3. SPONSOR: ICH E6 (R3) Guideline on good clinical practice (GCP) Step 2b

ICH HARMONISED GUIDELINE
GOOD CLINICAL PRACTICE (GCP) E6(R3)

Draft version
Endorsed on 19 May 2023

Currently under public consultation

The responsibility of the sponsor entails the implementation of risk-proportionate processes to ensure the safety of the trial participants and the reliability of the trial results throughout the clinical trial life cycle.

3.1 Trial Design

3.1.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials and/or real-world data are available to support human exposure by the route, at the dosages, for the duration and in the trial population to be studied.

3.1.2  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.

3.1.3 Sponsors should consider inputs from a wide variety of stakeholders, 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 material and any other participant-facing information.

3.1.4 The sponsor should ensure that all aspects of the trial are operationally feasible and should avoid unnecessary complexity, procedures and data collection. Protocols, data acquisition tools and other operational documents should be fit for purpose, clear, concise and consistent, when applicable.

3.2 Resources

The sponsor should ensure that sufficient resources are available to appropriately conduct the trial.


3.3 Allocation of Activities

Prior to initiating clinical trial activities, the sponsor should determine the roles and allocate trial-related activities accordingly.

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.

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.

3.5 Financing

The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.

3.6  Agreements

3.6.1     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.

3.6.2      Agreements should be updated when necessary to reflect significant changes in the activities delegated.

3.6.3  The sponsor should obtain the investigator’s/institution’s and, where applicable, service provider’s agreement:

(a) to conduct the trial in accordance with the approved protocol and in compliance with GCP and applicable regulatory requirement(s);
(b) to comply with procedures for data recording/reporting;
(c) to retain the trial-related 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 documents are no longer needed, whichever is longer;
(d) to permit monitoring, auditing and inspections by sponsors, IRB/IECs and regulatory authorities (domestic and foreign) including providing direct access to source records and facilities, including to those of service providers.

3.6.4  The responsibilities of coordinating investigator(s) and the other participating investigators should be documented prior to the start of the trial.

3.6.5     Any of the sponsor’s trial-related activities that are transferred to and assumed by a service provider should be documented in an agreement. The sponsor’s trial-related activities that are not specifically transferred to and assumed by a service provider are retained by the sponsor.

3.6.6    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. The responsibility for such activities remains with the investigator.

3.6.7    A sponsor may transfer any or all of the sponsor’s trial-related activities to a service provider; 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. Any service provider used for clinical trial activities should implement appropriate quality management and report to the sponsor any incidents that might have an impact on the safety of trial participants or/and trial results.

3.6.8   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. 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.

3.6.9    The sponsor should have access to relevant information (e.g., SOPs and performance metrics) for selection and oversight of service providers.

3.6.10  The sponsor should ensure appropriate oversight of important trial-related activities that are transferred to service providers and further subcontracted.

3.6.11  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 processes.

3.6.12  A clinical trial may have one or several sponsors where permitted under applicable regulatory requirements. 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. Where the documented agreement does not specify to which sponsor a given responsibility is attributed, that responsibility lies with all sponsors.

3.7 Investigator Selection

3.7.1 The sponsor is responsible for selecting the investigator(s)/institution(s). Each investigator should be qualified by education, training and experience and should demonstrate they have adequate resources and facilities to properly conduct the trial. If organisation of a coordinating committee and/or selection of coordinating investigator(s) are to be utilised in multicentre trials, their organisation and/or selection are the sponsor’s responsibility, and their roles should be documented prior to their involvement in the trial.

3.7.2  The sponsor should provide the 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.

3.8 Communication with IRB/IEC and Regulatory Authority(ies)

3.8.1 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). Any notification/submission should be dated and contain sufficient information to identify the protocol.

3.8.2 Confirmation of Review by IRB/IEC

(a) 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 (see section 1.5).

(b) The sponsor should ensure that the following is obtained: 

      (i) The name and address of the relevant IRB/IEC along with:

•  (aa) a statement that it is organised and operates according to GCP and the applicable regulatory requirements;
•  (bb) documented initial and subsequent IRB/IEC approval/favourable opinion as well as any termination of the trial or the suspension of approval/favourable opinion.

3.9 Sponsor Oversight

3.9.1  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 participant’s safety and appropriate decision making.

3.9.2  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.

