What’s New in E6 R3? Principles

It finally dropped – ICH’s Good Clinical Practice guideline E6, Revision 3 is here and available for public comment.  What’s new?  Let’s start with the GCP Principles.

Historically, GCP’s thirteen principles have been nearly unchanged since 1996, having been revised only slightly in Revision 2 to incorporate references to data integrity.  R3 rewrites the principles into eleven points with sub-points. The thirteen principles that formerly occupied just over a page are now more than four pages long.

In the first half of this section, a fair amount of verbiage is added to the principles without substantially changing them, with a few exceptions bolded below.

Former principles 1, 2, 3, 7, and 11 have been combined into principle 1 and its sub-principles, and the following information has been added:

• Concerning subject safety, “The safety of the participants should be reviewed periodically as new safety information becomes available, which could have an impact on the participant or the conduct of the trial.”
• The principle regarding design of clinical trials has been expanded to include considerations about subject population:  “When designing a clinical trial, the scientific goal and purpose should be carefully considered so as not to unnecessarily exclude particular participant populations. The participant selection process should be representative of the anticipated population who is likely to use the medicinal product in future clinical practice to allow for generalising the results across the broader population. Certain trials (e.g., early phase, proof of concept trials, bioequivalence studies) may not require a heterogeneous population.”
• The principle regarding medical decisions for clinical trial subjects now includes this statement:  “…however, the practical interactions and the delivery of medical care and decisions can be carried out by appropriately qualified healthcare professionals in accordance with applicable regulatory requirements,” seemingly a nod to the challenges of delegating clinical trial responsibilities in a hospital setting.

The principle regarding informed consent has been greatly expanded to include details about the consent process, the level of information provided to participants, and the overall goal of “enabling potential trial participants to evaluate the benefits and risks of participating in the trial and to make an informed decision on whether or not to participate in the trial.”

The principle regarding Institutional Review Board/Ethics Committee approval or favorable opinion of protocols has been expanded to specify the board’s continuing review conducted per “regulatory requirements.”

Former principles 4 and 5 (clinical trials should be scientifically sound and described in a clear and detailed protocol that takes into account available clinical and non-clinical information) have been combined into Principle 4, with the addition that protocols should “reflect the state of knowledge and experience with the investigational product(s), including, if applicable, the condition to be treated, diagnosed or prevented; the current understanding of the underlying biological mechanism (of both the condition and the treatment); and the population for which the investigational product is intended.”

Former principle 8 regarding education, training, and experience, has been expanded to list the types of people who might work on the study team (“Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). Clinical trials should be designed and conducted by qualified individuals. Individuals with different expertise and training may be needed across all phases of a clinical trial, such as physicians, scientists, ethicists, technology 158 experts, trial coordinators, monitors, auditors and statisticians. Individuals involved in a trial should be qualified by education, training and experience to perform their respective task(s).

We finally arrive at the first substantive change.  Former principle 13, “Systems with procedures that assure the quality of every aspect of the trial should be implemented,” has been replaced by specific requirements for “quality by design” and risk management.  Risk management was a significant addition to E6 R2, but quality by design is a new principle for this guideline.  This principle states,

Quality should be built into the scientific and operational design and conduct of clinical trials. Quality of a clinical trial is considered in this guideline as fit for purpose. The quality and amount of the information generated during a clinical trial should support good decision making. Factors critical to the quality of the trial should be identified. These factors are attributes of a trial that are fundamental to the protection of participants, the reliability and interpretability of the trial results and the decisions made based on those trial results. Quality by design involves focusing on the design of all components of the trial in order to maximise the likelihood of trial success (i.e., that the trial will answer the research question).Strategies should be implemented to avoid, detect and address serious non175 compliance with GCP, the trial protocol and applicable regulatory requirements to prevent recurrence.

Principles 7 states that “Clinical trial processes, measures and approaches should be implemented in a way that is proportionate to the risks to participants and to the importance of the data collected,” thus bringing the quality and risk management section newly added to R2 into the principles section. This principle emphasizes that the “focus should be on the risks to participants beyond those associated with standard medical care.”  It also notes that risks to data integrity should be consider along with risks to participants.

Principle 8 reiterates the requirement from previous principle 5 for a “clear, detailed protocol,” adding that “The clinical trial protocol as well as the plans or documents for the protocol
execution (e.g., statistical analysis plan, data management plan, monitoring plan) should be clear, concise and operationally feasible.”

Former principle 10 (All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification) has been both simplified (“Clinical trials should generate reliable results”) and expanded with sub-principles, which address the need for data to support decision-making; validation of data capture systems; the need for processes that “avoid unnecessary complexity”; data integrity; and record retention.

Principle 10 states that clinical trial roles and responsibilities should be clear and appropriately documented, which was formerly described as a sponsor responsibility. Sub-principles address other sponsor and investigator responsibilities, including transfer of regulatory obligations and delegation of responsibilities; financial agreements; and supervision of delegees.

Former principle 12, regarding the manufacture and use of investigational products, has also been expanded to include specific GMP requirements, including labeling and control during shipping.