Well, the changes to the IRB section were a bit of a snooze, but there are lots of fun little surprises in the Investigator Responsibilities section of the newly final E6 R3! New informed consent elements, clarity regarding oversight of contracted staff working at clinical sites, additional guidance regarding participant withdrawal processes, a bunch of IMP details, and some cleanup to eliminate redundancies.  Enjoy!

• Step 2.3.1 concerning the investigator’s delegation of trial-related activities to other parties now states that the investigator should maintain appropriate “oversight” of delegees, rather than “supervision.”  This substitution was also made in step 2.10.3. A new sentence was added to this step:  "The level of investigator oversight of the delegated activities should depend on the nature of the delegated activities and be proportionate to the importance of the data being collected and the risks to trial participant safety and data reliability."
• Step 2.3.2, which previously specified that the investigator should ensure that delegees should be adequately informed about the protocol, investigational products, and their assigned activities now states that they should be adequately informed about “relevant aspects” of those elements.  The step now states that, in addition to being informed of their assigned trial activities, delegees should be informed of “activities conducted by staff provided by other parties in accordance with local regulatory requirements,” a reference to staff hired by sponsors to work at clinical sites.  
• Step 2.3.3, regarding the need to capture staff on the delegation log, has been reworded slightly to emphasize that inclusion should be “proportionate to the significance of trial-related activities.”  
• Step 2.3.5 now states that, in addition to permitting review by the sponsor and regulatory authorities, sites should permit review by IRBs/IECs, “in accordance with applicable regulatory requirements.”
• Step 2.4.4 previously stated that investigators and sponsors were required to “provide updates to the participant information”; it now clarifies that they are providing updates to the IRB/IEC.
• Step 2.5.3, which discusses the investigator’s responsibility with regard to protocol deviations, now states that these responsibilities include PDs identified by the site or identified by the sponsor and communicated to the site.
• Step 2.5.4 previously stated that where deviations were undertaken to eliminate immediate hazards to participants, the investigator should inform the “sponsor, IRB/IEC, and regulatory authorities promptly.”  This step now states only that the investigator should inform the sponsor promptly. Step 2.5.5 still states that the investigator should report the situation to the IRB/IEC and regulatory authorities, but it appears that the only party the investigator needs to notify immediately is the sponsor. 
• Step 2.6.3 about requirements for study termination states that, in addition to informing the IRB/IEC and regulatory authorities, the sponsor or investigator should “provide an appropriate explanation.”
• Step 2.7.2 (a) regarding the investigator’s responsibility to report adverse events and abnormal test results to the sponsor per the protocol now includes this addendum:  “Unfavourable medical events occurring in participants before investigational product administration (e.g., during screening) should be considered and reported to the sponsor if required by the protocol.”
• Step 2.7.2 (b) regarding reporting of serious adverse events now includes the statement, “The investigator should also include an assessment of causality.”
• Step 2.8.1 (b), which addressed the use of clear and concise language so that participants could understand “their obligations,” now uses the language “what is expected of participants.”  This language is also substituted in Step 2.8.10 (e), which lists required elements of informed consent. 
• Step 2.8.1 (c) about the use of “varied approaches” such as video and other interactive methods for informed consent now adds, “"The characteristics of the potential trial population (e.g., participants may lack familiarity with computerised systems) and the suitability of the method of obtaining consent should be taken into consideration when developing the informed consent materials and process." This again is likely in consideration of the amended Declaration of Helsinki. Additionally, it now includes: "When computerised systems are used to obtain informed consent, trial participants may be given the option to use a paper-based approach as an alternative."
• Two new steps regarding obtaining informed consent have been added to 2.8.1:  (d) Obtaining consent remotely may be considered where appropriate.
• (e) Whether the informed consent process takes place in person or remotely, the investigator should assure themselves of the identity of the participant (or legally acceptable representative) in accordance with applicable regulatory requirements.
• Step 2.8.5, which discusses cases where participants are unable to provide consent, gives examples of such participants:  “e.g., minors, patients with severely impaired decision making capacity.” These examples have been removed from a step later in this section. 
• The following step has been removed, likely because it is redundant with 2.8.1 (b):  “The information provided during the informed consent process and translations should be relevant, clear, simple, concise and understandable to the participant or the participant’s legally acceptable representative and the impartial witness, where applicable.” 
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• Step 2.8.8 in the final version retains the requirement that "the informed consent form should be signed and dated by the participant or by the participant’s legally acceptable representative and, where appropriate, by an impartial witness and by the investigator or delegated investigator site staff who conducted the informed consent discussion." However, it introduces a new statement clarifying that "by signing the consent form, the investigator or delegated investigator site staff attests that the informed consent was freely given by the participant or the participant’s legally acceptable representative and the consent information was accurately explained to and apparently understood by the participant or the participant’s legally acceptable representative." Additionally, the final version specifies that "the informed consent process may involve a physical or an electronic signature and date," now referencing the glossary term “signature.”
