ICH E6(R2) vs ICH E6(R3) — Good Clinical Practice

## IRB/IEC Review Responsibilities ### Investigator Qualifications The IRB/IEC should consider the qualifications of the investigator for the proposed trial, as documented by a current curriculum vitae and/or by any other relevant documentation the IRB/IEC requests [E6R2-3.1.3]. ### Continuing Review The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least once per year [E6R2-3.1.4]. ### Additional Information for Subjects The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in the judgement of the IRB/IEC, the additional information would add meaningfully to the protection of the rights, safety and/or well-being of the subjects [E6R2-3.1.5]. ### Non-Therapeutic Trials When a non-therapeutic trial is to be carried out with the consent of the subject's legally acceptable representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials [E6R2-3.1.6]. ### Trials Without Prior Consent Where the protocol indicates that prior consent of the trial subject or the subject's legally acceptable representative is not possible (see 4.8.15), the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials (i.e. in emergency situations) [E6R2-3.1.7]. ### Payment to Subjects The IRB/IEC should review both the amount and method of payment to subjects to assure that neither presents problems of coercion or undue influence on the trial subjects [E6R2-3.1.8]. Payments to a subject should be prorated and not wholly contingent on completion of the trial by the subject [E6R2-3.1.8]. The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and schedule of payment to trial subjects, is set forth in the written informed consent form and any other written information to be provided to subjects [E6R2-3.1.9]. The way payment will be prorated should be specified [E6R2-3.1.9]. ## Composition, Functions and Operations ### Membership Requirements The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial [E6R2-3.2.1]. It is recommended that the IRB/IEC should include: - At least five members [E6R2-3.2.1]. - At least one member whose primary area of interest is in a nonscientific area [E6R2-3.2.1]. - At least one member who is independent of the institution/trial site [E6R2-3.2.1]. Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter [E6R2-3.2.1]. A list of IRB/IEC members and their qualifications should be maintained [E6R2-3.2.1]. ### Operating Procedures and Records The IRB/IEC should perform its functions according to written operating procedures, should maintain written records of its activities and minutes of its meetings, and should comply with GCP and with the applicable regulatory requirement(s) [E6R2-3.2.2]. ### Decision-Making An IRB/IEC should make its decisions at announced meetings at which at least a quorum, as stipulated in its written operating procedures, is present [E6R2-3.2.3]. Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advise [E6R2-3.2.4]. The investigator may provide information on any aspect of the trial, but should not participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC [E6R2-3.2.5]. An IRB/IEC may invite nonmembers with expertise in special areas for assistance [E6R2-3.2.6]. ## Procedures The IRB/IEC should establish, document in writing, and follow its procedures, which should include [E6R2-3.3]: - Determining its composition (names and qualifications of the members) and the authority under which it is established [E6R2-3.3.1]. - Scheduling, notifying its members of, and conducting its meetings [E6R2-3.3.2]. - Conducting initial and continuing review of trials [E6R2-3.3.3]. - Determining the frequency of continuing review, as appropriate [E6R2-3.3.4]. - Providing, according to the applicable regulatory requirements, expedited review and approval/favourable opinion of minor change(s) in ongoing trials that have the approval/favourable opinion of the IRB/IEC [E6R2-3.3.5]. - Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written approval/favourable opinion of the trial [E6R2-3.3.6]. - Specifying that no deviations from, or changes of, the protocol should be initiated without prior written IRB/IEC approval/favourable opinion of an appropriate amendment, except when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)) (see 4.5.2) [E6R2-3.3.7]. ### Investigator Reporting to IRB/IEC The IRB/IEC procedures should specify that the investigator should promptly report to the IRB/IEC [E6R2-3.3.8]: - Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7, 4.5.2, 4.5.4) [E6R2-3.3.8]. - Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2) [E6R2-3.3.8]. - All adverse drug reactions (ADRs) that are both serious and unexpected [E6R2-3.3.8]. - New information that may affect adversely the safety of the subjects or the conduct of the trial [E6R2-3.3.8]. ### IRB/IEC Notification to Investigator/Institution The IRB/IEC procedures should ensure that the IRB/IEC promptly notifies in writing the investigator/institution concerning [E6R2-3.3.9]: - Its trial-related decisions/opinions [E6R2-3.3.9]. - The reasons for its decisions/opinions [E6R2-3.3.9]. - Procedures for appeal of its decisions/opinions [E6R2-3.3.9].

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## Overview The IRB/IEC is responsible for the ethical review of the trial. [E6R3-1] The requirements for the IRB/IEC in this guideline should be read in conjunction with local regulatory requirements. [E6R3-1] ## Submission and Communication In most regions where there is also a requirement to make a submission to the relevant regulatory authority, submissions to or communications with the IRB/IEC may be combined in a single submission in accordance with applicable regulatory requirements. [E6R3-1.1] Submissions and communications with the IRB/IEC and regulatory authorities are made in some regions by the investigator/institution and by the sponsor in other regions, in accordance with applicable regulatory requirements. [E6R3-1.1] ## Responsibilities ### Purpose and Scope The purpose of an IRB/IEC is to safeguard the rights, safety and well-being of all trial participants. [E6R3-1.2.1] Appropriate consideration should be given to trials that intend to recruit vulnerable participants. [E6R3-1.2.1] ### Documents Subject to Review The IRB/IEC should review the following information, where applicable: [E6R3-1.2.2] - Protocol and amendments; [E6R3-1.2.2] - Informed consent material(s), assent material(s) where applicable, and any updates, including the description of the process for how informed consent and assent is to be obtained; [E6R3-1.2.2] - Investigator's Brochure or current scientific information, such as a basic product information brochure (e.g., Summary of Product Characteristics (SmPC), package leaflet or labelling), as appropriate, including their updates; [E6R3-1.2.2] - Other trial-related information to be provided to the trial participant(s), including a description of the media through which such information will be provided; [E6R3-1.2.2] - Advertisement for participant recruitment (if used) and information on the recruitment process; [E6R3-1.2.2] - Plans to compensate participants (if any); [E6R3-1.2.2] - Ongoing updates to safety information; [E6R3-1.2.2] - Investigator's current curriculum vitae and/or other documentation evidencing qualifications; [E6R3-1.2.2] - Any other documents that the IRB/IEC may need to fulfil its responsibilities. [E6R3-1.2.2] ### Review Timelines and Documentation The IRB/IEC should review a proposed clinical trial within a reasonable time and document its reviews, clearly identifying the trial, the documents reviewed and the dates for: approval/favourable opinion; modifications required prior to its approval/favourable opinion; disapproval/negative opinion; and termination/suspension of any prior approval/favourable opinion. [E6R3-1.2.3] ### Continuing Review The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to participants. [E6R3-1.2.4] ### Additional Information for Participants The IRB/IEC may request more information than is outlined in section 2.8.11 be given to participants when, in the judgement of the IRB/IEC, the additional information would add meaningfully to the protection of the rights, safety and/or well-being of the participants. [E6R3-1.2.5] ### Trials Without Prior Consent Where the protocol indicates that prior consent of the trial participant or the participant's legally acceptable representative is not possible, the IRB/IEC should determine that the proposed protocol and/or other document(s) adequately address relevant ethical concerns and meet applicable regulatory requirements for such trials (e.g., in emergency situations). [E6R3-1.2.6] ### Inclusion of Minors If minors are to be included in a trial, the IRB/IEC should review the assent information considering the age, maturity and psychological state of the minor population intended to be enrolled, as well as applicable regulatory requirements. [E6R3-1.2.7] ### Participant Compensation If the trial participants are compensated for their participation in the trial, the IRB/IEC should review both the amount and method of payment to participants to assure that neither presents problems of coercion or undue influence on the trial participants. [E6R3-1.2.8] Payments to a participant should be timely, prorated and not wholly contingent on completion of the trial by the participant. [E6R3-1.2.8] Reasonable reimbursement of expenses incurred by participants, such as for travel and lodging, is not coercive. [E6R3-1.2.8] The IRB/IEC should ensure that information regarding payment to participants, including the methods, amounts and schedule of payment to trial participants, is set forth in the informed consent materials and any other information to be provided to participants. [E6R3-1.2.9] ## Composition, Functions and Operations ### Membership Requirements The IRB/IEC should consist of a reasonable number of members who collectively have the qualifications and experience to review and evaluate the science, medical aspects and ethics of the proposed trial. [E6R3-1.3.1] It is recommended that the IRB/IEC should include: [E6R3-1.3.1] - At least five members; [E6R3-1.3.1] - At least one member whose primary area of interest is not in medical sciences; [E6R3-1.3.1] - At least one member who is independent of the institution/investigator site. [E6R3-1.3.1] Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide an opinion. [E6R3-1.3.1] A list of IRB/IEC members and their qualifications should be maintained. [E6R3-1.3.1] ### Operating Procedures and Records The IRB/IEC should perform its functions according to documented operating procedures, should maintain records of its activities and minutes of its meetings, and should comply with GCP and with the applicable regulatory requirement(s). [E6R3-1.3.2] ### Decision-Making An IRB/IEC should make its decisions at announced meetings at which at least a quorum, as stipulated in its documented operating procedures, is present. [E6R3-1.3.3] Alternative processes may be applicable for expedited review. [E6R3-1.3.3] Only members who participate in the IRB/IEC review and discussion should vote/provide their opinion and/or advice. [E6R3-1.3.4] The investigator, investigator site staff and/or sponsor, where appropriate, may provide information on any aspect of the trial but should not participate in the decision making of the IRB/IEC or in the vote/opinion of the IRB/IEC. [E6R3-1.3.5] An IRB/IEC may invite non-members with expertise in special areas for assistance. [E6R3-1.3.6] ## Procedures The IRB/IEC should establish, document and follow its procedures, which should include: [E6R3-1.4] - Determining its composition (names and qualifications of the members) and the authority under which it is established; [E6R3-1.4.1] - Scheduling, notifying its members of and conducting its meetings; [E6R3-1.4.2] - Conducting initial and continuing review of trials; [E6R3-1.4.3] - Determining the frequency of continuing review, as appropriate; [E6R3-1.4.4] - Providing, according to the applicable regulatory requirements, expedited review and approval/favourable opinion of minor change(s) in ongoing trials that have the approval/favourable opinion of the IRB/IEC; [E6R3-1.4.5] - Specifying that no participant should be enrolled in a trial before the IRB/IEC issues its documented approval/favourable opinion of the trial; [E6R3-1.4.6] - Specifying that no deviations from or changes to the protocol should be initiated without prior documented IRB/IEC approval/favourable opinion of an appropriate protocol amendment except when necessary to eliminate immediate hazards to the participants or, in accordance with applicable regulatory requirements, when the change(s) involves only logistical or administrative aspects of the trial; [E6R3-1.4.7] - Specifying that the investigator/institution should promptly report to the IRB/IEC: deviations from the protocol to eliminate immediate hazards to the trial participants; changes increasing the risk to participants and/or significantly affecting the conduct of the trial; all suspected unexpected serious adverse reactions (SUSARs) in accordance with applicable regulatory requirements; and new information that may adversely affect the safety of the participants or the conduct of the trial; [E6R3-1.4.8] - Ensuring that the IRB/IEC promptly notifies in writing (paper or electronically) the investigator/institution or sponsor concerning its trial-related decisions/opinions, the reasons for its decisions/opinions, and procedures for appeal of its decisions/opinions. [E6R3-1.4.9] ## Records The IRB/IEC should retain all relevant records (e.g., documented procedures, membership lists, lists of occupations/affiliations of members, submitted documents, minutes of meetings and correspondence) in accordance with applicable regulatory requirements and make them available upon request from the regulatory authority(ies). [E6R3-1.5.1] The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its documented procedures and membership lists. [E6R3-1.5.2]

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## Required Elements of Informed Consent Disclosure Subjects must be informed of the reasonably foreseeable risks or inconveniences to themselves and, when applicable, to an embryo, fetus, or nursing infant [E6R2-4.8.10g]. The reasonably expected benefits must also be disclosed; when there is no intended clinical benefit to the subject, the subject should be made aware of this [E6R2-4.8.10h]. Alternative procedures or courses of treatment that may be available to the subject, together with their important potential benefits and risks, must be communicated [E6R2-4.8.10i]. The compensation and/or treatment available to the subject in the event of trial-related injury must be disclosed [E6R2-4.8.10j]. The anticipated prorated payment, if any, to the subject for participating in the trial must be stated [E6R2-4.8.10k]. The anticipated expenses, if any, to the subject for participating in the trial must also be disclosed [E6R2-4.8.10l]. Subjects must be informed that their participation in the trial is voluntary and that they may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled [E6R2-4.8.10m]. Subjects must be informed that the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted direct access to the subject's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations, and that by signing a written informed consent form the subject or the subject's legally acceptable representative is authorizing such access [E6R2-4.8.10n]. Subjects must be informed that records identifying the subject will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available, and that if the results of the trial are published, the subject's identity will remain confidential [E6R2-4.8.10o]. Subjects must be informed that they or their legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the subject's willingness to continue participation in the trial [E6R2-4.8.10p]. The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to contact in the event of trial-related injury, must be identified [E6R2-4.8.10q]. The foreseeable circumstances and/or reasons under which the subject's participation in the trial may be terminated must be disclosed [E6R2-4.8.10r]. The expected duration of the subject's participation in the trial and the approximate number of subjects involved in the trial must also be communicated [E6R2-4.8.10s, E6R2-4.8.10t]. ## Provision of Consent Documentation to Subjects Prior to participation in the trial, the subject or the subject's legally acceptable representative should receive a copy of the signed and dated written informed consent form and any other written information provided to the subjects [E6R2-4.8.11]. During a subject's participation in the trial, the subject or the subject's legally acceptable representative should receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to subjects [E6R2-4.8.11]. ## Consent for Subjects Unable to Give Personal Consent When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled with the consent of the subject's legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be informed about the trial to the extent compatible with the subject's understanding and, if capable, the subject should sign and personally date the written informed consent [E6R2-4.8.12]. ## Non-Therapeutic Trials: General Rule Except as described in section 4.8.14, a non-therapeutic trial (i.e., a trial in which there is no anticipated direct clinical benefit to the subject) should be conducted in subjects who personally give consent and who sign and date the written informed consent form [E6R2-4.8.13]. ## Non-Therapeutic Trials: Consent via Legally Acceptable Representative Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled [E6R2-4.8.14]: - The objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally [E6R2-4.8.14a]. - The foreseeable risks to the subjects are low [E6R2-4.8.14b]. - The negative impact on the subject's well-being is minimized and low [E6R2-4.8.14c]. - The trial is not prohibited by law [E6R2-4.8.14d]. - The approval/favourable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/favourable opinion covers this aspect [E6R2-4.8.14d]. Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended [E6R2-4.8.14]. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed [E6R2-4.8.14]. ## Emergency Situations In emergency situations, when prior consent of the subject is not possible, the consent of the subject's legally acceptable representative, if present, should be requested [E6R2-4.8.15]. When prior consent of the subject is not possible and the subject's legally acceptable representative is not available, enrolment of the subject should require measures described in the protocol and/or elsewhere, with documented approval/favourable opinion by the IRB/IEC, to protect the rights, safety and well-being of the subject and to ensure compliance with applicable regulatory requirements [E6R2-4.8.15]. The subject or the subject's legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate should be requested [E6R2-4.8.15]. ## Records and Reports: Source Data Requirements The investigator/institution should maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site's trial subjects [E6R2-4.9.0]. Source data should be attributable, legible, contemporaneous, original, accurate, and complete [E6R2-4.9.0]. Changes to source data should be traceable, should not obscure the original entry, and should be explained if necessary (e.g., via an audit trail) [E6R2-4.9.0].

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## Safety Review and Risk-Benefit Assessment The safety of participants should be reviewed in a timely manner as new safety information becomes available that could have an impact on participant safety, their willingness to continue in the trial, or the conduct of the trial. [E6R3-1.2] Foreseeable risks and inconveniences should be weighed against the anticipated benefits for the individual participants and society. A trial should be initiated and continued only if the anticipated benefits justify the known and anticipated risks. [E6R3-1.3] ## Participant Selection and Representativeness When designing a clinical trial, the scientific goal and purpose should be carefully considered so as not to unnecessarily exclude particular participant populations. [E6R3-1.4] The participant selection process should be representative of the population groups that the investigational product is intended to benefit, once authorised, to allow for generalising the results across the broader population. [E6R3-1.4] Certain trials (e.g., early phase, proof of concept trials, bioequivalence studies) may not require such a heterogeneous population. [E6R3-1.4] ## Medical Oversight and Responsibility A qualified physician or, when appropriate, a qualified dentist (or other qualified healthcare professionals in accordance with local regulatory requirements) should have the overall responsibility for the trial-related medical care given to and medical decisions made on behalf of participants. [E6R3-1.5] 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. [E6R3-1.5] ## Confidentiality The confidentiality of information that could identify participants should be protected in accordance with applicable privacy and data protection requirements. [E6R3-1.6] ## Informed Consent: General Principles > "Informed consent is an integral feature of the ethical conduct of a trial. Clinical trial participation should be voluntary and based on a consent process that ensures participants (or their legally acceptable representatives, where applicable) are well-informed." [E6R3-2] ### Obtaining and Documenting Consent Freely given informed consent should be obtained and documented from every participant prior to clinical trial participation. [E6R3-2.1] For potential participants unable to provide informed consent, their legally acceptable representatives, acting in the participants' best interest, should provide consent prior to clinical trial participation. [E6R3-2.1] These potential participants should be informed about the trial in a manner that facilitates their understanding. [E6R3-2.1] In the event that a minor is a participant, assent should be collected from that minor, as appropriate, and in accordance with local regulatory requirements. [E6R3-2.1] ### Quality and Clarity of Information The process and information provided should be designed to achieve the primary objective of enabling potential trial participants to evaluate the benefits, risks and burden of participating in the trial and to make an informed decision on whether or not to participate. [E6R3-2.2] The information provided during the informed consent process should be clear and concise so as to be understandable by potential participants or legally acceptable representatives. [E6R3-2.2] ### Contextual Considerations The informed consent process should take into consideration relevant aspects of the trial, such as the characteristics of the participants, the trial design, the anticipated benefits and risks of medical intervention(s), the setting and context in which the trial will be conducted (e.g., trials in emergency situations), and the potential use of technology to inform participants (or their legally acceptable representatives) and obtain informed consent. [E6R3-2.3] ### Emergency Situations In emergency situations where consent cannot be obtained prior to trial participation, consent should be obtained from the participant or their legally acceptable representative as soon as possible. [E6R3-2.4]

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## 4.9 Records and Reports ### CRF Data Accuracy and Consistency The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the CRFs and in all required reports [E6R2-4.9.1]. Data reported on the CRF that are derived from source documents should be consistent with the source documents, or the discrepancies should be explained [E6R2-4.9.2]. ### Changes and Corrections to CRFs Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry, meaning an audit trail should be maintained; this applies to both written and electronic changes or corrections (see 5.18.4(n)) [E6R2-4.9.3]. Sponsors should provide guidance to investigators and/or the investigators' designated representatives on making such corrections [E6R2-4.9.3]. Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated representatives are documented, are necessary, and are endorsed by the investigator [E6R2-4.9.3]. The investigator should retain records of the changes and corrections [E6R2-4.9.3]. ### Maintenance of Trial Documents The investigator/institution should maintain the trial documents as specified in Essential Documents for the Conduct of a Clinical Trial (see section 8) and as required by the applicable regulatory requirement(s) [E6R2-4.9.4]. The investigator/institution should take measures to prevent accidental or premature destruction of these documents [E6R2-4.9.4]. ### Retention Period for Essential Documents Essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product [E6R2-4.9.5]. These documents should be retained for a longer period if required by the applicable regulatory requirements or by an agreement with the sponsor [E6R2-4.9.5]. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained (see 5.5.12) [E6R2-4.9.5]. ### Financial Documentation The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution [E6R2-4.9.6]. ### Access to Trial Records Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records [E6R2-4.9.7]. ## 4.10 Progress Reports The investigator should submit written summaries of the trial status to the IRB/IEC annually, or more frequently if requested by the IRB/IEC [E6R2-4.10.1]. The investigator should promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8), and, where applicable, the institution on any changes significantly affecting the conduct of the trial and/or increasing the risk to subjects [E6R2-4.10.2]. ## 4.11 Safety Reporting ### Serious Adverse Events All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting [E6R2-4.11.1]. The immediate reports should be followed promptly by detailed, written reports [E6R2-4.11.1]. The immediate and follow-up reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects' names, personal identification numbers, and/or addresses [E6R2-4.11.1]. The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC [E6R2-4.11.1]. ### Protocol-Specified Safety Evaluations Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol [E6R2-4.11.2]. ### Reported Deaths For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested information (e.g., autopsy reports and terminal medical reports) [E6R2-4.11.3]. ## 4.12 Premature Termination or Suspension of a Trial If the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, where required by the applicable regulatory requirement(s), should inform the regulatory authority(ies) [E6R2-4.12]. ### Investigator-Initiated Termination or Suspension If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of the termination or suspension [E6R2-4.12.1].

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## 2.6 Premature Termination or Suspension of a Trial ### 2.6.1 General Obligations Upon Termination or Suspension If the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform the trial participants and should ensure appropriate therapy and follow-up for the participants. [E6R3-2.6.1] ### 2.6.2 Investigator-Initiated Termination or Suspension Where the investigator terminates or suspends their involvement in a trial without prior agreement by the sponsor, the investigator should promptly inform the institution (where applicable), the sponsor, the IRB/IEC, and the regulatory authorities in accordance with applicable regulatory requirements. [E6R3-2.6.2] The investigator should also provide a detailed explanation of the reasons. [E6R3-2.6.2] ### 2.6.3 Sponsor-Initiated Termination or Suspension If the sponsor terminates or suspends a trial, the investigator/institution or the sponsor, in accordance with applicable regulatory requirement(s), should promptly inform the IRB/IEC and the regulatory authorities and should provide an appropriate explanation. [E6R3-2.6.3] ### 2.6.4 IRB/IEC-Initiated Termination or Suspension If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial, the investigator should inform the institution (where applicable), and the investigator/institution should promptly notify the sponsor. [E6R3-2.6.4] ## 2.7 Participant Medical Care and Safety Reporting ### 2.7.1 Medical Care of Trial Participants A qualified physician or, where appropriate, a qualified dentist (or other qualified healthcare professionals in accordance with local regulatory requirements) who is an investigator or a sub-investigator for the trial should have the responsibility for trial-related medical care and decisions. [E6R3-2.7.1] Other appropriately qualified healthcare professionals may be involved in the medical care of trial participants, in line with their normal activities and in accordance with local regulatory requirements. [E6R3-2.7.1] During and following participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a participant for any adverse events, including clinically significant laboratory values, related to the trial. [E6R3-2.7.1] The investigator/institution should inform a participant when medical care is needed for intercurrent illness(es) of which the investigator becomes aware. [E6R3-2.7.1] The investigator should inform the participant's primary physician about the participant's involvement in the trial if the participant has a primary physician and agrees to the primary physician being informed. [E6R3-2.7.1] ### 2.7.2 Safety Reporting Adverse events and/or abnormal test results required for safety evaluations (as outlined in the protocol) should be reported to the sponsor according to the reporting requirements and within the time periods specified in the protocol. [E6R3-2.7.2] 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. [E6R3-2.7.2] All serious adverse events (SAEs) should be reported immediately (after the investigator reasonably becomes aware of the event) to the sponsor. [E6R3-2.7.2] The investigator should also include an assessment of causality when reporting SAEs. [E6R3-2.7.2] In accordance with applicable regulatory requirements, the protocol may identify SAEs not requiring immediate reporting. [E6R3-2.7.2]

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## 4.1 Investigator's Qualifications and Agreements The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence of such qualifications through up-to-date curriculum vitae and/or other relevant documentation requested by the sponsor, the IRB/IEC, and/or the regulatory authority(ies) [E6R2-4.1.1]. The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described in the protocol, in the current Investigator's Brochure, in the product information and in other information sources provided by the sponsor [E6R2-4.1.2]. The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements [E6R2-4.1.3]. The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the appropriate regulatory authority(ies) [E6R2-4.1.4]. The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties [E6R2-4.1.5]. ## 4.2 Adequate Resources The investigator should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed recruitment period [E6R2-4.2.1]. The investigator should have sufficient time to properly conduct and complete the trial within the agreed trial period [E6R2-4.2.2]. The investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely [E6R2-4.2.3]. The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions [E6R2-4.2.4]. ### Delegation and Supervision (Addendum) The investigator is responsible for supervising any individual or party to whom the investigator delegates trial-related duties and functions conducted at the trial site [E6R2-4.2.5]. If the investigator/institution retains the services of any individual or party to perform trial-related duties and functions, the investigator/institution should ensure this individual or party is qualified to perform those trial-related duties and functions and should implement procedures to ensure the integrity of the trial-related duties and functions performed and any data generated [E6R2-4.2.6]. ## 4.3 Medical Care of Trial Subjects A qualified physician (or dentist, when appropriate), who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions [E6R2-4.3.1]. During and following a subject's participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial [E6R2-4.3.2]. The investigator/institution should inform a subject when medical care is needed for intercurrent illness(es) of which the investigator becomes aware [E6R2-4.3.2]. It is recommended that the investigator inform the subject's primary physician about the subject's participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed [E6R2-4.3.3].

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## Qualifications and Training The investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial and should provide evidence of such qualifications. [E6R3-2.1.1] The investigator should be familiar with the appropriate use of the investigational product(s) as described in the protocol, in the current Investigator's Brochure, in the product information, and/or in other information sources provided by the sponsor. [E6R3-2.1.2] ## Resources The investigator should be able to demonstrate (e.g., based on retrospective or currently available data) a potential for recruiting the proposed number of eligible participants within the recruitment period as agreed with the sponsor. [E6R3-2.2.1] The investigator should have sufficient time, an adequate number of available and qualified staff, and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely. [E6R3-2.2.2] ## Responsibilities ### Delegation of Trial-Related Activities The investigator may delegate trial-related activities to other persons or parties. [E6R3-2.3.1] The investigator may be supported by the sponsor in the identification of a suitable service provider(s); however, the investigator retains the final decision on whether the service provider intended to support the investigator is appropriate based on information provided by the sponsor. [E6R3-2.3.1] The investigator retains the ultimate responsibility and should maintain appropriate oversight of the persons or parties undertaking the delegated activities to ensure the rights, safety, and well-being of the trial participants and the reliability of data. [E6R3-2.3.1] 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. [E6R3-2.3.1] ### Qualification and Information of Delegated Persons The investigator should ensure that persons or parties to whom trial-related activities have been delegated are appropriately qualified and are adequately informed about relevant aspects of the protocol, the investigational product(s), and their assigned trial activities, including activities conducted by staff provided by other parties in accordance with local regulatory requirements. [E6R3-2.3.2] Trial-related training to persons assisting in the trial should correspond to what is necessary to enable them to fulfil their delegated trial activities that go beyond their usual training and experience. [E6R3-2.3.2] ### Documentation of Delegation The investigator should ensure a record is maintained of the persons and parties to whom trial-related activities have been delegated. [E6R3-2.3.3] Documentation of delegation should be proportionate to the significance of the trial-related activities. [E6R3-2.3.3] In situations where the activities are performed as part of clinical practice, delegation documentation may not be required. [E6R3-2.3.3] Agreements made by the investigator/institution with service providers for trial-related activities should be documented. [E6R3-2.3.4]

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## Subject Withdrawal Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights [E6R2-4.3.4]. ## Communication with IRB/IEC Before initiating a trial, the investigator/institution should have written and dated approval/favourable opinion from the IRB/IEC for the trial protocol, written informed consent form, consent form updates, subject recruitment procedures (e.g., advertisements), and any other written information to be provided to subjects [E6R2-4.4.1]. As part of the investigator's/institution's written application to the IRB/IEC, the investigator/institution should provide the IRB/IEC with a current copy of the Investigator's Brochure [E6R2-4.4.2]. If the Investigator's Brochure is updated during the trial, the investigator/institution should supply a copy of the updated Investigator's Brochure to the IRB/IEC [E6R2-4.4.2]. During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review [E6R2-4.4.3]. ## Compliance with Protocol The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favourable opinion by the IRB/IEC [E6R2-4.5.1]. The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm agreement [E6R2-4.5.1]. The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)) [E6R2-4.5.2]. The investigator, or person designated by the investigator, should document and explain any deviation from the approved protocol [E6R2-4.5.3]. ### Emergency Deviations The investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC approval/favourable opinion [E6R2-4.5.4]. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted: - to the IRB/IEC for review and approval/favourable opinion [E6R2-4.5.4]; - to the sponsor for agreement and, if required [E6R2-4.5.4]; - to the regulatory authority(ies) [E6R2-4.5.4]. ## Investigational Product(s) Responsibility for investigational product(s) accountability at the trial site(s) rests with the investigator/institution [E6R2-4.6.1]. Where allowed/required, the investigator/institution may/should assign some or all of the investigator's/institution's duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the supervision of the investigator/institution [E6R2-4.6.2]. The investigator/institution and/or a pharmacist or other appropriate individual, who is designated by the investigator/institution, should maintain records of the product's delivery to the trial site, the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused product(s) [E6R2-4.6.3]. These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial subjects [E6R2-4.6.3]. Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor [E6R2-4.6.3]. The investigational product(s) should be stored as specified by the sponsor (see 5.13.2 and 5.14.3) and in accordance with applicable regulatory requirement(s) [E6R2-4.6.4]. The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol [E6R2-4.6.5].