3.9.3  The sponsor should determine necessary trial-specific criteria for classifying protocol deviations as important (i.e., those that impact the rights, safety and well-being of trial participants and the reliability of results).

3.9.4  Decisions related to the trial should be appropriately assessed for their impact on participant’s rights, safety and well-being and the reliability of trial results. Risks related to such decisions should be suitably managed throughout the planning, conduct and reporting of the trial.

3.9.5  The range and extent of oversight measures should be fit for purpose and tailored to the complexity of and risks associated with the trial. The selection and oversight of investigators and service providers are fundamental features of the oversight process. Oversight by the sponsor includes quality assurance and quality control processes relating to the trial-related activities of investigators and service providers.

3.9.6 The sponsor should ensure appropriate and timely escalation and follow-up of issues to allow the implementation of appropriate actions in a timely manner.

3.9.7   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.

3.9.8  Where appropriate, sponsors may also establish an endpoint assessment/adjudication committee in certain trials to review important endpoints reported by investigators to determine whether the endpoints meet protocol-specified criteria. 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, to ensure that the data reviewed by committee are as free of bias as possible.

3.9.9  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.

3.10 Quality Management

The sponsor should implement an appropriate system to manage quality throughout all stages of the trial process. 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 support participant’s rights, safety and well-being and the reliability of trial results. 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 participant’s rights, safety and well-being and the reliability of the results (i.e., critical to quality factors as described in ICH E8(R1)). The sponsor should describe the quality management approach implemented in the trial in the clinical trial report (see ICH E3).

3.10.1 Risk Management

A proportionate approach to the identification and management of risk is described below:

3.10.1.1 Risk Identification

The sponsor should identify risks that may have a meaningful impact on critical to quality factors. Risks should be considered across the processes used in the clinical trial (e.g., patient selection, informed consent process, randomisation and investigational product administration, data handling, and service provider activities).

3.10.1.2 Risk Evaluation

The sponsor should evaluate potential risks by considering:

• (a) the likelihood of harm/hazard occurring;
• (b) the extent to which such harm/hazard would be detectable;
• (c) the impact of such harm/hazard on trial participant protection and the reliability of trial results.

3.10.1.3 Risk Control

• (a) Risk control should be proportionate to the importance of the risk to participants’ rights, safety and well-being and the reliability of trial results.
  
  Risk mitigation activities may be incorporated in protocol design and implementation, monitoring plans, agreements between parties defining roles and responsibilities, systematic safeguards to ensure adherence to SOPs, and training in processes and procedures.
   
• (b) The sponsor should set acceptable ranges to support this process within which variation can be accepted.              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.

3.10.1.4 Risk Communication

The sponsor should communicate the identified risks and mitigating activities, if applicable, to those who are involved in taking action or are affected by such activities. Communication also facilitates risk review and continual improvement during clinical trial conduct.

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.

3.10.1.6 Risk Reporting

The sponsor should summarise and report the risks and the remedial actions taken in relation to important deviations from the acceptable ranges as detailed in section 3.10.1.3(b) and document them in the clinical trial report (ICH E3).
 

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).

3.11.1 Quality Assurance

Quality assurance should be applied throughout the clinical trial and includes implementing strategies to identify potential or actual causes of serious non- compliance with the protocol, GCP and/or applicable regulatory requirements to enable their corrective and/or preventive actions.

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.

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 effective and compliant.

3.11.2.1 Selection and Qualification of Auditors

(a) The sponsor should appoint individuals who are independent of the clinical trial being audited.

(b) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly.

3.11.2.2 Auditing Procedures

(a) 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 or remote), the frequency of audits and the form and content of audit reports.

(b) The sponsor’s audit plan, program and procedures for a trial audit should be guided 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).

(c) The observations and findings of the auditor(s) should be documented.

(d) 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 when evidence of serious GCP non-compliance exists or in the course of legal proceedings.

(e) When required by applicable regulatory requirements, the sponsor should provide an audit certificate.

3.11.3 Quality Control 

Quality control should be applied to each stage of the data handling to ensure that data are reliable and have been processed correctly. Within clinical trials, monitoring and data management processes are the main quality control activities.

The quality control of sites (other than investigator sites, such as centralised imaging reading facilities), including on site and/or centralised activities, may be undertaken and reported using a risk-based approach.

3.11.4 Monitoring

The aim of monitoring is to ensure the participants’ rights, safety and well-being and the reliability of trial results as the trial progresses. Monitoring is one of the principal quality control activities.

