In our continuing series on implementing E6 R3, we look at aspects of the updated guidance that are new to industry and thus will likely require changes to implement.  Today, we look at the requirement for distributing information about the trial outcome, including treatment assignments, to participants. This requirement seems simple on the surface, but timing and the criticality of this information complicate matters. In short - it's fuzzy!

This requirement is mentioned in three places in E6 R3. In the Principles section, regarding transparency of results, step 9.6 states, "Communicating trial results to participants should be considered. Such communication should be objective and non-promotional."   In section III. 2.8.10 on elements of informed consent, the last required element is "(v) That trial results and information on the participant's actual treatment, if appropriate, will be made available to them should they desire it when this information is available from the sponsor." (Note that the draft E6 R3 published in May 2023 did not include the qualifier "when this information is available from the sponsor," suggesting that participants could learn their treatment assignments before unblinding. This version is the one that is still available on FDA's website, so caveat emptor.) Section III 2.9.3 on procedures for the end of a clinical trial states, "Where relevant, the investigator should inform the participant about the trial results and treatment received when this information is available from the sponsor after unblinding, with due respect to the participant's preference to be informed." Neither statement was included in E6 R2. 

Let's look at this process from beginning to end. 

Obviously, the statement that the trial results and treatment assignment will be made available to the participant must be included in the informed consent form.  Sponsors and CROs will need to modify their templates and add a check for this element on the QC forms.  Sponsors may wish to train their sites on this change so personnel administering informed consent will be alerted to cover this point during discussions with potential participants. 

"Should they desire it" is the sticky point.  Are sites expected to capture the participant's desire to be informed on the consent form itself (yet another part of the form to complete)? Should it be captured as a source note during consent, or as a source note during the termination visit, or both? Should a CRA note if the participant's wishes are not documented?  

"When this information is available from the sponsor after unblinding" also presents some interesting questions. In theory, treatment assignments are available as soon as the study is unblinded, but trial results are not available until the Clinical Study Report is published. Should treatment assignments be communicated in tandem with study results, or separately?  Should the trigger for release of results be finalization of the Clinical Study Report, which typically occurs within a few months of unblinding?  Or should it be public availability of results, which could be almost a year after unblinding? This also raises another question regarding the ICF:  Should the sponsor indicate a timeframe for receipt of this information?

After the sponsor chooses a timepoint for communication, they must implement appropriate controls.  For example, if they release treatment assignments before CSR finalization, they will need QC steps and perhaps an internal approval. If they release results prior to public disclosure, they may need to develop a participant-friendly format for communicating this information. It's hard to believe any sponsor would go through the extra work of developing a participant-facing results report - unless it was part of a program of overall patient retention, in which case it might need to be reviewed as promotional material. 

To show that information was distributed, sponsors will likely want to retain distribution emails and perhaps request (and of course file) acknowledgment of receipt from each investigator. The sponsor might also want to develop a communication to ensure the investigator understands how to identify the treatment assignment (i.e., by referring to their participant decode list to find the subject number).

Sites could communicate information to participants by sharing the individual treatment assignment with them or by handing the participant a copy of the listing with their information highlighted. We assume sites should take the former approach as there is no need for participants to know other participants' treatment assignments, so sponsors may wish to communicate these limits to investigators. If the investigator is sharing this information verbally, however, this introduces an opportunity for inconsistency with the source.  We assume that sites should note in source whether and when they informed the participant of their treatment assignment (e.g., "Dr. X informed patient that they had been administered placebo in the XYZ clinical trial"). If the communication occurs before the site closeout visit, or (for pivotal studies) prior to an inspection readiness visit, sponsors should consider whether their site monitors will be trained to review this information and how they would respond if they found the investigator had made an error.

Further Reading:

• See this article (2005) for a discussion of the ethics and practical ramifications of withholding this information from participants.
• The NIH has also published the book Sharing Clinical Trial Data:  Maximizing Benefits, Minimizing Risks (2015), which covers many of these issues.