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## Investigator Obligations: IRB/IEC Communication and Protocol Compliance ## Monitoring, Auditing, and Inspection The investigator/institution should permit monitoring and auditing by the sponsor, inspection by the appropriate regulatory authority(ies) and, in accordance with applicable regulatory requirements, review by IRB/IEC(s). [E6R3-2.3.5] ## Communication with IRB/IEC ### Submission to the IRB/IEC Submission to the IRB/IEC may be made by the investigator/institution or sponsor in accordance with applicable regulatory requirements. [E6R3-2.4.1] ### Pre-Trial Approval Before initiating a trial, the investigator/institution should have a documented and dated approval/favourable opinion from the IRB/IEC for the trial protocol, informed consent materials, participant recruitment procedures (e.g., advertisements) and any other trial-related information to be provided to participants. [E6R3-2.4.2] ### Investigator's Brochure Submission As part of the investigator's/institution's or sponsor's submission to the IRB/IEC, a current copy of the Investigator's Brochure or basic product information brochure should be provided. [E6R3-2.4.3] If the Investigator's Brochure or basic product information brochure is updated during the trial, the IRB/IEC should receive the current version in accordance with applicable regulatory requirements. [E6R3-2.4.3] ### Ongoing Updates to the IRB/IEC As the trial progresses, the investigator/institution or sponsor should provide any updates to the participant information to the IRB/IEC in accordance with applicable regulatory requirements. [E6R3-2.4.4] The investigator or the sponsor should submit documented summaries of the trial status to the IRB/IEC in accordance with local regulatory requirements or upon request. [E6R3-2.4.5] ### Reporting Significant Changes The investigator or the sponsor should promptly communicate to the IRB/IEC and, where applicable, to the institution any changes significantly affecting the conduct of the trial and/or increasing the risk to participants. [E6R3-2.4.6] ## Compliance with Protocol ### Agreement with the Sponsor The investigator/institution should sign the protocol or an alternative contract to confirm agreement with the sponsor. [E6R3-2.5.1] ### General Compliance Obligations The investigator should comply with the protocol, GCP and applicable regulatory requirements. [E6R3-2.5.2] ### Documentation of Protocol Deviations The investigator should document all protocol deviations. [E6R3-2.5.3] In addition to those identified by the investigator themselves, protocol deviations relevant to their trial participants and their conduct of the trial may be communicated to them by the sponsor. [E6R3-2.5.3] For those deviations deemed important, the investigator should explain the deviation and implement appropriate measures to prevent a recurrence, where applicable. [E6R3-2.5.3] ### Deviations to Eliminate Immediate Hazard The investigator should follow the protocol and deviate only where necessary to eliminate an immediate hazard(s) to trial participants. [E6R3-2.5.4] In case of deviations undertaken to eliminate immediate hazard to trial participants, the investigator should inform the sponsor promptly. [E6R3-2.5.4] ### Reporting Immediate Hazard Deviations The investigator should report information on the immediate hazard, the implemented change and the subsequent proposed protocol amendment, if any, to the IRB/IEC and, where applicable, regulatory authorities. [E6R3-2.5.5]

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## Monitor Responsibilities at the Trial Site The monitor is responsible for verifying that written informed consent was obtained before each subject's participation in the trial [E6R2-22]. The monitor must also ensure that the investigator receives the current Investigator's Brochure, all documents, and all trial supplies needed to conduct the trial properly and to comply with applicable regulatory requirements [E6R2-22]. The monitor is responsible for ensuring that the investigator and the investigator's trial staff are adequately informed about the trial [E6R2-22]. The monitor must verify that the investigator and trial staff are performing the specified trial functions in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and have not delegated these functions to unauthorized individuals [E6R2-22]. The monitor must verify that the investigator is enrolling only eligible subjects and must report the subject recruitment rate [E6R2-22]. The monitor is also responsible for verifying that source documents and other trial records are accurate, complete, kept up-to-date, and maintained [E6R2-22]. The monitor must verify that the investigator provides all required reports, notifications, applications, and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the trial [E6R2-22]. ## CRF and Source Document Verification The monitor is responsible for checking the accuracy and completeness of CRF entries, source documents, and other trial-related records against each other [E6R2-22]. Specifically, the monitor should verify that: - The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents [E6R2-22]. - Any dose and/or therapy modifications are well documented for each of the trial subjects [E6R2-22]. - Adverse events, concomitant medications, and intercurrent illnesses are reported in accordance with the protocol on the CRFs [E6R2-22]. - Visits that the subjects fail to make, tests that are not conducted, and examinations that are not performed are clearly reported as such on the CRFs [E6R2-22]. - All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs [E6R2-22]. The monitor must inform the investigator of any CRF entry error, omission, or illegibility, and ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialled by the investigator or by an authorized member of the investigator's trial staff [E6R2-22]. This authorization should be documented [E6R2-22]. ## Adverse Events and Essential Documents The monitor must determine whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirements [E6R2-22]. The monitor must also determine whether the investigator is maintaining the essential documents (see section 8, Essential Documents for the Conduct of a Clinical Trial) [E6R2-22]. The monitor must communicate deviations from the protocol, SOPs, GCP, and applicable regulatory requirements to the investigator and take appropriate action designed to prevent recurrence of the detected deviations [E6R2-22]. ## Monitoring Procedures (Section 5.18.5) The monitor(s) should follow the sponsor's established written SOPs as well as those procedures specified by the sponsor for monitoring a specific trial [E6R2-5.18.5]. ## Monitoring Report (Section 5.18.6) The monitor should submit a written report to the sponsor after each trial-site visit or trial-related communication [E6R2-5.18.6]. Reports should include the date, site, name of the monitor, and name of the investigator or other individual(s) contacted [E6R2-5.18.6]. Reports should include a summary of what the monitor reviewed and the monitor's statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken, and/or actions recommended to secure compliance [E6R2-5.18.6]. The review and follow-up of the monitoring report with the sponsor should be documented by the sponsor's designated representative [E6R2-5.18.6]. Reports of on-site and/or centralized monitoring should be provided to the sponsor (including appropriate management and staff responsible for trial and site oversight) in a timely manner for review and follow-up [E6R2-5.18.6]. Results of monitoring activities should be documented in sufficient detail to allow verification of compliance with the monitoring plan [E6R2-5.18.6]. Reporting of centralized monitoring activities should be regular and may be independent from site visits [E6R2-5.18.6]. ## Monitoring Plan (Section 5.18.7) The sponsor should develop a monitoring plan that is tailored to the specific human subject protection and data integrity risks of the trial [E6R2-5.18.7]. The plan should describe the monitoring strategy, the monitoring responsibilities of all the parties involved, the various monitoring methods to be used, and the rationale for their use [E6R2-5.18.7]. The plan should also emphasize the monitoring of critical data and processes [E6R2-5.18.7]. Particular attention should be given to those aspects that are not routine clinical practice and that require additional training [E6R2-5.18.7]. The monitoring plan should reference the applicable policies and procedures [E6R2-5.18.7]. ## Audit — Purpose (Section 5.19.1) If or when sponsors perform audits as part of implementing quality assurance, the purpose of a sponsor's audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements [E6R2-5.19.1].

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## Safety Reporting: Deaths and Serious Events For reported deaths, the investigator should supply the sponsor, the IRB/IEC, and, where applicable, the regulatory authority with any additional requested information (e.g., autopsy reports and terminal medical reports) when they become available. [E6R3-2.7] The investigator may delegate activities for safety reporting to qualified investigator site staff but retains overall responsibility for the safety of participants under their responsibility and compliance with the reporting requirements. [E6R3-2.7] ## Informed Consent of Trial Participants (Section 2.8) ### 2.8.1 Obtaining and Documenting Informed Consent In obtaining and documenting informed consent (paper or electronic format), the investigator should comply with the applicable regulatory requirement(s) and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. [E6R3-2.8.1] The informed consent process must include the following elements: - Prior to consenting and enrolling participants, the investigator should have the IRB/IEC's documented approval/favourable opinion of the informed consent materials and process. [E6R3-2.8.1] - The information should be as clear and concise as possible, use simple language, and avoid unnecessary volume and complexity, to ensure that trial participants or their legally acceptable representatives have an adequate understanding of the objectives of the trial, alternative treatments, potential benefits and risks, burdens, their rights, and what is expected of participants to be able to make an informed decision as to their participation. [E6R3-2.8.1] - Varied approaches (e.g., text, images, videos, and other interactive methods) may be used in the informed consent process, including for providing information to the participant. [E6R3-2.8.1] 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. [E6R3-2.8.1] 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. [E6R3-2.8.1] - Obtaining consent remotely may be considered where appropriate. [E6R3-2.8.1] - 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. [E6R3-2.8.1] ### 2.8.2 New Information and Re-Consent The participant or the participant's legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the participant's willingness to continue trial participation. [E6R3-2.8.2] The communication of this information and confirmation of the willingness to continue trial participation should be documented. [E6R3-2.8.2] New information that could impact a participant's willingness to continue participation should be assessed to determine if re-consent is needed (e.g., depending on the stage of the trial, consideration should be given to whether the new information is relevant only to new participants or to existing participants). [E6R3-2.8.2] If re-consent is needed (e.g., information on emerging safety concerns), new information should be clearly identified in the revised informed consent. [E6R3-2.8.2]

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## Correct Use of the Investigational Product The investigator, or a person designated by the investigator/institution, should explain the correct use of the investigational product(s) to each subject and should check, at intervals appropriate for the trial, that each subject is following the instructions properly [E6R2-4.6.6]. ## Randomization Procedures and Unblinding The investigator should follow the trial's randomization procedures, if any, and should ensure that the code is broken only in accordance with the protocol [E6R2-4.7]. If the trial is blinded, the investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational product(s) [E6R2-4.7]. ## Informed Consent of Trial Subjects ### Regulatory Compliance and IRB/IEC Approval In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki [E6R2-4.8.1]. Prior to the beginning of the trial, the investigator should have the IRB/IEC's written approval/favourable opinion of the written informed consent form and any other written information to be provided to subjects [E6R2-4.8.1]. ### Revision of Consent Documents The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject's consent [E6R2-4.8.2]. Any revised written informed consent form and written information should receive the IRB/IEC's approval/favourable opinion in advance of use [E6R2-4.8.2]. The subject or the subject's legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject's willingness to continue participation in the trial, and the communication of this information should be documented [E6R2-4.8.2]. ### Prohibition on Coercion Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in a trial [E6R2-4.8.3]. ### No Waiver of Legal Rights None of the oral and written information concerning the trial, including the written informed consent form, should contain any language that causes the subject or the subject's legally acceptable representative to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence [E6R2-4.8.4]. ### Full Information to Subjects The investigator, or a person designated by the investigator, should fully inform the subject or, if the subject is unable to provide informed consent, the subject's legally acceptable representative, of all pertinent aspects of the trial including the written information and the approval/favourable opinion by the IRB/IEC [E6R2-4.8.5]. ### Language and Comprehensibility The language used in the oral and written information about the trial, including the written informed consent form, should be as non-technical as practical and should be understandable to the subject or the subject's legally acceptable representative and the impartial witness, where applicable [E6R2-4.8.6]. ### Ample Time and Opportunity Before informed consent may be obtained, the investigator, or a person designated by the investigator, should provide the subject or the subject's legally acceptable representative ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial [E6R2-4.8.7]. All questions about the trial should be answered to the satisfaction of the subject or the subject's legally acceptable representative [E6R2-4.8.7]. ### Signing and Dating the Consent Form Prior to a subject's participation in the trial, the written informed consent form should be signed and personally dated by the subject or by the subject's legally acceptable representative, and by the person who conducted the informed consent discussion [E6R2-4.8.8]. ### Impartial Witness Requirements If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion [E6R2-4.8.9]. After the written informed consent form and any other written information to be provided to subjects is read and explained to the subject or the subject's legally acceptable representative, and after the subject or the subject's legally acceptable representative has orally consented to the subject's participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the witness should sign and personally date the consent form [E6R2-4.8.9]. By signing the consent form, the witness attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that informed consent was freely given by the subject or the subject's legally acceptable representative [E6R2-4.8.9]. ### Required Elements of Informed Consent Both the informed consent discussion and the written informed consent form and any other written information to be provided to subjects should include explanations of the following [E6R2-4.8.10]: - That the trial involves research [E6R2-4.8.10]. - The purpose of the trial [E6R2-4.8.10]. - The trial treatment(s) and the probability for random assignment to each treatment [E6R2-4.8.10]. - The trial procedures to be followed, including all invasive procedures [E6R2-4.8.10]. - The subject's responsibilities [E6R2-4.8.10]. - Those aspects of the trial that are experimental [E6R2-4.8.10].

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## Investigator Responsibilities for Informed Consent (Sections 2.8.3–2.8.9) ### IRB/IEC Approval of Revised Materials Revised informed consent materials should receive the IRB/IEC's approval/favourable opinion in advance of use. [E6R3-2.8] ### Prohibition on Coercion Neither the investigator nor the investigator site staff should coerce or unduly influence a participant to participate or to continue their participation in the trial. [E6R3-2.8.3] ### Prohibition on Waiver of Legal Rights None of the information provided to the participant or the participant's legally acceptable representative during the informed consent process should contain any language that causes the participant to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor or their service providers from liability for negligence. [E6R3-2.8.4] ### Who May Conduct the Informed Consent Process The informed consent process should be conducted by the investigator or other investigator site staff delegated by the investigator, in accordance with applicable regulatory requirements. [E6R3-2.8.5] If the participant is unable to provide consent themselves (e.g., minors, patients with severely impaired decision making capacity), the participant's legally acceptable representative should provide their consent on behalf of the participant. [E6R3-2.8.5] ### Adequate Time and Opportunity to Decide Before informed consent may be obtained, the investigator or investigator site staff delegated by the investigator, in accordance with the protocol and conditions of IRB/IEC favourable opinions/approvals, should provide the participant or the participant's legally acceptable representative ample time unless justified (e.g., in an emergency situation) and opportunity to enquire about trial details and to decide whether or not to participate in the trial. [E6R3-2.8.6] Questions about the trial should be answered to the satisfaction of the participant or the participant's legally acceptable representative. [E6R3-2.8.6] ### Signature and Dating Requirements Prior to trial participation, 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. [E6R3-2.8.7] 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. [E6R3-2.8.7] The informed consent process may involve a physical or an electronic signature and date. [E6R3-2.8.7] ### Emergency Situations In emergency situations, when prior consent of the participant is not possible, the consent of the participant's legally acceptable representative, if present, should be requested. [E6R3-2.8.8] When prior consent of the participant is not possible and the participant's legally acceptable representative is not available, enrolment of the participant should require measures described in the protocol and/or elsewhere, with documented approval/favourable opinion by the IRB/IEC, to protect the participant's rights, safety and well-being and to ensure compliance with applicable regulatory requirements. [E6R3-2.8.8] The participant or the participant's legally acceptable representative should be informed about the trial as soon as possible, and consent as appropriate should be requested. [E6R3-2.8.8] ### Participants Unable to Read — Role of Impartial Witness If a participant or the legally acceptable representative is unable to read, an impartial witness should be present (remotely or in-person) during the entire informed consent discussion. [E6R3-2.8.9] After the informed consent form and any other information is read and explained to the participant or the participant's legally acceptable representative and they have orally consented to the participant's trial participation and, if capable of doing so, have signed and dated the informed consent form, the witness should sign and date the consent form. [E6R3-2.8.9] By signing the consent form, the witness attests that the consent information was accurately explained to and apparently understood by the participant or the participant's legally acceptable representative. [E6R3-2.8.9]

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## Documents During Trial Conduct (Continued) The following essential documents are required during the conduct of the trial and must be maintained in the files of the investigator/institution, the sponsor, or both, as indicated. ### 8.3.17 Notification of Unexpected Serious Adverse Drug Reactions and Other Safety Information This document records notification by the sponsor and/or investigator, where applicable, to regulatory authorities and IRB(s)/IEC(s) of unexpected serious adverse drug reactions in accordance with sections 5.17 and 4.11.1, and of other safety information in accordance with sections 5.16.2 and 4.11.2 [E6R2-8.3.17]. It is located in the investigator/institution files where required, and in the sponsor files [E6R2-8.3.17]. ### 8.3.18 Notification by Sponsor to Investigators of Safety Information This document records notification by the sponsor to investigators of safety information in accordance with section 5.16.2 [E6R2-8.3.18]. It is located in both the investigator/institution files and the sponsor files [E6R2-8.3.18]. ### 8.3.19 Interim or Annual Reports to IRB/IEC and Authority(ies) This document covers interim or annual reports provided to the IRB/IEC in accordance with section 4.10, and to authority(ies) in accordance with section 5.17.3 [E6R2-8.3.19]. It is located in the investigator/institution files and in the sponsor files where required [E6R2-8.3.19]. ### 8.3.20 Subject Screening Log The purpose of this document is to record identification of subjects who entered pre-trial screening [E6R2-8.3.20]. It is located in the investigator/institution files and in the sponsor files where required [E6R2-8.3.20]. ### 8.3.21 Subject Identification Code List This document records that the investigator/institution keeps a confidential list of names of all subjects allocated to trial numbers on enrolling in the trial, and allows the investigator/institution to reveal the identity of any subject [E6R2-8.3.21]. It is located in the investigator/institution files only [E6R2-8.3.21]. ### 8.3.22 Subject Enrolment Log The purpose of this document is to record the chronological enrolment of subjects by trial number [E6R2-8.3.22]. It is located in the investigator/institution files [E6R2-8.3.22]. ### 8.3.23 Investigational Products Accountability at the Site This document records that investigational product(s) have been used according to the protocol [E6R2-8.3.23]. It is located in both the investigator/institution files and the sponsor files [E6R2-8.3.23]. ### 8.3.24 Signature Sheet The purpose of this document is to record signatures and initials of all persons authorised to make entries and/or corrections on CRFs [E6R2-8.3.24]. It is located in both the investigator/institution files and the sponsor files [E6R2-8.3.24]. ### 8.3.25 Record of Retained Body Fluids/Tissue Samples (if any) This document records the location and identification of retained samples if assays need to be repeated [E6R2-8.3.25]. It is located in both the investigator/institution files and the sponsor files [E6R2-8.3.25]. ## Documents After Completion or Termination of the Trial After completion or termination of the trial, all of the documents identified in sections 8.2 and 8.3 should be in the file together with the following documents [E6R2-8.4]. ### 8.4.1 Investigational Product(s) Accountability at Site This document records that the investigational product(s) have been used according to the protocol, and provides the final accounting of investigational product(s) received at the site, dispensed to subjects, returned by the subjects, and returned to the sponsor [E6R2-8.4.1]. It is located in both the investigator/institution files and the sponsor files [E6R2-8.4.1]. ### 8.4.2 Documentation of Investigational Product Destruction This document records destruction of unused investigational products by the sponsor or at the site [E6R2-8.4.2]. It is located in the investigator/institution files if destroyed at the site, and in the sponsor files [E6R2-8.4.2]. ### 8.4.3 Completed Subject Identification Code List This document permits identification of all subjects enrolled in the trial in case follow-up is required, and the list should be kept in a confidential manner and for an agreed upon time [E6R2-8.4.3]. It is located in the investigator/institution files only [E6R2-8.4.3]. ### 8.4.4 Audit Certificate (if available) This document records that an audit was performed [E6R2-8.4.4]. It is located in the sponsor files [E6R2-8.4.4]. ### 8.4.5 Final Trial Close-Out Monitoring Report This document records that all activities required for trial close-out are completed, and that copies of essential documents are held in the appropriate files [E6R2-8.4.5]. It is located in the sponsor files [E6R2-8.4.5]. ### 8.4.6 Treatment Allocation and Decoding Documentation This document is returned to the sponsor to record any decoding that may have occurred [E6R2-8.4.6]. It is located in the sponsor files [E6R2-8.4.6]. ### 8.4.7 Final Report by Investigator to IRB/IEC and, Where Applicable, to the Regulatory Authority(ies) This document records completion of the trial [E6R2-8.4.7]. It is located in the investigator/institution files [E6R2-8.4.7]. ### 8.4.8 Clinical Study Report This document records the results and interpretation of the trial [E6R2-8.4.8]. It is located in the investigator/institution files if applicable, and in the sponsor files [E6R2-8.4.8].

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## Investigator Records, Computerised Systems, and Trial Reports ## Data Protection for Investigator-Deployed Systems For systems deployed by the investigator/institution that maintain and retain trial data/information, the investigator/institution should ensure that such data are protected from unauthorised access, disclosure, dissemination or alteration and from inappropriate destruction or accidental loss. [E6R3-2.12.9] ## Requirements for Computerised Systems When using computerised systems in a clinical trial, the investigator/institution must address several obligations. [E6R3-2.12.10] - For systems deployed by the investigator/institution, ensure that appropriate individuals have secure and attributable access. [E6R3-2.12.10] - For systems deployed by the sponsor, notify the sponsor when access permissions need to be changed or revoked from an individual. [E6R3-2.12.10] - For systems deployed by the investigator/institution specifically for the purposes of clinical trials, ensure that the requirements for computerised systems in section 4 are addressed proportionate to the risks to participants and to the importance of the data. [E6R3-2.12.10] - Where equipment for data acquisition is provided to trial participants by the investigator, ensure that traceability is maintained and that participants are provided with appropriate training. [E6R3-2.12.10] - Ensure that incidents in the use and operation of computerised systems, which in the investigator's/institution's judgement may have a significant and/or persistent impact on the trial data or system security, are reported to the sponsor and, where applicable, to the IRB/IEC. [E6R3-2.12.10] ## Maintenance and Control of Trial Records The investigator/institution should maintain the trial records as specified in Appendix C and as required by the applicable regulatory requirement(s). [E6R3-2.12.11] The investigator/institution should have control of all essential records generated by the investigator/institution before and during the conduct of the trial. [E6R3-2.12.11] ## Retention of Essential Records The investigator/institution should retain the essential records for the required retention period in accordance with applicable regulatory requirements or until the sponsor informs the investigator/institution that these records are no longer needed, whichever is the longest. [E6R3-2.12.12] The investigator/institution should take measures to ensure availability, accessibility and readability and to prevent unauthorised access and accidental or premature destruction of these records. [E6R3-2.12.12] ## Responsibility for Records During Retention Period The investigator/institution should keep the sponsor informed of the name of the person responsible for maintaining the essential records during the retention period; for example, when the investigator site closes or an investigator leaves the site. [E6R3-2.12.13] ## Access to Trial Records Upon request of the monitor, auditor, IRB/IEC or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records. [E6R3-2.12.14] ## Trial Completion Reports Upon completion of the trial, the investigator, where applicable, should inform the institution. [E6R3-2.13] The investigator/institution should provide the IRB/IEC with a summary of the trial's outcome and, if applicable, the regulatory authority(ies) with any required reports. [E6R3-2.13]

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## 5.7 Allocation of Responsibilities Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions [E6R2-5.7]. ## 5.8 Compensation to Subjects and Investigators If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence [E6R2-5.8.1]. The sponsor's policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s) [E6R2-5.8.2]. When trial subjects receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s) [E6R2-5.8.3]. ## 5.9 Financing The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution [E6R2-5.9]. ## 5.10 Notification/Submission to Regulatory Authority(ies) Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if required by the applicable regulatory requirement(s)) should submit any required application(s) to the appropriate authority(ies) for review, acceptance, and/or permission to begin the trial(s) [E6R2-5.10]. Any notification/submission should be dated and contain sufficient information to identify the protocol [E6R2-5.10]. ## 5.11 Confirmation of Review by IRB/IEC ### 5.11.1 Information to Obtain from the Investigator/Institution The sponsor should obtain from the investigator/institution the following [E6R2-5.11.1]: - The name and address of the investigator's/institution's IRB/IEC [E6R2-5.11.1]. - A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations [E6R2-5.11.1]. - Documented IRB/IEC approval/favourable opinion and, if requested by the sponsor, a current copy of the protocol, written informed consent form(s) and any other written information to be provided to subjects, subject recruiting procedures, and documents related to payments and compensation available to the subjects, and any other documents that the IRB/IEC may have requested [E6R2-5.11.1]. ### 5.11.2 Conditional Approval If the IRB/IEC conditions its approval/favourable opinion upon change(s) in any aspect of the trial, such as modification(s) of the protocol, written informed consent form and any other written information to be provided to subjects, and/or other procedures, the sponsor should obtain from the investigator/institution a copy of the modification(s) made and the date approval/favourable opinion was given by the IRB/IEC [E6R2-5.11.2]. ### 5.11.3 Reapprovals and Withdrawals The sponsor should obtain from the investigator/institution documentation and dates of any IRB/IEC reapprovals/re-evaluations with favourable opinion, and of any withdrawals or suspensions of approval/favourable opinion [E6R2-5.11.3]. ## 5.12 Information on Investigational Product(s) When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied [E6R2-5.12.1]. The sponsor should update the Investigator's Brochure as significant new information becomes available (see 7. Investigator's Brochure) [E6R2-5.12.2]. ## 5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s) The sponsor should ensure that the investigational product(s) (including active comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable [E6R2-5.13.1]. In addition, the labelling should comply with applicable regulatory requirement(s) [E6R2-5.13.1]. The sponsor should determine, for the investigational product(s), acceptable storage temperatures, storage conditions (e.g. protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any [E6R2-5.13.2]. The sponsor should inform all involved parties (e.g. monitors, investigators, pharmacists, storage managers) of these determinations [E6R2-5.13.2]. ## Protocol Agreement The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement [E6R2-19].

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## Sponsor Obligations: Safety Reporting, Hazard Management, Insurance, and Investigational Products ## 3.13 Safety Reporting ### 3.13.2 Safety Reporting Requirements Safety reporting to regulatory authorities should be undertaken by assessing the expectedness of the reaction in relation to the applicable product information (e.g., the reference safety information (RSI) contained within the Investigator's Brochure or alternative documents) in accordance with applicable regulatory requirements. [E6R3-3.13.2] For further information about RSI, sponsors should refer to ICH E2F Development Safety Update Report. [E6R3-3.13.2] The reporting of SUSARs to investigator(s)/institution(s) and to the IRB(s)/IEC(s) should be undertaken in a manner that reflects the urgency of action required and should take into consideration the evolving knowledge of the safety profile of the product, performed in accordance with applicable regulatory requirements. [E6R3-3.13.2] In some regions, periodic reporting of line listings with an overall safety assessment may be appropriate. [E6R3-3.13.2] Urgent safety issues requiring immediate attention or action should be reported to the IRB/IEC and/or regulatory authority(ies) and investigators without undue delay and in accordance with applicable regulatory requirements. [E6R3-3.13.2] Alternative arrangements for safety reporting to regulatory authorities, IRBs/IECs, and investigators, and for reporting by investigators to the sponsor, should be prospectively agreed upon with the regulatory authority(ies) and, if applicable, the IRB/IEC, and described in the clinical trial protocol. [E6R3-3.13.2] Examples include SAEs considered efficacy or safety endpoints, which would not be subject to unblinding and expedited reporting (see ICH E2A). [E6R3-3.13.2] Sponsors should also refer to ICH E19 A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials. [E6R3-3.13.2] ### 3.13.3 Managing an Immediate Hazard The sponsor should take prompt action to address immediate hazards to participants. [E6R3-3.13.3] The sponsor should determine the causes of the hazard and, based on this, take appropriate remedial actions. [E6R3-3.13.3] The sponsor should consider whether the protocol requires amendment in response to an immediate hazard. [E6R3-3.13.3] The information on the immediate hazard, if required, and any subsequent protocol amendment should be submitted to the IRB/IEC and/or regulatory authorities by the investigator/institution or sponsor in accordance with applicable regulatory requirements. [E6R3-3.13.3] ## 3.14 Insurance/Indemnification/Compensation to Participants and Investigators If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence. [E6R3-3.14.1] The sponsor's policies and procedures should address the costs of treatment of trial participants in the event of trial-related injuries in accordance with the applicable regulatory requirement(s). [E6R3-3.14.2] The approach to compensating trial participants should comply with applicable regulatory requirement(s). [E6R3-3.14.3] ## 3.15 Investigational Product(s) ### 3.15.1 Information on Investigational Product(s) The sponsor should ensure that an Investigator's Brochure is developed and updated as significant new information on the investigational product becomes available. [E6R3-3.15.1]

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## Quality Assurance and Agreements (5.1) The sponsor is responsible for securing agreement from all involved parties to ensure direct access to all trial-related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities [E6R2-5.1.2]. Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly [E6R2-5.1.3]. Agreements made by the sponsor with the investigator/institution and any other parties involved with the clinical trial should be in writing, as part of the protocol or in a separate agreement [E6R2-5.1.4]. ## Contract Research Organization (CRO) (5.2) A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor [E6R2-5.2.1]. The CRO should implement quality assurance and quality control [E6R2-5.2.1]. The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor's contracted CRO(s) [E6R2-5.2.2]. Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing [E6R2-5.2.2]. Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor [E6R2-5.2.3]. All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the trial-related duties and functions of a sponsor [E6R2-5.2.4]. ## Medical Expertise (5.3) The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial-related medical questions or problems [E6R2-5.3]. If necessary, outside consultant(s) may be appointed for this purpose [E6R2-5.3]. ## Trial Design (5.4) The sponsor should utilize qualified individuals (e.g. biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports [E6R2-5.4.1]. For further guidance, reference is made to the Clinical Trial Protocol and Protocol Amendment(s) (see section 6), the ICH Guideline for Structure and Content of Clinical Study Reports, and other appropriate ICH guidance on trial design, protocol and conduct [E6R2-5.4.2]. ## Trial Management, Data Handling, and Record Keeping (5.5) The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports [E6R2-5.5.1]. The sponsor may consider establishing an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial [E6R2-5.5.2]. The IDMC should have written operating procedures and maintain written records of all its meetings [E6R2-5.5.2]. ### Electronic Trial Data Systems When using electronic trial data handling and/or remote electronic trial data systems, the sponsor must meet several requirements [E6R2-5.5.3]. - The sponsor should ensure and document that the electronic data processing system(s) conforms to the sponsor's established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e. validation) [E6R2-5.5.3]. The sponsor should base their approach to validation of such systems on a risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of trial results [E6R2-5.5.3]. - The sponsor should maintain SOPs for using these systems [E6R2-5.5.3]. The SOPs should cover system setup, installation, and use, and should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning [E6R2-5.5.3]. The responsibilities of the sponsor, investigator, and other parties with respect to the use of these computerized systems should be clear, and the users should be provided with training in their use [E6R2-5.5.3].