Monitoring involves a broad range of activities including, but not limited to, communication with investigator sites, verification of the investigator and investigator site staff qualifications and site resources, training and review of trial documents and information using a range of approaches including source data review, source data verification, data analytics and visits to institutional facilities undertaking trial-related activities. Some of these monitoring activities may be conducted by different methods and persons with different roles. However, monitoring should be performed by persons not involved in the clinical conduct of the trial being monitored. The monitoring approach should consider the activities and services involved, including decentralised settings, and be included in the monitoring plan. 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.

Monitoring activities may include site monitoring (performed on-site or remotely) and centralised monitoring, depending on the monitoring strategy and the design of the clinical trial.

The sponsor should determine the appropriate extent and nature of monitoring, based on identified risks. Factors such as the objective, purpose, design, complexity, blinding, number of trial participants, investigational product, current knowledge of the safety profile and endpoints of the trial should be considered.

3.11.4.1 Investigator Site Monitoring

(a) Monitoring may be performed in relation to the clinical trial activities at the investigator sites (e.g., including their pharmacies and local laboratories, as appropriate). The frequency of monitoring activities should also be determined based on identified risks. Monitoring activities and their frequency should be modified as appropriate using knowledge gained.

(b) This monitoring activity may be performed on-site or remotely depending on the nature of the activity and its objectives.

(c) Monitoring may include secure, remote, direct read-only access to source records, other data acquisition tools and essential record retention systems.

3.11.4.2 Centralised Monitoring

(a) 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).

(b) Centralised monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of site monitoring or be used on its own. Use of centralised data analytics can help identify systemic or site-specific issues, including protocol non-compliance and potentially unreliable data.

(c) Centralised monitoring may support the selection of sites and/or processes for targeted site monitoring.

3.11.4.3 Monitoring Plan

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. Particular attention should be given to procedures relevant to participant safety and to trial endpoints. 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. The monitoring strategy should ensure appropriate oversight of trial conduct and consider site capabilities and the potential burden. The plan should focus on aspects that are critical to quality. The monitoring plan should reference the sponsor’s applicable policies and procedures.

Monitoring of key data and processes (e.g., those related to primary endpoints and key secondary endpoints and processes intended to assure patient safety) performed outside the investigator site (e.g., central reading facilities, central laboratories) should be addressed in the monitoring plan.

3.11.4.4 Monitoring Procedures

Persons performing monitoring should follow the sponsor’s monitoring plan and applicable monitoring procedures.

3.11.4.5 Monitoring Activities

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.

3.11.4.5.1 Communication with Parties Conducting the Trial

(a) 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.

(b) Informing the investigator or other parties and individuals involved in the trial conduct of identified deviations from the protocol, GCP and the applicable regulatory requirements and 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.

(c) Informing the investigator or other parties and individuals involved in the trial conduct of source record(s) or entry errors or omissions in data acquisition tools and ensuring that corrections, additions or deletions are made as appropriate, dated, explained (if necessary) and that approval of the change is properly documented.

(d) Actions taken in relation to the deviations, errors or omissions should be proportionate to their importance.

3.11.4.5.2 Investigator Site Selection, Initiation, Management and Close-out

(a) Selecting the site and confirming that the investigator and individuals or parties involved in the trial conduct have adequate qualifications, resources (see sections 3.1, 3.2, and 4.7) and facilities, including laboratories, equipment and investigator site staff, to safely and properly conduct the trial.

(b) Confirming 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 and instructions related to their delegated activities.

(c) Confirming that the investigator is maintaining the essential records (see Appendix C).

(d) Confirming that informed consent was obtained before participation in the trial (see section 2.8) for all enrolled participants at the site.

(e) Determining whether adverse events are appropriately reported within the time periods required by the protocol, GCP and the applicable regulatory requirement(s).

(f) Clarifying the sponsor’s protocol requirements for source records and the site’s location of such data.

(g) Verifying that the blinding is maintained, where applicable.

(h) Reviewing and reporting the participant recruitment and retention rates.

(i) Confirming that the investigator provides the required reports, notifications or other information in accordance with the protocol and trial procedures.

(j) 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.

