What’s New in E6 R3? Structure

Yesterday we compared the GCP principles in the new ICH Good Clinical Practice E6 R3 guideline with R2 and noted some key additions.  Next in our series, we consider the structure of the revised guideline for clues as to the major changes.

R2 had a relatively simply structure:

• Introduction, which was not a numbered section
• 1. Glossary
• 2. Principles
• Then, three sections on the responsibilities of key roles in clinical research:
  • 3. Institutional Review Board/Independent Ethics Committee
  • 4. Investigator
  • 5. Sponsor
• Two sections on the contents of key documents:
  • 6. Protocol and amendment
  • 7. Investigator’s Brochure
• 8.Essential Documents

R3 makes the introduction the first numbered section (I) and references the new structure, which we will discuss below.

Section II covers the Principles, which we discussed yesterday.

Section III is now Annex 1, which is not titled, but which (the introduction tells us) is intended to provide information on “how principles can be appropriately applied to clinical trials.”  There is no Annex 2; the intro tells us that additional annexes may be developed to address emerging conditions in clinical trials.  From the run-up, we know that such annexes might eventually address decentralized trials and other innovations.

Within Annex 1, we have the three responsibilities sections:

• 1. Institutional Review Board/Independent Ethics Committee, which is structured similarly to Section 3 in R2.  This section is structured similarly to R2, with the addition of a new subjection titled Submission and Communication.
• 2. Investigator.  This section has been rearranged.  A new section on Responsibilities covers delegation.  The section on Premature Termination or Suspension of a Trial has been moved up; Medical Care has been moved down and combined with Safety Reporting; Progress Reports has been folded into the Communication with IRB section. Note that people who sign informed consents in clinical trials are now referred to as “participants” rather than “patients” or “subjects,” emphasizing their active role.
• 3. Sponsors.  The 23 topics covered in separate subsections in R2 have been re-organized into 17 sections, headed by the section on Trial Design.
  • Previously, the Trial Design section noted only that trials should utilize qualified individuals, but now it requires sufficient safety and efficacy data, quality-by-design, input of stakeholders, and operational feasibility.
  • Short new sections on Resources and Allocation of Activities require sponsors to have adequate staff for the trial and to define roles and responsibilities.  The Contract Research Organization sub-section has been eliminated; all vendors are now called Service Providers, and requirements for transfer of obligations are now covered in the Principles.
  • A new section on Qualifications and Training includes the training and qualification requirements formerly in the Trial Design section and combines it with the content from R2’s Medical Expertise section.
  • Monitoring is now included in Quality Assurance and Quality Control
  • The former Trial Management, Data Handling, and Record Keeping section is now called Data and Records and has been greatly expanded, including a section on Statistical Programming and Data Analysis
  • Information on Insurance and Indemnification has been added to the section on Compensation to Participants and Investigators.
• 4.  Data Governance – Investigator and Sponsor.  This new section addresses blinding, the life cycle of data, computerized systems, and user management

An unnumbered Glossary has been moved from the beginning to the near-end of the guideline.

The contents of the Investigator’s Brochure and Clinical Trial Protocol/Amendments are now in two Appendices, with the order switched from R2.

Next, we’ll dive into the substantive changes within the structure.