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## Overview The responsibility of the sponsor entails the implementation of risk-proportionate approaches to ensure the rights, safety and well-being of the trial participants and the reliability of the trial results throughout the clinical trial life cycle. [E6R3-3] ## 3.1 Trial Design When planning trials, the sponsor should ensure that sufficient safety and efficacy data (e.g., from nonclinical studies and/or clinical trials and/or real-world sources) are available to support human exposure by the route, at the dosages, for the duration and in the trial population to be studied. [E6R3-3.1.1] Sponsors should incorporate quality into the design of the clinical trial by identifying factors that are critical to the quality of the trial and by managing risks to those factors. [E6R3-3.1.2] Sponsors should consider inputs from a wide variety of interested parties, for example, healthcare professionals and patients, to support the development plan and clinical trial protocols as described in ICH E8(R1) and when developing the informed consent materials and any other participant-facing information. [E6R3-3.1.3] The sponsor should ensure that all aspects of the trial are operationally feasible and should avoid unnecessary complexity, procedures and data collection. [E6R3-3.1.4] Protocols, data acquisition tools and other operational documents should be fit for purpose, clear, concise and consistent. [E6R3-3.1.4] The sponsor should not place unnecessary burden on participants and investigators. [E6R3-3.1.4] ## 3.2 Resources The sponsor should ensure that sufficient resources are available to appropriately conduct the trial. [E6R3-3.2] ## 3.3 Allocation of Activities Prior to initiating clinical trial activities, the sponsor should determine the roles and allocate their trial-related activities accordingly. [E6R3-3.3] ## 3.4 Qualification and Training The sponsor should utilise appropriately qualified individuals for the activities to which they are assigned (e.g., biostatisticians, clinical pharmacologists, physicians, data scientists/data managers, auditors and monitors) throughout the trial process. [E6R3-3.4] ### 3.4.1 Medical Expertise The sponsor should have medical personnel readily available who will be able to advise on specific trial-related medical questions or problems. [E6R3-3.4.1] ## 3.5 Financing The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution. [E6R3-3.5] ## 3.6 Agreements ### 3.6.1 Documentation of Agreements Agreements made by the sponsor with the investigator/institution, service providers and any other parties (e.g., independent data monitoring committee (IDMC), adjudication committee) involved with the clinical trial should be documented prior to initiating the activities. [E6R3-3.6.1] ### 3.6.2 Updating Agreements Agreements should be updated when necessary to reflect significant changes in the activities transferred. [E6R3-3.6.2] ### 3.6.3 Required Investigator/Institution Agreements The sponsor should obtain the investigator's/institution's and, where applicable, service provider's agreements on the following points: [E6R3-3.6.3] - To conduct the trial in accordance with the approved protocol and in compliance with GCP and applicable regulatory requirement(s); [E6R3-3.6.3] - To comply with procedures for data recording/reporting; [E6R3-3.6.3] - To retain the essential records for the required retention period in accordance with applicable regulatory requirements or until the sponsor informs the investigator/institution or, where applicable, the service provider that these records are no longer needed, whichever is longest; [E6R3-3.6.3] - To permit monitoring and auditing by sponsors, inspections by regulatory authorities (domestic and foreign) and, in accordance with applicable regulatory requirements, review by IRBs/IECs, including providing direct access to source records and facilities, including to those of service providers. [E6R3-3.6.3] ### 3.6.4 Transfer of Activities to Service Providers Any of the sponsor's trial-related activities that are transferred to and assumed by a service provider should be documented in an agreement. [E6R3-3.6.4] The sponsor's trial-related activities that are not specifically transferred to and assumed by a service provider are retained by the sponsor. [E6R3-3.6.4] ### 3.6.5 Information to Investigators Regarding Service Providers The sponsor should provide information to the investigator on any service provider identified by the sponsor to undertake any activities under the responsibility of the investigator. [E6R3-3.6.5] The responsibility for such activities remains with the investigator. [E6R3-3.6.5] ### 3.6.6 Ultimate Sponsor Responsibility A sponsor may transfer any or all of the sponsor's trial-related activities to a service provider in accordance with applicable regulatory requirements; however, the ultimate responsibility for the sponsor's trial-related activities, including protection of participants' rights, safety and well-being and reliability of the trial data, resides with the sponsor. [E6R3-3.6.6] Any service provider used to perform clinical trial activities should implement appropriate quality management and report to the sponsor incidents that might have an impact on the safety of trial participants or/and trial results. [E6R3-3.6.6] ### 3.6.7 Selection and Support of Service Providers The sponsor is responsible for assessing the suitability of and selecting the service provider to ensure that they can adequately undertake the activities transferred to them. [E6R3-3.6.7] The sponsor should provide the service providers with the protocol where necessary as well as any other documents required for them to perform their activities. [E6R3-3.6.7] ### 3.6.8 Access to Service Provider Information The sponsor should have access to relevant information (e.g., SOPs and performance metrics) for selection and oversight of service providers. [E6R3-3.6.8] ### 3.6.9 Oversight of Transferred Activities The sponsor should ensure appropriate oversight of important trial-related activities that are transferred to service providers, including activities further subcontracted by the service provider. [E6R3-3.6.9]

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## Investigator Reporting Obligations on Trial Termination or Suspension If the sponsor terminates or suspends a trial, the investigator should promptly inform the institution where applicable, and the investigator/institution should promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or suspension [E6R2-4.12.2]. If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial, the investigator should inform the institution where applicable, and the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension [E6R2-4.12.3]. ## Final Report by Investigator Upon completion of the trial, the investigator, where applicable, should inform the institution; the investigator/institution should provide the IRB/IEC with a summary of the trial's outcome, and the regulatory authority(ies) with any reports required [E6R2-4.13]. ## Sponsor Quality Management (Section 5.0) The sponsor should implement a system to manage quality throughout all stages of the trial process [E6R2-5.0]. Sponsors should focus on trial activities essential to ensuring human subject protection and the reliability of trial results [E6R2-5.0]. Quality management includes the design of efficient clinical trial protocols and tools and procedures for data collection and processing, as well as the collection of information that is essential to decision making [E6R2-5.0]. The methods used to assure and control the quality of the trial should be proportionate to the risks inherent in the trial and the importance of the information collected [E6R2-5.0]. The sponsor should ensure that all aspects of the trial are operationally feasible and should avoid unnecessary complexity, procedures, and data collection [E6R2-5.0]. Protocols, case report forms, and other operational documents should be clear, concise, and consistent [E6R2-5.0]. The quality management system should use a risk-based approach as described in sections 5.0.1 through 5.0.7 [E6R2-5.0]. ### 5.0.1 Critical Process and Data Identification During protocol development, the sponsor should identify those processes and data that are critical to ensure human subject protection and the reliability of trial results [E6R2-5.0.1]. ### 5.0.2 Risk Identification The sponsor should identify risks to critical trial processes and data [E6R2-5.0.2]. Risks should be considered at both the system level (e.g., standard operating procedures, computerized systems, personnel) and clinical trial level (e.g., trial design, data collection, informed consent process) [E6R2-5.0.2]. ### 5.0.3 Risk Evaluation The sponsor should evaluate the identified risks against existing risk controls by considering the following [E6R2-5.0.3]: - The likelihood of errors occurring [E6R2-5.0.3]. - The extent to which such errors would be detectable [E6R2-5.0.3]. - The impact of such errors on human subject protection and reliability of trial results [E6R2-5.0.3]. ### 5.0.4 Risk Control The sponsor should decide which risks to reduce and/or which risks to accept [E6R2-5.0.4]. The approach used to reduce risk to an acceptable level should be proportionate to the significance of the risk [E6R2-5.0.4]. Risk reduction activities may be incorporated in protocol design and implementation, monitoring plans, agreements between parties defining roles and responsibilities, systematic safeguards to ensure adherence to standard operating procedures, and training in processes and procedures [E6R2-5.0.4]. Predefined quality tolerance limits should be established, taking into consideration the medical and statistical characteristics of the variables as well as the statistical design of the trial, to identify systematic issues that can impact subject safety or reliability of trial results [E6R2-5.0.4]. Detection of deviations from the predefined quality tolerance limits should trigger an evaluation to determine if action is needed [E6R2-5.0.4]. ### 5.0.5 Risk Communication The sponsor should document quality management activities [E6R2-5.0.5]. The sponsor should communicate quality management activities to those who are involved in or affected by such activities, to facilitate risk review and continual improvement during clinical trial execution [E6R2-5.0.5]. ### 5.0.6 Risk Review The sponsor should periodically review risk control measures to ascertain whether the implemented quality management activities remain effective and relevant, taking into account emerging knowledge and experience [E6R2-5.0.6]. ### 5.0.7 Risk Reporting The sponsor should describe the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken in the clinical study report (ICH E3, Section 9.6 Data Quality Assurance) [E6R2-5.0.7]. ## Quality Assurance and Quality Control (Section 5.1) The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s) [E6R2-5.1.1].

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## 3.10.1 Risk Management A proportionate approach to the identification and management of risk is required of sponsors throughout the clinical trial lifecycle. [E6R3-3.10.1] ### 3.10.1.1 Risk Identification The sponsor should identify risks that may have a meaningful impact on critical to quality factors prior to trial initiation and throughout trial conduct. [E6R3-3.10.1.1] Risks should be considered across the processes and systems, including computerised systems, used in the clinical trial—for example, trial design, participant selection, informed consent process, randomisation, blinding, investigational product administration, data handling, and service provider activities. [E6R3-3.10.1.1] ### 3.10.1.2 Risk Evaluation The sponsor should evaluate identified risks and existing controls in place to mitigate the risk by considering the following factors: [E6R3-3.10.1.2] - The likelihood of harm/hazard occurring; [E6R3-3.10.1.2] - The extent to which such harm/hazard would be detectable; [E6R3-3.10.1.2] - The impact of such harm/hazard on trial participant protection and the reliability of trial results. [E6R3-3.10.1.2] ### 3.10.1.3 Risk Control Risk control should be proportionate to the importance of the risk to participants' rights, safety and well-being and the reliability of trial results. [E6R3-3.10.1.3] Risk mitigation activities may be incorporated, for example, in protocol design and implementation, monitoring plans, agreements between parties defining roles and responsibilities, and training. [E6R3-3.10.1.3] Where relevant, the sponsor should set pre-specified acceptable ranges (e.g., quality tolerance limits at the trial level) to support the control of risks to critical to quality factors. [E6R3-3.10.1.3] These pre-specified ranges reflect limits that when exceeded have the potential to impact participant safety or the reliability of trial results. [E6R3-3.10.1.3] Where deviation beyond these ranges is detected, an evaluation should be performed to determine if there is a possible systemic issue and if action is needed. [E6R3-3.10.1.3] ### 3.10.1.4 Risk Communication The sponsor should document and communicate the identified risks and mitigating activities, if applicable, to those who are involved in taking action or are affected by such activities. [E6R3-3.10.1.4] Communication also facilitates risk review and continual improvement during clinical trial conduct. [E6R3-3.10.1.4] ### 3.10.1.5 Risk Review The sponsor should periodically review risk control measures to ascertain whether the implemented quality management activities remain effective and relevant, taking into account emerging knowledge and experience. [E6R3-3.10.1.5] Additional risk control measures may be implemented as needed. [E6R3-3.10.1.5] ### 3.10.1.6 Risk Reporting The sponsor should summarise and report important quality issues—including instances in which acceptable ranges are exceeded, as detailed in section 3.10.1.3—and the remedial actions taken, and document them in the clinical trial report (see ICH E3). [E6R3-3.10.1.6] ## 3.11 Quality Assurance and Quality Control The sponsor is responsible for establishing, implementing and maintaining appropriate quality assurance and quality control processes and documented procedures to ensure that trials are conducted and data are generated, recorded and reported in compliance with the protocol, GCP and the applicable regulatory requirement(s). [E6R3-3.11] ### 3.11.1 Quality Assurance Quality assurance should be applied throughout the clinical trial and includes implementing risk-based strategies to identify potential or actual causes of serious noncompliance with the protocol, GCP and/or applicable regulatory requirements to enable their corrective and preventive actions. [E6R3-3.11.1] ### 3.11.2 Audit When performed, audits should be conducted in a manner that is proportionate to the risks associated with the conduct of the trial. [E6R3-3.11.2] The purpose of a sponsor's audit, which is independent of and separate from routine monitoring or quality control functions, is to evaluate whether the processes put in place to manage and conduct the trial are appropriate to ensure compliance with the protocol, GCP and the applicable regulatory requirements. [E6R3-3.11.2] #### 3.11.2.1 Selection and Qualification of Auditors - The sponsor should appoint individuals who are independent of the clinical trial/processes being audited. [E6R3-3.11.2.1] - The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. [E6R3-3.11.2.1] #### 3.11.2.2 Auditing Procedures - The sponsor should ensure that the auditing of clinical trials/processes is conducted in accordance with the sponsor's documented procedures on what to audit, how to audit (i.e., on-site and/or remote), the frequency of audits and the form and content of audit reports. [E6R3-3.11.2.2] - The sponsor's audit plan, program and procedures for a trial audit should be guided, for example, by the importance of the trial to submissions to regulatory authorities, the number of participants in the trial, the type and complexity of the trial, the level of risks to the trial participants and any identified problem(s). [E6R3-3.11.2.2] - The observations and findings of the auditor(s) should be documented. [E6R3-3.11.2.2] - To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely request the audit reports; regulatory authority(ies) may seek access to an audit report on a case-by-case basis (i.e., when evidence or suspicion of serious GCP noncompliance exists or in the course of legal proceedings). [E6R3-3.11.2.2] - When required by applicable regulatory requirements, the sponsor should provide an audit certificate. [E6R3-3.11.2.2]

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## 5.19.2 Selection and Qualification of Auditors The sponsor should appoint individuals who are independent of the clinical trials/systems to conduct audits [E6R2-5.19.2]. The sponsor should ensure that auditors are qualified by training and experience to conduct audits properly, and an auditor's qualifications should be documented [E6R2-5.19.2]. ## 5.19.3 Auditing Procedures The sponsor should ensure that auditing of clinical trials/systems is conducted in accordance with the sponsor's written procedures covering what to audit, how to audit, the frequency of audits, and the form and content of audit reports [E6R2-5.19.3]. The sponsor's audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s) [E6R2-5.19.3]. The observations and findings of the auditor(s) should be documented [E6R2-5.19.3]. To preserve the independence and value of the audit function, regulatory authority(ies) should not routinely request audit reports [E6R2-5.19.3]. Regulatory authority(ies) may seek access to an audit report on a case-by-case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings [E6R2-5.19.3]. When required by applicable law or regulation, the sponsor should provide an audit certificate [E6R2-5.19.3]. ## 5.20 Noncompliance ### 5.20.1 General Noncompliance Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the sponsor's staff, should lead to prompt action by the sponsor to secure compliance [E6R2-5.20.1]. If noncompliance that significantly affects or has the potential to significantly affect human subject protection or reliability of trial results is discovered, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions [E6R2-5.20.1]. ### 5.20.2 Serious or Persistent Noncompliance If monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator's/institution's participation in the trial [E6R2-5.20.2]. When an investigator's/institution's participation is terminated because of noncompliance, the sponsor should promptly notify the regulatory authority(ies) [E6R2-5.20.2]. ## 5.21 Premature Termination or Suspension of a Trial If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions and the regulatory authority(ies) of the termination or suspension and the reason(s) for it [E6R2-5.21]. The IRB/IEC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s) [E6R2-5.21]. ## 5.22 Clinical Trial/Study Reports Whether the trial is completed or prematurely terminated, the sponsor should ensure that clinical trial reports are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory requirement(s) [E6R2-5.22]. The sponsor should also ensure that clinical trial reports in marketing applications meet the standards of the ICH Guideline for Structure and Content of Clinical Study Reports [E6R2-5.22]. Abbreviated study reports may be acceptable in certain cases, as specified in that ICH Guideline [E6R2-5.22]. ## 5.23 Multicentre Trials For multicentre trials, the sponsor should ensure that all investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies), and given approval/favourable opinion by the IRB/IEC [E6R2-5.23.1]. The CRFs should be designed to capture the required data at all multicentre trial sites; for investigators collecting additional data, supplemental CRFs should also be provided to capture that additional data [E6R2-5.23.2]. The responsibilities of coordinating investigator(s) and the other participating investigators should be documented prior to the start of the trial [E6R2-5.23.3]. All investigators should be given instructions on following the protocol, on complying with a uniform set of standards for the assessment of clinical and laboratory findings, and on completing the CRFs [E6R2-5.23.4]. Communication between investigators should be facilitated [E6R2-5.23.5].

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## Sponsor Responsibilities: Investigational Product Manufacturing, Labelling, and Supply ### 3.15.2 Manufacturing, Packaging, Labelling and Coding Investigational Product(s) #### Characterisation, GMP, and Labelling The sponsor should ensure that the investigational product(s) — including active control(s) and placebo, if applicable — is characterised as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable. [E6R3-3.15.2] In addition, the labelling should comply with applicable regulatory requirement(s). [E6R3-3.15.2] #### Storage, Reconstitution, and Administration The sponsor should determine acceptable storage temperatures, storage conditions (e.g., protection from light), and shelf life for the investigational product(s), as well as appropriate reconstitution fluids and procedures, and devices for product administration, if any. [E6R3-3.15.2] The sponsor should inform all involved parties — such as monitors, investigators, pharmacists, and storage managers — of these determinations. [E6R3-3.15.2] #### Packaging The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage. [E6R3-3.15.2] #### Blinding Requirements In blinded trials, the sponsor should implement the following measures: [E6R3-3.15.2] - A process to blind individuals — including sponsor staff, trial participants, investigators, and/or investigator site staff, as appropriate — to the investigational product identity and assignment, and a process to prevent and detect inappropriate unblinding. [E6R3-3.15.2] - A procedure and mechanism that permits the investigator to rapidly identify the product(s) in case of a medical emergency where unblinding is considered necessary, while protecting the identity of the treatment assignment of the other trial participants. [E6R3-3.15.2] - A mechanism that protects the blinding of the trial where a participant's treatment assignment is unblinded for the purpose of safety reporting to regulatory authorities and/or IRB/IEC, where appropriate. [E6R3-3.15.2] #### Significant Formulation Changes If significant formulation changes are made in the investigational product(s) — including active control(s) and placebo, if applicable — during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials. [E6R3-3.15.2] ### 3.15.3 Supplying and Handling Investigational Product(s) The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s). [E6R3-3.15.3] Where appropriate, the sponsor may supply the investigational product(s) to the trial participants in accordance with applicable regulatory requirements. [E6R3-3.15.3] Investigational product should be supplied only after obtaining the required approval/favourable opinion from the IRB/IEC and the regulatory authority(ies) for the trial. [E6R3-3.15.3] Various approaches for shipping and dispensing may be undertaken — for example, by taking into consideration the characteristics of the investigational products, the route and complexity of administration, and the level of existing knowledge about the investigational product's safety profile. [E6R3-3.15.3]

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## Packaging of Investigational Products Investigational products should be packaged to prevent contamination and unacceptable deterioration during transport and storage [E6R2-5.13.3]. ## Blinded Trial Coding Systems In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding [E6R2-5.13.4]. ## Formulation Changes During Clinical Development If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g. stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials [E6R2-5.13.5]. ## Supplying and Handling Investigational Products ### Sponsor Responsibility for Supply The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s) [E6R2-5.14.1]. The sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains all required documentation (e.g. approval/favourable opinion from IRB/IEC and regulatory authority(ies)) [E6R2-5.14.2]. ### Written Procedures for Handling and Storage The sponsor should ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of investigational product(s) for the trial and documentation thereof [E6R2-5.14.3]. The procedures should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s)) [E6R2-5.14.3]. ### Sponsor Obligations Regarding Shipment and Retrieval The sponsor should ensure timely delivery of investigational product(s) to the investigator(s) [E6R2-5.14.4]. The sponsor should maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s) (see 8. Essential Documents for the Conduct of a Clinical Trial) [E6R2-5.14.4]. The sponsor should also maintain a system for retrieving investigational products and documenting this retrieval (e.g. for deficient product recall, reclaim after trial completion, expired product reclaim), as well as a system for the disposition of unused investigational product(s) and for the documentation of this disposition [E6R2-5.14.4]. ### Stability and Batch Retention The sponsor should take steps to ensure that the investigational product(s) are stable over the period of use [E6R2-5.14.5]. The sponsor should maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics [E6R2-5.14.5]. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period [E6R2-5.14.5]. ## Record Access The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory inspection [E6R2-5.15.1]. The sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection [E6R2-5.15.2]. ## Safety Information The sponsor is responsible for the ongoing safety evaluation of the investigational product(s) [E6R2-5.16.1]. The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC's approval/favourable opinion to continue the trial [E6R2-5.16.2]. ## Adverse Drug Reaction Reporting The sponsor should expedite the reporting to all concerned investigator(s)/institution(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected [E6R2-5.17.1].

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## Investigational Product Records and Handling ### Instructions and Procedures The sponsor should ensure that instructions are available for the investigator/institution or trial participants on the handling and storage of investigational product(s). [E6R3-3.15] The procedures should consider adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from participants and return of unused investigational product(s) to the sponsor (or alternative disposition if authorised by the sponsor and in compliance with the applicable regulatory requirement(s)). [E6R3-3.15] ### Sponsor Obligations for Investigational Products The sponsor must ensure timely provision of investigational product(s) to the investigator(s) or, where appropriate, to trial participants in accordance with applicable regulatory requirements to avoid any interruption to the trial as well as for the continuation of treatment for participants. [E6R3-3.15] The sponsor must maintain records that document the identity, shipment, receipt, return and destruction or alternative disposition of the investigational product(s). [E6R3-3.15] A process for retrieving investigational products and documenting this retrieval must also be maintained (e.g., for deficient product recall, return and destruction or alternative disposition after trial completion, or expired product reclaim). [E6R3-3.15] The sponsor must maintain a process for the disposition of unused investigational product(s) and for the documentation of this disposition. [E6R3-3.15] Steps must be taken to ensure that the investigational product(s) are stable over the period of use and only used within the current shelf life. [E6R3-3.15] The sponsor must maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications should this become necessary, and must maintain records of batch sample analyses and characteristics. [E6R3-3.15] The samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period. [E6R3-3.15] The samples may not need to be kept by the sponsor in trials where an authorised medicinal product is used as an investigational product unmodified from its authorised state in accordance with local regulatory requirements; in this situation, samples are typically kept by the manufacturer. [E6R3-3.15] ## 3.16 Data and Records ### 3.16.1 Data Handling ### Integrity and Confidentiality The sponsor should ensure the integrity and confidentiality of data generated and managed. [E6R3-3.16.1] The sponsor should apply quality control to the relevant stages of data handling to ensure that the data are of sufficient quality to generate reliable results. [E6R3-3.16.1] The sponsor should focus their quality assurance and quality control activities, including data review, on data of higher criticality and relevant metadata. [E6R3-3.16.1] ### Data Pre-specification and Acquisition Tools The sponsor should pre-specify data to be collected and the method of its collection in the protocol. [E6R3-3.16.1] Where necessary, additional details, including a data flow diagram, should be contained in a protocol-related document (e.g., a data management plan). [E6R3-3.16.1] The sponsor should ensure that data acquisition tools are fit for purpose and designed to capture the information required by the protocol. [E6R3-3.16.1] They should be validated and ready for use prior to their required use in the trial. [E6R3-3.16.1] ### Data Integrity Across the Full Data Life Cycle The sponsor should ensure that documented processes are implemented to ensure the data integrity for the full data life cycle. [E6R3-3.16.1] ### Blinding Safeguards The sponsor should implement measures to ensure the safeguarding of the blinding, if any (e.g., maintain the blinding during data entry and processing). [E6R3-3.16.1] The sponsor should put procedures in place to describe unblinding, where applicable; these descriptions should include: - Who were unblinded, at what timepoint and for what purpose they were unblinded; [E6R3-3.16.1] - Who should remain blinded; [E6R3-3.16.1] - The safeguards in place to preserve the blinding. [E6R3-3.16.1] ### Guidance to Investigators and Participants The sponsor should provide guidance to investigators/institutions, service providers and trial participants, where relevant, on the expectations for data capture, data changes, data retention and data disposal. [E6R3-3.16.1] ### Data Changes and Corrections The sponsor should not make changes to data entered by the investigator or trial participants unless justified, agreed upon in advance by the investigator and documented. [E6R3-3.16.1] The sponsor should allow correction of errors to data, including data entered by participants, where requested by the investigators/participants. [E6R3-3.16.1] Such data corrections should be justified and supported by source records around the time of original entry. [E6R3-3.16.1] ### Investigator Access to Data The sponsor should ensure that the investigator has timely access to data collected in accordance with the protocol during the course of the trial, including relevant data from external sources (e.g., central laboratory data, centrally read imaging data and, if appropriate, ePRO data). [E6R3-3.16.1] This enables the investigators to make decisions (e.g., on eligibility, treatment, continuing participation in the trial and care for the safety of the individual trial participants). [E6R3-3.16.1] The sponsor should not share data that may unblind the investigator and should include the appropriate provisions in the protocol. [E6R3-3.16.1] The sponsor should not have exclusive control of data captured in data acquisition tools in order to prevent undetectable changes. [E6R3-3.16.1] The sponsor should ensure that the investigator has access to the required data for retention purposes. [E6R3-3.16.1] The sponsor should ensure that the investigator receives instructions on how to navigate systems, data and relevant metadata for the trial participants under their responsibility. [E6R3-3.16.1] ### Investigator Endorsement The sponsor should seek investigator endorsement of their reported data at predetermined important milestones. [E6R3-3.16.1]

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## Data Integrity and Computerized Systems Systems must be designed to permit data changes in a documented manner, ensuring no deletion of entered data — that is, maintaining an audit trail, data trail, or edit trail [E6R2-5.5.3c]. A security system must be maintained to prevent unauthorized access to the data [E6R2-5.5.3d]. A list of individuals authorized to make data changes must be maintained (see 4.1.5 and 4.9.3) [E6R2-5.5.3e]. Adequate backup of the data must be maintained [E6R2-5.5.3f]. Where blinding exists, it must be safeguarded during data entry and processing [E6R2-5.5.3g]. The integrity of the data — including data that describe the context, content, and structure — must be ensured; this is particularly important when making changes to computerized systems, such as software upgrades or data migration [E6R2-5.5.3h]. ## Data Transformation If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data [E6R2-5.5.4]. ## Subject Identification Code The sponsor should use an unambiguous subject identification code (see 1.58) that allows identification of all the data reported for each subject [E6R2-5.5.5]. ## Retention of Essential Documents The sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial (see section 8, Essential Documents for the Conduct of a Clinical Trial) [E6R2-5.5.6]. The sponsor should retain all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of the country or countries where the product is approved, and/or where the sponsor intends to apply for approval(s) [E6R2-5.5.7]. If the sponsor discontinues the clinical development of an investigational product — for any or all indications, routes of administration, or dosage forms — the sponsor should maintain all sponsor-specific essential documents for at least 2 years after formal discontinuation or in conformance with the applicable regulatory requirement(s) [E6R2-5.5.8]. Upon such discontinuation, the sponsor should notify all trial investigators/institutions and all regulatory authorities [E6R2-5.5.9]. Any transfer of ownership of the data should be reported to the appropriate authority or authorities, as required by the applicable regulatory requirement(s) [E6R2-5.5.10]. Sponsor-specific essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product [E6R2-5.5.11]. These documents should be retained for a longer period if required by the applicable regulatory requirement(s) or if needed by the sponsor [E6R2-5.5.11]. The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) in writing when the trial-related records are no longer needed [E6R2-5.5.12]. ## Investigator Selection The sponsor is responsible for selecting the investigator(s)/institution(s) [E6R2-5.6.1]. Each investigator should be qualified by training and experience and should have adequate resources (see 4.1, 4.2) to properly conduct the trial for which the investigator is selected [E6R2-5.6.1]. If a coordinating committee and/or coordinating investigator(s) are to be utilized in multicentre trials, their organization and/or selection are the sponsor's responsibility [E6R2-5.6.1]. Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator's Brochure, and should provide sufficient time for the investigator/institution to review the protocol and the information provided [E6R2-5.6.2]. ## Investigator/Institution Agreement The sponsor should obtain the investigator's/institution's agreement on the following points [E6R2-5.6.3]: - To conduct the trial in compliance with GCP, with the applicable regulatory requirement(s) (see 4.1.3), and with the protocol agreed to by the sponsor and given approval/favourable opinion by the IRB/IEC (see 4.5.1) [E6R2-5.6.3a]. - To comply with procedures for data recording/reporting [E6R2-5.6.3b]. - To permit monitoring, auditing, and inspection (see 4.1.4) [E6R2-5.6.3c]. - To retain the trial-related essential documents until the sponsor informs the investigator/institution these documents are no longer needed (see 4.9.4 and 5.5.12) [E6R2-5.6.3d].

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## Sponsor Obligations: Records, Retention, Access, and Reports ## 3.16 Data Management and Records ### 3.16.2 Statistical Programming Records The sponsor should retain the statistical programming records that relate to the output contained or used in reports of the trial results, including quality control and validation activities performed. [E6R3-3.16.2] Outputs should be traceable to the statistical software programs, dated and time stamped, protected against any changes, and have access controls implemented to avoid inappropriate viewing of information that may introduce bias. [E6R3-3.16.2] Post-unblinding data changes and deviations from the planned statistical analyses should be reported in the clinical trial report. [E6R3-3.16.2] ### 3.16.3 Record Keeping and Retention The sponsor (or subsequent owners of the data) should retain the sponsor-specific essential records pertaining to the trial in accordance with the applicable regulatory requirement(s). [E6R3-3.16.3] The sponsor should inform the investigator(s)/institution(s) and service providers, when appropriate, in writing of the requirements for the retention of essential records. [E6R3-3.16.3] The sponsor should also notify the investigator(s)/institution(s) and service providers, when appropriate, in writing when the trial-related records are no longer needed in accordance with applicable regulatory requirements. [E6R3-3.16.3] The sponsor should report to the appropriate authority(ies) any transfer of ownership of the essential records as required by the applicable regulatory requirement(s). [E6R3-3.16.3] The sponsor should also inform the investigator if sponsorship of the trial changes. [E6R3-3.16.3] ### 3.16.4 Record Access The sponsor should ensure that it is specified in the protocol or other documented agreement that the investigator(s)/institution(s) provide direct access to source records for trial-related monitoring, audits, regulatory inspection and, in accordance with applicable regulatory requirements, IRB/IEC review. [E6R3-3.16.4] The sponsor should ensure that trial participants have consented to direct access to source records for the purposes outlined in section 3.16.4(a). [E6R3-3.16.4] ## 3.17 Reports ### 3.17.1 Premature Termination or Suspension of a Trial If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. [E6R3-3.17.1] The IRB/IEC should also be informed promptly and provided with the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, in accordance with applicable regulatory requirement(s). [E6R3-3.17.1] Where appropriate, the sponsor should provide the investigator with information about potential subsequent therapy(ies) and follow-up for the participants. [E6R3-3.17.1] ### 3.17.2 Clinical Trial/Study Reports Whether the trial is completed or prematurely terminated, or an interim analysis is undertaken for regulatory submission, the sponsor should ensure that the clinical trial reports, including interim reports, are prepared and provided to the regulatory authority(ies) as required by the applicable regulatory requirement(s). [E6R3-3.17.2] The sponsor should also ensure that the clinical trial reports in marketing applications meet the standards of ICH E3 or are otherwise in accordance with applicable regulatory requirements. [E6R3-3.17.2] Where a coordinating investigator is involved in a trial, consideration should be given to them being a signatory on the clinical trial report (see ICH E3). [E6R3-3.17.2] Once the trial has been unblinded and relevant analyses/conclusions have been completed and finalised, the sponsor should generally, in accordance with applicable regulatory requirements: [E6R3-3.17.2] - Make trial results publicly available; [E6R3-3.17.2] - Provide the investigator with information about the treatment taken by their participants for blinded trials; [E6R3-3.17.2] - Provide investigators with the trial results. [E6R3-3.17.2] Where a summary of trial results is provided to participants, this should have language that is non-technical, understandable to a layperson and non-promotional. [E6R3-3.17.2]

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## Confidentiality Statement The sponsor may wish to include a statement instructing the investigator/recipients to treat the IB as a confidential document for the sole information and use of the investigator's team and the IRB/IEC [E6R2-7.2.2]. ## Contents of the Investigator's Brochure The IB should contain the following sections, each with literature references where appropriate [E6R2-7.3]. ### Table of Contents An example of the Table of Contents is given in Appendix 2 [E6R2-7.3.1]. ### Summary A brief summary (preferably not exceeding two pages) should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product [E6R2-7.3.2]. ### Introduction A brief introductory statement should be provided that contains the chemical name (and generic and trade name(s) when approved) of the investigational product(s), all active ingredients, the investigational product's pharmacological class and its expected position within this class (e.g., advantages), the rationale for performing research with the investigational product(s), and the anticipated prophylactic, therapeutic, or diagnostic indication(s) [E6R2-7.3.3]. The introductory statement should also provide the general approach to be followed in evaluating the investigational product [E6R2-7.3.3]. ### Physical, Chemical, and Pharmaceutical Properties and Formulation A description should be provided of the investigational product substance(s) (including the chemical and/or structural formula(e)), and a brief summary should be given of the relevant physical, chemical, and pharmaceutical properties [E6R2-7.3.4]. To permit appropriate safety measures to be taken in the course of the trial, a description of the formulation(s) to be used, including excipients, should be provided and justified if clinically relevant [E6R2-7.3.4]. Instructions for the storage and handling of the dosage form(s) should also be given [E6R2-7.3.4]. Any structural similarities to other known compounds should be mentioned [E6R2-7.3.4]. ### Nonclinical Studies The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and investigational product metabolism studies should be provided in summary form [E6R2-7.3.5]. This summary should address the methodology used, the results, and a discussion of the relevance of the findings to the investigated therapeutic and the possible unfavourable and unintended effects in humans [E6R2-7.3.5]. The information provided may include the following, as appropriate, if known/available [E6R2-7.3.5]: - Species tested [E6R2-7.3.5] - Number and sex of animals in each group [E6R2-7.3.5] - Unit dose (e.g., milligram/kilogram (mg/kg)) [E6R2-7.3.5] - Dose interval [E6R2-7.3.5] - Route of administration [E6R2-7.3.5] - Duration of dosing [E6R2-7.3.5] - Information on systemic distribution [E6R2-7.3.5] - Duration of post-exposure follow-up [E6R2-7.3.5] - Results, including: nature and frequency of pharmacological or toxic effects; severity or intensity of pharmacological or toxic effects; time to onset of effects; reversibility of effects; duration of effects; dose response [E6R2-7.3.5] Tabular format/listings should be used whenever possible to enhance the clarity of the presentation [E6R2-7.3.5]. The following sections should discuss the most important findings from the studies, including the dose response of observed effects, the relevance to humans, and any aspects to be studied in humans [E6R2-7.3.5]. If applicable, the effective and nontoxic dose findings in the same animal species should be compared (i.e., the therapeutic index should be discussed) [E6R2-7.3.5]. The relevance of this information to the proposed human dosing should be addressed, and whenever possible, comparisons should be made in terms of blood/tissue levels rather than on a mg/kg basis [E6R2-7.3.5]. #### a) Nonclinical Pharmacology A summary of the pharmacological aspects of the investigational product and, where appropriate, its significant metabolites studied in animals, should be included [E6R2-7.3.5]. Such a summary should incorporate studies that assess potential therapeutic activity (e.g., efficacy models, receptor binding, and specificity) as well as those that assess safety (e.g., special studies to assess pharmacological actions other than the intended therapeutic effect(s)) [E6R2-7.3.5]. #### b) Pharmacokinetics and Product Metabolism in Animals A summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied should be given [E6R2-7.3.5]. The discussion of the findings should address the absorption and the local and systemic bioavailability of the investigational product and its metabolites, and their relationship to the pharmacological and toxicological findings in animal species [E6R2-7.3.5]. #### c) Toxicology A summary of the toxicological effects found in relevant studies conducted in different animal species should be described under appropriate headings [E6R2-7.3.5].

