Good clinical practice and trial quality

Roles, responsibilities and oversight in a clinical trial

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In a clinical trial run to ICH E6(R3), an ethics committee reviews the trial, an investigator conducts it, and a sponsor initiates and manages it and arranges its financing. Each has its own duties to discharge and to be able to show. Agreements, the sponsor's quality management and oversight, and action on noncompliance hold those duties in place, and responsibility for a duty stays with the party that holds it, whoever does the work.

The parties and where responsibility stays

The investigator is the person responsible for the conduct of the trial, including the participants for whom that person has responsibility; where a team conducts the trial, the investigator is its responsible leader and may be called the principal investigator. The guideline's term "investigator/institution" describes expectations that may apply to the investigator and/or the institution in some regions, and where regulatory requirements so require, "investigator" should be read as "investigator and/or the institution". A sub-investigator is any member of the team, such as an associate, resident or research fellow, who is designated by and under the oversight of the investigator to perform significant trial-related procedures or make important trial-related decisions. The institution is any public or private entity, agency, or medical or dental organisation in whose remit trials are conducted, and the investigator site is the location or locations where trial-related activities are conducted or coordinated under the investigator's or institution's oversight. A multicentre trial is conducted according to a single protocol at more than one investigator site, and a coordinating investigator is the investigator assigned to coordinate the investigators at those sites.

The sponsor is the individual, company, institution or organisation that takes responsibility for initiating, managing and arranging the financing of a trial. Where regulatory requirements permit, a trial may have one or several sponsors, and every sponsor has the responsibilities of a sponsor. In a trial with more than one sponsor, the sponsors should have a documented agreement that sets out their respective responsibilities, in accordance with local regulatory requirements or practice. Where that agreement does not specify to which sponsor a responsibility is attributed, the responsibility lies with all of them. A sponsor-investigator is an individual who both initiates and conducts a trial, alone or with others, and under whose immediate direction the investigational product is administered to, dispensed to or used by a participant. The term covers only an individual, not, for example, a corporation or an agency, and a sponsor-investigator carries the obligations of both a sponsor and an investigator.

A service provider is any person or organisation, commercial, academic or other, that provides a service the sponsor or the investigator uses to fulfil trial-related activities; the guideline gives a contract research organisation no definition of its own and refers to this one.

A sponsor may transfer any or all of its trial-related activities to a service provider in accordance with applicable regulatory requirements, but the ultimate responsibility for those activities, including the protection of participants' rights, safety and well-being and the reliability of the trial data, stays with the sponsor. An investigator may delegate trial-related activities to other persons or parties and retains the ultimate responsibility.

The ethics committee

ICH E6(R3) defines the institutional review board or independent ethics committee as an independent body, whether a board or a committee and whether institutional, regional, national or supranational, made up of medical professionals and non-medical members. Its responsibility is to ensure the protection of the rights, safety and well-being of participants and to provide public assurance of that protection by, among other things, reviewing and approving or giving a favourable opinion on the protocol, the suitability of the investigators, the facilities, and the methods and material used to obtain and document consent. Its legal status, composition, function, operations and regulatory requirements may differ between countries, but they should allow it to act in agreement with GCP. It is responsible for the ethical review of the trial, and the guideline's requirements for it should be read together with local regulatory requirements. Its purpose is to safeguard the rights, safety and well-being of all participants, and trials that intend to recruit vulnerable participants should be given appropriate consideration. The ethical principles and standards by which ethics committees evaluate trials provide a sound basis for conducting trials, including those that incorporate decentralised elements, pragmatic elements or real-world data, and particular attention should be given to, for example, measures that ensure participants' rights, safety and well-being, protect their privacy and confidentiality, and secure their data.

The committee should review the following, where applicable:

The protocol and its amendments.
Informed consent and assent materials and their updates, including a description of how consent and assent will be obtained.
The investigator's brochure or current scientific information, such as a basic product information brochure, as appropriate, with its updates.
Other trial-related information to be given to participants, including a description of the media through which it will be provided.
Recruitment advertising, if used, and information on the recruitment process.
Plans to compensate participants.
Ongoing updates to safety information.
The investigator's current curriculum vitae or other evidence of qualifications.
Any other documents the committee needs to fulfil its responsibilities.

The committee should review a proposed trial within a reasonable time and document its review, identifying the trial, the documents reviewed and the dates of its decisions: approval or favourable opinion, modifications required before approval, disapproval or negative opinion, and termination or suspension of a prior approval. It should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to participants. It may ask for participants to be given more information than the guideline's informed consent requirements set out, where in its judgement the addition would meaningfully protect them. Where the protocol indicates that prior consent of the participant or their legally acceptable representative is not possible, as in an emergency, the committee should determine that the proposed protocol and other documents adequately address the relevant ethical concerns and meet the applicable regulatory requirements for such trials. Where minors are to be included, it should review the assent information considering the age, maturity and psychological state of the minors intended to be enrolled, as well as the applicable regulatory requirements.

