by Elizabeth Peterson

These Are the Droids We Were Looking For: FDA Adopts the E6(R2) Good Clinical Practice: Integrated Addendum to E6(R1)

On March 1, 2018, the FDA announced that there is a New Hope for the continued efforts to create mutual acceptance of clinical trials data in galaxies near and far, far away. The FDA adopted its version of the addendum to the International Council for Harmonisation’s (ICH) Good Clinical Practice (GCP) guideline, known as the E6(R2) Good Clinical Practice: Integrated Addendum to E6(R1), which “encourage[s] implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting, and also updates standards regarding electronic records and essential documents.”1 The FDA’s version avoids any significant substantive changes to the E6(R2), opting instead to incorporate the E6(R2) principles into its guidance library. Although this guidance is not legally binding, it is impactful. Guidance of this nature sheds light on the FDA’s position regarding these issues, which is helpful in anticipating the FDA’s future decisions.

The E6(R2)’s goal is to adapt ICH GCP to reflect current methods of clinical trial design and conduct while providing an alliance of good clinical practices globally (specifically in the European Union, Australia, the United States, Canada, Japan, the Nordic countries, and the World Health Organization). This is the first update to the ICH GCP E6 since 1996.

There are five parts of the E6(R2) that deserve special attention:

I. The Glossary

Although glossaries aren’t generally the most exciting parts of guidance, the updates brought by E6(R2) are worth noting. New definitions of “certified copy,” “monitoring plan,” and “validation of computerized systems” are added to the canon. These updates reflect research’s ascent into the digital age. For example, the definition of “certified copy” incorporates copies of records in any media type.  Similarly, the inclusion of “validation of computerized systems” shows that maintaining consistently functional computerized systems is important for the proper execution of a study. The addition of “monitoring plan” speaks to the emphasis of E6(R2)  on reliable trial results — ensuring that these results are acceptable beyond their local context.

II. Updates to the Principles of the ICH GCP

The changes to this section of the E6(R2) are both impactful and short. First, it expands the meaning of “all clinical trial information” in section 2.10 to include all records referenced in the guidance regardless of the type of media used. As a result, all clinical trial information, regardless of media type, should be recorded, handled, and stored in a way that allows for accurate reporting, interpretation, and validation. Second, the E6(R2) specifies that quality assurance systems for trials should be focused on human subject protection and the reliability of trial results. Both of these changes emphasize the addendum’s focus on data reliability and inclusion of not just paper, but digital media in clinical research.

III. Investigator Responsibilities

The E6(R2) clarifies that an investigator holds the ultimate responsibility for trial-related duties and functions.  As such, E6(R2) stipulates that investigators should ensure that their team is up to the challenge, qualified and ready. To do this, investigators should institute procedures to ensure data integrity and proper trial functions.

In the same vein, E6(R2) implements the ALCOA framework, a standard for evidence that the FDA has embraced for years.  ALCOA stands for attributable, legible, contemporaneous, original, and accurate. However, E6(R2) adds one element to this list- complete. Using this ALCOA-C framework, E6(R2) reinforces the goal of data reliability, stating that the investigator or institution should maintain adequate and accurate source documents and trial records with the ability to trace source data changes.

IV. Sponsor Responsibilities

It isn’t just the investigator who is on the hook under E6(R2); this addendum ensures that the sponsor is too.  E6(R2) includes new information about sponsors’ responsibilities regarding quality management and trial oversight.  Like investigators, sponsors are accountable for overseeing work conducted on its behalf for trial-related duties and functions. Additionally, the addendum stipulates that the sponsor should implement a risk-based quality management and monitoring system that runs throughout clinical trials. It explains that monitoring can be done in a centralized fashion or deployed on-site depending on which method the sponsor feels is most appropriate.

V. Essential Documents

E6(R2) assigns the maintenance of essential documents and source documents to investigators and sponsors. The addendum specifically states that the investigator should have control of the case report form; the sponsor should not have exclusive control. Documents should be stored securely and accessibly.


It is possible that many of the changes made through the E6(R2) are already part of your normal battle plan, but it is always a good idea to do a “preflight check.” Proper clinical trial conduct requires the creation and retention of reliable, reproducible trial results.  Do you think your research sites could use a hyperdrive tune-up? Kinetiq can help you get shipshape and back to light speed in no time!

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