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## General Considerations (A.2) The considerations in section A.2 delineate the minimum information that should be included in an Investigator's Brochure (IB). [E6R3-A.2] It is expected that the type and extent of information available will vary with the stage of development of the investigational product. [E6R3-A.2] ### Title Page (A.2.1) The title page should provide the sponsor's name, the identity of each investigational product (i.e., research number, chemical or approved generic name and trade name(s) where legally permissible and desired by the sponsor), and the release date. [E6R3-A.2.1] It is also suggested that an edition number and a reference to the number and date of the edition it supersedes be provided, along with the cut-off date for data inclusion in the version. [E6R3-A.2.1] Where appropriate, a signature page may be included. [E6R3-A.2.1] ### Confidentiality Statement (A.2.2) The sponsor may wish to include a statement instructing the investigator and other recipients to treat the IB as a confidential document for the sole information and use of the investigator/institution, investigator site staff, regulatory authorities, and the IRB/IEC. [E6R3-A.2.2] ## Contents of the Investigator's Brochure (A.3) The IB should contain the following sections, each with literature references (publications or reports) included at the end of each chapter, where appropriate. [E6R3-A.3] ### Table of Contents (A.3.1) A table of contents must be included in the IB. [E6R3-A.3.1] ### Summary (A.3.2) A brief summary, preferably not exceeding two pages, should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product. [E6R3-A.3.2] ### Introduction (A.3.3) A brief introductory statement should be provided that contains the chemical name (and generic and trade name(s) when approved) of the investigational product(s), all active ingredients, the pharmacological class of the investigational product(s) and its expected position within this class (e.g., advantages), the rationale for performing research with the investigational product(s), and the anticipated prophylactic, therapeutic, or diagnostic indication(s). [E6R3-A.3.3] The introductory statement should also provide the general approach to be followed in evaluating the investigational product. [E6R3-A.3.3] ### Physical, Chemical and Pharmaceutical Properties and Formulation (A.3.4) A description should be provided of the investigational product substance(s), including the chemical and/or structural formula(e), and a brief summary should be given of the relevant physical, chemical, and pharmaceutical properties. [E6R3-A.3.4] To permit appropriate safety measures to be taken in the course of the trial, a description of the formulation(s) to be used, including excipients, should be provided and justified if clinically relevant. [E6R3-A.3.4] Instructions for the storage and handling of the dosage form(s) should also be given. [E6R3-A.3.4] Any structural similarities to other known compounds should be mentioned. [E6R3-A.3.4] ### Nonclinical Studies (A.3.5) The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and investigational product metabolism studies should be provided in summary form. [E6R3-A.3.5] This summary should address the methodology used, the results, and a discussion of the relevance of the findings to the investigated product and the possible unfavourable and unintended effects in humans. [E6R3-A.3.5] The information provided may include the following, as appropriate, if known or available: [E6R3-A.3.5] - Species tested [E6R3-A.3.5] - Number and sex of animals in each group [E6R3-A.3.5] - Unit dose (e.g., milligram/kilogram (mg/kg)) [E6R3-A.3.5] - Dose interval [E6R3-A.3.5] - Route of administration [E6R3-A.3.5] - Duration of dosing [E6R3-A.3.5] - Information on systemic distribution [E6R3-A.3.5] - Duration of post-exposure follow-up [E6R3-A.3.5] - Results, including: nature and frequency of pharmacological or toxic effects; severity or intensity of pharmacological or toxic effects; time to onset of effects; reversibility of effects; duration of effects; and dose response [E6R3-A.3.5] Tabular format/listings should be used whenever possible to enhance the clarity of the presentation. [E6R3-A.3.5] The nonclinical sections should discuss the most important findings from the studies, including the dose response of observed effects, the relevance to humans, and any aspects to be studied in humans. [E6R3-A.3.5] If applicable, the effective and nontoxic dose findings in the same animal species should be compared (i.e., the therapeutic index should be discussed), and the relevance of this information to the proposed human dosing should be addressed. [E6R3-A.3.5] Whenever possible, comparisons should be made in terms of blood/tissue levels or human equivalent dose rather than on a mg/kg basis. [E6R3-A.3.5] #### Nonclinical Pharmacology (A.3.5(a)) A summary of the pharmacological aspects of the investigational product and, where appropriate, its significant metabolites studied in animals should be included. [E6R3-A.3.5] Such a summary should incorporate studies that assess potential therapeutic activity (e.g., efficacy models, receptor binding and specificity) as well as those that assess safety (e.g., special studies to assess pharmacological actions other than the intended therapeutic effect(s)). [E6R3-A.3.5]

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## Effects in Humans (Section 7.3.6) A thorough discussion of the known effects of the investigational product(s) in humans should be provided, including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities [E6R2-7.3.6]. Where possible, a summary of each completed clinical trial should be provided [E6R2-7.3.6]. Information should also be provided regarding results of any use of the investigational product(s) other than from clinical trials, such as from experience during marketing [E6R2-7.3.6]. ### Pharmacokinetics and Product Metabolism in Humans A summary of information on the pharmacokinetics of the investigational product(s) should be presented, including the following, if available [E6R2-7.3.6]: - Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and elimination) [E6R2-7.3.6] - Bioavailability of the investigational product (absolute, where possible, and/or relative) using a reference dosage form [E6R2-7.3.6] - Population subgroups (e.g., gender, age, and impaired organ function) [E6R2-7.3.6] - Interactions (e.g., product-product interactions and effects of food) [E6R2-7.3.6] - Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s)) [E6R2-7.3.6] ### Safety and Efficacy A summary of information should be provided about the investigational product's safety, pharmacodynamics, efficacy, and dose response obtained from preceding trials in humans (healthy volunteers and/or patients), and the implications of this information should be discussed [E6R2-7.3.6]. Where a number of clinical trials have been completed, the use of summaries of safety and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data [E6R2-7.3.6]. Tabular summaries of adverse drug reactions for all clinical trials (including those for all studied indications) would be useful, and important differences in adverse drug reaction patterns/incidences across indications or subgroups should be discussed [E6R2-7.3.6]. The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis of prior experiences with the product under investigation and with related products [E6R2-7.3.6]. A description should also be provided of the precautions or special monitoring to be done as part of the investigational use of the product(s) [E6R2-7.3.6]. ### Marketing Experience The IB should identify countries where the investigational product has been marketed or approved [E6R2-7.3.6]. Any significant information arising from the marketed use should be summarised (e.g., formulations, dosages, routes of administration, and adverse product reactions) [E6R2-7.3.6]. The IB should also identify all the countries where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/registration [E6R2-7.3.6]. ## Summary of Data and Guidance for the Investigator (Section 7.3.7) This section should provide an overall discussion of the nonclinical and clinical data, and should summarise the information from various sources on different aspects of the investigational product(s), wherever possible [E6R2-7.3.7]. In this way, the investigator can be provided with the most informative interpretation of the available data and with an assessment of the implications of the information for future clinical trials [E6R2-7.3.7]. Where appropriate, the published reports on related products should be discussed, which could help the investigator to anticipate adverse drug reactions or other problems in clinical trials [E6R2-7.3.7]. The overall aim of this section is stated as follows: > The overall aim of this section is to provide the investigator with a clear understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial. This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investigational product(s). Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that is based on previous human experience and on the pharmacology of the investigational product. [E6R2-7.3.7] ## Appendix 1: Title Page (Section 7.4) Section 7.4 provides an example title page format for the Investigator's Brochure [E6R2-7.4]. The title page should include the sponsor's name, product name, research number, chemical and generic name(s) (if approved), and trade name(s) if legally permissible and desired by the sponsor [E6R2-7.4]. It should also include the edition number, release date, and the edition number and date of any previous edition it replaces [E6R2-7.4].

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## Nonclinical Pharmacokinetics and Toxicology (Animals) ### Pharmacokinetics and Product Metabolism in Animals A summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied should be given. [E6R3-A.3.5] The discussion of the findings should address the absorption and the local and systemic bioavailability of the investigational product and its metabolites and their relationship to the pharmacological and toxicological findings in animal species. [E6R3-A.3.5] ### Toxicology A summary of the toxicological effects found in relevant studies conducted in different animal species should be described under the following headings where appropriate: [E6R3-A.3.5] - Single toxicity [E6R3-A.3.5] - Repeated dose toxicity [E6R3-A.3.5] - Genotoxicity [E6R3-A.3.5] - Carcinogenicity [E6R3-A.3.5] - Reproductive and developmental toxicity [E6R3-A.3.5] - Local tolerance [E6R3-A.3.5] - Other toxicity studies [E6R3-A.3.5] ## Effects in Humans (Section A.3.6) ### Introduction A thorough discussion of the known effects of the investigational product(s) in humans should be provided, including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy and other pharmacological activities. [E6R3-A.3.6] Where possible, a summary of each completed clinical trial and ongoing trials where interim results are available that may inform the safety evaluation should be provided. [E6R3-A.3.6] Information should also be provided regarding results of any use of the investigational product(s) other than from clinical trials, such as from experience during marketing. [E6R3-A.3.6] ### Pharmacokinetics and Product Metabolism in Humans A summary of information on the pharmacokinetics of the investigational product(s) should be presented, including the following, if available: [E6R3-A.3.6] - Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution and elimination) [E6R3-A.3.6] - Bioavailability of the investigational product (absolute, where possible, and/or relative) using a reference dosage form [E6R3-A.3.6] - Population subgroups (e.g., sex, age and impaired organ function) [E6R3-A.3.6] - Interactions (e.g., product-product interactions and effects of food) [E6R3-A.3.6] - Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s)) [E6R3-A.3.6] ### Safety and Efficacy A summary of information should be provided about the investigational product's/products' (including metabolites, where appropriate) safety. [E6R3-A.3.6]

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## Overview The contents of a trial protocol should generally include the topics described in this section [E6R2-6]. Site-specific information may be provided on separate protocol page(s), or addressed in a separate agreement, and some of the information listed may be contained in other protocol-referenced documents, such as an Investigator's Brochure [E6R2-6]. ## 6.1 General Information The protocol should include the protocol title, protocol identifying number, and date [E6R2-6.1.1]. Any amendment(s) should also bear the amendment number(s) and date(s) [E6R2-6.1.1]. The name and address of the sponsor and monitor (if other than the sponsor) must be included [E6R2-6.1.2]. The name and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for the sponsor must also be provided [E6R2-6.1.3]. The protocol should include the name, title, address, and telephone number(s) of the sponsor's medical expert (or dentist when appropriate) for the trial [E6R2-6.1.4]. The name and title of the investigator(s) responsible for conducting the trial, and the address and telephone number(s) of the trial site(s), must be stated [E6R2-6.1.5]. Where the qualified physician (or dentist, if applicable) responsible for all trial-site related medical (or dental) decisions is other than the investigator, their name, title, address, and telephone number(s) must be included [E6R2-6.1.6]. The name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the trial must also be provided [E6R2-6.1.7]. ## 6.2 Background Information The protocol should include the name and description of the investigational product(s) [E6R2-6.2.1]. A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial must be provided [E6R2-6.2.2]. A summary of the known and potential risks and benefits, if any, to human subjects must be included [E6R2-6.2.3]. The protocol should also include a description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s) [E6R2-6.2.4]. A statement that the trial will be conducted in compliance with the protocol, GCP, and the applicable regulatory requirement(s) must be included [E6R2-6.2.5]. The protocol should provide a description of the population to be studied [E6R2-6.2.6], as well as references to literature and data that are relevant to the trial and that provide background for the trial [E6R2-6.2.7]. ## 6.3 Trial Objectives and Purpose The protocol should contain a detailed description of the objectives and the purpose of the trial [E6R2-6.3]. ## 6.4 Trial Design The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design [E6R2-6.4]. A description of the trial design should include the elements set out in sections 6.4.1 through 6.4.9 [E6R2-6.4]. ### Primary and Secondary Endpoints A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial must be provided [E6R2-6.4.1]. ### Type and Design of Trial A description of the type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures, and stages must be included [E6R2-6.4.2]. ### Minimizing Bias A description of the measures taken to minimize/avoid bias must be provided, including randomization and blinding [E6R2-6.4.3]. ### Trial Treatments and Dosage A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s) must be included, along with a description of the dosage form, packaging, and labelling of the investigational product(s) [E6R2-6.4.4]. ### Duration and Sequence The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up if any, must be stated [E6R2-6.4.5]. ### Stopping Rules and Discontinuation Criteria A description of the stopping rules or discontinuation criteria for individual subjects, parts of the trial, and the entire trial must be included [E6R2-6.4.6]. ### Accountability Procedures Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s) if any, must be described [E6R2-6.4.7]. ### Randomization Codes The maintenance of trial treatment randomization codes and procedures for breaking codes must be addressed [E6R2-6.4.8]. ### Source Data Identification The identification of any data to be recorded directly on the CRFs (i.e. no prior written or electronic record of data), and to be considered to be source data, must be specified [E6R2-6.4.9]. ## 6.5 Selection and Withdrawal of Subjects The protocol must specify subject inclusion criteria and subject exclusion criteria [E6R2-6.5.1] [E6R2-6.5.2]. Subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment) and procedures must be included, specifying: - When and how to withdraw subjects from the trial/investigational product treatment [E6R2-6.5.3]. - The type and timing of the data to be collected for withdrawn subjects [E6R2-6.5.3]. - Whether and how subjects are to be replaced [E6R2-6.5.3]. - The follow-up for subjects withdrawn from investigational product treatment/trial treatment [E6R2-6.5.3]. ## 6.6 Treatment of Subjects The protocol must describe the treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial [E6R2-6.6.1]. Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial must be specified [E6R2-6.6.2]. Procedures for monitoring subject compliance must also be included [E6R2-6.6.3]. ## 6.7 Assessment of Efficacy The protocol must include specification of the efficacy parameters [E6R2-6.7.1], as well as the methods and timing for assessing, recording, and analysing efficacy parameters [E6R2-6.7.2]. ## 6.8 Assessment of Safety The protocol must include specification of safety parameters [E6R2-6.8.1] and the methods and timing for assessing, recording, and analysing safety parameters [E6R2-6.8.2]. Procedures for eliciting reports of and for recording and reporting adverse events and intercurrent illnesses must be described [E6R2-6.8.3]. The type and duration of the follow-up of subjects after adverse events must also be specified [E6R2-6.8.4].

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## Overview The contents of a trial protocol should generally include the following topics, which may vary depending on the trial design [E6R3-B]. Investigator site-specific information may be provided on separate protocol page(s) or addressed in a separate agreement, and some of the information listed may be contained in other protocol referenced documents, such as an Investigator's Brochure [E6R3-B]. ## B.1 General Information The protocol must include the protocol title, unique protocol identifying number and date; any amendment(s) should also bear the amendment number(s) and date(s) [E6R3-B.1.1]. The name and address of the sponsor must be provided [E6R3-B.1.2]. The name and title of the person(s) authorised to sign the protocol and the protocol amendment(s) for the sponsor must also be included [E6R3-B.1.3]. ## B.2 Background Information The background information section must include the name and description of the investigational product(s) [E6R3-B.2.1]. A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial must be provided [E6R3-B.2.2]. The protocol must also include a summary of the known and potential risks and benefits, if any, to human participants [E6R3-B.2.3]. A description of and justification for the route of administration, dosage, dosage regimen and treatment period(s) is required [E6R3-B.2.4]. The protocol must contain a statement that the trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and the applicable regulatory requirement(s) [E6R3-B.2.5]. A description of the population to be studied must be included [E6R3-B.2.6], along with references to literature and data that are relevant to the trial and that provide background for the trial [E6R3-B.2.7]. ## B.3 Trial Objectives and Purpose The protocol must contain a clear description of the scientific objectives and the purpose of the trial, including information on estimands, when defined (see ICH E9(R1)) [E6R3-B.3]. ## B.4 Trial Design The scientific integrity of the trial and the reliability of the results from the trial substantially depend on the trial design [E6R3-B.4]. A description of the trial design should include the following elements. - A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial [E6R3-B.4.1]. - A description of the type and design of trial to be conducted (e.g., double-blind, placebo-controlled, parallel design, adaptive design, platform/umbrella/basket, trials with decentralised elements) and a schematic diagram of trial design, procedures and stages [E6R3-B.4.2]. - A description of the measures taken to minimise/avoid bias, including randomisation and blinding [E6R3-B.4.3]. - A description of the investigational product(s) and the dosage and dosage regimen of the investigational product(s), including a description of the dosage form, packaging and labelling [E6R3-B.4.4]. - Preparation (e.g., reconstitution) and administration instructions where applicable, unless described elsewhere [E6R3-B.4.5]. - A description of the schedule of events (e.g., trial visits, interventions and assessments) [E6R3-B.4.6]. - The expected duration of the participant's involvement in the trial and a description of the sequence and duration of all trial periods, including follow-up, if any [E6R3-B.4.7]. - A description of the stopping rules or discontinuation criteria and dose adjustment or dose interruption for individual participants, for parts of the trial or for the entire trial [E6R3-B.4.8]. - Accountability procedures for the investigational product(s), including the placebo(s) and other comparator(s), if any [E6R3-B.4.9]. - Maintenance of treatment randomisation codes and procedures for breaking codes [E6R3-B.4.10]. ## B.5 Selection of Participants The protocol must specify participant inclusion criteria and participant exclusion criteria [E6R3-B.5.1] [E6R3-B.5.2]. The mechanism for pre-screening, where appropriate, and screening of participants must also be described [E6R3-B.5.3]. ## B.6 Discontinuation of Trial Intervention and Participant Withdrawal The investigator may choose to discontinue the participant from the trial, and conversely, the participant may decide to withdraw from the trial or stop treatment with the investigational product [E6R3-B.6]. The protocol should specify: - When and how to discontinue participants from the trial/investigational product treatment [E6R3-B.6]. - The type and timing of the data to be collected for withdrawn/discontinued participants, including the process by which the data are handled, in accordance with applicable regulatory requirements [E6R3-B.6]. - Whether and how participants are to be replaced [E6R3-B.6]. - The follow-up for participants who have discontinued the use of the investigational product [E6R3-B.6]. ## B.7 Treatment and Interventions for Participants The protocol must specify the treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the criteria for dose adjustment(s), the route/mode(s) of administration and the treatment period(s), including the follow-up period(s) for participants for each investigational product treatment/trial treatment group/arm of the trial [E6R3-B.7.1]. Medication(s)/treatment(s) permitted (including concomitant and rescue medication) and not permitted before and/or during the trial must also be specified [E6R3-B.7.2].

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## 6.9 Statistics The protocol must include a description of the statistical methods to be employed, including the timing of any planned interim analysis(ses) [E6R2-6.9.1]. The number of subjects planned to be enrolled must be stated, and in multicentre trials the numbers projected for each trial site should be specified, along with the reason for the choice of sample size, including reflections on or calculations of the power of the trial and clinical justification [E6R2-6.9.2]. The level of significance to be used must be specified [E6R2-6.9.3]. The protocol must include criteria for the termination of the trial [E6R2-6.9.4]. Procedures for accounting for missing, unused, and spurious data must be described [E6R2-6.9.5]. Procedures for reporting any deviation(s) from the original statistical plan must be included; any such deviation(s) should be described and justified in the protocol and/or in the final report, as appropriate [E6R2-6.9.6]. The selection of subjects to be included in the analyses must be specified, for example all randomized subjects, all dosed subjects, all eligible subjects, or evaluable subjects [E6R2-6.9.7]. ## 6.10 Direct Access to Source Data/Documents The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents [E6R2-6.10]. ## 6.11 Quality Control and Quality Assurance The protocol must address quality control and quality assurance [E6R2-6.11]. ## 6.12 Ethics The protocol must include a description of ethical considerations relating to the trial [E6R2-6.12]. ## 6.13 Data Handling and Record Keeping The protocol must address data handling and record keeping [E6R2-6.13]. ## 6.14 Financing and Insurance Financing and insurance must be addressed in the protocol if not covered in a separate agreement [E6R2-6.14]. ## 6.15 Publication Policy Publication policy must be addressed in the protocol if not covered in a separate agreement [E6R2-6.15]. ## 6.16 Supplements Since the protocol and the clinical trial/study report are closely related, further relevant information can be found in the ICH Guideline for Structure and Content of Clinical Study Reports [E6R2-6.16]. ## 7. Investigator's Brochure ### 7.1 Introduction The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects [E6R2-7.1]. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety monitoring procedures [E6R2-7.1]. The IB also provides insight to support the clinical management of the study subjects during the course of the clinical trial [E6R2-7.1]. The information should be presented in a concise, simple, objective, balanced, and non-promotional form that enables a clinician, or potential investigator, to understand it and make his/her own unbiased risk-benefit assessment of the appropriateness of the proposed trial [E6R2-7.1]. For this reason, a medically qualified person should generally participate in the editing of an IB, but the contents of the IB should be approved by the disciplines that generated the described data [E6R2-7.1]. This guideline delineates the minimum information that should be included in an IB and provides suggestions for its layout [E6R2-7.1]. The type and extent of information available will vary with the stage of development of the investigational product [E6R2-7.1]. Where permitted by regulatory authorities, a basic product information brochure, package leaflet, or labelling may be an appropriate alternative to an extensive IB, provided that it includes current, comprehensive, and detailed information on all aspects of the investigational product that might be of importance to the investigator [E6R2-7.1]. If a marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared [E6R2-7.1]. The IB should be reviewed at least annually and revised as necessary in compliance with a sponsor's written procedures [E6R2-7.1]. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information [E6R2-7.1]. In accordance with Good Clinical Practice, relevant new information may be so important that it should be communicated to the investigators, and possibly to the IRBs/IECs and/or regulatory authorities before it is included in a revised IB [E6R2-7.1]. Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator(s), and the investigators are responsible for providing the up-to-date IB to the responsible IRBs/IECs [E6R2-7.1]. In the case of an investigator sponsored trial, the sponsor-investigator should determine whether a brochure is available from the commercial manufacturer [E6R2-7.1]. If the investigational product is provided by the sponsor-investigator, then he or she should provide the necessary information to the trial personnel [E6R2-7.1]. In cases where preparation of a formal IB is impractical, the sponsor-investigator should provide, as a substitute, an expanded background information section in the trial protocol that contains the minimum current information described in this guideline [E6R2-7.1]. ### 7.2 General Considerations The IB should include a title page that provides the sponsor's name, the identity of each investigational product (i.e., research number, chemical or approved generic name, and trade name(s) where legally permissible and desired) [E6R2-7.2.1].

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## Appendix B: Protocol Content Requirements ### B.7–B.8: Treatment Adherence and Efficacy Assessment The protocol must include strategies to monitor the participant's adherence to treatment. [E6R3-B.7.3] Efficacy parameters must be specified, along with the methods and timing for assessing, recording, and analysing them. [E6R3-B.8.1] Where trial-related committees such as an independent data monitoring committee (IDMC) or adjudication committees are used to assess efficacy data, their procedures, timing, and activities must be described in the protocol or a separate document. [E6R3-B.8.2] ### B.9: Assessment of Safety The protocol must specify safety parameters and the methods, extent, and timing for recording and assessing them. [E6R3-B.9.1] Where committees such as an IDMC are used to assess safety data, their procedures, timing, and activities must be described in the protocol or a separate document. [E6R3-B.9.2] The protocol must include procedures for obtaining reports of, and for recording and reporting, adverse events. [E6R3-B.9.3] It must also specify the type and duration of follow-up of participants after adverse events and other events such as pregnancies. [E6R3-B.9.4] ### B.10: Statistical Considerations The protocol must describe the statistical methods to be employed, including the timing and purpose of any planned interim analyses and the statistical criteria for stopping the trial. [E6R3-B.10.1] The number of participants planned to be enrolled must be stated, along with the reason for the choice of sample size, including reflections on or calculations of the power of the trial and clinical justification. [E6R3-B.10.2] The level of significance to be used, or the threshold for success on the posterior probability in a Bayesian design, must be specified. [E6R3-B.10.3] The selection of participants to be included in planned analyses must be described, along with the statistical methods to be employed and procedures for handling intercurrent events and accounting for missing, unused, and spurious data; these should be aligned with the target estimands, when defined, in accordance with ICH E9(R1). [E6R3-B.10.4] The protocol must include a statement that any deviations from the statistical analysis plan will be described and justified in the clinical trial report. [E6R3-B.10.5] ### B.11: Direct Access to Source Records The sponsor must ensure that it is specified in the protocol or other documented agreement that the investigator(s)/institution(s)/service provider(s) will permit trial-related monitoring, audits, regulatory inspections, and, in accordance with applicable regulatory requirements, review by the IRB/IEC, providing direct access to source records. [E6R3-B.11] ### B.12: Quality Control and Quality Assurance The protocol must include a description of identified critical-to-quality factors, associated risks, and risk mitigation strategies, unless documented elsewhere. [E6R3-B.12.1] It must also include a summary of the monitoring approaches that are part of the quality control process for the clinical trial. [E6R3-B.12.2] A description of the process for handling noncompliance with the protocol or GCP must be provided. [E6R3-B.12.3] ### B.13: Ethics The protocol must include a description of ethical considerations relating to the trial. [E6R3-B.13] ### B.14: Data Handling and Record Keeping The protocol must specify the data to be collected and the method of its collection, with additional details contained in a clinical trial-related document where necessary. [E6R3-B.14.1] It must identify data to be recorded directly into data acquisition tools (i.e., with no prior written or electronic record of data) and considered to be the source record. [E6R3-B.14.2] A statement must be included that records should be retained in accordance with applicable regulatory requirements. [E6R3-B.14.3] ### B.15–B.16: Financing, Insurance, and Publication Policy Financing and insurance must be addressed in the protocol if not covered in a separate agreement. [E6R3-B.15] Publication policy must similarly be addressed in the protocol if not covered in a separate agreement. [E6R3-B.16] ## Appendix C: Essential Records for the Conduct of a Clinical Trial ### C.1: Introduction Many records are generated before and during the conduct of a clinical trial, and the nature and extent of those records generated and maintained are dependent on the trial design, its conduct, application of risk-proportionate approaches, and the importance and relevance of that record to the trial. [E6R3-C.1.1] Determining which records are essential will be based on consideration of the guidance in Appendix C. [E6R3-C.1.2] The essential records permit and contribute to the evaluation of the conduct of a trial in relation to the compliance of the investigator and sponsor with GCP and applicable regulatory requirements, and the reliability of the results produced. [E6R3-C.1.3] These records are used as part of investigator oversight and sponsor oversight (including monitoring) of the trial, and by the sponsor's independent audit function and during inspections by regulatory authorities to assess trial conduct and the reliability of trial results. [E6R3-C.1.3] Certain essential records may also be reviewed by the IRB/IEC in accordance with applicable regulatory requirements. [E6R3-C.1.3] The investigator/institution should have access to and the ability to maintain the essential records generated before and during the conduct of the trial, and retain them in accordance with applicable regulatory requirements. [E6R3-C.1.3]

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## Ethical Conduct Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s) [E6R2-2.1]. ## Risk-Benefit Assessment Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society [E6R2-2.2]. A trial should be initiated and continued only if the anticipated benefits justify the risks [E6R2-2.2]. ## Subject Protection The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society [E6R2-2.3]. ## Adequacy of Nonclinical and Clinical Information The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial [E6R2-2.4]. ## Scientific Soundness and Protocol Clinical trials should be scientifically sound, and described in a clear, detailed protocol [E6R2-2.5]. A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion [E6R2-2.6]. ## Medical Responsibility The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist [E6R2-2.7]. ## Qualifications of Trial Personnel Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s) [E6R2-2.8]. ## Informed Consent Freely given informed consent should be obtained from every subject prior to clinical trial participation [E6R2-2.9]. ## Data Recording, Handling, and Storage All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification [E6R2-2.10]. This principle applies to all records referenced in this guideline, irrespective of the type of media used [E6R2-2.10]. ## Confidentiality The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s) [E6R2-2.11]. ## Manufacturing and Use of Investigational Products Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP) [E6R2-2.12]. They should be used in accordance with the approved protocol [E6R2-2.12]. ## Quality Systems Systems with procedures that assure the quality of every aspect of the trial should be implemented [E6R2-2.13]. Aspects of the trial that are essential to ensure human subject protection and reliability of trial results should be the focus of such systems [E6R2-2.13].