3.11.4.5.3 Monitoring of Investigational Product Management

(a) Confirming, for the investigational product(s):

• (i) that storage conditions are acceptable and in accordance with the storage requirement specified in the protocol;
• (ii) that supplies are sufficient throughout the trial and are used within their shelf-life;
• (iii) 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;
• (iv) that the participants, investigator, investigator site staff and other relevant parties and individuals involved in the trial conduct are provided with necessary instruction on properly using, handling, storing, returning and destroying, or alternative disposition of the investigational product(s);
• (v) that the receipt, use, return and destruction, or alternative disposition of the investigational product(s) are controlled and documented adequately;
• (vi) that the disposition of unused investigational product(s) complies with applicable regulatory requirement(s) and is in accordance with the sponsor requirements;
•  (vii) where 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.

3.11.4.5.4 Monitoring of Clinical Trial Data 

(a) Verifying that the investigator is enrolling only eligible trial participants.

(b) 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. This can be done on the basis of using samples and supported by data analytics, as appropriate. The sample size may need adjustment based on previous monitoring results or other indications of insufficient data quality. Monitoring should:

• (i) verify that the data required by the protocol and identified as critical in the monitoring plan are consistent with the source;
• (ii) identify missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations;
• (iii) examine data trends, such as the range, consistency and variability of data within and across sites;

(c) Identifying significant errors in data collection and reporting at a site or across sites, potential data manipulation and data integrity problems.

3.11.4.6 Monitoring Report

(a) 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. The requirements of monitoring reports (including their content and frequency) should be described in the sponsor’s procedures.

(b) 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.

(c) When needed, the report should describe findings requiring escalation for action and resolution. 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.

3.12 Noncompliance

3.12.1 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 appropriate and proportionate action by the sponsor to secure compliance.

3.12.2 If noncompliance that significantly affects or has the potential to significantly affect trial participant’s rights, safety or well-being 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. Where the sponsor identifies issues that could significantly impact participant’s rights, safety and well-being or the reliability of trial results, the sponsor should notify the regulatory authority and/or IRB/IEC in line with applicable regulatory requirements.

3.12.3 If the monitoring and/or auditing identifies serious noncompliance on the part of an investigator/institution that persists despite efforts at remediation, the sponsor should terminate the investigator’s/institution’s participation in the trial. When an investigator’s/institution’s participation is terminated because of noncompliance, the sponsor should promptly notify the regulatory authority(ies) and IRB/IEC as appropriate.

3.13 Safety Assessment and Reporting

The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).

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. For further information, see Appendix A.

3.13.1 Sponsor Review of Safety Information

The sponsor should aggregate, as appropriate, and periodically review relevant safety information. This may result in the update of the protocol, Investigator’s Brochure, informed consent materials and related documents.
The sponsor should review the 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. Any information of this nature should be communicated to the participants, investigator, IRB/IEC and regulatory authorities, as applicable, in a timely manner.

3.13.2 Safety Reporting

(a) 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.

(b) 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 adverse drug reactions (ADRs) that meet three criteria: suspected, unexpected and serious (i.e., SUSARs).

(c) 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. Refer to ICH E2F Development Safety Update Report for more information about RSI.

(d) The reporting of SUSARs to investigator(s)/institutions(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. Reporting of SUSARs to the investigators/institutions should be made in accordance with regulatory requirements. In some regions, periodic reporting of line listings with an overall safety assessment may be appropriate.

(e) 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 as specified in regulatory requirements.

(f) 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 the IRB/IEC if applicable, and described in the clinical trial protocol, (e.g., SAEs considered efficacy or safety endpoints, which would not be subject to unblinding and expedited reporting; see ICH E2A). See ICH E19.

3.13.3 Managing an Immediate Hazard 

The sponsor should take prompt action to address immediate hazards to participants. The sponsor should determine the causes of the hazard and based on this, take appropriate remedial actions.

The sponsor should consider whether the protocol requires amendment in response to an immediate hazard. 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).
 

3.14 Insurance/Indemnification/Compensation to Participants and Investigators

3.14.1 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.

3.14.2 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).

3.14.3 The approach to compensating trial participants should comply with applicable regulatory requirement(s).
 

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. Alternatively, for authorised medicinal products, the sponsor should identify the basic product information to be used in the trial (see Appendix A).

3.15.2 Manufacturing, Packaging, Labelling and Coding Investigational Product(s)

(a) 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. In addition, the labelling should comply with applicable regulatory requirement(s).

