Audits in Clinical Trial
This content discusses the importance of audits in clinical trials, focusing on the Integrated Addendum to ICH E6(R1) guideline for Good Clinical Practice. It covers the purpose of audits, selection and qualification of auditors, auditing procedures, and key definitions related to audits in clinical research.
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Audits in Clinical Trial By Dnyaneshwar Wadhe, M. Pharm (Pharmacology) Email: dnyaneshwar.wadhe@gmail.com Email: dnyaneshwar.w@navitaslifesciences.com Mob: +91 9028120077 LinkedIn: https://www.linkedin.com/in/dnyanis7world Privileged \ Personal
What Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice says about Audit? Audit and CAPA case study Bioresearch monitoring no of 483 issued Investigation and CAPA course freely available for learning purpose from USFDA What's in it for you and take away 2 Privileged \ Personal
5.19 Audit If or when sponsors perform audits, as part of implementing quality assurance, they should consider: What Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice says about Audit? 5.19.1 Purpose The purpose of a sponsor's audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements. 5.19.2 Selection and Qualification of Auditors (a) The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits. (b) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor s qualifications should be documented. 3 Privileged \ Personal
5.19.3 Auditing Procedures (a) The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports. (b) The sponsor's audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s). (c) The observations and findings of the auditor(s) should be documented. (d) To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings. (e) When required by applicable law or regulation, the sponsor should provide an audit certificate. 4 Privileged \ Personal
1. Glossary 1.6 Audit A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s). 1.7 Audit Certificate: A declaration of confirmation by the auditor that an audit has taken place. 1.8 Audit Report: A written evaluation by the sponsor's auditor of the results of the audit. 1.9 Audit Trail: Documentation that allows reconstruction of the course of events. 1.21 Direct Access Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects' identities and sponsor s proprietary information. 5 Privileged \ Personal
1.24 Good Clinical Practice (GCP) A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. 4. INVESTIGATOR 4.1 Investigator's Qualifications and Agreements 4.1.4 The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies). 5.1 Quality Assurance and Quality Control 5.1.2 The sponsor is responsible for securing agreement from all involved parties to ensure direct access (see 1.21) to all trial related sites, source data/documents , and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities. 6 Privileged \ Personal
5.20.2 If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator's/institution s participation in the trial. When an investigator's/institution s participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authority(ies). 6.10 Direct Access to Source Data/Documents The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents. 7 Privileged \ Personal
8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL 8.1 Introduction Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor and monitor. These documents are also the ones which are usually audited by the sponsor's independent audit function and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected. Any or all of the documents addressed in this guideline may be subject to, and should be available for, audit by the sponsor s auditor and inspection by the regulatory authority(ies). 8.4.4 AUDIT CERTIFICATE (if available) To document that audit was performed : to filed in sponsor file TMF 8 Privileged \ Personal
During investigator site audit at site# 005, you observed that 06 out of 10 subject s patient diaries were not completed. You observed that data is available in the CRFs for the respective subjects. The subjects with incomplete diaries are Subject 01, 03, 05, subjects 06, 08 and 09. The Study Coordinator at site explained during interview that data were collected by the coordinator himself for these subjects when subject visits the hospital and entered into a piece of paper which was later destroyed after entering the data to respective CRF. The monitor didn t raise the problem during the site monitoring visit. Audit and CAPA - Case study The study coordinator suggested the below CAPA actions: Corrective Action: SC enters the data into patient diary for all the impacted subjects based on the CRF data. Preventative Action: Not Applicable 9 Privileged \ Personal
Evaluate the above scenario and write Short Description of Finding Brief Description of finding How do you grade the Severity of finding? Do you find the above CAPA actions appropriate and adequate? What actions would you recommend from the site level and project Level? 10 Privileged \ Personal
Case study and Bioresearch monitoring no of 483 issued Inspection observations https://www.fda.gov/inspections-compliance-enforcement-and- criminal-investigations/inspection-references/inspection-observations 11 Privileged \ Personal
CASE 1 During investigator site audit at site# 005, you observed that 06 out of 10 subject s patient diaries were not completed. You observed that data is available in the CRFs for the respective subjects. The subjects with incomplete diaries are Subject 01, 03, 05, subjects 06, 08 and 09. The Study Coordinator at site explained during interview that data were collected by the coordinator himself for these subjects when subject visits the hospital and entered into a piece of paper which was later destroyed after entering the data to respective CRF. The monitor didn t raise the problem during the site monitoring visit. The study coordinator suggested the below CAPA actions: Corrective Action: SC enters the data into patient diary for all the impacted subjects based on the CRF data. Preventative Action: Not Applicable Evaluate the above scenario and write: Short Description of Finding : Original source data/ documents and/or certified copies of it not maintained before its destruction. Data reported in the CRF is not verifiable from source data/ documents. Inadequate monitoring and oversight by investigator/ institution, ethics committee and sponsor/ CRO. No proper monitoring at this site. Brief Description of finding : Site # 005, Subject # 01, 03, 05, 06, 08 and 09: Following observations noted: 1. Data in patient diary was not reported in contemporaneous manner by subject, as a) It was evident from the incomplete information in the patient diary that subject didn t fill the diary as and when required as per the instruction provided. Same was noticed by study coordinator (SC). Also, b) Subject could have completed the missing information in diary on current date but same was not done. 1. On the day of subject s visit at site, SC recorded incomplete/missing subjects diary data/information on a piece of paper after discussion with subject. SC transcribed information/ data recorded on paper to CRF and destroyed it. Furthermore, a) SC didn t bring it to the notice of PI. b) Original source data/ documents (paper notes) were not reviewed and approved by PI. c) Certified copies of original source data/ documents not made before its destructions. 12 d) Original source data/ documents were not available for CRF entries verification by monitor, PI, auditor, EC and inspector etc. Privileged \ Personal e) No proper training to SC on protocol, SOP and ICH GCP E6 R2 and other applicable guidelines.
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Investigation and CAPA course freely available for learning purpose from USFDA Step 1 Go to FDA website https://www.fda.gov/ Step 2 Select Menu option and click on Training on Continuing Education https://www.fda.gov/training-and-continuing-education Step 3 Select FDA Continuing Education Programs https://www.fda.gov/training-and-continuing-education/fda-continuing-education- programs Step 4 Select Continuing Education Portal https://ceportal.fda.gov/ Step 5 It will take you to ceportal https://ceportal.fda.gov/ Step 6 Create account on ceportal https://ceportal.fda.gov/index.cfm?do=att.newProfile Step 7 Go to online learning https://ceportal.fda.gov/index.cfm?do=cnt.page&pg=2003 Investigations and Corrective and Preventative Actions (CAPA) Step 8 You will find the course title Investigation and CAPA under enduring material or online learning tab Step 9 Once you enrol for the course, it will direct you to external site train.org where you can complete the course https://www.train.org/main/welcome Step Instruction will provided by train.org and FDA on how to complete the course get credits and certificate https://www.train.org/main/welcome 17 Privileged \ Personal
Question and answers 18 Privileged \ Personal
Thank You! 19 Privileged \ Personal
