Additional Requirements for Clinical Trials (ICH-GCP)

(Guidance on when and how to apply ICH-GCP or GCP as adopted by the FDA can be found here)

1. The clinical trial should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with good clinical practice (GCP) and the applicable regulatory requirements. The rights, safety and well-being of the participants are the most important considerations and should prevail over interests of science and society.
2. Clinical trials should be scientifically sound for their intended purpose and based on adequate and current scientific knowledge and approaches.
   • The available nonclinical and clinical information on an investigational product(s) should be adequate to support the proposed clinical trial.
   • Clinical trials should be scientifically sound and reflect the state of knowledge and experience with the investigational product(s), including, if applicable, the condition being 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.
   • 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.
3. Investigator’s Qualifications and Training
   • The investigator 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 requirements, and should provide evidence of such qualifications.
   • 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/or in other information sources provided by the sponsor.
4. Resources
   • The investigator should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of eligible participants within the recruitment period as agreed with the sponsor.
   • 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.
5. Responsibilities
   • The investigator may delegate trial-specific activities to other persons or parties. 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 to the sponsor. The investigator retains the ultimate responsibility and should maintain appropriate oversight of the persons or parties undertaking the activities delegated to ensure the rights, safety and well-being of the trial participants and reliability of the data. 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 protected and the risks to trial participant safety and data reliability.
   • The investigator should ensure that all persons or parties to whom the investigator has delegated trial-related activities are appropriately qualified and are adequately informed about the 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). Trial-related training to persons assisting in the trial should correspond to what is necessary to enable them to fulfill their delegated trial activities that go beyond their usual training and experience.
   • The investigator should ensure a record is maintained of the persons and parties to whom the investigator has delegated trial-related activities. Documentation of delegation should be proportionate to the significance of the trial-related activities. In situations where the activities are performed as part of clinical practice, delegation documentation may not be required.
   • Agreements made by the investigator/institution with service providers for trial-related activities should de documented.
   • 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(s).
6. Communication with IRB
   • Submission to the IRB may be made by the investigator/institution or sponsor in accordance with applicable regulatory requirements.
   • Before initiating a trial, the investigator/institution should have a documented and dated approval from the IRB for the trial protocol, informed consent materials, participant recruitment procedures (e.g., advertisements), and any other trial-related information to be provided to participants.
   • As part of the investigator’s/institution’s or sponsor’s (in accordance with applicable regulatory requirements) submission to the IRB, a current copy of the Investigator’s Brochure or basic product information brochure should be provided. If the Investigator’s Brochure or basic product information brochure is updated during the trial, the IRB should receive the current version in accordance with applicable regulatory requirements.
   • As the trial progresses, the investigator/institution or sponsor should provide any updates to the participant information to the IRB in accordance with applicable regulatory requirements.
   • The investigator or sponsor should submit documented summaries of the trial status to the IRB in accordance with local regulatory requirements or upon request.
   • The investigator or the sponsor should promptly communicate to the IRB and where applicable, to the institution any changes significantly affecting the conduct of the trial and/or increasing risk to participants.
7. Compliance with Protocol
   • The investigator/institution should sign the protocol, or an alternative contract, to confirm agreement with the sponsor.
   • The investigator/institution should comply with the protocol, GCP and applicable regulatory requirements.
   • The investigator should document all protocol deviations. In addition to those identified by the investigator themselves, protocol deviations related to their trial participants and their conduct of the trial may be communicated to them by the sponsor. In either case, the investigator should review the deviations, and for those deviations deemed important, the investigator should explain the deviation and implement appropriate measures to prevent a recurrence, when applicable.
   • The investigator should follow the protocol and deviate only where necessary to eliminate an immediate hazard(s) to trial participants. In case of deviations undertaken to eliminate immediate hazard to trial participants, the investigator should inform the sponsor promptly.
   • The investigator should report information on the immediate hazard, the implemented change and the subsequent proposed protocol amendment, if any, to the IRB and, where applicable, regulatory authorities.