• Step 2.8.9, which describes use of a witness in informed consent processes where a participant or legally acceptable representative is unable to read, now states that the witness “should sign and date the consent form” rather “contemporaneously sign and personally date the consent form.” It is not clear why these words have been deleted, unless the framers thought it was evident that a witness’s signature must be “contemporaneous and personal” if they witnessed the informed consent process.
• Step 2.8.10 (l), from the list of required informed consent elements, previously stated that the informed consent must state that a participant may "refuse to participate or may withdraw," whereas the final version uses the language "decide to stop taking the investigational product or withdraw from the trial," thus making an important distinction between withdrawing from treatment and withdrawing from participation. 
• A new required element of informed consent has been added in step 2.8.10 (m):  “The follow-up procedure for participants who stopped taking the investigational product, withdrew from the trial or were discontinued from the trial.”
• In step 2.8.10 (o), from the list of required informed consent elements, the term “original medical records” has been changed to “source records” (i.e., the informed consent must state that “the participant or their legally acceptable representative allows direct access to source records”). The phrase "and in accordance with applicable regulatory requirements" has been added to clarify the conditions under which the IRB/IEC(s) may access these records.
• The requirement in step 2.8.11 (v) to include a statement in the informed consent that trial results and treatment information will be made available to participants if they desire it is now modified “when this information is available from the sponsor.”
• Step 2.8.11 regarding the requirement to give participants/LARs a copy of the informed consent form now states that they are to receive a “signed and dated” copy, whereas previously it stated that the copy was “signed.”
• The following statement has been removed from the end of section 2.8 regarding informed consent: “In exceptional circumstances (e.g., public health emergencies), when the usual methods to obtain and document informed consent are not possible, the use of alternative measures and technologies in accordance with local IRBs/IECs and applicable regulatory requirements should be considered.” Note that “varied approaches” to informed consent 
• Step 2.9.1 about the end of participation in a clinical trial includes new instructions to be provided to participants who did not reach the routine end of the trial: “This may include instructions to avoid loss of already collected data, in accordance with applicable regulatory requirements, to ensure that trial results are reliable.” The final version also emphasizes that “loss of already collected data may bias results and may lead to, for example, inaccurate conclusions regarding the safety profile of the investigational product.”   
• Step 2.9.2 regarding participant withdrawal now adds that withdrawal discussions “should focus on the reasons for withdrawal to determine if there are ways to address the concerns such that the participant could reconsider their withdrawal without unduly influencing the participant’s decision.” The final also clarifies that the investigator or delegated site staff “should consider explaining” rather than “should make an effort to explain,” and adds that “the investigator should ensure that it does not interfere with the participant’s decision to refuse or withdraw participation at any time.” These changes likely address concerns that such discussions could be considered coercive.
• Step 2.10.1, which previously stated that “responsibility for investigational product(s) accountability rests with the investigator/institution,” now replaces “accountability” with “management, including accountability, handling, dispensing, administration and return.”  This step gives examples of how a sponsor may facilitate investigational product management (e.g., by providing forms and technical solutions, such as computerized systems, and arranging distribution of investigational product to trial participants.”
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• A new step 2.10.3 has been added to explain the investigator’s responsibility in cases where they have delegated investigational product management to another party, or the sponsor is facilitating these activities:  “The level of investigator oversight will depend on a number of factors, including the characteristics of the investigational product, route and complexity of administration, level of existing knowledge about the investigational product’s safety and marketing status.”
• Step 2.10.8 has been added regarding IMP management: “The investigational product may be shipped to the participant’s location or supplied to/dispensed at a location closer to the participant (e.g., at a local pharmacy or a local healthcare centre). The investigational product may be administered at the participant’s location by investigator site staff, the participant themselves, a caregiver or a healthcare professional.”
• Step 2.10.9 has been added regarding IMP management: “Investigational product management should be arranged and conducted in accordance with applicable regulatory requirements, and safeguards should be in place to ensure product integrity, product use per protocol and participant safety.”
• Step 2.12.10, regarding the investigator’s use of computerized systems, adds two steps:  (c) “For systems deployed by the sponsor, notify the sponsor when access permissions need to be changed or revoked from an individual” and (d) “For systems deployed by the investigator/institution specifically for the purpose of clinical trials, ensure that the requirements for computerized systems in section 4 are addressed proportionate to the risks to participants and to the importance of the data.”
• Step 2.12.11 regarding record retention now states that investigators should have control of all essential records generated by the investigator/institution “before and during conduct of the trial” instead of “before, during, and after the trial,” perhaps in recognition that sites don’t generate records after a trial is closed out. The step regarding the site’s continued responsibility for records has been reworded and rearranged, but it is substantially the same.