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## Definition and Purpose of Good Clinical Practice Good Clinical Practice (GCP) is an international, ethical, scientific, and quality standard for the conduct of trials that involve human participants. [E6R3-I] Clinical trials conducted in accordance with this standard will help to assure that the rights, safety, and well-being of trial participants are protected; that the conduct is consistent with the principles that have their origin in the Declaration of Helsinki; and that the clinical trial results are reliable. [E6R3-I] The term "trial conduct" in this document includes processes from planning to reporting, including planning, initiating, performing, recording, oversight, evaluation, analysis, and reporting activities as appropriate. [E6R3-I] The objective of this ICH GCP Guideline is to provide a unified standard to facilitate the mutual acceptance of clinical trial data for ICH member countries and regions by applicable regulatory authorities. [E6R3-I] ## Relationship to ICH E8(R1) This guideline builds on key concepts outlined in ICH E8(R1) General Considerations for Clinical Studies. [E6R3-I] This includes fostering a quality culture and proactively designing quality into clinical trials and drug development planning, identifying factors critical to trial quality, engaging interested parties as appropriate, and using a proportionate risk-based approach. [E6R3-I] Clinical trials vary widely in scale, complexity, and cost. [E6R3-I] Careful evaluation of critical to quality factors involved in each trial and the risks associated with these factors will help ensure efficiency by focusing on activities critical to achieving the trial objectives. [E6R3-I] ## Guideline Scope This guideline applies to interventional clinical trials of investigational products that are intended to be submitted to regulatory authorities. [E6R3-I] The Principles of GCP in this guideline may also be applicable to other interventional clinical trials of investigational products that are not intended to support marketing authorisation applications in accordance with local requirements. [E6R3-I] > "For the purpose of this guideline, the term 'investigational products' should be considered synonymous with drugs, medicines, medicinal products, vaccines and biological products." [E6R3-I] The Annexes provide the basis for the appropriate interpretation and application of the principles and should therefore be appropriately considered; however, various approaches to the provisions in the Annexes may be considered provided they are justified and achieve the intended purpose of the application of the principles. [E6R3-I] This guideline encourages a risk-based and proportionate approach to the conduct of a clinical trial. [E6R3-I] ## Guideline Structure This ICH GCP Guideline is composed of Principles and Annexes that expand on the principles, with specific details for different types of clinical trials. [E6R3-I] The principles are intended to apply across clinical trial types and settings and to remain relevant as technological and methodological advances occur. [E6R3-I] The principles outlined in this guideline may be satisfied using differing approaches and should be applied to fit the intended purpose of the clinical trial. [E6R3-I] Annex 1, including its Appendices, is intended to provide information on how the Principles can be appropriately applied to clinical trials. [E6R3-I] Additional annexes may be developed to respond to the needs of interested parties and to address emerging innovations in trial design and conduct. [E6R3-I] This guideline should be read in conjunction with other ICH guidelines relevant to the design and conduct of clinical trials, including multiregional trials. [E6R3-I]

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## Adverse Drug Reaction (ADR) In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established, all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions [E6R2-1.1]. > "The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out." [E6R2-1.1] Regarding marketed medicinal products, an ADR is a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting) [E6R2-1.1]. ## Adverse Event (AE) > "Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment." [E6R2-1.2] An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting) [E6R2-1.2]. ## Amendment (to the Protocol) See Protocol Amendment [E6R2-1.3]. ## Applicable Regulatory Requirement(s) > "Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products." [E6R2-1.4] ## Approval (in Relation to Institutional Review Boards) > "The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and the applicable regulatory requirements." [E6R2-1.5] ## Audit > "A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s)." [E6R2-1.6] ## Audit Certificate > "A declaration of confirmation by the auditor that an audit has taken place." [E6R2-1.7] ## Audit Report > "A written evaluation by the sponsor's auditor of the results of the audit." [E6R2-1.8] ## Audit Trail > "Documentation that allows reconstruction of the course of events." [E6R2-1.9] ## Blinding/Masking > "A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s)." [E6R2-1.10] Single-blinding usually refers to the subject(s) being unaware, and double-blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s) [E6R2-1.10]. ## Case Report Form (CRF) > "A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject." [E6R2-1.11] ## Clinical Trial/Study > "Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy." [E6R2-1.12] The terms clinical trial and clinical study are synonymous [E6R2-1.12]. ## Clinical Trial/Study Report > "A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report (see the ICH Guideline for Structure and Content of Clinical Study Reports)." [E6R2-1.13] ## Comparator (Product) > "An investigational or marketed product (i.e., active control), or placebo, used as a reference in a clinical trial." [E6R2-1.14] ## Compliance (in Relation to Trials) > "Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements." [E6R2-1.15] ## Confidentiality > "Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a subject's identity." [E6R2-1.16]

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## Adverse Events and Adverse Reaction-Related Definitions ### Adverse Event (AE) An Adverse Event is defined as follows: [E6R3-Glossary] > Any unfavourable medical occurrence in a trial participant administered the investigational product. The adverse event does not necessarily have a causal relationship with the treatment. ### Adverse Drug Reaction (ADR) The definition of an Adverse Drug Reaction differs depending on whether the product is pre-approval or marketed. [E6R3-Glossary] In the pre-approval clinical experience with a new investigational product or its new usages, an ADR refers to unfavourable and unintended responses, such as a sign (e.g., laboratory results), symptom or disease related to any dose of a medicinal product where a causal relationship between a medicinal product and an adverse event is a reasonable possibility. [E6R3-Glossary] The level of certainty about the relatedness of the adverse drug reaction to an investigational product will vary. [E6R3-Glossary] If the ADR is suspected to be medicinal product-related with a high level of certainty, it should be included in the reference safety information (RSI) and/or the Investigator's Brochure (IB). [E6R3-Glossary] For marketed medicinal products, an ADR is defined as a response to a drug that is noxious and unintended and that occurs at doses normally used in humans for prophylaxis, diagnosis or therapy of diseases or for modification of physiological function. [E6R3-Glossary] The guideline cross-references ICH E2A (Clinical Safety Data Management: Definitions and Standards for Expedited Reporting) for further guidance. [E6R3-Glossary] ### Serious Adverse Event (SAE) A Serious Adverse Event is defined as follows: [E6R3-Glossary] > Any unfavourable medical occurrence that is considered serious at any dose if it: results in death; is life-threatening; requires inpatient hospitalisation or prolongation of existing hospitalisation; results in persistent or significant disability/incapacity; or is a congenital anomaly/birth defect. An important medical event that may not be immediately life-threatening or result in death or hospitalisation, that may jeopardise the participant or that may require intervention to prevent serious outcomes, should generally be considered as serious (see ICH E2A and E19). [E6R3-Glossary] ### Suspected Unexpected Serious Adverse Reaction (SUSAR) A SUSAR is an adverse reaction that meets three criteria: suspected, unexpected, and serious. [E6R3-Glossary] - **Suspected:** There is a reasonable possibility that the drug caused the adverse drug reaction. [E6R3-Glossary] - **Unexpected:** An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure or alternative documents according to applicable regulatory requirements; see RSI). [E6R3-Glossary] - **Serious:** Meets the SAE criteria described above. [E6R3-Glossary] ## General Procedural and Documentation Definitions ### Agreement An Agreement is defined as a document or set of documents describing the details of any arrangements on delegation or transfer, distribution and/or sharing of activities and, if appropriate, on financial matters between two or more parties. [E6R3-Glossary] This could be in the form of a contract, and the protocol may serve as the basis of an agreement. [E6R3-Glossary] ### Applicable Regulatory Requirement(s) Applicable Regulatory Requirements are defined as any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products. [E6R3-Glossary] ### Assent Assent is defined as the affirmative agreement of a minor to participate in a clinical trial. [E6R3-Glossary] The absence of expression of agreement or disagreement should not be interpreted as assent. [E6R3-Glossary] ### Audit An Audit is defined as follows: [E6R3-Glossary] > A systematic and independent examination of trial-related activities and records performed by the sponsor, service provider (including contract research organisation (CRO)) or institution to determine whether the evaluated trial-related activities were conducted and the data were recorded, analysed and accurately reported according to the protocol, applicable standard operating procedures (SOPs), Good Clinical Practice (GCP) and the applicable regulatory requirement(s). ### Audit Certificate An Audit Certificate is a declaration of confirmation by the auditor that an audit has taken place. [E6R3-Glossary] ### Audit Report An Audit Report is a record describing the conduct and outcome of the audit. [E6R3-Glossary] ### Audit Trail An Audit Trail is defined as follows: [E6R3-Glossary] > Metadata records that allow the appropriate evaluation of the course of events by capturing details on actions (manual or automated) performed relating to information and data collection and, where applicable, to activities in computerised systems. The audit trail should show activities, initial entry and changes to data fields or records, by whom, when and, where applicable, why. In computerised systems, the audit trail should be secure, computer-generated and time stamped. ### Blinding/Masking Blinding/Masking is defined as a procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). [E6R3-Glossary] Single-blinding usually refers to the participant(s) being unaware, and double-blinding usually refers to the participant(s) and investigator(s) and, if appropriate, other investigator site staff or sponsor staff being unaware of the treatment assignment(s). [E6R3-Glossary] ### Case Report Form (CRF) A Case Report Form is defined as a data acquisition tool designed to record protocol-required information to be reported by the investigator to the sponsor on each trial participant (see Data Acquisition Tool). [E6R3-Glossary] ### Certified Copy A Certified Copy is defined as a copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated signature or by generation through a validated process) to have the same information as the original, including relevant metadata, where applicable. [E6R3-Glossary]

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## Document Status and Adoption The guideline was adopted by CHMP for release for consultation on 23 July 2015, with public consultation running from 4 August 2015 to 3 February 2016 [E6R2-1]. Final adoption by CHMP took place on 15 December 2016, with the guideline coming into effect on 14 June 2017 [E6R2-1]. ## Codification History The original E6 guideline was approved by the CPMP under Step 3 and released for public consultation in May 1995 [E6R2-1]. It was subsequently approved under Step 4 and released for information in July 1996 [E6R2-1]. Post-Step 4 editorial corrections were approved by the CPMP in July 2002 [E6R2-1]. ## Current E6(R2) Addendum The current E6(R2) version was adopted by the Regulatory Members of the ICH Assembly under Step 4 on 9 November 2016 [E6R2-1]. It constitutes an integrated addendum to the ICH E6(R1) document, with changes integrated directly into the following sections of the parent guideline: Introduction, 1.63, 1.64, 1.65, 2.10, 2.13, 4.2.5, 4.2.6, 4.9.0, 5.0, 5.0.1, 5.0.2, 5.0.3, 5.0.4, 5.0.5, 5.0.6, 5.0.7, 5.2.2, 5.5.3(a), 5.5.3(b), 5.5.3(h), 5.18.3, 5.18.6(e), 5.18.7, 5.20.1, and 8.1 [E6R2-1].

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## Overview ICH E6(R3) is the third revision of the International Council for Harmonisation (ICH) guideline on Good Clinical Practice (GCP). The guideline carries the EMA reference code EMA/CHMP/ICH/135/1995. [E6R3-cover] ## Regulatory Milestones for E6(R3) The E6(R3) revision was endorsed by the Members of the ICH Assembly under Step 2 and released for public consultation on 19 May 2023. [E6R3-history] It was subsequently transmitted to the CHMP and adopted by the CHMP on 25 May 2023, with release for public consultation on 26 May 2023 and a deadline for comments of 26 September 2023. [E6R3-cover] Final adoption by the CHMP occurred on 12 December 2024, and the guideline is scheduled to come into effect on 23 July 2025. [E6R3-cover] Endorsement by the Regulatory Members of the ICH Assembly under Step 4 took place on 6 January 2025. [E6R3-history] ## Version History of the E6 Guideline Series ### E6 (Original) The original E6 guideline was approved by the Steering Committee under Step 2 and released for public consultation on 27 April 1995. [E6R3-history] It was subsequently approved by the Steering Committee under Step 4 and recommended for adoption to the three ICH regulatory bodies on 1 May 1996. [E6R3-history] ### E6(R1) E6(R1) consisted of post-Step 4 editorial corrections approved by the Steering Committee on 10 June 1996. [E6R3-history] ### E6(R2) E6(R2) was adopted by the Regulatory Members of the ICH Assembly under Step 4 on 9 November 2016 as an Integrated Addendum to the ICH E6(R1) document. [E6R3-history] Changes were integrated directly into the following sections of the parent guideline: Introduction, 1.63, 1.64, 1.65, 2.10, 2.13, 4.2.5, 4.2.6, 4.9.0, 5.0, 5.0.1, 5.0.2, 5.0.3, 5.0.4, 5.0.5, 5.0.6, 5.0.7, 5.2.2, 5.5.3(a), 5.5.3(b), 5.5.3(h), 5.18.3, 5.18.6(e), 5.18.7, 5.20.1, and 8.1. [E6R3-history] ### E6(R3) E6(R3) was endorsed by the Members of the ICH Assembly under Step 2 and released for public consultation on 19 May 2023. [E6R3-history] Final endorsement by the Regulatory Members of the ICH Assembly under Step 4 occurred on 6 January 2025. [E6R3-history]

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## Contract (1.17) > A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract. [E6R2-1.17] ## Coordinating Committee (1.18) > A committee that a sponsor may organize to coordinate the conduct of a multicentre trial. [E6R2-1.18] ## Coordinating Investigator (1.19) > An investigator assigned the responsibility for the coordination of investigators at different centres participating in a multicentre trial. [E6R2-1.19] ## Contract Research Organization (CRO) (1.20) > A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions. [E6R2-1.20] ## Direct Access (1.21) > Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. [E6R2-1.21] Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects' identities and sponsor's proprietary information [E6R2-1.21]. ## Documentation (1.22) > All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken. [E6R2-1.22] ## Essential Documents (1.23) > Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced (see 8. Essential Documents for the Conduct of a Clinical Trial). [E6R2-1.23] ## Good Clinical Practice (GCP) (1.24) > A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. [E6R2-1.24] ## Independent Data-Monitoring Committee (IDMC) (1.25) Also referred to as a data and safety monitoring board, monitoring committee, or data monitoring committee [E6R2-1.25]. > An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial. [E6R2-1.25] ## Impartial Witness (1.26) > A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject's legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject. [E6R2-1.26] ## Independent Ethics Committee (IEC) (1.27) > An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving / providing favourable opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects. [E6R2-1.27] The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline [E6R2-1.27]. ## Informed Consent (1.28) > A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form. [E6R2-1.28] ## Inspection (1.29) > The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organization's (CRO's) facilities, or at other establishments deemed appropriate by the regulatory authority(ies). [E6R2-1.29] ## Institution (Medical) (1.30) > Any public or private entity or agency or medical or dental facility where clinical trials are conducted. [E6R2-1.30] ## Institutional Review Board (IRB) (1.31) > An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects. [E6R2-1.31] ## Interim Clinical Trial/Study Report (1.32) > A report of intermediate results and their evaluation based on analyses performed during the course of a trial. [E6R2-1.32]

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## Overview The ICH E6(R3) Glossary establishes binding definitions for key terms used throughout the Good Clinical Practice guideline. These definitions are essential for consistent interpretation of GCP requirements across sponsors, investigators, and regulatory authorities. [E6R3-Glossary] ## Clinical Trial > "Any interventional investigation in human participants intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s); and/or to identify any adverse reactions to an investigational product(s); and/or to study absorption, distribution, metabolism and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy." [E6R3-Glossary] ## Clinical Trial/Study Report (CSR) > "A documented description of a trial of any investigational product conducted in human participants, in which the clinical and statistical description, presentations and analyses are fully integrated into a single report (see ICH E3 Structure and Content of Clinical Study Reports)." [E6R3-Glossary] ## Comparator > "An investigational or authorised medicinal product (i.e., active control), placebo or standard of care used as a reference in a clinical trial." [E6R3-Glossary] ## Compliance (in Relation to Trials) > "Adherence to the trial-related requirements, GCP requirements and the applicable regulatory requirements." [E6R3-Glossary] ## Confidentiality > "Prevention of disclosure to other than authorised individuals of a sponsor's proprietary information or of a participant's identity or their confidential information." [E6R3-Glossary] ## Coordinating Investigator > "An investigator assigned the responsibility for the coordination of investigators at different investigator sites participating in a multicentre trial." [E6R3-Glossary] ## Computerised Systems Validation > "A process of establishing and documenting that the specified requirements of a computerised system can be consistently fulfilled from design until decommissioning of the system or transition to a new system. The approach to validation should be based on a risk assessment that takes into consideration the intended use of the system and the potential of the system to affect trial participant protection and the reliability of trial results." [E6R3-Glossary] ## Contract Research Organisation (CRO) The guideline directs readers to the definition under *Service Provider*. [E6R3-Glossary] ## Data Acquisition Tool (DAT) > "A paper or electronic tool designed to collect data and associated metadata from a data originator in a clinical trial according to the protocol and to report the data to the sponsor." [E6R3-Glossary] The data originator may be a human (e.g., the participant or trial staff), a machine (e.g., wearables and sensors), or a computer system from which electronic transfer of data from one system to another has been undertaken (e.g., extraction of data from an electronic health record or laboratory system). [E6R3-Glossary] Examples of DATs include, but are not limited to, CRFs, interactive response technologies (IRTs), clinical outcome assessments (COAs) including patient-reported outcomes (PROs), and wearable devices, irrespective of the media used. [E6R3-Glossary] ## Data Integrity > "Data integrity includes the degree to which data fulfil key criteria of being attributable, legible, contemporaneous, original, accurate, complete, secure and reliable such that data are fit for purpose." [E6R3-Glossary] ## Direct Access > "Permission to examine, analyse and verify records that are important to the evaluation of a clinical trial and may be performed on-site or remotely. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with direct access should take reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of participants' identities and their data and sponsor's proprietary information." [E6R3-Glossary] ## Essential Records > "Essential records are the documents and data (and relevant metadata), in any format, associated with a clinical trial that facilitate the ongoing management of the trial and collectively allow the evaluation of the methods used, the factors affecting a trial and the actions taken during the trial conduct to determine the reliability of the trial results produced and the verification that the trial was conducted in accordance with GCP and applicable regulatory requirements (see Appendix C)." [E6R3-Glossary] ## Good Clinical Practice (GCP) > "A standard for the planning, initiating, performing, recording, oversight, evaluation, analysis and reporting of clinical trials that provides assurance that the data and reported results are reliable and that the rights, safety and well-being of trial participants are protected." [E6R3-Glossary] ## Impartial Witness > "A person who is independent of the trial who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the participant or the participant's legally acceptable representative cannot read, and who reads the informed consent form and any other documented information supplied or read to the participant and/or their legally acceptable representative." [E6R3-Glossary] ## Independent Data Monitoring Committee (IDMC) > "An independent data monitoring committee (e.g., data safety monitoring board) that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety and relevant efficacy data, and to recommend to the sponsor whether to continue, modify or stop a trial." [E6R3-Glossary] ## Informed Consent > "A process by which a participant or their legally acceptable representative voluntarily confirms their willingness to participate in a trial after having been informed and been provided with the opportunity to discuss all aspects of the trial that are relevant to the participant's decision to participate. Varied approaches to the provision of information and the discussion about the trial can be used. This may include, for example, providing text in different formats, images and videos and using telephone or video conferencing with investigator site staff. Informed consent is documented by means of a written (paper or electronic), signed and dated informed consent form. Obtaining consent remotely may be considered when appropriate." [E6R3-Glossary]

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## Source Data Source data encompasses all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial [E6R2-1.51]. Source data are contained in source documents (original records or certified copies) [E6R2-1.51]. ## Source Documents Source documents are defined as original documents, data, and records [E6R2-1.52]. > "Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial)." [E6R2-1.52] ## Sponsor A sponsor is an individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial [E6R2-1.53]. ## Sponsor-Investigator A sponsor-investigator is an individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject [E6R2-1.54]. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency) [E6R2-1.54]. The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator [E6R2-1.54]. ## Standard Operating Procedures (SOPs) Standard Operating Procedures are defined as detailed, written instructions to achieve uniformity of the performance of a specific function [E6R2-1.55]. ## Subinvestigator A subinvestigator is any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows) [E6R2-1.56]. See also Investigator [E6R2-1.56]. ## Subject / Trial Subject A subject or trial subject is an individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control [E6R2-1.57]. ## Subject Identification Code A subject identification code is a unique identifier assigned by the investigator to each trial subject to protect the subject's identity and used in lieu of the subject's name when the investigator reports adverse events and/or other trial related data [E6R2-1.58]. ## Trial Site A trial site refers to the location(s) where trial-related activities are actually conducted [E6R2-1.59]. ## Unexpected Adverse Drug Reaction An unexpected adverse drug reaction is an adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product) [E6R2-1.60]. See also the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting [E6R2-1.60]. ## Vulnerable Subjects Vulnerable subjects are individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate [E6R2-1.61]. Examples include members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention [E6R2-1.61]. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent [E6R2-1.61]. ## Well-being (of the Trial Subjects) The well-being of trial subjects refers to the physical and mental integrity of the subjects participating in a clinical trial [E6R2-1.62]. ## Addendum Definitions ### Certified Copy A certified copy is a copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated signature or by generation through a validated process) to have the same information, including data that describe the context, content, and structure, as the original [E6R2-1.63]. ### Monitoring Plan A monitoring plan is a document that describes the strategy, methods, responsibilities, and requirements for monitoring the trial [E6R2-1.64]. ### Validation of Computerized Systems Validation of computerized systems is a process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled from design until decommissioning of the system or transition to a new system [E6R2-1.65]. The approach to validation should be based on a risk assessment that takes into consideration the intended use of the system [E6R2-1.65].

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## Randomisation > "The process of deliberately including an element of chance when assigning participants to groups that receive different treatments in order to reduce bias." [E6R3-Glossary] ## Reference Safety Information (RSI) The RSI contains a cumulative list of adverse drug reactions (ADRs) that are expected for the investigational product being administered to participants in a clinical trial. [E6R3-Glossary] The RSI is included in the Investigator's Brochure or alternative documents according to applicable regulatory requirements. [E6R3-Glossary] Further information about RSI is provided in ICH E2F Development Safety Update Report. [E6R3-Glossary] ## Regulatory Authorities Regulatory authorities are bodies having the power to regulate, including those that review submitted protocols and clinical data and those that conduct inspections. [E6R3-Glossary] These bodies are sometimes referred to as competent authorities. [E6R3-Glossary] ## Service Provider A service provider is a person or organisation (commercial, academic or other) providing a service used by either the sponsor or the investigator to fulfil trial-related activities. [E6R3-Glossary] ## Signature > "A unique mark, symbol or entry executed, adopted or authorised by an individual, in accordance with applicable regulatory requirements and/or practice to show expression of will and allow authentication of the signatory (i.e., establish a high degree of certainty that a record was signed by the claimed signatory). A signature may be physical or electronic." [E6R3-Glossary] ## Source Records > "Original documents or data (which includes relevant metadata) or certified copies of the original documents or data, irrespective of the media used." [E6R3-Glossary] Source records may include trial participants' medical/health records, notes, charts, and data provided or entered by trial participants such as electronic patient-reported outcomes (ePROs). [E6R3-Glossary] They may also include healthcare professionals' records from pharmacies, laboratories and other facilities involved in the clinical trial, as well as data from automated instruments such as wearables and sensors. [E6R3-Glossary] ## Sponsor > "An individual, company, institution or organisation that takes responsibility for the initiation, management and arrangement of the financing of a clinical trial." [E6R3-Glossary] A clinical trial may have one or several sponsors where permitted under regulatory requirements, and all sponsors have the responsibilities of a sponsor set out in the guideline. [E6R3-Glossary] Sponsors may decide in a documented agreement setting out their respective responsibilities in accordance with applicable regulatory requirements. [E6R3-Glossary] Where the documented agreement does not specify to which sponsor a given responsibility is attributed, that responsibility lies with all sponsors. [E6R3-Glossary] ## Sponsor-Investigator > "An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to or used by a participant." [E6R3-Glossary] The term does not include any person other than an individual — for example, it does not include a corporation or an agency. [E6R3-Glossary] The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator. [E6R3-Glossary] ## Standard Operating Procedures (SOPs) > "Detailed, documented instructions to achieve uniformity of the performance of a specific activity." [E6R3-Glossary] ## Sub-Investigator A sub-investigator is any individual member of the clinical trial team designated and under the oversight of the investigator to perform significant trial-related procedures and/or to make important trial-related decisions. [E6R3-Glossary] Examples include associates, residents, and research fellows. [E6R3-Glossary] ## Trial Participant A trial participant is an individual who participates in a clinical trial who is expected to receive the investigational product(s) or act as a control. [E6R3-Glossary] In the guideline, the terms "trial participant" and "participant" are used interchangeably. [E6R3-Glossary] ## Trial Participant Identification Code A trial participant identification code is a unique identifier assigned to each trial participant to protect the participant's identity. [E6R3-Glossary] It is used in lieu of the participant's name when the investigator reports adverse events and/or other trial-related data. [E6R3-Glossary] ## Vulnerable Participants > "Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation or of a retaliatory response from senior members of a hierarchy in case of refusal to participate." [E6R3-Glossary] Examples of vulnerable participants include members of groups with a hierarchical structure, such as medical, pharmacy, dental and nursing students; subordinate hospital and laboratory personnel; employees of the pharmaceutical industry; members of the armed forces; and persons kept in detention. [E6R3-Glossary] Other vulnerable participants may include persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent. [E6R3-Glossary]

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## Overview The source text provided for Part 7 consists of glossary definitions from the ICH E6(R2) guideline, spanning sections 1.33 through 1.50. These definitions establish the terminology used throughout the guideline. ## Investigational Product An investigational product is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use [E6R2-1.33]. ## Investigator An investigator is a person responsible for the conduct of the clinical trial at a trial site [E6R2-1.34]. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator [E6R2-1.34]. ## Investigator / Institution The expression "investigator and/or institution" means "the investigator and/or institution, where required by the applicable regulatory requirements" [E6R2-1.35]. ## Investigator's Brochure The Investigator's Brochure is defined as: > A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to the study of the investigational product(s) in human subjects (see 7. Investigator's Brochure). [E6R2-1.36] ## Legally Acceptable Representative A legally acceptable representative is an individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial [E6R2-1.37]. ## Monitoring Monitoring is defined as the act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s) [E6R2-1.38]. ## Monitoring Report A monitoring report is a written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor's SOPs [E6R2-1.39]. ## Multicentre Trial A multicentre trial is a clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator [E6R2-1.40]. ## Nonclinical Study A nonclinical study refers to biomedical studies not performed on human subjects [E6R2-1.41]. ## Opinion (in Relation to Independent Ethics Committee) An opinion, in relation to an Independent Ethics Committee, is the judgement and/or the advice provided by an Independent Ethics Committee (IEC) [E6R2-1.42]. ## Original Medical Record Original medical record is defined by reference to Source Documents [E6R2-1.43]. ## Protocol A protocol is a document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial [E6R2-1.44]. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents [E6R2-1.44]. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol amendments [E6R2-1.44]. ## Protocol Amendment A protocol amendment is a written description of a change(s) to or formal clarification of a protocol [E6R2-1.45]. ## Quality Assurance (QA) Quality Assurance (QA) encompasses all those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s) [E6R2-1.46]. ## Quality Control (QC) Quality Control (QC) refers to the operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled [E6R2-1.47]. ## Randomization Randomization is the process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias [E6R2-1.48]. ## Regulatory Authorities Regulatory authorities are bodies having the power to regulate [E6R2-1.49]. In the ICH GCP guideline, the expression Regulatory Authorities includes the authorities that review submitted clinical data and those that conduct inspections (see 1.29) [E6R2-1.49]. These bodies are sometimes referred to as competent authorities [E6R2-1.49]. ## Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR) A Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR) is any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect [E6R2-1.50].

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## Overview The following definitions are drawn from the Glossary of ICH E6(R3) Good Clinical Practice and establish the authoritative meaning of key terms used throughout the guideline. Regulatory professionals should apply these definitions consistently when interpreting GCP requirements. ## Inspection > "The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be accessed at the investigator site, at the sponsor's and/or service provider's (including CRO's) facilities, or at other establishments deemed appropriate by the regulatory authority(ies). Some aspects of the inspection may be conducted remotely." [E6R3-Glossary] ## Institution > "Any public or private entity or agency or medical or dental organisation in whose remit clinical trials are conducted." [E6R3-Glossary] ## Institutional Review Board (IRB) / Independent Ethics Committee (IEC) > "An independent body (a review board or a committee, institutional, regional, national or supranational) constituted of medical professionals and non-medical members whose responsibility it is to ensure the protection of the rights, safety and well-being of human participants involved in a trial and to provide public assurance of that protection by, among other things, reviewing and approving/providing favourable opinion on the trial protocol, the suitability of the investigator(s), the facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial participants." [E6R3-Glossary] The legal status, composition, function, operations, and regulatory requirements pertaining to IRBs/IECs may differ among countries, but should allow the IRB/IEC to act in agreement with GCP as described in the guideline. [E6R3-Glossary] ## Interim Clinical Trial/Study Report > "A report of intermediate results and their evaluation based on analyses performed during the course of a trial." [E6R3-Glossary] ## Investigational Product > "A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorisation when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use." [E6R3-Glossary] Investigational products should be considered synonymous with drugs, medicines, medicinal products, vaccines, and biological products. [E6R3-Glossary] ## Investigator > "A person responsible for the conduct of the clinical trial, including the trial participants for whom that person has responsibility during the conduct of the trial. If a trial is conducted by a team of individuals, the investigator is the responsible leader of the team and may be called the principal investigator." [E6R3-Glossary] Where an investigator/institution is referenced in the guideline, it describes expectations that may be applicable to the investigator and/or the institution in some regions. [E6R3-Glossary] Where required by applicable regulatory requirements, the term "investigator" should be read as "investigator and/or the institution." [E6R3-Glossary] ## Investigator's Brochure (IB) > "A compilation of the clinical and nonclinical data on the investigational product(s) that is relevant to the study of the investigational product(s) in human participants (see Appendix A)." [E6R3-Glossary] ## Investigator Site > "The location(s) where trial-related activities are conducted and/or coordinated under the investigator's/institution's oversight." [E6R3-Glossary] ## Legally Acceptable Representative > "An individual or juridical or other body authorised under applicable law to consent, on behalf of a prospective participant, to the participant's participation in the clinical trial." [E6R3-Glossary] When a legally acceptable representative provides consent on behalf of a prospective participant, activities related to the consenting process (and re-consent, if applicable) and, where relevant, activities associated with the withdrawal of consent described in the guideline are applicable to the participant's legally acceptable representative. [E6R3-Glossary] ## Metadata > "The contextual information required to understand a given data element. Metadata is structured information that describes, explains or otherwise makes it easier to retrieve, use or manage data." [E6R3-Glossary] For the purpose of the guideline, relevant metadata are those needed to allow the appropriate evaluation of the trial conduct. [E6R3-Glossary] ## Monitoring > "The act of overseeing the progress of a clinical trial and of ensuring that the clinical trial is conducted, recorded and reported in accordance with the protocol, SOPs, GCP and the applicable regulatory requirement(s)." [E6R3-Glossary] ## Monitoring Plan > "A document that describes the strategy, methods, responsibilities and requirements for monitoring the trial." [E6R3-Glossary] ## Monitoring Report > "A documented report following site and/or centralised monitoring activities." [E6R3-Glossary] ## Multicentre Trial > "A clinical trial conducted according to a single protocol but at more than one investigator site." [E6R3-Glossary] ## Nonclinical Study > "Biomedical studies not performed on human participants." [E6R3-Glossary] ## Protocol > "A document that describes the objective(s), design, methodology, statistical considerations and organisation of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents." [E6R3-Glossary] Throughout the ICH GCP Guideline, the term "protocol" refers to protocol and protocol amendments. [E6R3-Glossary] ## Protocol Amendment > "A documented description of a change(s) to a protocol." [E6R3-Glossary] ## Quality Assurance (QA) > "All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded) and reported in compliance with GCP and the applicable regulatory requirement(s)." [E6R3-Glossary] ## Quality Control (QC) > "The operational techniques and activities undertaken to verify that the requirements for quality of the trial-related activities have been fulfilled." [E6R3-Glossary]

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## Expedited Safety Reporting and Periodic Reports Expedited safety reports should comply with the applicable regulatory requirements and with the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting [E6R2-5.17.2]. The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required by applicable regulatory requirements [E6R2-5.17.3]. ## Purpose of Trial Monitoring The purposes of trial monitoring are to verify that: (a) the rights and well-being of human subjects are protected; (b) the reported trial data are accurate, complete, and verifiable from source documents; and (c) the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirements [E6R2-5.18.1]. ## Selection and Qualifications of Monitors Monitors should be appointed by the sponsor [E6R2-5.18.2]. Monitors should be appropriately trained and should have the scientific and/or clinical knowledge needed to monitor the trial adequately, and a monitor's qualifications should be documented [E6R2-5.18.2]. Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor's SOPs, GCP, and the applicable regulatory requirements [E6R2-5.18.2]. ## Extent and Nature of Monitoring The sponsor should ensure that the trials are adequately monitored, and should determine the appropriate extent and nature of monitoring based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial [E6R2-5.18.3]. In general there is a need for on-site monitoring before, during, and after the trial; however, in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators' training and meetings and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP [E6R2-5.18.3]. Statistically controlled sampling may be an acceptable method for selecting the data to be verified [E6R2-5.18.3]. ### Risk-Based Monitoring Approach (Addendum) The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials [E6R2-5.18.3]. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring, and should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan) [E6R2-5.18.3]. On-site monitoring is performed at the sites at which the clinical trial is being conducted [E6R2-5.18.3]. Centralized monitoring is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons (e.g., data managers, biostatisticians) [E6R2-5.18.3]. Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially unreliable data [E6R2-5.18.3]. Review, that may include statistical analyses, of accumulating data from centralized monitoring can be used to: - Identify missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations [E6R2-5.18.3]. - Examine data trends such as the range, consistency, and variability of data within and across sites [E6R2-5.18.3]. - Evaluate for systematic or significant errors in data collection and reporting at a site or across sites, or potential data manipulation or data integrity problems [E6R2-5.18.3]. - Analyze site characteristics and performance metrics [E6R2-5.18.3]. - Select sites and/or processes for targeted on-site monitoring [E6R2-5.18.3]. ## Monitor's Responsibilities The monitor(s), in accordance with the sponsor's requirements, should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site [E6R2-5.18.4]: - Acting as the main line of communication between the sponsor and the investigator [E6R2-5.18.4]. - Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2, 5.6) and that these remain adequate throughout the trial period, and that facilities, including laboratories, equipment, and staff, are adequate to safely and properly conduct the trial and remain adequate throughout the trial period [E6R2-5.18.4]. - Verifying, for the investigational product(s): that storage times and conditions are acceptable and that supplies are sufficient throughout the trial; that the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s); that subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational product(s); that the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately; and that the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirements and is in accordance with the sponsor [E6R2-5.18.4]. - Verifying that the investigator follows the approved protocol and all approved amendment(s), if any [E6R2-5.18.4].