(b) The sponsor should determine acceptable storage temperatures and other storage conditions (e.g., protection from light) for the investigational product(s), appropriate reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties (e.g., monitors, investigators, pharmacists, storage managers) of these determinations.

(c) The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage.

(d) In blinded trials, the sponsor should implement: 

(i)  a process to blind the sponsor staff, trial participant and/or investigator as appropriate to the investigational product identity and assignment to prevent and detect inappropriate unblinding;

(ii) 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;

(iii) 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.

(e) 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.

3.15.3 Supplying and Handling Investigational Product(s)

(a) The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s) or, where appropriate, supplying trial participants in accordance with applicable regulatory requirements and after obtaining the required approval/favourable opinion from the IRB/IEC and the regulatory authority(ies) for the trial.

(b) The sponsor should ensure that instructions are available for the investigator/institution or trial participants on the handling and storage of investigational product(s). 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)).

(c) The sponsor should: 

• (i) ensure timely delivery 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.
• (ii) maintain records that document the identity, shipment, receipt, return and destruction, or alternative disposition of the investigational product(s) (see Appendix C);
• (iii) maintain a system for retrieving investigational products and documenting this retrieval (e.g., for deficient product recall, return and destruction, or alternative disposition after trial completion, or expired product reclaim);
• (iv) maintain a system for the disposition of unused investigational product(s) and for the documentation of this disposition;
• (v) take steps to ensure that the investigational product(s) are stable over the period of use and only used within the current shelf-life;
• (vi) 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. 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. The samples do 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, since samples are kept by the manufacturer.
   

3.16 Data and Records

3.16.1 Data Handling

(a) The sponsor should ensure the integrity and confidentiality of data generated and managed.

(b) 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. The sponsor should focus their quality assurance and quality control activities and data review on critical data, including its relevant metadata.

(c) The sponsor should pre-specify data to be collected and the method of its collection in the protocol (see Appendix B. Clinical Trial Protocol and Protocol Amendment(s)). Where necessary, additional details, including a data flow diagram, should be contained in a protocol-related document (e.g., a data management plan).

(d) The sponsor should ensure that data acquisition tools are fit for purpose and designed to capture the information required by the protocol. They should be validated and ready for use prior to their required use in the trial.

(e) The sponsor should ensure that documented processes are implemented to ensure the data integrity for the full data life cycle.

(f) The sponsor should implement measures to ensure the safeguarding of the blinding, if any (e.g., maintain the blinding during data entry and processing).

(g) 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.

(h) The sponsor should not make changes to data entered by the investigator or trial participants unless justified and documented by the sponsor and agreed upon by the investigator.

(i) The sponsor should allow correction of errors to data, including data entered by participants, where requested by the investigators/participants. Such data corrections should be justified and supported by source records around the time of original entry.

(j) The sponsor should ensure that the investigator has access to data collected in accordance with the protocol during the course of the trial including relevant data from external sources, for example, central laboratory data, centrally read imaging data and, if appropriate, ePRO data that are necessary to enable 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). The sponsor should pay special attention to data that may unblind the investigator and include the appropriate provisions in the protocol.

(k) The sponsor should not have exclusive control of data captured in data acquisition tools.

(l) The sponsor should ensure that the investigator has access to the required data for retention purposes.

(m) 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.

(n) The sponsor should seek investigator endorsement of their data at predetermined milestones.

(o) The sponsor should document the data management steps to be undertaken prior to data analysis. 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).

(p) Prior to provision of the data for analysis, edit access to the data acquisition tools should be restricted as appropriate to the purpose of the analysis; for example, for interim analysis, the restriction may only be temporary or managed differently compared to the final analysis.

(q) Deviations from the planned statistical analysis or changes made to the data analysis set 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 resolved for the reliability of the trial results). Data changes should be authorised by the investigator and reflected in an audit trail. Post-unblinding data changes and deviations from the planned statistical analyses should be reported in the clinical trial report.

(r) The sponsor should use an unambiguous trial participant identification code (see glossary term) that allows identification of all the data reported for each participant.

(s) 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.

(t) In accordance with applicable regulatory requirements, the sponsor should document what happens to data when a participant withdraws or discontinues from the trial.

(u) The sponsor should ensure that trial data are protected from unauthorised access, disclosure, dissemination or alteration and from inappropriate destruction or accidental loss.

(v) The sponsor should have processes and procedures in place for reporting incidents (including security breaches) that have a significant impact on the trial data to relevant parties, including regulatory authorities, where relevant.