8. 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 participants and should assure appropriate therapy and follow-up for the participants.
   • Where the investigator terminates or suspends their involvement in a trial without prior agreement by the sponsors, the investigator should promptly inform the institution, where applicable, the sponsor, the IRB, and the regulatory authorities in accordance with applicable regulatory requirements and should provide a detailed explanation of the reasons.
   • 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 and the regulatory authorities and should provide an appropriate explanation.
   • If the IRB terminates or suspends its approval of a trial, the investigator should inform the institution, where applicable, and the investigator/institution should promptly notify the sponsor.
9. Participant Medical Care and Safety Reporting
   • 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.
     • 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.
     • 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. The investigator/institution should inform a participant when medical care is needed for intercurrent illness(es) of which the investigator becomes aware.
     • 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.
   • 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 specific in the protocol. Unfavorable 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.
     • All serious adverse events (SAEs) should be reported immediately (after the investigator reasonably becomes aware of the event) to the sponsor. The investigator should also include an assessment of causality. In accordance with applicable regulatory requirements, the protocol may identify SAEs not requiring immediate reporting, for example, deaths or other events that are endpoints. Subsequent information should be submitted as a follow-up report, as necessary.
     • For reported deaths, the investigator should supply the sponsor, the IRB and, where applicable, the regulatory authority with any additional requested information (e.g., autopsy reports and terminal medical reports) when they become available.
     • The investigator may delegate activities for safety reporting to qualified investigator site staff but retains the overall responsibility for safety of participants under their responsibility and compliance with the reporting requirements.
10. Informed Consent of Trial Participants
    • In obtaining and documenting informed consent (paper or electronic format), the investigator should comply with the applicable regulatory requirements and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki. The informed consent process should include the following:
      • Prior to consenting and enrolling participants, the investigator should have the IRB’s documented approval of the informed consent materials and process;
      • The information should be as clear and concise as possible, use simple language and avoid unnecessary volume and complexity. This is to ensure that the 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 the participants to be able to make an informed decision as to their participant in the trial.
      • 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. The characteristics of the potential trial population (e.g., participants may lack familiarity with computerized systems) and the suitability of the method of obtaining consent should be taken into consideration when developing the informed consent materials and process. When computerized systems are used to obtain informed consent, trial participants may be given the option to use a paper-based approach as an alternative.
      • Obtaining consent remotely may be considered where appropriate.
      • 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.
    • 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. The communication of this information and confirmation of the willingness to continue trial participation should be documented. 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). If re-consent is needed (e.g., information on emerging safety concerns), new information should be clearly identified in the revised informed consent materials. Revised informed consent materials should receive the IRB’s approval in advance of use.
    • Neither the investigator, nor the investigator site staff, should coerce or unduly influence a participant to participate or to continue their participation in a trial.
    • 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.
    • 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. 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.
    • The information provided during the informed consent process and translations should be relevant, clear, simple, concise and understandable to the participant or the participant’s legally acceptable representative and the impartial witness, where applicable.
    • 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 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 inquire about trial details and to decide whether or not to participate in the trial. Questions about the trial should be answered to the satisfaction of the participant or the participant’s legally acceptable representative.
    • Prior to trial participation, the informed consent form should be signed and dated by the participant or by the participant’s legally acceptable representative, where appropriate, by an impartial witness and by the investigator or delegated investigator site staff who conducted the informed consent discussion. 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. The informed consent process may involve a physical or an electronic signature and date.
    • 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. When prior consent of the participant is not possible and the participant’s legally acceptable representative is not possible and the participant’s legally acceptable representative is not available, enrollment of the participant should require measures described in the protocol and/or elsewhere, with documented approval by the IRB, to protect the participant’s rights, safety and well-being and to ensure compliance with applicable regulatory requirements. 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.
    • 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. 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. 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, and that informed consent was freely given by the participant or the participant’s legally acceptable representative.