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## Definition and Purpose of Essential Documents Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced [E6R2-8.1]. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements [E6R2-8.1]. Essential Documents also serve a number of other important purposes [E6R2-8.1]. Filing essential documents at the investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor and monitor [E6R2-8.1]. These documents are also the ones which are usually audited by the sponsor's independent audit function and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected [E6R2-8.1]. ## Organisation of Essential Documents The minimum list of essential documents which has been developed is grouped in three sections according to the stage of the trial during which they will normally be generated: 1) before the clinical phase of the trial commences, 2) during the clinical conduct of the trial, and 3) after completion or termination of the trial [E6R2-8.1]. A description is given of the purpose of each document, and whether it should be filed in either the investigator/institution or sponsor files, or both [E6R2-8.1]. It is acceptable to combine some of the documents, provided the individual elements are readily identifiable [E6R2-8.1]. ## Trial Master Files Trial master files should be established at the beginning of the trial, both at the investigator/institution's site and at the sponsor's office [E6R2-8.1]. A final close-out of a trial can only be done when the monitor has reviewed both investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate files [E6R2-8.1]. Any or all of the documents addressed in this guideline may be subject to, and should be available for, audit by the sponsor's auditor and inspection by the regulatory authority(ies) [E6R2-8.1]. ## Addendum: Storage and Supplementation The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents [E6R2-8.1]. The storage system used during the trial and for archiving (irrespective of the type of media used) should provide for document identification, version history, search, and retrieval [E6R2-8.1]. Essential documents for the trial should be supplemented or may be reduced where justified (in advance of trial initiation) based on the importance and relevance of the specific documents to the trial [E6R2-8.1].

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## General Principles for Data and Document Control The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the sponsor, and the sponsor should not have exclusive control of those data [E6R2-29]. When a copy is used to replace an original document (e.g., source documents, CRF), the copy should fulfill the requirements for certified copies [E6R2-29]. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial [E6R2-29]. ## 8.2 Before the Clinical Phase of the Trial Commences During the planning stage, the following documents should be generated and should be on file before the trial formally starts [E6R2-29]. | Section | Title of Document | Purpose | Investigator/Institution | Sponsor | |---------|-------------------|---------|-------------------------|---------| | 8.2.1 | Investigator's Brochure | To document that relevant and current scientific information about the investigational product has been provided to the investigator [E6R2-29] | X | X | | 8.2.2 | Signed Protocol and Amendments, if any, and Sample Case Report Form (CRF) | To document investigator and sponsor agreement to the protocol/amendment(s) and CRF [E6R2-29] | X | X | | 8.2.3 | Information Given to Trial Subject: Informed Consent Form (including all applicable translations); Any Other Written Information; Advertisement for Subject Recruitment (if used) | To document the informed consent; to document that subjects will be given appropriate written information (content and wording) to support their ability to give fully informed consent; to document that recruitment measures are appropriate and not coercive [E6R2-29] | X | X (ICF and written information); X (advertisement) | | 8.2.4 | Financial Aspects of the Trial | To document the financial agreement between the investigator/institution and the sponsor for the trial [E6R2-29] | X | X | | 8.2.5 | Insurance Statement (where required) | To document that compensation to subject(s) for trial-related injury will be available [E6R2-29] | X | X | | 8.2.6 | Signed Agreement Between Involved Parties (e.g., investigator/institution and sponsor; investigator/institution and CRO; sponsor and CRO; investigator/institution and authority(ies), where required) | To document agreements [E6R2-29] | X | X | | 8.2.7 | Dated, Documented Approval/Favourable Opinion of IRB/IEC of the following: protocol and any amendments; CRF (if applicable); informed consent form(s); any other written information to be provided to the subject(s); advertisement for subject recruitment (if used); subject compensation (if any); any other documents given approval/favourable opinion | To document that the trial has been subject to IRB/IEC review and given approval/favourable opinion; to identify the version number and date of the document(s) [E6R2-29] | X | X | | 8.2.8 | Institutional Review Board/Independent Ethics Committee Composition | To document that the IRB/IEC is constituted in agreement with GCP [E6R2-29] | X | X (where required) | | 8.2.9 | Regulatory Authority(ies) Authorisation/Approval/Notification of Protocol (where required) | To document appropriate authorisation/approval/notification by the regulatory authority(ies) has been obtained prior to initiation of the trial in compliance with the applicable regulatory requirement(s) [E6R2-29] | X (where required) | X (where required) | | 8.2.10 | Curriculum Vitae and/or Other Relevant Documents Evidencing Qualifications of Investigator(s) and Sub-Investigator(s) | To document qualifications and eligibility to conduct trial and/or provide medical supervision of subjects [E6R2-29] | X | X | | 8.2.11 | Normal Value(s)/Range(s) for Medical/Laboratory/Technical Procedure(s) and/or Test(s) Included in the Protocol | To document normal values and/or ranges of the tests [E6R2-29] | X | X | | 8.2.12 | Medical/Laboratory/Technical Procedures/Tests: certification; or accreditation; or established quality control and/or external quality assessment; or other validation (where required) | To document competence of facility to perform required test(s), and support reliability of results [E6R2-29] | X (where required) | X |

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## Before the Trial Begins: Additional Pre-Trial Essential Documents (8.2.13–8.2.20) ### 8.2.13 Sample of Label(s) Attached to Investigational Product Container(s) This document serves to document compliance with applicable labelling regulations and appropriateness of instructions provided to the subjects [E6R2-8.2.13]. It is located in the files of the investigator/institution [E6R2-8.2.13]. ### 8.2.14 Instructions for Handling of Investigational Product(s) and Trial-Related Materials This document (if not included in the protocol or Investigator's Brochure) serves to document instructions needed to ensure proper storage, packaging, dispensing and disposition of investigational products and trial-related materials [E6R2-8.2.14]. It is located in the files of both the investigator/institution and the sponsor [E6R2-8.2.14]. ### 8.2.15 Shipping Records for Investigational Product(s) and Trial-Related Materials This document serves to document shipment dates, batch numbers and method of shipment of investigational product(s) and trial-related materials, and allows tracking of product batch, review of shipping conditions, and accountability [E6R2-8.2.15]. It is located in the files of both the investigator/institution and the sponsor [E6R2-8.2.15]. ### 8.2.16 Certificate(s) of Analysis of Investigational Product(s) Shipped This document serves to document identity, purity, and strength of investigational product(s) to be used in the trial [E6R2-8.2.16]. It is located in the files of the sponsor [E6R2-8.2.16]. ### 8.2.17 Decoding Procedures for Blinded Trials This document serves to document how, in case of an emergency, identity of blinded investigational product can be revealed without breaking the blind for the remaining subjects' treatment [E6R2-8.2.17]. It is located in the files of both the investigator/institution and the sponsor, and a third party if applicable [E6R2-8.2.17]. ### 8.2.18 Master Randomisation List This document serves to document the method for randomisation of trial population [E6R2-8.2.18]. It is located in the files of the sponsor, or a third party if applicable [E6R2-8.2.18]. ### 8.2.19 Pre-Trial Monitoring Report This document serves to document that the site is suitable for the trial, and may be combined with 8.2.20 [E6R2-8.2.19]. It is located in the files of the sponsor [E6R2-8.2.19]. ### 8.2.20 Trial Initiation Monitoring Report This document serves to document that trial procedures were reviewed with the investigator and the investigator's trial staff, and may be combined with 8.2.19 [E6R2-8.2.20]. It is located in the files of both the investigator/institution and the sponsor [E6R2-8.2.20]. ## During the Clinical Conduct of the Trial (8.3) In addition to having on file the above documents, the following should be added to the files during the trial as evidence that all new relevant information is documented as it becomes available [E6R2-8.3]. ### 8.3.1 Investigator's Brochure Updates This document serves to document that the investigator is informed in a timely manner of relevant information as it becomes available [E6R2-8.3.1]. It is located in the files of both the investigator/institution and the sponsor [E6R2-8.3.1]. ### 8.3.2 Any Revision to Trial-Related Documents This document covers any revision to the protocol/amendment(s) and CRF, informed consent form, any other written information provided to subjects, and advertisement for subject recruitment (if used) [E6R2-8.3.2]. It serves to document revisions of these trial-related documents that take effect during the trial [E6R2-8.3.2]. It is located in the files of both the investigator/institution and the sponsor [E6R2-8.3.2]. ### 8.3.3 Dated, Documented Approval/Favourable Opinion of IRB/IEC This document covers IRB/IEC approval or favourable opinion of the following: protocol amendment(s); revisions of the informed consent form, any other written information to be provided to the subject, and advertisement for subject recruitment (if used); any other documents given approval/favourable opinion; and continuing review of the trial (where required) [E6R2-8.3.3]. It serves to document that the amendment(s) and/or revision(s) have been subject to IRB/IEC review and were given approval/favourable opinion, and to identify the version number and date of the document(s) [E6R2-8.3.3]. It is located in the files of both the investigator/institution and the sponsor [E6R2-8.3.3]. ### 8.3.4 Regulatory Authority(ies) Authorisations/Approvals/Notifications This document covers regulatory authority authorisations, approvals, or notifications where required for protocol amendment(s) and other documents [E6R2-8.3.4]. It serves to document compliance with applicable regulatory requirements [E6R2-8.3.4]. It is located in the files of the investigator/institution (where required) and the sponsor [E6R2-8.3.4]. ### 8.3.5 Curriculum Vitae for New Investigator(s) and/or Sub-Investigator(s) This document is located in the files of both the investigator/institution and the sponsor (see 8.2.10) [E6R2-8.3.5]. ### 8.3.6 Updates to Normal Value(s)/Range(s) for Medical/Laboratory/Technical Procedures/Tests This document serves to document normal values and ranges that are revised during the trial (see 8.2.11) [E6R2-8.3.6]. It is located in the files of both the investigator/institution and the sponsor [E6R2-8.3.6]. ### 8.3.7 Updates of Medical/Laboratory/Technical Procedures/Tests This document covers certification, accreditation, established quality control and/or external quality assessment, or other validation (where required) [E6R2-8.3.7]. It serves to document that tests remain adequate throughout the trial period (see 8.2.12) [E6R2-8.3.7]. It is located in the files of the investigator/institution (where required) and the sponsor [E6R2-8.3.7]. ### 8.3.8 Documentation of Investigational Product(s) and Trial-Related Materials Shipment This document is located in the files of both the investigator/institution and the sponsor (see 8.2.15) [E6R2-8.3.8]. ### 8.3.9 Certificate(s) of Analysis for New Batches of Investigational Products This document is located in the files of the sponsor (see 8.2.16) [E6R2-8.3.9]. ### 8.3.10 Monitoring Visit Reports This document serves to document site visits by, and findings of, the monitor [E6R2-8.3.10]. It is located in the files of the sponsor [E6R2-8.3.10]. ### 8.3.11 Relevant Communications Other Than Site Visits This document covers letters, meeting notes, and notes of telephone calls [E6R2-8.3.11]. It serves to document any agreements or significant discussions regarding trial administration, protocol violations, trial conduct, and adverse event (AE) reporting [E6R2-8.3.11]. It is located in the files of both the investigator/institution and the sponsor [E6R2-8.3.11]. ### 8.3.12 Signed Informed Consent Forms This document serves to document that consent is obtained in accordance with GCP and the protocol and dated prior to participation of each subject in the trial, and also to document direct access permission (see 8.2.3) [E6R2-8.3.12]. It is located in the files of the investigator/institution [E6R2-8.3.12]. ### 8.3.13 Source Documents This document serves to document the existence of the subject and substantiate integrity of trial data collected, and includes original documents related to the trial, to medical treatment, and history of subject [E6R2-8.3.13]. It is located in the files of the investigator/institution [E6R2-8.3.13]. ### 8.3.14 Signed, Dated and Completed Case Report Forms (CRF) This document serves to document that the investigator or authorised member of the investigator's staff confirms the observations recorded [E6R2-8.3.14]. A copy is located in the files of the investigator/institution and the original is located in the files of the sponsor [E6R2-8.3.14]. ### 8.3.15 Documentation of CRF Corrections This document serves to document all changes/additions or corrections made to the CRF after initial data were recorded [E6R2-8.3.15]. A copy is located in the files of the investigator/institution and the original is located in the files of the sponsor [E6R2-8.3.15]. ### 8.3.16 Notification by Originating Investigator to Sponsor of Serious Adverse Events and Related Reports This document covers notification by the originating investigator to the sponsor of serious adverse events and related reports in accordance with 4.11 [E6R2-8.3.16]. It is located in the files of both the investigator/institution and the sponsor [E6R2-8.3.16].

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## Informed Consent Documentation and Copies Participants or their legally acceptable representatives must be informed in a timely manner if information becomes available that may be relevant to their willingness to continue trial participation. [E6R3-2.8.10(q)] They must also be provided with the contact details of persons to reach for further trial information, for questions about participant rights, and in the event of suspected trial-related injury. [E6R3-2.8.10(r)] The informed consent process must also cover the foreseeable circumstances and/or reasons under which the participant's trial participation may be terminated, the expected duration of participation, and the approximate number of participants involved in the trial. [E6R3-2.8.10(s)(t)(u)] Participants must additionally be informed that trial results and information on their actual treatment, if appropriate, will be made available to them should they desire it when this information is available from the sponsor. [E6R3-2.8.10(v)] Prior to participation, the participant or the participant's legally acceptable representative should receive a copy (paper or electronic) of the signed and dated informed consent form and any other informed consent materials provided, in accordance with applicable regulatory requirements. [E6R3-2.8.11] During trial participation, the participant or the participant's legally acceptable representative should receive a copy of the consent form updates and any other updated informed consent materials provided. [E6R3-2.8.11] ## Minor Participants and Age-Appropriate Assent Where a minor is to be included as a participant, age-appropriate assent information should be provided and discussed with the minor as part of the consent process, and assent from the minor to enrol in the trial should be obtained as appropriate. [E6R3-2.8.12] A process for consent should be considered if, during the course of the trial, the minor reaches the age of legal consent, in accordance with applicable regulatory requirements. [E6R3-2.8.12] ## Participants Requiring Legally Acceptable Representative Consent When a clinical trial includes participants who may only be enrolled with the consent of the participant's legally acceptable representative, the participants should be informed about the trial in a manner that facilitates their understanding. [E6R3-2.8.13] If capable, the participant should sign and date the informed consent form or assent form as appropriate. [E6R3-2.8.13] ## End of Participation in a Clinical Trial ### Discontinuation and Data Retention When a participant decides to stop treatment with the investigational product or withdraw from a trial, is discontinued from the trial, or reaches the routine end of the trial, the investigator should follow the protocol and/or other protocol-related documents. [E6R3-2.9.1] For 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. [E6R3-2.9.1] In general, loss of already collected data may bias results and may lead to, for example, inaccurate conclusions regarding the safety profile of the investigational product. [E6R3-2.9.1] ### Premature Withdrawal Although a participant is not obliged to provide a reason(s) for withdrawing prematurely from a trial, the investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the participant's rights. [E6R3-2.9.2] The investigator should consider if a discussion with the participant or the participant's legally acceptable representative is appropriate. [E6R3-2.9.2] This discussion 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. [E6R3-2.9.2]

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## Randomisation Procedures and Unblinding The investigator should follow the trial's randomisation procedures, if any, and in the case of an investigator-blinded trial, should ensure that the treatment randomisation code is broken only in accordance with the protocol. [E6R3-2.11] In the case of an emergency, to protect participant safety, the investigator should be prepared and capable from the start of the trial to perform unblinding without undue delay and hindrance. [E6R3-2.11] The investigator should promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding, emergency unblinding to protect trial participant, unblinding due to an SAE) of the investigational product(s). [E6R3-2.11] ## Records and Data Integrity ### General Data Integrity In generating, recording and reporting trial data, the investigator should ensure the integrity of data under their responsibility, irrespective of the media used. [E6R3-2.12.1] ### Source Records The investigator/institution should maintain adequate source records that include pertinent observations on each of the trial participants under their responsibility. [E6R3-2.12.2] Source records should be attributable, legible, contemporaneous, original, accurate and complete. [E6R3-2.12.2] Changes to source records should be traceable, should not obscure the original entry and should be explained if necessary (via an audit trail). [E6R3-2.12.2] The investigator should define what is considered to be a source record(s), the methods of data capture and their location prior to starting the trial and should update this definition when needed. [E6R3-2.12.2] Unnecessary transcription steps between the source record and the data acquisition tool should be avoided. [E6R3-2.12.2] ### Timely Access to and Review of Data The investigator should be provided with timely access to data by the sponsor and be responsible for the timely review of data, including relevant data from external sources that can have an impact on, for example, participant eligibility, treatment or safety (e.g., central laboratory data, centrally read imaging data, other institution's records and, if appropriate, electronic patient-reported outcome (ePRO) data). [E6R3-2.12.3] The protocol may provide exceptions for access, for instance, to protect blinding. [E6R3-2.12.3] ### Use of Data Acquisition Tools The investigator should ensure that data acquisition tools and other systems deployed by the sponsor are used as specified in the protocol or trial-related instructions. [E6R3-2.12.4] ### Accuracy and Completeness of Reported Data The investigator should ensure the accuracy, completeness, legibility and timeliness of the data reported to the sponsor in the data acquisition tools completed by the investigator site (e.g., case report form (CRF)) and in any other required reports (e.g., SAE reports). [E6R3-2.12.5] The investigator should review and endorse the reported data at important milestones agreed upon with the sponsor (e.g., interim analysis). [E6R3-2.12.5] ### Consistency Between Source Records and Reported Data Data reported to the sponsor should be consistent with the source records or the discrepancies explained. [E6R3-2.12.6] Changes or corrections in the reported data should be traceable, should be explained (if necessary) and should not obscure the original entry. [E6R3-2.12.6] ### Privacy and Confidentiality The investigator/institution should implement appropriate measures to protect the privacy and confidentiality of personal information of trial participants in accordance with applicable regulatory requirements on personal data protection. [E6R3-2.12.7] ### Participant Identification Data reported to the sponsor should be identified by an unambiguous participant code that can be traced back to the identity of the participant by the investigator/institution. [E6R3-2.12.8] ## Investigational Product 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. [E6R3-2.10.9]

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## Informed Consent Discussion and Materials: Required Content Elements The informed consent discussion and the informed consent materials to be provided to participants must explain a defined set of elements as applicable. [E6R3-2.8.10] ### Trial Overview and Procedures Participants must be informed of the purpose of the trial. [E6R3-2.8.10] They must also be told that the trial involves research, along with a summary of the experimental aspects of the trial. [E6R3-2.8.10] The informed consent materials must describe the trial's investigational product(s) and, if applicable, the probability for random assignment to the investigational product. [E6R3-2.8.10] All trial procedures to be followed, including all invasive procedures, must be explained. [E6R3-2.8.10] What is expected of the participants must also be communicated. [E6R3-2.8.10] ### Risks, Benefits, and Alternatives The reasonably foreseeable risks or inconveniences to the participant must be disclosed, and where applicable, risks to the participant's partner, to an embryo, foetus, or nursing infant must also be addressed. [E6R3-2.8.10] The reasonably expected benefits must be explained. [E6R3-2.8.10] When there is no intended clinical benefit to the participant, the participant must be made aware of this. [E6R3-2.8.10] Alternative procedures or courses of treatment that may be available to the participant, along with their important potential benefits and risks, must be described. [E6R3-2.8.10] ### Compensation, Expenses, and Injury The compensation and/or treatment available to the participant in the event of trial-related injury must be disclosed. [E6R3-2.8.10] Any anticipated prorated compensation to the participant for trial participation must be communicated. [E6R3-2.8.10] Any anticipated expenses to the participant for trial participation must also be explained. [E6R3-2.8.10] ### Voluntariness and Withdrawal Participants must be informed that their trial participation is voluntary, and that they may decide to stop taking the investigational product or withdraw from the trial at any time, without penalty or loss of benefits to which the participant is otherwise entitled. [E6R3-2.8.10] The follow-up procedure for participants who stopped taking the investigational product, withdrew from the trial, or were discontinued from the trial must be explained. [E6R3-2.8.10] ### Data Handling and Confidentiality The process by which the participant's data will be handled, including in the event of withdrawal or discontinuation of participation, must be explained in accordance with applicable regulatory requirements. [E6R3-2.8.10] Participants must be informed that by agreeing to participate in the trial, the participant or their legally acceptable representative allows direct access to source records, based on the understanding that the confidentiality of the participant's medical record will be safeguarded. [E6R3-2.8.10] This access is limited for the purpose of reviewing trial activities and/or reviewing or verifying data and records by the regulatory authority(ies) and the sponsor's representatives — for example, monitors or auditors — and in accordance with applicable regulatory requirements, the IRB/IEC(s). [E6R3-2.8.10] Participants must be told that records identifying the participant will be kept confidential and, to the extent permitted by applicable regulatory requirements, will not be made publicly available. [E6R3-2.8.10] If the trial results are published, the participant's identity will remain confidential. [E6R3-2.8.10] Participants must also be informed that the trial may be registered on publicly accessible and recognised databases, per applicable regulatory requirements. [E6R3-2.8.10] ### Summary of Required Elements - Purpose of the trial [E6R3-2.8.10] - That the trial involves research and a summary of experimental aspects [E6R3-2.8.10] - Investigational product(s) and probability of random assignment, if applicable [E6R3-2.8.10] - Trial procedures, including all invasive procedures [E6R3-2.8.10] - What is expected of participants [E6R3-2.8.10] - Reasonably foreseeable risks or inconveniences to the participant and, where applicable, to the participant's partner, embryo, foetus, or nursing infant [E6R3-2.8.10] - Reasonably expected benefits, or disclosure that no clinical benefit is intended [E6R3-2.8.10] - Alternative procedures or treatments and their potential benefits and risks [E6R3-2.8.10] - Compensation and/or treatment available in the event of trial-related injury [E6R3-2.8.10] - Anticipated prorated compensation for participation [E6R3-2.8.10] - Anticipated expenses for participation [E6R3-2.8.10] - Voluntary nature of participation and right to withdraw without penalty [E6R3-2.8.10] - Follow-up procedures for participants who stop, withdraw, or are discontinued [E6R3-2.8.10] - Data handling process, including upon withdrawal or discontinuation [E6R3-2.8.10] - Direct access to source records by authorised parties, with confidentiality safeguards [E6R3-2.8.10] - Confidentiality of identifying records and potential trial registration on public databases [E6R3-2.8.10]

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## Investigational Product Management ### Primary Responsibility Responsibility for investigational product(s) management, including accountability, handling, dispensing, administration, and return, rests with the investigator/institution. [E6R3-2.10.1] The sponsor may facilitate aspects of investigational product management — for example, by providing forms and technical solutions such as computerised systems, and by arranging distribution of investigational product to trial participants. [E6R3-2.10.1] ### Delegation of Management Activities When the investigator/institution delegates some or all of their activities for investigational product(s) management to a pharmacist or another individual, this must be done in accordance with local regulatory requirements, and the delegated individual should be under the oversight of the investigator/institution. [E6R3-2.10.2] Where the investigator has delegated activities related to investigational product management, or where aspects of these activities have been facilitated by the sponsor, the level of investigator oversight will depend on a number of factors. [E6R3-2.10.3] These factors include the characteristics of the investigational product, the route and complexity of administration, and the level of existing knowledge about the investigational product's safety and marketing status. [E6R3-2.10.3] ### Record-Keeping Requirements The investigator/institution and/or a pharmacist or other appropriate individual should maintain records of the product's delivery, the inventory, the use by each participant, and the return to the sponsor and destruction or alternative disposition of unused product(s). [E6R3-2.10.4] Records documenting that participants were provided the doses specified by the protocol are required. [E6R3-2.10.4] These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the investigational product(s) and trial participants. [E6R3-2.10.4] For authorised medicinal products, alternative approaches to the aforementioned may be considered, in accordance with local regulatory requirements. [E6R3-2.10.4] ### Storage The investigational product(s) should be stored as specified by the sponsor and in accordance with applicable regulatory requirement(s). [E6R3-2.10.5] ### Protocol Compliance The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol. [E6R3-2.10.6] ### Participant Instructions Where applicable, the investigator or a person designated by the investigator/institution should explain the correct use of the investigational product(s) to each participant. [E6R3-2.10.7] The designated person should also check, at intervals appropriate for the trial, that each participant is following the instructions properly. [E6R3-2.10.7] ### Flexible Delivery and Administration The investigational product may be shipped to the participant's location or supplied to/dispensed at a location closer to the participant, such as a local pharmacy or a local healthcare centre. [E6R3-2.10.8] The investigational product may be administered at the participant's location by investigator site staff, the participant themselves, a caregiver, or a healthcare professional. [E6R3-2.10.8] ### Informing Participants of Trial Results 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. [E6R3-2.9.3]

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## Service Providers Trial-related activities performed by service providers should be conducted in accordance with relevant GCP requirements, which may be fulfilled by a service provider's existing quality management processes that were not designed specifically to be GCP-compliant but are fit for purpose in the context of the trial. [E6R3-3.6.10] ## Multi-Sponsor Trials A clinical trial may have one or several sponsors where permitted in accordance with applicable regulatory requirements. [E6R3-3.6.11] In trials with more than one sponsor, the sponsors should have a documented agreement that sets out their respective responsibilities, in accordance with local regulatory requirements and/or practice. [E6R3-3.6.11] Where the documented agreement does not specify to which sponsor a given responsibility is attributed, that responsibility lies with all sponsors. [E6R3-3.6.11] ## Investigator Selection The sponsor is responsible for selecting the investigator(s)/institution(s). [E6R3-3.7.1] Each investigator should be qualified by education, training and experience and should demonstrate they have adequate resources and facilities to properly conduct the trial. [E6R3-3.7.1] If a coordinating committee and/or coordinating investigator(s) are to be utilised in multicentre trials, their organisation and/or selection are the sponsor's responsibility, and their roles and responsibilities should be documented prior to their involvement in the trial. [E6R3-3.7.1] The sponsor should provide the potential investigator(s)/institution(s) with the protocol and an up-to-date Investigator's Brochure as well as sufficient time for the review of the protocol and the information provided. [E6R3-3.7.2] ## Communication with IRB/IEC and Regulatory Authority(ies) ### Notification/Submission to Regulatory Authority(ies) In accordance with applicable regulatory requirement(s), before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator) should submit any required application(s) to the appropriate regulatory authority(ies) for review, acceptance and/or permission to begin the trial(s). [E6R3-3.8.1] Any notification/submission should be dated and contain sufficient information to identify the protocol. [E6R3-3.8.1] ### Confirmation of Review by IRB/IEC Where reference is made to a submission to the IRB/IEC, this can be made by the investigator/institution or sponsor in accordance with applicable regulatory requirements. [E6R3-3.8.2] The sponsor should ensure that the following is obtained: [E6R3-3.8.2] - The name and address of the relevant IRB/IEC, along with: [E6R3-3.8.2] - A statement that it is organised and operates according to GCP and the applicable regulatory requirements; [E6R3-3.8.2] - Documented initial and subsequent IRB/IEC approval/favourable opinion as well as any termination of the trial or the suspension of approval/favourable opinion. [E6R3-3.8.2]

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## Sponsor Data Management, Privacy, Security, and Computerised Systems ### Data Quality Steps Prior to Analysis The sponsor should determine the data management steps to be undertaken prior to analysis to ensure the data are of sufficient quality. [E6R3-3] These steps may vary depending on the purpose of the analysis to be conducted (e.g., data for IDMC, for interim analysis or the final analysis). [E6R3-3] Completion of these steps should be documented. [E6R3-3] For planned interim analyses, the ability to access and change data should be managed depending on the steps required to achieve data of sufficient quality for analysis. [E6R3-3] Prior to provision of the data for final analysis and, where applicable, before unblinding the trial, edit access to the data acquisition tools should be restricted. [E6R3-3] ### Participant Identification The sponsor should use an unambiguous trial participant identification code that allows identification of all the data reported for each participant. [E6R3-3] ### Privacy and Confidentiality The sponsor should implement appropriate measures to protect the privacy and confidentiality of personal information of trial participants, in accordance with applicable regulatory requirements on personal data protection. [E6R3-3] In accordance with applicable regulatory requirements and in alignment with the protocol, the sponsor should describe the process by which the participant's data will be handled when a participant withdraws or discontinues from the trial. [E6R3-3] ### Data Security and Incident Reporting The sponsor should ensure that trial data are protected from unauthorised access, disclosure, dissemination or alteration and from inappropriate destruction or accidental loss. [E6R3-3] The sponsor should have processes and procedures in place for reporting to relevant parties, including regulatory authorities, incidents (including security breaches) that have a significant impact on the trial data. [E6R3-3] ### Requirements for Computerised Systems When using computerised systems in a clinical trial, the sponsor must meet a number of requirements for systems deployed by the sponsor. [E6R3-3] #### System Records The sponsor should have a record of the important computerised systems used in a clinical trial. [E6R3-3] This record should include the use, functionality, interfaces and validation status of each computerised system, and who is responsible for its management. [E6R3-3] The record should also include a description of implemented access controls and internal and external security measures. [E6R3-3] #### Validation and Procedural Requirements The sponsor should ensure that requirements for computerised systems — including requirements for validation, audit trails, user management, backup, disaster recovery and IT security — are addressed and implemented. [E6R3-3] Documented procedures and adequate training must be in place to ensure the correct development, maintenance and use of computerised systems in clinical trials. [E6R3-3] These requirements should be proportionate to the importance of the computerised system and the data or activities they are expected to process. [E6R3-3] #### User Access Management The sponsor should maintain a record of the individual users who are authorised to access the system, their roles and their access permissions. [E6R3-3] The sponsor should ensure that access permissions granted to investigator site staff are in accordance with delegations by the investigator and visible to the investigator. [E6R3-3] #### Defect Reporting The sponsor should ensure that there is a process in place for service providers and investigators to inform the sponsor of system defects identified. [E6R3-3]

