol and GCP - Check medical records * Consent forms * Eligibility * AEs - Source Data Verification ( SDV)

9. Monitoring Process Continued.. 9 Before Monitoring Visit : - Review the status of data entry - Review action item from last visit - Review regulatory binder - Check PI & site staff availability - Get the internal team approval - Send confirmation/agenda of monitoring visit

10. Monitoring Process Continued.. 10 2) During Monitoring Visit. - The monitor will assess or discuss : Site, staffing, research labs or other facilities Regulatory file and study records Clinical procedures if possible or appropriate Any problems and issues identified Debrief at end of visit

11. Monitoring Process Continued.. 11 3 ) After Monitoring Visit. The monitor will……… Complete site visit report Submit the report to the sponsor

12. 4 Types Monitoring Visits 12 1) Site assessment(pre trial ) Visit Site initiation Visit Routine(interim ) visit Close Out Visit

13. 4 Types Monitoring Visits 13 1) Site assessment(pre trial ) Visit Purpose : It’s a face to face meeting with the investigator to explore the overall feasibility of the site and the investigator to participate into the study.

14. 4 Types Monitoring Visits Cont.. 14 Site assessment(pre trial ) Visit

15. 4 Types Monitoring Visits Cont.. 15 2 ) Site Initiation Visit Purpose : to uniformly provide study specific information to investigator(s) and study staff prior to study start up . reassess resources and capability to conduct a research study .

16. 4 Types Monitoring Visits Cont.. 16 2 ) Site Initiation Visit Cont.. The monitor will meet with the study staff to discuss research obligations under GCP: Investigator administrative responsibilities IRB approvals and communications Regulatory file requirements(ICH GCP E6 8.2) Informed consent forms and process Protocol and protocol amendments Source documentation Study product handling and accountability Safety reporting Protocol specific training Archiving of study documents

17. 4 Types Monitoring Visits Cont.. 17 Site Initiation Visit Cont.. The monitor will Review sponsor policies , standards and procedures for the conduct of clinical trials . Reassess the site facilities Provide additional guidance to the site as determined by his/her findings.

18. 4 Types Monitoring Visits Cont.. 18 Site Initiation Visit Cont.. The monitor will Review sponsor policies , standards and procedures for the conduct of clinical trials . Reassess the site facilities Provide additional guidance to the site as determined by his/her findings.

19. 4 Types Monitoring Visits Cont.. 19 3) Routine(interim) visit Purpose : Protection of human subjects rights and wellbeing. Accuracy, completeness and verification of reported trial data. Trial conduct in compliance with protocol/amendments, GCP and regulatory requirements.

20. 4 Types Monitoring Visits Cont.. 20 3) Routine(interim) visit Cont.. Review /assess the following: A) Enrollment status, rate and any drop outs of study subjects B) Resources C) Laboratory D) Study supplies E) Investigational Product F) Compliance & Progress G) CRF (Case Report Form) H) SDV (Source Data Verification) I) Informed Consent Form J) Reporting K) Regulatory files L) AEs/SAEs Follow up on previously identified issues.

21. 4 Types Monitoring Visits Cont.. 21 3) Routine(interim) visit Cont.. B) Resources: Verifying 1 that the investigator has adequate qualifications and resources and remain adequate throughout the trial period, 2 that facilities, including laboratories , equipment, and staff , are adequate to safely and properly conduct the trial and remain adequate throughout the trial period.

22. 4 Types Monitoring Visits Cont.. 22 3) Routine(interim) visit Cont.. C ) Laboratory: Verifying Relevant SOP QC/QA process-Facility , reagents, equipment, results etc. Appropriate specimen storage Functionality of equipment Tracking subject-specimen-result-CRF

23. 4 Types Monitoring Visits Cont.. 23 3) Routine(interim) visit Cont.. D) Study Supplies: Ensuring that the investigator receives the current Investigator's Brochure, all documents , and all trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement's. - Shipment process, temperature maintenance, storage of product/reagents, disposal mechanism etc.

24. 4 Types Monitoring Visits Cont.. 24 3) Routine(interim) visit Cont.. E ) Investigational Product : That storage times and conditions are acceptable , and that supplies are sufficient throughout the trial . (ii) That the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s ). (iii) That subjects are provided with necessary instruction on properly using, handling , storing, and returning the investigational product(s ). ( iv) That the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately. (v) That the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor.

25. 4 Types Monitoring Visits Cont.. 25 3) Routine(interim) visit Cont.. F) Compliance & Progress : Verifying that the investigator and the investigator's trial staff are performing the specified trial functions, in written accordance with the protocol and any other agreement between the sponsor and the investigator / institution, and have not delegated these functions to unauthorized individuals. - that the investigator is enrolling only eligible subjects. that written informed consent was obtained before each subject's participation in the trial that source documents and other trial records are accurate, complete , kept up-to-date and maintained.