(w) When using computerised systems in a clinical trial, the sponsor should:

• (i) have a record of the computerised systems used in a clinical trial. This should include the use, functionality, interfaces and validation status of each computerised system, and who is responsible for its management should be described. The record should also include a description of implemented access controls and internal and external security measures;
• (ii) ensure that the requirements for computerised systems deployed by the sponsor (e.g., requirements for validation, audit trails, user management, backup, disaster recovery and IT security) are addressed and implemented and that documented procedures and adequate training are in place to ensure the correct development, maintenance and use of computerised systems in clinical trials (see section 4). These equirements should be proportionate to the importance of the computerised system and the data or activities  they are expected to process;
• (iii) maintain a record of the individual users who are authorised to access the system, their roles and their access privileges:
• (iv) ensure that access rights granted to investigator site staff are in accordance with delegations by the  investigator and visible to the investigator;
• (v) for systems deployed by the investigator/institution, assess whether such systems, if identified as      containing   source records in the trial, (e.g., electronic health records and other record keeping systems for source data collection and investigator site files) are fit for purpose or whether the known issue(s) can be appropriately mitigated. This assessment should occur during the process of selecting clinical trial sites and should be documented;
• (vi) ensure that there is a process in place for service providers and investigators to inform the sponsor of system defects identified or incidents that could potentially constitute a serious non-compliance with the  clinical trial protocol, trial procedures or GCP in accordance with section 3.13.

3.16.2 Statistical Programming and Data Analysis

This section concerning documentation of operational aspects of clinical trial statistical activities should be read in conjunction with ICH E9 Statistical Principles for Clinical Trials, which provides detailed guidance on statistical principles for clinical development, trial design, conduct, analysis and reporting.

(a) The sponsor should ensure that appropriate and documented quality control of statistical programming and data analysis is implemented (e.g., for sample size calculations, results for IDMC, outputs for clinical trial report, statistical or centralised monitoring).

(b) The sponsor should ensure the traceability of data transformations and derivations during data processing and analysis.

(c) The sponsor should ensure that the allocation to or exclusion of each trial participant from any analysis set is predefined (e.g., in the protocol or the statistical analysis plan). The rationale for inclusion or exclusion for any participant (or particular data point) should be clearly described and documented.

(d) Procedures should be in place to describe unblinding; these descriptions should include:

• (i) who was unblinded, at what timepoint and for what purpose they were unblinded;
• (ii) who should remain blinded;
• (iii) the safeguards in place to preserve the blinding.

(e) 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/validation activities performed. Outputs should be traceable to the statistical software programs, and they should be dated and time stamped and protected against any changes.

3.16.3 Record Keeping and Retention

(a) The sponsor (or subsequent owners of the data) should retain all of the sponsor-specific essential records pertaining to the trial in conformance with the applicable regulatory requirement(s).

(b) The sponsor should inform the investigator(s)/institution(s) and service providers, when appropriate, in writing of the need for essential records retention and should notify the investigator(s)/institution(s) and service providers, when appropriate, in writing when the trial-related records are no longer needed.

(c) The sponsor should report any transfer of ownership of the essential records to the appropriate authority(ies) as required by the applicable regulatory requirement(s).

3.16.4 Record Access

(a) 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, IRB/IEC review and regulatory inspection.

(b) The sponsor should ensure that trial participants have consented to direct access to their original medical records and other participant-related trial documents for trial-related monitoring, audit, IRB/IEC review and regulatory inspection as part of the informed consent.

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. 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).

3.17.2 Clinical Trial/Study Reports

(a) 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 agency(ies) as required by the applicable regulatory requirement(s). 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. (Note: ICH E3 specifies that abbreviated study reports may be acceptable in certain cases.)

(b) Investigators should be provided with a summary of the trial results.

(c) Consideration should be given to providing the investigator with information about the final treatment taken by their participants for blinded trials and a brief summary of the overall outcome of the trial. Where this information is provided to participants, the language should be non-technical, understandable to a layperson and non-promotional. The sponsor should only supply this information after the trial has been unblinded and all relevant analyses/conclusions have been completed and finalised.

Author: European Medicines Agency.

At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate ICH Expert Working Group, is transmitted by the ICH Assembly to the regulatory authorities of the ICH regions for internal and external consultation, according to national or regional procedures.