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## Independent Review by an IRB/IEC (Principle 3) Clinical trials should be subject to an independent review by an IRB/IEC. [E6R3-3] A trial should be conducted in compliance with the protocol that received prior IRB/IEC approval or favourable opinion. [E6R3-3.1] Periodic review of the trial by the IRB/IEC should also be conducted in accordance with applicable regulatory requirements. [E6R3-3.2] ## Scientific Soundness (Principle 4) Clinical trials should be scientifically sound for their intended purpose and based on adequate and current scientific knowledge and approaches. [E6R3-4] The available nonclinical and clinical information on an investigational product(s) should be adequate to support the proposed clinical trial. [E6R3-4.1] Clinical trials should be scientifically sound and 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 investigational product); and the population for which the investigational product is intended. [E6R3-4.2] There should be periodic review of current scientific knowledge and approaches to determine whether modifications to the trial are needed, since new or unanticipated information may arise once the trial has begun. [E6R3-4.3] ## Qualified Individuals (Principle 5) Clinical trials should be designed and conducted by qualified individuals. [E6R3-5] Individuals with different expertise and training may be needed across all phases of a clinical trial, such as physicians, nurses, pharmacists, scientists, ethicists, technology experts, trial coordinators, monitors, auditors and biostatisticians. [E6R3-5.1] Individuals involved in a trial should be qualified by education, training and experience to perform their respective task(s). [E6R3-5.1] ## Quality Built into Trial Design and Conduct (Principle 6) Quality should be built into the scientific and operational design and conduct of clinical trials. [E6R3-6] > "Quality of a clinical trial is considered in this guideline as fitness for purpose." [E6R3-6.1] Factors critical to the quality of the trial should be identified prospectively. [E6R3-6.2] 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. [E6R3-6.2] Quality by design involves focusing on critical to quality factors of the trial in order to maximise the likelihood of the trial meeting its objectives. [E6R3-6.2] Strategies should be implemented to avoid, detect, address and prevent recurrence of serious noncompliance with GCP, the trial protocol and applicable regulatory requirements. [E6R3-6.3] ## Proportionality (Principle 7) 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 and that avoids unnecessary burden on participants and investigators. [E6R3-7] Trial processes should be proportionate to the risks inherent in the trial and the importance of the information collected. [E6R3-7.1] Risks in this context include risks to the rights, safety and well-being of trial participants as well as risks to the reliability of the trial results. [E6R3-7.1] The focus should be on the risks associated with trial participation. [E6R3-7.2] For clinical trials involving patients, the focus should be on risks that go beyond those associated with usual medical care. [E6R3-7.2]

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## Sponsor Oversight and Quality Management in Clinical Trials ## Sponsor Oversight (Section 3.9) ### General Oversight Obligations The sponsor should ensure that the trial design and trial conduct, the processes undertaken, and the information and data generated are of sufficient quality to ensure reliable trial results, trial participants' safety, and appropriate decision making. [E6R3-3.9.1] The sponsor should ensure that trial processes are conducted in compliance with the trial protocol and related documents as well as with applicable regulatory requirements and ethical standards. [E6R3-3.9.2] ### Protocol Deviations The sponsor should determine necessary trial-specific criteria for classifying protocol deviations as important. [E6R3-3.9.3] > "Important protocol deviations are a subset of protocol deviations that may significantly impact the completeness, accuracy and/or reliability of the trial data or that may significantly affect a participant's rights, safety or well-being." [E6R3-3.9.3] ### Risk Management and Decision Making Decisions related to the trial should be appropriately assessed for their impact on participants' rights, safety and well-being and the reliability of trial results. [E6R3-3.9.4] Risks related to such decisions should be suitably managed throughout the planning, conduct, and reporting of the trial. [E6R3-3.9.4] ### Scope and Tailoring of Oversight The range and extent of oversight measures should be fit for purpose and tailored to the complexity of and risks associated with the trial. [E6R3-3.9.5] The selection and oversight of investigators and service providers are fundamental features of the oversight process. [E6R3-3.9.5] Oversight by the sponsor includes quality assurance and quality control processes relating to the trial-related activities of investigators and service providers. [E6R3-3.9.5] The sponsor should ensure appropriate and timely escalation and follow-up of issues to allow the implementation of appropriate actions in a timely manner. [E6R3-3.9.6] ### Independent Data Monitoring Committee (IDMC) The sponsor may consider establishing an IDMC to assess the progress of a clinical trial, including the safety data and the efficacy endpoints, at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. [E6R3-3.9.7] ### Endpoint Assessment/Adjudication Committee Where appropriate, sponsors may also establish an endpoint assessment/adjudication committee in certain trials to review endpoints reported by investigators to determine whether the endpoints meet protocol-specified criteria. [E6R3-3.9.8] To minimise bias, such committees should typically be blinded to the assigned treatments when performing their assessments, regardless of whether the trial itself is conducted in a blinded manner. [E6R3-3.9.8] ### Requirements for Committees Committees established for purposes that could impact participant safety or the reliability of trial results should include members with relevant expertise and with managed conflicts of interest, have written operating procedures (e.g., charters), and document their decisions. [E6R3-3.9.9] ## Quality Management (Section 3.10) The sponsor should implement an appropriate system to manage quality throughout all stages of the trial process. [E6R3-3.10] Quality management includes the design and implementation of efficient clinical trial protocols, including tools and procedures for trial conduct (including for data collection and management), in order to ensure the protection of participants' rights, safety and well-being and the reliability of trial results. [E6R3-3.10] The sponsor should adopt a proportionate and risk-based approach to quality management, which involves incorporating quality into the design of the clinical trial (i.e., quality by design) and identifying those factors that are likely to have a meaningful impact on participants' rights, safety and well-being and the reliability of the results (i.e., critical to quality factors as described in ICH E8(R1)). [E6R3-3.10] The sponsor should describe the quality management approach implemented in the trial in the clinical trial report (see ICH E3 Structure and Content of Clinical Study Reports). [E6R3-3.10]

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## Quality Control (Section 3.11.3) Quality control should be applied using a risk-based approach to each stage of data handling to ensure that data are reliable and have been processed correctly. [E6R3-3.11.3] Within clinical trials, monitoring and data management processes are the main quality control activities. [E6R3-3.11.3] Where appropriate, quality control activities may also be applied to facilities outside of investigator sites, such as central image reading facilities. [E6R3-3.11.3] ## Monitoring — Purpose and Scope (Section 3.11.4) The aim of monitoring is to ensure the participants' rights, safety and well-being and the reliability of trial results as the trial progresses. [E6R3-3.11.4] Monitoring is one of the principal quality control activities. [E6R3-3.11.4] Monitoring involves a broad range of activities including, but not limited to: - Communication with investigator sites [E6R3-3.11.4] - Verification of the investigator and investigator site staff qualifications and site resources [E6R3-3.11.4] - Training and review of trial documents and information using approaches including source data review, source data verification, data analytics, and visits to institutional facilities undertaking trial-related activities [E6R3-3.11.4] Some monitoring activities, such as centralised monitoring, may be conducted by different methods and persons with different roles, for example a data scientist. [E6R3-3.11.4] However, monitoring should be performed by persons not involved in the clinical conduct of the trial at the site being monitored. [E6R3-3.11.4] The monitoring approach should consider the activities and services involved, including decentralised settings, and be included in the monitoring plan. [E6R3-3.11.4] Monitors and other trial staff should adhere to data protection and confidentiality requirements in accordance with applicable regulatory requirements, institution policy and established data security standards. [E6R3-3.11.4] ### Determining the Extent and Nature of Monitoring Monitoring may include site monitoring (performed on-site and/or remotely) and centralised monitoring, depending on the monitoring strategy and the design of the clinical trial. [E6R3-3.11.4] The sponsor should determine the appropriate extent and nature of monitoring based on identified risks. [E6R3-3.11.4] Factors to be considered include the objective, purpose, design, complexity, blinding, number of trial participants, investigational product, current knowledge of the safety profile, and endpoints of the trial. [E6R3-3.11.4] ## Investigator Site Monitoring (Section 3.11.4.1) Monitoring may be performed in relation to the clinical trial activities at the investigator sites, including their pharmacies and local laboratories as appropriate. [E6R3-3.11.4.1] The frequency of monitoring activities should also be determined based on identified risks, and monitoring activities and their frequency should be modified as appropriate using knowledge gained. [E6R3-3.11.4.1] This monitoring activity may be performed on-site and/or remotely depending on the nature of the activity and its objectives. [E6R3-3.11.4.1] Monitoring may include remote and secure, direct read-only access to source records, other data acquisition tools and essential record retention systems. [E6R3-3.11.4.1] ## Centralised Monitoring (Section 3.11.4.2) Centralised monitoring is defined in the guideline as follows: > Centralised monitoring is an evaluation of accumulated data, performed in a timely manner, by the sponsor's qualified and trained persons (e.g., medical monitor, data scientist/data manager, biostatistician). [E6R3-3.11.4.2]

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## Sponsor Monitoring Plan, Procedures, and Activities in Clinical Trials ## Overview of Monitoring Approaches Centralised monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of site monitoring or be used on their own. [E6R3-3.11.4.2] Use of centralised data analytics can help identify systemic or site-specific issues, including protocol noncompliance and potentially unreliable data. [E6R3-3.11.4.2] Centralised monitoring may also support the selection of sites and/or processes for targeted site monitoring. [E6R3-3.11.4.2] ## Monitoring Plan (Section 3.11.4.3) The sponsor should develop a monitoring plan that is tailored to the identified potential safety risks, the risks to data quality and/or other risks to the reliability of the trial results. [E6R3-3.11.4.3] Particular attention should be given to procedures relevant to participant safety and to trial endpoints. [E6R3-3.11.4.3] The plan should describe the monitoring strategy, the monitoring activities of all the parties involved, the various monitoring methods and tools to be used, and the rationale for their use. [E6R3-3.11.4.3] The monitoring strategy should ensure appropriate oversight of trial conduct and consider site capabilities and the potential burden. [E6R3-3.11.4.3] The plan should focus on aspects that are critical to quality, and should reference the sponsor's applicable policies and procedures. [E6R3-3.11.4.3] Monitoring of important data and processes (e.g., those related to primary endpoints and key secondary endpoints and processes intended to ensure participant safety) performed outside the investigator site (e.g., central image reading facilities, central laboratories) should be addressed in the monitoring plan. [E6R3-3.11.4.3] ## Monitoring Procedures (Section 3.11.4.4) Persons performing monitoring should follow the sponsor's monitoring plan and applicable monitoring procedures. [E6R3-3.11.4.4] ## Monitoring Activities (Section 3.11.4.5) Monitoring in accordance with the sponsor's requirements and monitoring plan should generally include the following activities across the clinical trial life cycle, as applicable. [E6R3-3.11.4.5] ### Communication with Parties Conducting the Trial (Section 3.11.4.5.1) - Establishing and maintaining a line of communication between the sponsor and the investigator and other parties and individuals involved in the trial conduct (e.g., centrally performed activities); in general, each site should have an assigned monitor as their contact point. [E6R3-3.11.4.5.1] - Informing the investigator or other parties and individuals involved in the trial conduct of relevant deviations from the protocol, GCP and the applicable regulatory requirements and, if necessary, taking appropriate action designed to prevent recurrence of the detected deviations; important deviations should be highlighted and should be the focus of remediation efforts as appropriate. [E6R3-3.11.4.5.1] - Informing the investigator or other parties and individuals involved in the trial conduct of entry errors or omissions in source record(s) and/or data acquisition tools and ensuring that corrections, additions or deletions are made as appropriate, dated and explained (if necessary) and that approval of the change is properly documented. [E6R3-3.11.4.5.1] - Actions taken in relation to the deviations, errors or omissions should be proportionate to their importance. [E6R3-3.11.4.5.1] ### Investigator Site Selection, Initiation, Management and Close-out (Section 3.11.4.5.2) - Selecting the site and confirming that the investigator and individuals or parties involved in the trial conduct have adequate qualifications, resources and facilities, including laboratories, equipment and investigator site staff, to conduct the trial safely and properly. [E6R3-3.11.4.5.2] - Confirming, with consideration of their delegated activities and experience, that the investigator, investigator site staff and other parties, and individuals involved in the trial conduct are adequately informed about the trial and follow the current approved protocol and other protocol-related documents, such as the current Investigator's Brochure and relevant information related to the investigational product. [E6R3-3.11.4.5.2] - Confirming that the investigator is maintaining the essential records (see Appendix C). [E6R3-3.11.4.5.2] - Confirming that informed consent was obtained before participation in the trial for trial participants at the site. [E6R3-3.11.4.5.2] - Determining whether adverse events are appropriately reported within the time periods required by the protocol, GCP and the applicable regulatory requirement(s). [E6R3-3.11.4.5.2] - Confirming the protocol requirements for source records and the site's location of such data. [E6R3-3.11.4.5.2] - Verifying that the blinding is maintained, where applicable. [E6R3-3.11.4.5.2] - Reviewing and reporting the participant recruitment and retention rates. [E6R3-3.11.4.5.2] - Confirming that the investigator provides the required reports, notifications or other information in accordance with the protocol and trial procedures. [E6R3-3.11.4.5.2] - Confirming the arrangement for the retention of the essential records and the final accountability of the investigational product (e.g., return and destruction or alternative disposition, if appropriate) during site close-out activity. [E6R3-3.11.4.5.2] ### Monitoring of Investigational Product Management (Section 3.11.4.5.3) Monitoring activities should confirm, for the investigational product(s): [E6R3-3.11.4.5.3] - That storage conditions are acceptable and in accordance with the storage requirements specified in the protocol or other relevant documents. [E6R3-3.11.4.5.3] - That supplies are sufficient throughout the trial and are used within their shelf life. [E6R3-3.11.4.5.3] - That the correct investigational product(s) are supplied only to participants who are eligible to receive it at the protocol-specified dose(s) and, where appropriate, in accordance with the randomisation procedures. [E6R3-3.11.4.5.3] - That the participants, investigator, investigator site staff and other relevant parties and individuals involved in the trial conduct are provided with necessary information regarding the investigational product. [E6R3-3.11.4.5.3]

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## Monitoring of Clinical Trial Data ### Participant Eligibility The sponsor must verify that the investigator is enrolling only eligible trial participants. [E6R3-3.11.4.5.4] ### Data Accuracy, Completeness and Consistency Monitoring must include checking the accuracy, completeness and consistency of the reported trial data against the source records and other trial-related records, and whether these were reported in a timely manner. [E6R3-3.11.4.5.4] This checking can be done on the basis of using samples and supported by data analytics, as appropriate. [E6R3-3.11.4.5.4] The sample size and the types of data or records may need adjustment based on previous monitoring results or other indications of insufficient data quality. [E6R3-3.11.4.5.4] Specifically, monitoring should: - Verify that the data required by the protocol and identified as data of higher criticality in the monitoring plan are consistent with the source. [E6R3-3.11.4.5.4] - Identify missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations. [E6R3-3.11.4.5.4] - Examine data trends, such as the range, consistency and variability of data within and across sites. [E6R3-3.11.4.5.4] ### Data Errors and Integrity Monitoring must also identify significant errors in data collection and reporting at a site or across sites, potential data manipulation and data integrity problems. [E6R3-3.11.4.5.4] ## Monitoring Reports ### Content of Reports Reports of monitoring activities should include a summary of what was reviewed, a description of significant findings, conclusions and actions required to resolve them, and follow-up on their resolution including those not resolved in previous reports. [E6R3-3.11.4.6] The requirements of monitoring reports, including their content and frequency, should be described in the sponsor's procedures. [E6R3-3.11.4.6] ### Distribution and Timeliness Reports of investigator site and/or centralised monitoring should be provided to the appropriate sponsor staff as described in the sponsor's procedures in a timely manner for review and follow-up. [E6R3-3.11.4.6] ### Escalation When needed, the report should describe findings requiring escalation for action and resolution. [E6R3-3.11.4.6] The sponsor should decide on the appropriate action to be taken, and these decisions and the resolution of the actions involved, where needed, should be recorded. [E6R3-3.11.4.6] ## Investigational Product Considerations The sponsor must ensure that the receipt, storage, use, handling, return and destruction or alternative disposition of the investigational product(s) are controlled and documented adequately. [E6R3-3.11.4.5.4] The disposition of unused investigational product(s) must comply with applicable regulatory requirements and be in accordance with sponsor requirements. [E6R3-3.11.4.5.4] Where a product available on the market is dispensed and used in accordance with applicable regulatory requirements, some of the previously outlined considerations may not be applicable. [E6R3-3.11.4.5.4]

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## Noncompliance (Section 3.12) ### General Obligations (3.12.1) Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirements by an investigator/institution or by members of the sponsor's staff should lead to appropriate and proportionate action by the sponsor to secure compliance. [E6R3-3.12.1] ### Serious Noncompliance and Root Cause Analysis (3.12.2) If noncompliance that significantly affects or has the potential to significantly affect the rights, safety, or well-being of trial participants or the reliability of trial results is discovered, the sponsor should perform a root cause analysis, implement appropriate corrective and preventive actions, and confirm their adequacy unless otherwise justified. [E6R3-3.12.2] Where the sponsor identifies issues that are likely to significantly impact the rights, safety, or well-being of trial participants or the reliability of trial results (i.e., serious noncompliance), the sponsor should notify the regulatory authority and/or IRB/IEC, in accordance with applicable regulatory requirements, and/or the investigator, as appropriate. [E6R3-3.12.2] ### Termination of Participation (3.12.3) If significant noncompliance is identified on the part of an investigator/institution or service provider that persists despite efforts at remediation, the sponsor should consider terminating the investigator's/institution's or service provider's participation in the trial. [E6R3-3.12.3] In these circumstances, the sponsor should promptly notify the regulatory authority(ies) and IRB/IEC of the serious noncompliance, as appropriate, and take actions to minimise the impact on the trial participants and the reliability of the results. [E6R3-3.12.3] ## Safety Assessment and Reporting (Section 3.13) The sponsor is responsible for the ongoing safety evaluation of the investigational product(s). [E6R3-3.13] The Investigator's Brochure or, where applicable, the current scientific information such as a basic product information brochure, forms the basis of safety assessment and reporting for the clinical trial. [E6R3-3.13] ### Sponsor Review of Safety Information (3.13.1) The sponsor should aggregate, as appropriate, and review in a timely manner relevant safety information, including the review of any reported unfavourable medical events occurring in participants before investigational product administration (e.g., during screening). [E6R3-3.13.1] This review may result in the update of the protocol, Investigator's Brochure, informed consent materials, and related documents. [E6R3-3.13.1] The sponsor should review available emerging safety information to assess whether there is any new data that may affect the participant's willingness to continue in the trial, impact the conduct of the trial, or alter the approval/favourable opinion of the IRB/IEC and/or regulatory authority(ies), as applicable. [E6R3-3.13.1] Any information of this nature should be communicated to the participants, investigator, IRB/IEC, and regulatory authorities, as applicable, in a timely manner. [E6R3-3.13.1] ### Safety Reporting (3.13.2) - The sponsor should submit to the regulatory authority(ies) safety updates and periodic reports, including changes to the Investigator's Brochure, as required by applicable regulatory requirements. [E6R3-3.13.2] - The sponsor should, in accordance with the applicable regulatory requirement(s) and with ICH E2A *Clinical Safety Data Management: Definitions and Standards for Expedited Reporting*, expedite the reporting to the regulatory authority(ies) of all suspected, unexpected and serious adverse reactions (i.e., SUSARs). [E6R3-3.13.2]

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## Sponsor Responsibilities: Systems Assessment, Statistical Programming and Data Analysis ## Systems Used or Deployed by the Investigator/Institution The sponsor must assess whether systems identified as containing source records in the trial—such as electronic health records, other record-keeping systems for source data collection, and investigator site files—are fit for purpose, or whether risks from known issues can be appropriately mitigated. [E6R3-3.16.1] This assessment should occur during the process of selecting clinical trial sites and must be documented. [E6R3-3.16.1] Where clinical practice computerised systems are being considered for use in clinical trials (e.g., electronic health records or imaging systems used or deployed by the investigator/institution), these systems should be assessed for their fitness for purpose in the context of the trial. [E6R3-3.16.1] The assessment should be performed before the system is used in the trial and should be proportionate to the importance of the data managed in the system. [E6R3-3.16.1] Factors such as data security (including measures for backup), user management, and audit trails—which help ensure the protection of confidentiality and integrity of the trial data—should be considered as appropriate. [E6R3-3.16.1] ## Requirements Applicable to All Systems The sponsor must ensure that a process is in place for service providers and investigators/institutions to inform the sponsor of incidents that could potentially constitute a serious noncompliance with the clinical trial protocol, trial procedures, applicable regulatory requirements, or GCP, in accordance with section 3.12. [E6R3-3.16.1] ## Statistical Programming and Data Analysis Section 3.16.2 concerning documentation of operational aspects of clinical trial statistical activities should be read in conjunction with ICH E9 *Statistical Principles for Clinical Trials* and ICH E9(R1) *Addendum on Estimands and Sensitivity Analysis in Clinical Trials*, which provide detailed guidance on statistical principles for clinical development, trial design, conduct, analysis, and reporting. [E6R3-3.16.2] ### Statistical Analysis Plan The sponsor should develop a statistical analysis plan that is consistent with the trial protocol and that details the approach to data analysis, unless the approach to data analysis is sufficiently described in the protocol. [E6R3-3.16.2] ### Quality Control of Statistical Programming The sponsor should ensure that appropriate and documented quality control of statistical programming and data analysis is implemented—for example, for sample size calculations, analysis results for IDMC review, outputs for clinical trial reports, and statistical or centralised monitoring. [E6R3-3.16.2] ### Traceability of Data Transformations The sponsor should ensure the traceability of data transformations and derivations during data processing and analysis. [E6R3-3.16.2] ### Pre-defined Analysis Sets The sponsor should ensure that the criteria for inclusion or exclusion of trial participants from any analysis set are pre-defined, for example in the protocol or the statistical analysis plan. [E6R3-3.16.2] The rationale for exclusion of any participant (or particular data point) should be clearly described and documented. [E6R3-3.16.2] ### Deviations from Planned Statistical Analysis Deviations from the planned statistical analysis or changes made to the data after the trial has been unblinded (where applicable) should be clearly documented and justified, and should only occur in exceptional circumstances (e.g., data discrepancies that must be addressed). [E6R3-3.16.2]

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## Overview Section 4 provides guidance to responsible parties — investigators and sponsors — on the appropriate management of data integrity, traceability, and security, thereby allowing the accurate reporting, verification, and interpretation of clinical trial-related information. [E6R3-4] This section should be read in conjunction with corresponding responsibilities for the investigator and the sponsor as defined in sections 2 and 3, along with ICH E8(R1), ICH E9, and ICH E9(R1). [E6R3-4] The quality and amount of information generated in a clinical trial should be sufficient to address trial objectives, provide confidence in the trial's results, and support good decision making. [E6R3-4] The systems and processes that help ensure this quality should be designed and implemented in a way that is proportionate to the risks to participants and the reliability of trial results. [E6R3-4] ### Key Processes Addressing the Full Data Life Cycle The following key processes should address the full data life cycle with a focus on the criticality of the data and should be implemented proportionately and documented appropriately: [E6R3-4] - Processes to ensure the protection of the confidentiality of trial participants' data; [E6R3-4] - Processes for managing computerised systems to ensure that they are fit for purpose and used appropriately; [E6R3-4] - Processes to safeguard essential elements of the clinical trial, such as randomisation, dose adjustments, and blinding; [E6R3-4] - Processes to support key decision making, such as data finalisation prior to analysis, unblinding, allocation to analysis data sets, changes in clinical trial design and, where applicable, the activities of, for example, an IDMC. [E6R3-4] ## 4.1 Safeguard Blinding in Data Governance Maintaining the integrity of the blinding is important in particular in the design of systems, management of users' accounts, delegation of responsibilities with respect to data handling and provision of data access at sites, data transfers, database review prior to planned unblinding, and statistical analysis across all appropriate stages of the trial. [E6R3-4.1.1] Roles, responsibilities, and procedures for access to unblinded information should be defined and documented by all relevant parties according to the protocol; this information may also be included in the data management plans and statistical analysis plans or other trial-specific plans/instructions and site staff delegation records. [E6R3-4.1.2] For example, in blinded trials, sponsor staff or service providers who are involved in operation of the trial and directly or indirectly interact with investigator site staff should not have access to unblinding information except when justified by the trial design (e.g., use of unblinded monitors). [E6R3-4.1.2] In such cases, suitable mitigation strategies should be implemented to reduce the risk of inadvertent unblinding of the blinded investigator site staff. [E6R3-4.1.3] The potential for unblinding should be part of the risk assessment of a blinded trial. [E6R3-4.1.4] Any planned or unplanned unblinding, including inadvertent or emergency unblinding, should be documented. [E6R3-4.1.4] Any unplanned unblinding should be assessed for its impact on the trial results, and actions should be taken as appropriate. [E6R3-4.1.4] ## 4.2 Data Life Cycle Elements Procedures should be in place to cover the full data life cycle. [E6R3-4.2] ### 4.2.1 Data Capture - When data captured on paper or in an electronic health record are manually transcribed into a computerised system (e.g., data acquisition tool), the need for and the extent of data verification should take the criticality of the data into account. [E6R3-4.2.1] - Acquired data from any source, including data directly captured in a computerised system (e.g., data acquisition tool), should be accompanied by relevant metadata. [E6R3-4.2.1] - At the point of data capture, automated data validation checks to raise data queries should be considered as required based on risk, and their implementation should be controlled and documented. [E6R3-4.2.1] ### 4.2.2 Relevant Metadata, Including Audit Trails The approach used by the responsible party for implementing, evaluating, accessing, managing, and reviewing relevant metadata associated with data of higher criticality should entail the following: [E6R3-4.2.2] - Evaluating the system for the types and content of metadata available to ensure that: [E6R3-4.2.2] - Computerised systems maintain logs of user account creation, changes to user roles and permissions, and user access; [E6R3-4.2.2] - Systems are designed to permit data changes in such a way that the initial data entry and any subsequent changes or deletions are documented, including, where appropriate, the reason for the change; [E6R3-4.2.2] - Systems record and maintain workflow actions in addition to direct data entry/changes into the system. [E6R3-4.2.2] - Ensuring that audit trails, reports, and logs are not disabled. [E6R3-4.2.2] Audit trails should not be modified except in rare circumstances (e.g., when a participant's personal information is involved). [E6R3-4.2.2]

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## 4.2 Data Governance – Investigator and Sponsor (Part 2) ### 4.2.3 Review of Data and Metadata Procedures for review of trial-specific data, audit trails and other relevant metadata should be in place. [E6R3-4.2.3] Review should be a planned activity, and the extent and nature should be risk-based, adapted to the individual trial and adjusted based on experience during the trial. [E6R3-4.2.3] ### 4.2.4 Data Corrections There should be processes to correct data errors that could impact the reliability of the trial results. [E6R3-4.2.4] Corrections should be attributed to the person or computerised system making the correction, justified and supported by source records around the time of original entry and performed in a timely manner. [E6R3-4.2.4] ### 4.2.5 Data Transfer, Exchange and Migration Validated processes and/or other appropriate processes such as reconciliation should be in place to ensure that electronic data, including relevant metadata, transferred between computerised systems retains its integrity and preserves its confidentiality. [E6R3-4.2.5] The data exchange/transfer process or system migration should be documented to ensure traceability, and data reconciliation should be implemented as appropriate to avoid data loss and unintended modifications. [E6R3-4.2.5] ### 4.2.6 Finalisation of Data Sets Prior to Analysis Data of sufficient quality for interim and final analysis should be defined and are achieved by implementing timely and reliable processes for data capture, verification, validation, review and rectification of errors and, where possible, omissions that have a meaningful impact on the safety of trial participants and/or the reliability of the trial results. [E6R3-4.2.6] Activities undertaken to finalise the data sets prior to analysis should be confirmed and documented in accordance with pre-specified procedures. [E6R3-4.2.6] These activities may include reconciliation of entered data and data sets or reconciliation of relevant databases, rectification of data errors and, where possible, omissions, medical coding and compilation of and addressing the impact of noncompliance issues, including protocol deviations. [E6R3-4.2.6] Data extraction and determination of data analysis sets should take place in accordance with the planned statistical analysis and should be documented. [E6R3-4.2.6] ### 4.2.7 Retention and Access The trial data and relevant metadata should be archived in a way that allows for their retrieval and readability and should be protected from unauthorised access and alterations throughout the retention period. [E6R3-4.2.7] ### 4.2.8 Destruction The trial data and metadata may be permanently destroyed when no longer required as determined by applicable regulatory requirements. [E6R3-4.2.8] ## 4.3 Computerised Systems The responsibilities of the sponsor, investigator and the activities of other parties with respect to a computerised system used in clinical trials should be clear and documented. [E6R3-4.3] The responsible party should ensure that those developing computerised systems for clinical trials on their behalf are aware of the intended purpose and the regulatory requirements that apply to them. [E6R3-4.3] It is recommended that representatives of intended participant populations and healthcare professionals are involved in the design of the system, where relevant, to ensure that computerised systems are suitable for use by the intended user population. [E6R3-4.3] ### 4.3.1 Procedures for the Use of Computerised Systems Documented procedures should be in place to ensure the appropriate use of computerised systems in clinical trials for essential activities related to data collection, handling and management. [E6R3-4.3.1] ### 4.3.2 Training The responsible party should ensure that those using computerised systems are appropriately trained in their use. [E6R3-4.3.2] ### 4.3.3 Security The security of the trial data and records should be managed throughout the data life cycle. [E6R3-4.3.3] The responsible party should ensure that security controls are implemented and maintained for computerised systems, including user management and ongoing measures to prevent, detect and/or mitigate security breaches. [E6R3-4.3.3] Aspects such as user authentication requirements and password management, firewall settings, antivirus software, security patching, system monitoring and penetration testing should be considered. [E6R3-4.3.3] The responsible party should maintain adequate backup of the data. [E6R3-4.3.3] Procedures should cover system security measures, data backup and disaster recovery to ensure that unauthorised access and data loss are prevented, and such measures should be periodically tested, as appropriate. [E6R3-4.3.3] ### 4.3.4 Validation The responsible party is responsible for the validation status of the system throughout its life cycle. [E6R3-4.3.4] The approach to validation of computerised systems should be based on a risk assessment that considers the intended use of the system; the purpose and importance of the data/record that are collected/generated, maintained and retained in the system; and the potential of the system to affect the well-being, rights and safety of trial participants and the reliability of trial results. [E6R3-4.3.4] ### Additional Metadata Requirements (Section 4.2 Preamble) Audit trails and logs should be interpretable and able to support review. [E6R3-4.2] The automatic capture of date and time of data entries or transfer should be unambiguous, for example by using coordinated universal time (UTC). [E6R3-4.2] The responsible party should determine which of the identified metadata require review and retention. [E6R3-4.2]