26. 4 Types Monitoring Visits Cont.. 26 3) Routine(interim) visit Cont.. G ) CRF : Verify that CRF’s are : Correct and accurately completed Consistent with corresponding SD where Separate Only authorized persons complete Corrections made are signed, dated & backed by accurate SD Data related queries accurately documented Storage and/or shipment is secured

27. 4 Types Monitoring Visits Cont.. 27 3) Routine(interim) visit Cont.. H) Source Data Verification (SDV): Source data: all information in original records and certified copies of original records of clinical findings, observations or other activities in a clinical trial necessary for the reconstruction an evaluation of the trial. (ICH GCP 1.51 ) Source documents: original documents, data and records(e.g. hospital records, lab notes, clinical charts, subjects diaries, pharmacy dispensing records, x-rays, subject files etc.) (ICH GCP 1.52)

28. 4 Types Monitoring Visits Cont.. 28 3) Routine(interim) visit Cont .. H) Source Data Verification (SDV) Cont..: SDV: evaluation of the conformity of the data presented in CRFs with source data. Main aim: confirm that the data collected is complete, accurate, reliable and verifiable so as to give confidence to sponsor and regulatory authorities in the data being used to support a marketing application. Without SDV , no scientist can have confidence in data presented and conclusions derived .

29. 4 Types Monitoring Visits Cont.. 29 3) Routine(interim) visit Cont.. H ) Source Data Verification (SDV) Cont..: Key data : 1 efficacy data Inclusion/exclusion criteria Medical/medication history Physical exam/vital signs visit dates Adverse events Concomitant medication Record that patient entered clinical study and date of consent Any gross errors in these might be detrimental to the scientific and ethical quality of the clinical trial .

30. 4 Types Monitoring Visits Cont.. 30 3) Routine(interim) visit Cont.. H ) Source Data Verification (SDV) Cont..: Methods of SDV: Back to back Direct method- monitor has direct access to source data (ICH GCP E6 1.21,5.15) Extent of SDV ??? Depends on: clinical trial phase, quantity of data, time availability , man power availability, investigator research experience , company policy.

31. 4 Types Monitoring Visits Cont.. 31 3) Routine(interim) visit Cont.. H ) Source Data Verification (SDV) Cont..: Methods of SDV: Back to back Direct method- monitor has direct access to source data (ICH GCP E6 1.21,5.15) Extent of SDV ??? Depends on: clinical trial phase, quantity of data, time availability , man power availability, investigator research experience , company policy.

32. 4 Types Monitoring Visits Cont.. 32 3) Routine(interim) visit Cont.. H) Source Data Verification (SDV) Cont..: Common approach: Critical data: focal to aims and objectives of study and must be correct . Informed consent to participate Clinical notes Conformance to inclusion/exclusion criteria Primary efficacy endpoints Secondary efficacy endpoints Recording and reporting of SAEs Documentation that that study drug was prescribed and at the specified dosage. Visit dates as per protocol Non-critical data e.g. very neat, high numbers of overwriting, rapid recruitment, lack of SAEs when they would be expected etc.

33. 4 Types Monitoring Visits Cont.. 33 3) Routine(interim) visit Cont.. H) Source Data Verification (SDV) Cont..: Common problems Data entered directly to CRF Brief medical history/ scanty clinical notes Several volumes of SD SD/CRF mismatch Illegible handwriting Maximum acceptable error rate Document the SDV process SD examined CRFs checked and why they were selected Critical and non-critical data items checked Nature and frequency of errors Any corrective actions undertaken

34. 4 Types Monitoring Visits Cont.. 34 3) Routine(interim) visit Cont.. I) Informed Consent Document. What to check : Each participant has personally signed and dated ICD prior to study procedures . Appropriate use of independent witness Correct version being used Names of subjects/person giving consent, date and time Investigator appropriately signed ICD and dated. All pages of ICD present

35. 4 Types Monitoring Visits Cont.. 35 3) Routine(interim) visit Cont.. J ) Reporting Reporting - Reporting the subject recruitment rate - Trial progress - Problems at site - Needs at site - Solicit solutions

36. 4 Types Monitoring Visits Cont.. 36 3) Routine(interim) visit Cont.. J ) Regulatory files Review all relevant section of files Ensure it is up to date Ensure documents are placed in relevant section

37. 4 Types Monitoring Visits Cont.. 37 3) Routine(interim) visit Cont.. J ) AEs/SAEs Ensure AEs are captured in CRF Ensure no AEs are unreported Ensure proper reporting and documents are placed in case of SAE

38. 38 MONITORING & AUDITS

39. 39 References: E6R2, ICH GCP, Indian GCP, CT Rules 20119

40. Q ? 40

41. 41 Thank you