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What’s New in E6 R3? Investigator Responsibilities, Part 3

In this edition of What’s New in E6 R3, we look at investigator responsibilities for ending participants’ participation in a clinical trial, managing investigational product, randomization and unblinding, and records management.  Spoiler alert:  For those of you still clinging to your paper CRFs, “initialing and dating changes” is now on the scrap heap of history.

End of Participation in a Clinical Trial. This new section instructs investigators to follow protocol instructions when participants withdraw consent or are discontinued to “avoid unnecessary loss of already collected critical data in accordance with applicable regulatory requirements.”  Because data that are “already collected” cannot be “lost,” we assume this is a reference to privacy regulations, but it is not at all clear. A statement about obtaining a participant’s reason for withdrawal has been moved from the “Medical Care of Trial Subjects” section to this one, with two additions specifying that investigators should try to address any concerns that led to withdrawal and try to explain the value and importance of continuing trial participation.

Another addition states that investigators should inform participants about trial results and treatment assignments, assuming participants wish to receive this information.

Investigational Product Management. R3 still states that investigators are responsible for IP accountability, but adds that “the sponsor may facilitate this process.”

Steps describing investigator/pharmacist responsibilities for maintaining IP records now note that “alternative approaches” to recordkeeping may be used for authorized medicinal products.

Steps have been added to require storage of IP as specified by the sponsor; to require site staff to explain the correct use of the IP to participants; and to confirm that participants are following these instructions.

Randomization Procedures and Unblinding. This section has been modified to specify that the “investigator should be prepared and capable from the start of the trial to perform unblinding without undue delay and hindrance,” a clear reference to situations in which principal investigators do not obtain access to IRT systems required to break the blind until after the first subject is enrolled.

Records. This long section is prefaced with a new general statement requiring investigators to ensure integrity of data irrespective of media used.

The term “source data” in the previous ALCOA+ step in R2 has been replaced with “source records.” This step has been modified to add that investigators should define what they consider to be source records, the methods of data capture, and their location prior to starting the trial. Throughout the trial, investigators should avoid “unnecessary transcription steps” between the source record and data capture system, which appears to discourage the use of CRF “worksheets.”

R3 emphasizes the need for timely access to and review of data from external sources such as laboratory data or ePRO data, especially when these data have implications for eligibility, treatment, or safety. This step notes that “the protocol may provide exceptions for access, for instance, to protect blinding.”

Another new statement notes the investigator’s responsibility to use EDC systems and other data capture tools per the protocol or study-specific instructions.

A new statement requires investigators to review and endorse data reported in data capture systems at agreed-upon milestones.

The extremely dated step 4.9.3 in R2 about initialing and dating corrections to CRFs has been replaced with step 2.12.6 stating that changes or corrections should be traceable, explained “if necessary,” and should not obscure the original entry.

Section 2.12.9 describing general controls for computerized systems to maintain data integrity, including ensuring that appropriate site staff have access; ensuring that any equipment provided to participants is traceable; and ensuring that any “incidents” that might have an impact on data integrity are reported to the sponsor and, if appropriate, IRB/IEC.

Several references to data capture system maintained by the investigator, such as electronic medical records systems, have been added. Investigators are required to ensure integrity of data and address all requirements in the new Section 4 on Data Governance.

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