    • The informed consent discussion and the informed consent materials to be provided to participant should explain the following as applicable:
      • The purpose of the trial;
      • That the trial involves research and summary of the experimental aspects of the trial;
      • The trial’s investigational product(s) and the probability for random assignment to the investigational product, if applicable;
      • The trial procedures to be followed, including all invasive procedures;
      • What is expected of the participants;
      • The reasonably foreseeable risks or inconveniences to the participant and, when applicable, the participant’s partner, to an embryo, fetus, or nursing infant;
      • The reasonably expected benefits. When there is no intended clinical benefit to the participant, the participant should be made aware of this;
      • The alternative procedure(s) or course(s) of treatment that may be available to the participant, and their important potential benefits and risks;
      • The compensation and/or treatment available to the participant in the event of trial related injury;
      • Any anticipated prorated compensation to the participant for trial participation;
      • Any anticipated expenses to the participant for trial participation;
      • That the participant’s trial participation is voluntary, and the participant 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;
      • The follow-up procedure for participants who stopped taking the investigational product, withdrew from the trial or were discontinued from the trial;
      • The process by which the participant’s data will be handled, including in the event of the withdrawal or discontinuation of participation in accordance with applicable regulatory requirements;
      • That by agreeing to participant 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. 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, monitor(s) or auditor(s), and in accordance with applicable regulatory requirements, IRB;
      • That records identifying the participant will be kept confidential and, to the extent permitted by the applicable regulatory requirements, will not be made publicly available. If the results of the trial are published, the participant’s identity will remain confidential. The trial may be registered on publicly accessible and recognized databases, per applicable regulatory requirements;
      • That the participant or the participant’s legally acceptable representative will be informed in a timely manner if information becomes available that may be relevant to the participant’s willingness to continue trial participation;
      • The person(s) to contact for further trial information and the trial participant’s rights, and whom to contact in the event of suspected trial-related injury;
      • The foreseeable circumstances and/or reasons under which the participant’s trial participation may be terminated.
      • The expected duration of the participant’s trial participation;
      • The approximate number of participants involved in the trial;
      • That trial results and information on the participant’s actual treatment, if appropriate, will be made available to them should they desire it when this information is available from the sponsor.
    • Prior to participation, the participant or the participant’s legally acceptable representative should receive a copy (paper or electronic) of the signed informed consent form and any other informed consent materials provided, in accordance with applicable regulatory requirements. 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.
    • When 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 enroll in the trial should be obtained as appropriate. As process for re-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.
    • When a clinical trial includes participant who may only be enrolled in the trial 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 and, if capable, the participant should sign and date the informed consent form or assent form as appropriate.
11. End of Participation in a Clinical Trial
    • When a participant decides to stop treatment with the investigational product, stop trial visits or completely withdraw from a trial; is discontinued from the trial; or reaches the routine end of the trial, the investigator should follow the protocol and other sponsor instructions to determine appropriate follow-up measures. This may include instructions to avoid unnecessary loss of already collected critical data in accordance with applicable regulatory requirements.
    • 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. The investigator should consider if a discussion with the participant or the participant’s legally acceptable representative is appropriate. 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 withdrawal without unduly influencing the participant’s decision. The investigator or delegated investigator site staff should consider explaining to the participant the value of continuing their participation to minimize trial participants withdrawal. In this process, the investigator should ensure that it does not interfere with the participant’s decision to refuse or withdraw participation at any time.
    • 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.
12. Investigational Product Management
    • Responsibility for investigational product(s), including accountability, handling, dispensing, administration and return, rests with the investigator/institution. The sponsor may facilitate aspects of investigational product management (e.g., by providing forms and technical solutions, such as computerized systems, and arranging distribution of investigational product to trial participants).
    • When the investigator/institution delegates some or all of their activities for investigational product(s) management to a pharmacist or another individual in accordance with local regulatory requirements, the delegated individual should be under the oversight of the investigator/institution.
    • Where the investigator has delegated activities related to investigational product management or aspects of these activities have been facilitated by the sponsor, the level of investigator oversight will depend on a number of factors, including the characteristics of the investigational product, route and complexity of administration, level of existing knowledge about the investigational product’s safety and marketing status.