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## Computerised Systems: Validation, Release, Failure, Support, and User Management ## 4.3.4 Validation Validation should demonstrate that the system conforms to the established requirements for completeness, accuracy and reliability and that its performance is consistent with its intended purpose. [E6R3-4.3.4] Systems should be appropriately validated prior to use. [E6R3-4.3.4] Subsequent changes to the system should be validated based on risk and should consider both previously collected and new data in line with change control procedures. [E6R3-4.3.4] Periodic review may be appropriate to ensure that computerised systems remain in a validated state throughout the life cycle of the system. [E6R3-4.3.4] Both standard system functionality and protocol-specific configurations and customisations, including automated data entry checks and calculations, should be validated. [E6R3-4.3.4] Interfaces between systems should also be defined and validated. [E6R3-4.3.4] Different degrees of validation may be needed for bespoke systems, systems designed to be configured or systems where no alterations are needed. [E6R3-4.3.4] Where relevant, validation procedures (until decommissioning) should cover the following: system design, system requirement, functionality testing, configuration, release, setup, installation and change control. [E6R3-4.3.4] The responsible party should ensure that the computerised systems are validated as fit for purpose for use in the trial, including those developed by other parties. [E6R3-4.3.4] They should ensure that validation documentation is maintained and retained. [E6R3-4.3.4] Validation should generally include defining the requirements and specifications for the system and their testing, along with the associated documentation, to ensure the system is fit for purpose for use in the trial, especially for critical functionality, such as randomisation, dosing and dose titrations and reductions, and collection of endpoint data. [E6R3-4.3.4] Unresolved issues, if any, should be justified and, where relevant, the risks identified from such issues should be addressed by mitigation strategies prior to and/or during the continued use of the system. [E6R3-4.3.4] ## 4.3.5 System Release The trial-specific systems (including updates resulting from protocol amendments) should only be implemented, released or activated for individual investigator sites after all necessary approvals for the clinical trial relevant to that investigator site have been received. [E6R3-4.3.5] ## 4.3.6 System Failure Contingency procedures should be in place to prevent loss or lack of accessibility to data essential to participant safety, trial decisions or trial outcomes. [E6R3-4.3.6] ## 4.3.7 Technical Support Where appropriate, there should be mechanisms (e.g., help desk support) in place to document, evaluate and manage issues with the computerised systems (e.g., raised by users), and there should be periodic review of these cumulative issues to identify those that are repeated and/or systemic. [E6R3-4.3.7] Defects and issues should be resolved according to their criticality. [E6R3-4.3.7] Issues with high criticality should be resolved in a timely manner. [E6R3-4.3.7] ## 4.3.8 User Management Access controls are integral to computerised systems used in clinical trials to limit system access to authorised users and to ensure attributability to an individual. [E6R3-4.3.8] The security measures should be selected in such a way that they achieve the intended security. [E6R3-4.3.8] Procedures should be in place to ensure that user access permissions are appropriately assigned based on a user's duties and functions, blinding arrangements and the organisation to which users belong. [E6R3-4.3.8] Access permissions should be revoked when they are no longer needed. [E6R3-4.3.8] A process should be in place to ensure that user access and assigned roles and permissions are periodically reviewed, where relevant. [E6R3-4.3.8] Authorised users and access permissions should be clearly documented, maintained and retained. [E6R3-4.3.8] These records should include any updates to a user's roles, access permissions and time of access permission being granted (e.g., time stamp). [E6R3-4.3.8]

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## Investigator's Brochure: Purpose, Development, and Reference Safety Information ### Introduction The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human participants. [E6R3-A.1] Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for and their compliance with many key features of the protocol, such as the dose, dose frequency/interval, methods of administration, and safety monitoring procedures. [E6R3-A.1] ### Development of the Investigator's Brochure Generally, the sponsor is responsible for ensuring that an up-to-date IB is developed. [E6R3-A.1.1] In the case of an investigator-initiated trial, the sponsor-investigator should determine whether a brochure is available from the product license/marketing authorisation holder. [E6R3-A.1.1] If the investigational product is provided by the sponsor-investigator, then they should provide the necessary information to the investigator site staff. [E6R3-A.1.1] Where permitted by regulatory authorities, current scientific information such as a basic product information brochure (e.g., summary of product characteristics, package leaflet, or labelling) may be an appropriate alternative, provided that it includes current, comprehensive and detailed information on all aspects of the investigational product that might be of importance to the investigator. [E6R3-A.1.1] If an authorised medicinal product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared unless there is a rationale for only one IB. [E6R3-A.1.1] The IB should be reviewed at least annually and revised as necessary in compliance with a sponsor's documented procedures. [E6R3-A.1.1] More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. [E6R3-A.1.1] Relevant new information may be so important that it needs to be communicated to the investigators and possibly to the institutional review boards/independent ethics committees (IRBs/IECs) and/or regulatory authorities before it is included in a revised IB. [E6R3-A.1.1] ### Reference Safety Information and Risk-Benefit Assessment The reference safety information (RSI) contained in the IB provides an important reference point for expedited reporting of suspected unexpected serious adverse reactions (SUSARs) in the clinical trial. [E6R3-A.1.2] This RSI should include a list of adverse reactions, including information on their frequency and nature. [E6R3-A.1.2] This list should be used for determining the expectedness of a suspected serious adverse reaction and subsequently whether reporting needs to be expedited in accordance with applicable regulatory requirements. [E6R3-A.1.2] The IB also provides insight to support the clinical management of the participants during the course of the clinical trial. [E6R3-A.1.2] The information should be presented in a concise, simple, objective, balanced and non-promotional form that enables a clinician or potential investigator to understand it and make their own unbiased risk-benefit assessment of the appropriateness of the proposed trial. [E6R3-A.1.2] For this reason, a medically qualified person should be involved in the generation of an IB, but the contents of the IB should be approved by the disciplines that generated the described data. [E6R3-A.1.2] ### Scope Note on Investigational Products For the purpose of this guideline, the term *investigational products* should be considered synonymous with drugs, medicines, medicinal products, vaccines, and biological products. [E6R3-A.1]

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## Investigator's Brochure: Summary of Data and Guidance (Section A.3.7) ### Purpose and Scope Section A.3.7 of the Investigator's Brochure (IB) must provide an overall discussion of the nonclinical and clinical data and summarise information from various sources on different aspects of the investigational product(s), wherever possible. [E6R3-A.3.7] Through this synthesis, the investigator can be provided with the most informative interpretation of the available data and with an assessment of the implications of the information for future clinical trials. [E6R3-A.3.7] ### Related Products Where appropriate, published reports on related products should be discussed, as this could help the investigator to anticipate adverse drug reactions or other problems in clinical trials. [E6R3-A.3.7] ### Overall Aim The overall aim of this section is to provide the investigator with a clear understanding of the possible risks and adverse reactions and of the specific tests, observations and precautions that may be needed for a clinical trial. [E6R3-A.3.7] This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological and clinical information on the investigational product(s). [E6R3-A.3.7] Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions, based on previous clinical and nonclinical experience and on the pharmacology of the investigational product. [E6R3-A.3.7] ### Marketing Experience (Preceding Context) The IB should identify countries where the investigational product has been marketed or approved, and any significant information arising from the marketed use should be summarised (e.g., formulations, dosages, routes of administration, adverse drug reactions). [E6R3-A.3.7] The IB should also identify all countries where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/registration. [E6R3-A.3.7] The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis of prior experiences with the product under investigation and with related products, as well as a description of the precautions or special monitoring to be done as part of the investigational use of the product(s). [E6R3-A.3.7] ## Appendix B: Clinical Trial Protocol and Protocol Amendment(s) ### General Requirements Clinical trials should be described in a clear, concise and operationally feasible protocol. [E6R3-B] The protocol should be designed in such a way as to minimise unnecessary complexity and to mitigate or eliminate important risks to the rights, safety, and well-being of trial participants and the reliability of data. [E6R3-B] ### Protocol Development Protocol development processes should incorporate input from relevant interested parties, where appropriate. [E6R3-B] ### Adaptability Building adaptability into the protocol — for example, by including acceptable ranges for specific protocol provisions — can reduce the number of deviations or, in some instances, the requirement for a protocol amendment. [E6R3-B] Such adaptability should not adversely affect participant safety or the scientific validity of the trial. [E6R3-B]

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## Management of Essential Records (ICH E6(R3) Appendix C.2) ### Identification and Version Control Records should be identifiable and version controlled (when appropriate) and should include authors, reviewers, and approvers as appropriate, along with date and signature (electronic or physical), where necessary. [E6R3-C.2.1] ### Delegated and Transferred Activities For activities that are transferred or delegated to service providers by the sponsor or investigator/institution, respectively, arrangements should be made for the access and management of the essential records throughout the trial and for their retention following completion of the trial. [E6R3-C.2.2] ### Repositories: Trial Master File and Investigator Site File Essential records should be maintained in or referred to from repositories held by the sponsor and by the investigator/institution for their respective records. [E6R3-C.2.3] These repositories may be referred to as a **trial master file (TMF)**, and the repository held by the investigator/institution may also be referred to as the **investigator site file (ISF)**. [E6R3-C.2.3] ### Record Location and Storage Systems The sponsor and investigator/institution should maintain a record of where essential records are located, including source records. [E6R3-C.2.4] The storage system(s) used during the trial and for archiving (irrespective of the type of media used) should provide for appropriate identification, version history, search, and retrieval of trial records. [E6R3-C.2.4] ### Timely Collection and Filing The sponsor and investigator/institution should ensure that the essential records are collected and filed in a timely manner, which can greatly assist in the successful management of a trial. [E6R3-C.2.5] Some essential records should generally be in place prior to the start of the trial and may be subsequently updated during the trial. [E6R3-C.2.5] ### Accessibility, Readability, and Traceability The sponsor and investigator/institution should retain the essential records in a way that ensures that they remain complete, readable, and readily available and are directly accessible upon request by regulatory authorities, monitors, and auditors. [E6R3-C.2.6] Alterations to the essential records should be traceable. [E6R3-C.2.6] ### Retention Responsibilities The sponsor and investigator/institution should ensure the retention of the essential records required to fulfil their responsibility. [E6R3-C.2.7] The original records should generally be retained by the responsible party who generated them. [E6R3-C.2.7] ### Access to and Sharing of Records Between Parties In order to fulfil their responsibilities in the conduct of the trial, the sponsor and investigator/institution may need access to or copies of one another's relevant essential records before and during the conduct of the trial. [E6R3-C.2.8] At the end of the trial, each party should retain their essential records (see sections 2.12.11 and 3.16.3(a)). [E6R3-C.2.8] The record location may vary during the trial depending on the nature of the record; for example, the investigator may access relevant essential records from the sponsor (e.g., suspected unexpected serious adverse reactions (SUSAR) reports) via a sponsor-provided portal, and these essential records would need to be retained by the investigator/institution at the end of the trial. [E6R3-C.2.8] ### Certified Copies When a copy is used to permanently replace the original essential record, the copy should fulfil the requirements for certified copies. [E6R3-C.2.9] ### Records Held by One or Both Parties Some records are typically maintained and retained only by the sponsor (e.g., those related solely to sponsor activities such as data analysis) or only by the investigator/institution (e.g., those that contain confidential participant information). [E6R3-C.2.10] Some records may be retained by the sponsor and/or the investigator/institution. [E6R3-C.2.10] ### Blinding and Data Protection Considerations Careful consideration should be given to the sharing of records when there are blinding considerations and when the records are subject to applicable data protection legislation. [E6R3-C.2.11] For the sharing of essential records with service providers, the requirements set out in section C.2.2 apply. [E6R3-C.2.11]

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## Non-Trial-Specific Essential Records Certain essential records may not be specific to a single trial but may instead relate to the investigational product, facilities, or processes and systems—including computerised systems—involved in running multiple trials. Such records may be retained outside trial-specific repositories and include documents such as the Investigator's Brochure, master services agreements, standard operating procedures, and validation records. [E6R3-C.2.12] ## Essentiality of Trial Records (Section C.3) ### Assessment Framework The assessment of whether a record is essential and must be retained should take into account the criteria set out in C.3.1. [E6R3-C.3.1] Such an assessment, whilst important, is not required to be documented. [E6R3-C.3.1] A structured content list for storage repository or repositories may be used to prospectively identify essential records. [E6R3-C.3.1] ### Criteria for an Essential Record An essential record meets one or more of the following criteria: [E6R3-C.3.1] - **(a) Regulatory and IRB/IEC submissions:** Is a document that is submitted to or issued by the regulatory authority or IRB/IEC, including related correspondence and those documenting regulatory decisions or approvals/favourable opinions. [E6R3-C.3.1] - **(b) Trial-specific procedures or plans:** Is a trial-specific procedure or plan. [E6R3-C.3.1] - **(c) Relevant correspondence and meeting documentation:** Is relevant correspondence or documentation of meetings related to important discussions and/or trial-related decisions that have been made related to the conduct of the trial and the processes being used. [E6R3-C.3.1] - **(d) Documentation of trial procedures:** Documents the conduct of relevant trial procedures (e.g., database lock checklist produced from following data management standard operating procedures). [E6R3-C.3.1] - **(e) Arrangements and insurance/indemnity:** Documents the arrangements between parties and insurance/indemnity arrangements. [E6R3-C.3.1] - **(f) Compliance with approval conditions:** Documents the compliance with the requirements and any conditions of approval from the regulatory authority or the favourable opinion of the IRB/IEC. [E6R3-C.3.1] - **(g) Committees involved in trial approval or conduct:** Documents the composition and, where appropriate, the functions, correspondence and decisions of any committees involved in the trial approval or its conduct. [E6R3-C.3.1] - **(h) Computerised system validation and fitness for purpose:** Demonstrates that a trial-specific computerised system is validated and that non-trial-specific systems (e.g., clinical practice computerised systems) have been assessed as fit for purpose for their intended use in the trial. [E6R3-C.3.1] - **(i) Authorised/signed documents:** Is a document that has been authorised/signed by the sponsor and/or investigator to confirm review or approval. [E6R3-C.3.1] - **(j) Staff signatures for significant activities:** Is, where necessary, documentation that demonstrates signatures/initials of staff undertaking significant trial-related activities; for example, completing data acquisition tools. [E6R3-C.3.1] - **(k) Informed consent documentation:** Documents what information was provided to potential trial participants and that participants' informed consent was appropriately obtained and maintained. [E6R3-C.3.1] - **(l) Sponsor personnel qualifications:** Documents that sponsor personnel involved in the trial conduct and individuals performing significant trial-related activities on their behalf are qualified by education, training and experience to undertake their activities. [E6R3-C.3.1] - **(m) Investigator and delegated individuals' qualifications:** Documents that the investigator and those individuals delegated significant trial-related activities by the investigator are qualified by education, training and experience to undertake their activities, particularly where the activities are not part of their normal role. [E6R3-C.3.1]

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## Criteria for Essential Trial Records (C.3.1) The source text identifies a range of functional criteria that characterise essential trial records. A record may be essential if it contains the data as well as relevant metadata that would be needed to allow the appropriate evaluation of the conduct of the trial [E6R3-C.3.1]. A record is also essential if it is a document related to the sponsor or investigator oversight of trial participant safety during the trial, including compliance with safety reporting requirements between sponsors and investigators, regulatory authorities and IRBs/IECs, and informing trial participants of safety information as necessary [E6R3-C.3.1]. Additional criteria include documents that service providers are suitably qualified for conducting their delegated or transferred activities, and documents that laboratory activities and other tests used in the trial are fit for purpose [E6R3-C.3.1]. Records that document sponsor oversight of investigator site selection and monitoring and audit of the trial, where appropriate, and provide information on arising issues/noncompliance and deviations detected and implementation of corrective and preventative actions are also considered essential [E6R3-C.3.1]. Further criteria cover records that document compliance with the protocol and/or procedures for management and statistical analysis of the data and production of any interim report and the final report, as well as records documenting the collection, chain of custody, processing, analysis and retention or destruction of biological samples [E6R3-C.3.1]. Records that provide relevant information on the investigational product and its labelling, and information about the shipment, storage, packaging, dispensing, randomisation and blinding of the investigational product, are also captured [E6R3-C.3.1]. Where appropriate, traceability and accountability information about the investigational product from release from the manufacturer to dispensation, administration to trial participants, return and destruction or alternative disposition must be provided [E6R3-C.3.1]. Records that provide information on the identity and quality of the investigational product used in the trial, and those that document processes and activities relating to unblinding, are similarly essential [E6R3-C.3.1]. Records that document the recruitment, pre-trial screening and consenting process of trial participants and their identity and chronological enrolment as appropriate are essential [E6R3-C.3.1]. Records that document the existence of the trial participants and substantiate the integrity of trial data collected, including source records related to the trial and medical treatments and history of the trial participants, are also essential [E6R3-C.3.1]. Finally, records that define processes/practices in place in the event of a security breach in order to protect participants' rights, safety and well-being and the integrity of the data are considered essential [E6R3-C.3.1]. ## Application of Criteria and the Essential Records Table (C.3.2) Applying the criteria in section C.3.1, the trial records that are considered essential are listed in the Essential Records Table, and these should be retained when produced [E6R3-C.3.2]. This table is not an exhaustive list, and other trial records may also be considered essential by the sponsor or the investigator [E6R3-C.3.2]. ## Conditional Nature of Some Records (C.3.3) For some trial records listed in the Essential Records Table, their presence and nature are dependent on the trial design, trial conduct and risk proportionate management of the trial and may not be produced [E6R3-C.3.3]. ## Essential Records Table If these trial records are produced, they are considered essential and should be retained (see sections C.3.1 and C.3.2) [E6R3-C.3.2]. An asterisk (*) identifies those essential records that should generally be in place prior to the start of the trial [E6R3-C.3.2]. - Investigator's Brochure or basic product information brochure (e.g., summary of product characteristics, package leaflet or labelling)* [E6R3-C.3.2] - Signed protocol* and subsequent amendments during the trial [E6R3-C.3.2] - Dated, documented approval/favourable opinion of IRB/IEC of information provided to the IRB/IEC* [E6R3-C.3.2] - IRB/IEC composition* [E6R3-C.3.2] - Regulatory authority(ies) authorisation, approval and/or notification of the protocol* and of subsequent amendments during the trial (where required) [E6R3-C.3.2] - Completed signed and dated informed consent forms [E6R3-C.3.2] - Completed participant identification code list and enrolment log [E6R3-C.3.2] - Notification by originating investigator to sponsor of serious adverse events (SAEs) and related reports, where required [E6R3-C.3.2] - Notification by sponsor and/or investigator, where required, to regulatory authority(ies) and IRB(s)/IEC(s) of suspected unexpected serious adverse reactions (SUSARs) and of other safety information [E6R3-C.3.2] - Notification by sponsor to investigators of safety information, where required [E6R3-C.3.2] - Interim or annual reports to IRB/IEC and regulatory authority(ies) (where required) [E6R3-C.3.2] - Source records [E6R3-C.3.2] - Data and relevant metadata (including documentation of data corrections) in the data acquisition tools [E6R3-C.3.2] - Final report to IRB/IEC and regulatory authority(ies), where required [E6R3-C.3.2] - Interim (where applicable) and final clinical trial reports [E6R3-C.3.2] - Sample of data acquisition tools (e.g., case report forms (CRFs), diaries, clinical outcome assessments, including patient-reported outcomes) that are provided to the investigator and/or IRB/IEC* [E6R3-C.3.2] - Sample of information given to trial participants* [E6R3-C.3.2] - Informed consent materials (including all applicable translations) [E6R3-C.3.2] - Any other documented information (e.g., instructions for use of an investigational product or a device) [E6R3-C.3.2] - Advertisement for participant recruitment [E6R3-C.3.2] - Arrangement between parties on the financial aspects of the trial* [E6R3-C.3.2] - Insurance statement* [E6R3-C.3.2]

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## Overview Clinical trials are a fundamental part of clinical research that support the development of new medicines or uses of existing medicines. [E6R3-II] Well-designed and conducted clinical trials help answer key questions in healthcare and drug development, and their results are essential for evidence-based healthcare decisions. [E6R3-II] Trials with inadequate design and/or poorly conducted trials may place participant safety at risk, yield inadequate or unreliable results, and are considered unethical, wasting resources and the efforts and time of investigators and participants. [E6R3-II] ## Scope and Flexibility of the Principles The Principles of GCP are designed to be flexible and applicable to a broad range of clinical trials. [E6R3-II] This guideline, along with ICH E8(R1), encourages thoughtful consideration and planning to address specific and potentially unique aspects of an individual clinical trial. [E6R3-II] This includes evaluation of trial characteristics such as the design elements, the investigational product being evaluated, the medical condition being addressed, the characteristics of the participants, the setting in which the clinical trial is being conducted, and the type of data being collected. [E6R3-II] Careful consideration of factors relevant to ensuring trial quality is needed for each clinical trial. [E6R3-II] ## Technology and Innovation The principles are intended to support efficient approaches to trial design and conduct. [E6R3-II] Digital health technologies, such as wearables and sensors, may expand the possible approaches to trial conduct, and such technologies can be incorporated into existing healthcare infrastructures and enable the use of a variety of relevant data sources in clinical trials. [E6R3-II] The use of technology in the conduct of clinical trials should be adapted to fit the participant characteristics and the particular trial design. [E6R3-II] This guideline is intended to be media neutral to enable the use of different technologies. [E6R3-II] ## Stakeholder Perspectives and Diversity The design and conduct of the clinical trial may be supported by obtaining the perspectives of interested parties, such as patients and their communities, patient advocacy groups, and healthcare professionals. [E6R3-II] Their input can help to reduce unnecessary complexity, improve feasibility, and increase the likelihood of meaningful trial outcomes. [E6R3-II] The use of innovative trial designs and technologies may enable the inclusion of a wider and more diverse population of participants and thereby broaden the applicability of trial outcomes. [E6R3-II] ## Quality by Design and Proportionality Clinical trials should be designed to protect the rights, safety, and well-being of participants and assure the reliability of results. [E6R3-II] Quality by design should be implemented to identify the factors (i.e., data and processes) that are critical to ensuring trial quality and the risks that threaten the integrity of those factors and ultimately the reliability of the trial results. [E6R3-II] Clinical trial processes and risk mitigation strategies implemented to support the conduct of the trial should be proportionate to the importance of the data being collected and the risks to trial participant safety and the reliability of trial results. [E6R3-II] Trial designs should be operationally feasible and avoid unnecessary complexity. [E6R3-II] ## Structure and Interdependence of the Principles The overarching principles provide a flexible framework for clinical trial conduct and are structured to provide guidance throughout the life cycle of the clinical trial. [E6R3-II] These principles are applicable to trials involving human participants. [E6R3-II] The principles are interdependent and should be considered in their totality to assure ethical trial conduct and reliable results. [E6R3-II] ## Principle 1: Ethical Conduct and Participant Protection Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with GCP and applicable regulatory requirement(s). [E6R3-II] Clinical trials should be designed and conducted in ways that ensure the rights, safety, and well-being of participants. [E6R3-II] ### Principle 1.1: Primacy of Participant Rights, Safety, and Well-Being > "The rights, safety and well-being of the participants are the most important considerations and should prevail over interests of science and society." [E6R3-1.1]

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## Risk Management and Trial Feasibility The risks relating to investigational products that hold a marketing authorisation may differ from usual patient care when used in a clinical trial context, and these differences should be taken into consideration. [E6R3-7.2] Risks to critical-to-quality factors should be managed proactively and adjusted when new or unanticipated issues arise once the trial has begun. [E6R3-7.3] Trial processes should be operationally feasible and avoid unnecessary complexity, procedures, and data collection. [E6R3-7.4] Trial processes should support the key trial objectives, and the sponsor should not place unnecessary burden on participants and investigators. [E6R3-7.4] ## Protocol Design Clinical trials should be described in a clear, concise, scientifically sound, and operationally feasible protocol. [E6R3-8] A well-designed trial protocol is fundamental to the protection of participants and for the generation of reliable results. [E6R3-8.1] The scientific objectives of any trial should be clear and explicitly stated in the protocol. [E6R3-8.2] The clinical trial protocol, as well as the plans or documents for protocol execution (e.g., statistical analysis plan, data management plan, monitoring plan), should be clear, concise, and operationally feasible. [E6R3-8.3] ## Reliability of Trial Results Clinical trials should generate reliable results. [E6R3-9] The quality and amount of information generated in a clinical trial should be fit for purpose and sufficient to provide confidence in the trial's results and support good decision making. [E6R3-9.1] Systems and processes that aid in data capture, management, and analyses, as well as those that help ensure the quality of information generated from the trial, should be fit for purpose, should capture the data required by the protocol, and should be implemented in a way that is proportionate to the risks to participants and the importance of acquired data. [E6R3-9.2] Computerised systems used in clinical trials should be fit for purpose (e.g., through risk-based validation, if appropriate), and factors critical to their quality should be addressed in their design or adaptation for clinical trial purposes to ensure the integrity of relevant trial data. [E6R3-9.3] ## Records Management and Transparency Clinical trials should incorporate efficient and robust processes for managing records (including data) to help ensure that record integrity and traceability are maintained and that personal information is protected, thereby allowing the accurate reporting, interpretation, and verification of the relevant clinical trial-related information. [E6R3-9.4] Essential records should be retained securely by sponsors and investigators for the required period in accordance with applicable regulatory requirements. [E6R3-9.5] These essential records should be available to regulatory authorities, monitors, auditors, and IRBs/IECs (as appropriate) upon request to enable appropriate evaluation of trial conduct and to ensure the reliability of trial results. [E6R3-9.5] The transparency of clinical trials includes timely registration on publicly accessible and recognised databases and the public posting of clinical trial results. [E6R3-9.6] Communicating trial results to participants should be considered, and such communication should be objective and non-promotional. [E6R3-9.6] ## Roles and Responsibilities Roles and responsibilities in clinical trials should be clear and documented appropriately. [E6R3-10] The sponsor may transfer, or the investigator may delegate, their tasks, duties, or functions (referred to as activities), but they retain overall responsibility for their respective activities. [E6R3-10.1] Agreements should clearly define the roles, activities, and responsibilities for the clinical trial and be documented appropriately. [E6R3-10.2] Where activities have been transferred or delegated to service providers, the responsibility for the conduct of the trial, including quality and integrity of the trial data, resides with the sponsor or investigator, respectively. [E6R3-10.2] The sponsor or investigator should maintain appropriate oversight of the aforementioned activities. [E6R3-10.3] ## Investigational Products Investigational products used in a clinical trial should be manufactured in accordance with applicable Good Manufacturing Practice (GMP) standards and be managed in accordance with the product specifications and the trial protocol. [E6R3-11] Measures should be in place to ensure that the investigational product provided to trial participants retains its quality. [E6R3-11.2] Investigational products should be used in accordance with the protocol and relevant trial documents. [E6R3-11.3] Manufacturing, handling, and labelling of investigational products should be undertaken in a manner that aligns with treatment assignment and maintains blinding, where applicable. [E6R3-11.4] Investigational product labelling should follow applicable regulatory requirements. [E6R3-11.5] Appropriate processes should be implemented for the handling, shipping, storage, dispensing, returning, and destroying or alternatively disposing of the investigational product. [E6R3-11.6]

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## Overview The Essential Records Table in ICH E6(R3) specifies that if certain trial records are produced, they are considered essential and should be retained (see sections C3.1 and C3.2). [E6R3-EssentialRecordsTable] Records marked with an asterisk (*) should generally be in place prior to the start of the trial (see section C2.5). [E6R3-EssentialRecordsTable] ## Agreements and Personnel Documentation Signed agreements between involved parties are required prior to trial start, including agreements between the investigator/institution and sponsor, investigator/institution and service providers, sponsor and service providers, and sponsor and IDMC and/or adjudication committee members. [E6R3-EssentialRecordsTable] Documentation of selection, assessment, and oversight of service providers conducting important trial-related activities must be retained. [E6R3-EssentialRecordsTable] Relevant documents evidencing qualifications of investigators and sub-investigators (e.g., curriculum vitae) involved in conducting the trial are required prior to trial start. [E6R3-EssentialRecordsTable] Trial-specific training records and documentation of delegation of trial-related activities by the investigator must be in place prior to trial start. [E6R3-EssentialRecordsTable] A signature sheet documenting signatures and initials (unless only electronic signatures are used) of the investigator and individuals delegated by the investigator is required, and may be combined with the delegation documentation. [E6R3-EssentialRecordsTable] ## Medical, Laboratory, and Technical Procedures Normal values and ranges for medical, laboratory, and technical procedures and tests included in the protocol must be documented prior to trial start. [E6R3-EssentialRecordsTable] Certification, accreditation, or other documentation including validation (where required) to confirm the suitability of medical, laboratory, and technical procedures and tests used during trial conduct is also required prior to trial start. [E6R3-EssentialRecordsTable] ## Body Fluids and Tissue Samples Documentation of collection, processing, and shipment of body fluids and tissue samples must be retained. [E6R3-EssentialRecordsTable] Documentation of body fluids and tissue sample storage conditions, as well as a record of retained body fluids and tissue samples at the end of the trial, are also required. [E6R3-EssentialRecordsTable] ## Investigational Product Records A sample of labels attached to investigational product containers must be retained. [E6R3-EssentialRecordsTable] Instructions for handling of investigational products and trial-related materials (if not included in the protocol or Investigator's Brochure), for example a pharmacy manual, are required prior to trial start. [E6R3-EssentialRecordsTable] Shipping records for investigational products and trial-related materials, and certificates of analysis of investigational products shipped, must be in place prior to trial start. [E6R3-EssentialRecordsTable] Investigational product accountability at the investigator site, documentation of storage conditions including during shipment, records of relabelling at the investigator site, and documentation of destruction or alternative disposition must all be retained. [E6R3-EssentialRecordsTable] ## Randomisation and Blinding Emergency decoding procedures for blinded trials and the master randomisation list are required prior to trial start. [E6R3-EssentialRecordsTable] Treatment allocation and decoding documentation must also be retained. [E6R3-EssentialRecordsTable] ## Systems, Equipment, and Computerised Systems Instructions for use of important trial-specific systems (e.g., interactive response technologies (IRTs) user manual, electronic CRF (eCRF) manual) are required prior to trial start. [E6R3-EssentialRecordsTable] Records demonstrating fitness for purpose (e.g., maintenance and calibration) for equipment used for important trial activities must be in place prior to trial start. [E6R3-EssentialRecordsTable] Documentation of trial-specific computerised system validation (e.g., specifications, testing, validation report, change control) is required prior to trial start. [E6R3-EssentialRecordsTable] Documentation of the assessment of fitness for purpose for non-trial-specific computerised systems used in the trial (e.g., clinical practice computerised systems) must also be retained prior to trial start. [E6R3-EssentialRecordsTable] ## Monitoring and Compliance A completed participants screening log must be retained. [E6R3-EssentialRecordsTable] Site monitoring reports, including those for site selection, initiation, routine, and close-out visits, as well as centralised monitoring reports, are required. [E6R3-EssentialRecordsTable] Records and reports of noncompliance including protocol deviations and corrective and preventative actions must be retained. [E6R3-EssentialRecordsTable] Documentation of relevant communications and meetings, and audit certificates, must also be retained. [E6R3-EssentialRecordsTable] ## Data Management and Statistical Records Documentation relating to data finalisation for analysis (e.g., query resolutions, SAE reconciliation, quality control reports, coding completion, output data sets) must be retained. [E6R3-EssentialRecordsTable] Documentation relating to statistical considerations and analysis (e.g., sample size calculations, analysis sets decisions, analysis data sets, analysis programs, quality control records and outputs) is required, with sample size calculations required prior to trial start. [E6R3-EssentialRecordsTable] ## Trial-Specific Plans and IDMC/Adjudication Committee Records Trial-specific plans (e.g., risk management, monitoring, safety, data management, data validation, and statistical analysis) and procedures are required prior to trial start. [E6R3-EssentialRecordsTable] Procedures, meeting minutes, and submissions to the IDMC and/or adjudication committee(s) must also be retained. [E6R3-EssentialRecordsTable]

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