What’s New in E6 R3? The Take-Away

We hope you’ve enjoyed our series on what’s new in the new draft ICH Good Clinical Practice guideline E6, Revision 3. After 16 blog posts, what’s the take-away?

To sum it up, changes in R3 can be divided into two categories:

• Revisions to reflect changes that industry has already implemented
• New or new-ish requirements, most of which the EMA and MHRA have been promoting for years through their guidances and Q&A

If you’re a sponsor, below are some changes in Revision 3 that you’ve probably been doing for years:

• Implementing processes for investigators to review protocol deviations identified by the sponsor and take actions to prevent recurrence (2.5.2)
• Including the following in informed consents:
  • Summary of experimental aspects of the trial (2.8.11 (b))
  • Statement in the informed consent that the trial may be registered on a “publicly accessible and recognized databases”(2.8.11 (o))
• Providing investigators with tools for managing IMP accountability (2.10.1)
• Requiring investigators to use data capture systems per your instructions (2.12.4)
• Considering input from healthcare providers and patients in protocol design (3.1.3)
• Qualifying vendors (3.6.8)
• Performing effectiveness checks for CAPAs (3.12.2)
• Reporting SUSARs to investigators and IRBs/Ethics Committees in a timely way (3.13.2)
• Defining roles, permissions, and processes for making changes to data in data capture systems, including restrictions on the sponsor’s ability to change data (3.16.1 (h))
• Taking steps to protect confidentiality of participant data stored in data capture systems (4 (a))
• Documenting processes that support key decision-making, such as data finalization, unblinding, allocation to analysis datasets, changes in clinical trial design, and DMC processes (4 (d)), and then documenting activities as they occur per the processes (4.2.6)
• Putting processes in place to manage the study blind (4.1)
• Using validated systems, processes, or quality control checks to verify that data transferred between systems maintains integrity (4.2.5)
• Employing controls such as user authentication, firewalls, antivirus software, security patching, system monitoring, and penetration testing on computerized systems (4.4.2)
• Following a defined software development lifecycle to validate and maintain regulated systems (4.5)
• Retaining DMC documentation, trial-specific training records, sample management records, centralized monitoring reports, statistical outputs, trial-specific plans, and protocol deviations and CAPAs (documents that are not in the R2 essential documents list) (Appendix C)

And following are newly-added steps you may not currently be performing:

• Providing investigators with information on third parties that you hire to support them (3.6.6) and permitting investigators to have final approval over those parties (2.3.1).
• Training investigators to address concerns of participants who wish to withdraw from the trial while explaining the “value and importance” of continuing (2.9.2)
• Distributing clinical study results and treatment assignments to investigators post-unblinding (2.9.3)
• Encouraging investigators to inform participants of treatment assignments and results, if hey want to know (2.9.3)
• Avoiding “unnecessary volume and complexity” in the informed consent (2.8.1)
• Including the following information in the informed consent:
  • Statement regarding risks and inconveniences to the participant’s partner (2.8.11 (f))
  • Process by which the participant’s data will be handled, including in the event of withdrawal of participation (2.8.11 (m))
  • Statement that trial results and treatment assignment will be made available to participants (2.8.11 (u))
• Ensuring that the Principal Investigator and at least one backup investigator with authority to unblind treatment assignments for emergency purposes have active accounts in the IRT system or have access to the unblinding mechanism before the site is activated (2.11)
• Confirming arrangements for a “selective approach”  to safety reporting (as described in E19)  with regulatory authorities and IRBs/Ethics Committees (3.13.2 (f))
• Ensuring that the sponsor does not have “exclusive control over study data” by permitting sites to download final data directly from the clinical database, or arranging for a third party (not the CRO!) to download and distribute data which impacts how final representations of clinical data are distributed to investigators (3.16.1 (k))
• Ensuring that study participants can make corrections to responses on participant-reported outcome assessments (3.16.1 (h))
• Downloading user audit histories from data capture systems at the end of the study (3.16.1 (w))
• Ensuring that audit trails for all systems (not just EDC) are decipherable, reflect all data changes (including “back-end” changes), and capture date and time unambiguously (4.2.2)
• Implementing processes to review metadata and audit trails as part of quality control procedures (4.2.3)
• Involving patients and healthcare professionals in design of participant- and site-facing computerized systems (4.3)
• Reviewing help desk reports for data capture systems periodically to identify needs for corrective and preventive actions (4.7.1)

Although the guidance hasn’t been adopted yet, most sponsors will want to start reviewing SOPs, forms and templates, and study-specific plans (sponsor and vendor) to determine which revisions, if any, are necessary to ensure coverage. Many of these new requirements are too granular to be covered in high-level SOPs, so a gap analysis may need to be undertaken study by study.

The council’s intention with the revision was to focus more on principles and less on prescriptions.  We’re not sure that this new revision succeeds in achieving this goal, but we would encourage sponsors to be guided by this approach during implementation.  In other words, the point of a gap analysis isn’t to add words to SOPs to show that you’ve implementing R3, but to identify and address areas of risk.  R3 spotlights data integrity, an area that presents significant risk to clinical trials due to the proliferation of data capture and documentation systems and the risks inherent in transferring data and documents from one system to another.

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