    • The investigator/institution and/or pharmacist or other appropriate individual, should maintain records of the product’s delivery, the inventory, the use by each participant (including documenting that the participants were provided the doses specified by the protocol), and the return to the sponsor and destruction or alternative disposition of unused product(s). 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. For authorized medicinal products, alternative approaches to the aforementioned may be considered, in accordance with local regulatory requirements.
    • The investigational product(s) should be stored as specified by the sponsor and in accordance with applicable regulatory requirement(s).
    • The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol.
    • When applicable, the investigator or a person designated by the investigator/institution should explain the correct use of the investigational product(s) to each participant and should check, at intervals appropriate for the trial, that each participant is following the instructions properly.
    • The investigational product may be shipped to the participant’s location or supplied to/dispensed at a location closer to the participant (e.g., at a local pharmacy or local healthcare center). The investigational product may be administered at the participant’s location by investigator site staff, the participant themselves, or a caregiver or a healthcare professional.
    • 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.
13. Randomization Procedures and Unblinding
    • The investigator should follow the trial’s randomization procedures, if any, and in the case of an investigator-blinded trial, should ensure that the treatment randomization code is broken only in accordance with the protocol. 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 hinderance. 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).
14. Records
    • In generating, recording and reporting trial data, the investigator should ensure the integrity of data under their responsibility, irrespective of the media used.
    • The investigator/institution should maintain adequate source records that include pertinent observations on each of the trial participants under their responsibility. Source records should be attributable, legible, contemporaneous, original, accurate and complete. Changes to source records should be traceable, should not obscure the original entry and should be explained if necessary (via an audit trail). 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. Unnecessary transcription steps in between the source record and the data acquisition tool should be avoided.
    • 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. The protocol may provide exceptions for access, for instance, to protect blinding.
    • 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.
    • 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). The investigator should review and endorse the reported data at important milestones agreed upon with the sponsor (e.g., interim analysis).
    • Data reported to the sponsor should be consistent with the source records or the discrepancies explained. Changes or corrections in the reported data should be traceable, should be explained (if necessary) and should not obscure the original entry.
    • The investigator/institution should implement appropriate measures to protect the privacy and confidentiality of personal information or trial participants in accordance with applicable regulatory requirements on personal data protection.
    • Data reported to the sponsor should be identified by an unambiguous participant code that can be tracked back to the identity of the participant by the investigator/institution.
    • 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 unauthorized access, disclosure, dissemination or alteration and from inappropriate destruction or accidental loss.
    • When using computerized systems in a clinical trial, the investigator/institution should do the following:
      • For systems deployed by the investigator/institution, ensure that appropriate individuals have secure and attributable access;
      • For systems deployed by the sponsor, notify the sponsor when access permissions need to be changed or revoked from an individual;
      • For system deployed by the investigator/institution specifically for the purposes of clinical trials, ensure the requirements for computerized systems in section 4 of ICH GCP Annex 1 are addressed proportionate to the risks to participants and to the importance of the data;
      • Where equipment for data acquisition is provided to trial participants by the investigator, ensure that traceability is maintained and participants are provided with appropriate training;
      • Ensure that incidents in the use and operation of computerized systems, which in the investigator/institution’s judgment 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.
    • The investigator/institution should maintain the trial records as specified in Appendix C of ICH GCP Annex 1 and as required by the applicable regulatory requirement(s). The investigator/institution should have control of all essential records generated by the investigator/institution before and during the conduct of the trial.
    • 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. The investigator/institution should take measures to ensure availability, accessibility and readability and to prevent unauthorized access and accidental or premature destruction of these records.
    • 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.
    • Upon request of the monitor, auditor, IRB, or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records.
15. Reports
    • Upon completion of the trial, the investigator, where applicable, should inform the institution. The investigator/institution should provide the IRB with a summary of the trial’s outcome, and, if applicable, the regulatory authorities with any required reports.