P. Michael Dubinsky - The Fundamentals of Clinical Research

Permits monitoring and auditing by the sponsor (ICH E6(R2) 4.1 Investigator’s Qualifications and Agreements; Chapter 22Monitoring Overview).

Communicates the study status and information per the IRB/IEC requirements and sponsor and regulatory requirements (ICH E6(R2) 4.10 Progress Reports; Chapter 29Essential Documents; Chapter 25Investigator/Institution Interim Monitoring; Chapter 8IRB/IEC Roles and Responsibilities).

Oversees and reviews the progress of the investigation to ensure protection of subject rights and safety, data integrity, and compliance with the protocol, SOPs, GCP, and regulatory requirements.

Selects qualified monitors and implements procedures for on‐ and off‐site and centralized monitoring of the progress of the investigation using a risk‐based approach and methods as outlined in a Monitoring Plan for the trial (ICH E6(R2) 5.18 Monitoring; Chapter 22Monitoring Overview)

Collects, reviews, and assesses adverse events for ongoing risk‐benefit evaluation of the investigational product and to notify all concerned investigator(s) and the regulatory authority(ies) of findings that could adversely affect the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC's approval/favorable opinion to continue the trial (ICH E6(R2) 5.16 Safety Information). These notifications may be as single reports, protocol amendments, and/or updates to the investigator's brochure ( Chapter 21Safety Monitoring and Reporting; Chapter 25Investigator/Institution Interim Monitoring; Chapter 16The Investigator's Brochure; Chapter 18The Clinical Trial Protocol and Amendments)

Reports adverse drug reactions that are both serious and unexpected as per ICH E2A Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting and applicable regulatory requirements [2] (ICH E6(R2) 5.17 Adverse Drug Reaction Reporting; Chapter 21Safety Monitoring and Reporting)

Assesses and manages risk for quality management (ICH E6(R2) 5.0; Chapter 13Risk Assessment and Quality Management).

Selects qualified independent auditors to conduct audits per the Audit Plan and/or for an unplanned cause (ICH E6(R2) 5.19 Audit, Chapter 33Quality Assurance Components; Chapter 34Regulatory Authority Inspections) and promptly secures compliance and implements corrective and preventive actions for deviations from the protocol, SOPs, GCP, and regulatory requirements that significantly impact or have the potential to significantly impact subject safety and data integrity. If monitoring or audit observations reflect serious or persistent noncompliance on the part of an investigator/institution then the sponsor should terminate the investigator's/institution's participation in the investigation and promptly notify the regulatory authority(ies). (ICH E6(R2) 5.20 Noncompliance, Chapter 25Investigator/Institution Interim Monitoring, Chapter 33Quality Assurance Components, Chapter 34Regulatory Authority Inspections, Chapter 31Quality Responsibilities).

Submits reports of final trial status and outcome to IRB/IEC and regulatory authority(ies) as required (ICH E6(R2) 4.13 Final Report(s) by Investigator; Chapter 29Essential Documents; Chapter 26Investigator/Institution Close‐out; Chapter 8IRB/IEC Roles and Responsibilities).

In the event of premature termination or suspension of a trial, promptly informs the trial subject, arranges for appropriate medical care follow‐up for the subject, and informs the sponsor, IRB/IEC, and/or regulatory authority(ies) as applicable, (ICH E6(R2) 4.12 Premature Termination or Suspension of a Trial; Chapter 29Essential Documents; Chapter 26Investigator/Institution Close‐out; Chapter 8IRB/IEC Roles and Responsibilities).

Permits audits/inspections by Sponsor, IRB, and Regulatory Authority(ies) at ANY time! (ICH E6(R2) 4.1 Investigator's Qualifications and Agreements; Chapter 24Investigator/Institution Initiation)

In the event of premature termination or suspension of a trial, promptly informs the investigator(s), the regulatory authority(ies), and IRB/IEC as applicable, of the termination or suspension and the reason(s) for termination or suspension (ICH E6(R2) 5.21 Premature Termination or Suspension of a Trial; Chapter 18Clinical Trial Protocol and Amendments; Chapter 26Investigator/Institution Close‐out; Chapter 8IRB/IEC Roles and Responsibilities).

Closes trial sites upon study completion ( Chapter 26Investigator/Institution Close‐out).

Prepares and submits clinical trial/study reports of trial results to the regulatory authority(ies) whether the trial is completed or prematurely terminated as required by the regulatory requirements. The clinical trial reports in marketing applications will meet the standards of the ICH E3 Guideline for Structure and Content of Clinical Study Reports [3,4]. (ICH E6(R2) 5.22 Clinical Trial/Study Reports; Chapter 28).

Permits audits/inspections by Regulatory Authority(ies) at ANY time! (ICH E6(R2) 5.1 Quality Assurance and Quality Control; Chapter 31Quality Responsibilities).

Maintain and archive records (evidence of trial conduct). Maintain records that demonstrate the conduct of the trial. Archive records so that they are retrievable and for the duration required by applicable regulations. The investigator will have access to trial data at all times. (ICH E6(R2) 4.9 Records and Reports, 5.5 Trial Management, Data Handling, and Record Keeping, Chapter 29Essential Documents).

The sponsor and investigator are two key players in the clinical trial process. The sponsor is “an individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial” (ICH E6(R2) 1.53). The investigator is “a person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator” (ICH E6(R2) 1.34). The sponsor and investigator must comply with the GCP guidelines and regulatory requirements that clearly describe their respective trial‐related duties and responsibilities. The sponsor may transfer any or all of their study‐related duties to a CRO and the regulatory obligations that are associated with the transferred task; however, the sponsor retains regulatory responsibility for the oversight of the CRO and the overall safety of trial subjects and integrity of the trial data. The investigator may also delegate trial‐related duties to staff or subcontractors; however, the investigator retains all regulatory obligations associated with delegated or subcontracted tasks.

1 What is the role of the sponsor?

2 What other individuals or parties may assist the sponsor with trial‐related duties, and under what conditions?

3 What is the role of the investigator?

4 What other individuals or parties may assist the investigator with trial‐related duties, and under what conditions?

5 What are the sponsor's responsibilities before the trial commences, during the conduct of the trial, and after completion or termination of a trial?

6 What are the investigator's responsibilities before the trial commences, during the conduct of the trial, and after completion or termination of a trial?

7 Overheard:“We should have ethics committee approval of the protocol tomorrow so we will enroll the patient the following day. We can then submit to the study to the regulatory authority.”Physician at a clinic who received donated study drug from a manufacturer to conduct their own clinical trial. This physician will otherwise wholly finance and resource the study.Comment and discuss:What are the GCP and regulatory responsibilities of this “investigator”?Is the investigator violating any GCP requirement? If yes, which?