Where participants are compensated, the committee should review both the amount and the method of payment to assure that neither presents problems of coercion or undue influence. Payments should be timely, prorated and not wholly contingent on the participant completing the trial, and reasonable reimbursement of expenses such as travel and lodging is not coercive. The committee should also ensure that the methods, amounts and schedule of payment are set out in the informed consent materials and any other information given to participants.

The committee should have a reasonable number of members who collectively have the qualifications and experience to review the science, medical aspects and ethics of the trial; the guideline recommends at least five members, at least one whose primary area of interest is not in the medical sciences, and at least one independent of the institution or investigator site. Only members independent of the investigator and the sponsor should vote or give an opinion, and a list of members and their qualifications should be maintained. The committee should perform its functions according to documented operating procedures, maintain records of its activities and minutes of its meetings, and comply with GCP and the applicable regulatory requirements. It should make its decisions at announced meetings with at least the quorum its documented procedures stipulate, and alternative processes may apply for expedited review. Only members who took part in the review and discussion should vote. The investigator, site staff and sponsor may supply information on any aspect of the trial but should not take part in the decision or the vote, and the committee may invite non-members with expertise in special areas to assist.

The committee's documented procedures cover how it is composed, with the names and qualifications of its members, and under what authority it is established; how its meetings are scheduled, notified to its members and conducted; how it carries out initial and continuing review and how often continuing review takes place; and how it provides expedited review and approval of minor changes in ongoing trials. The procedures also specify that no participant should be enrolled before the committee has issued its documented approval or favourable opinion of the trial. They specify that no deviation from or change to the protocol should be initiated without the committee's prior documented approval or favourable opinion of an appropriate amendment, except where necessary to eliminate immediate hazards to participants or, where applicable requirements allow, where the change involves only logistical or administrative aspects.

The procedures specify that the investigator or institution should promptly report to the committee:

Deviations from the protocol made to eliminate immediate hazards to participants.
Changes increasing the risk to participants or significantly affecting the conduct of the trial.
All suspected unexpected serious adverse reactions, in accordance with applicable regulatory requirements.
New information that may adversely affect participants' safety or the conduct of the trial.

The procedures also ensure that the committee promptly notifies the investigator or institution, or the sponsor, in writing, on paper or electronically, of its decisions and opinions, the reasons for them, and the procedures for appeal.

Depending on the region and its applicable requirements, submissions to and communications with the committee and the regulatory authorities are made by the investigator or institution or by the sponsor. In most regions where a submission to the regulatory authority is also required, the two may be combined into a single submission in accordance with applicable regulatory requirements. Before initiating a trial, the investigator or institution should have a documented and dated approval or favourable opinion from the committee for the protocol, the informed consent materials, the participant recruitment procedures, such as advertisements, and any other trial-related information to be given to participants. A current copy of the investigator's brochure or basic product information brochure should be provided as part of the submission to the committee, and if it is updated during the trial, the committee should receive the current version in accordance with applicable regulatory requirements. As the trial progresses, the investigator or institution or the sponsor should provide the committee with any updates to the participant information in accordance with applicable regulatory requirements, and the investigator or the sponsor should submit documented summaries of the trial status in accordance with local regulatory requirements or on request. The investigator or the sponsor should promptly communicate to the committee and, where applicable, to the institution any changes significantly affecting the conduct of the trial or increasing the risk to participants.

The committee should keep its records, such as documented procedures, membership lists, lists of members' occupations and affiliations, submitted documents, minutes and correspondence, in accordance with applicable requirements, and make them available on request from a regulatory authority. Investigators, sponsors and regulatory authorities may also ask it for its documented procedures and membership lists.

The investigator

An investigator should be qualified by education, training and experience to take responsibility for the proper conduct of the trial and should provide evidence of those qualifications. The investigator should be familiar with the appropriate use of the investigational product as described in the protocol, the current investigator's brochure, the product information or other sources supplied by the sponsor. The investigator should be able to demonstrate, for example from retrospective or currently available data, a potential for recruiting the proposed number of eligible participants within the recruitment period 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 it properly and safely, and should demonstrate adequate resources and facilities.

The investigator retains ultimate responsibility and should maintain appropriate and proportionate oversight of trial-related activities, including delegated ones, to ensure participants' rights, safety and well-being and the reliability of the data. The level of that oversight should depend on the nature of the activities and be proportionate to the importance of the data and to the risks to participants and to data reliability. The appropriate level depends on context, such as the trial design, population, investigational product and data sources, and it may range from direct supervision, through less intensive oversight in person or by remote means such as video, telephone or email, to review of essential records, including source records, alone. The investigator should ensure that those to whom activities are delegated, including staff provided by other parties in accordance with local regulatory requirements, are appropriately qualified and adequately informed about the relevant aspects of the protocol, the investigational product and their assigned activities. Trial-related training for those assisting in the trial should correspond to what they need to fulfil delegated activities that go beyond their usual training and experience. A record should be kept of the persons and parties to whom activities are delegated, documented in proportion to the significance of those activities, and where the activities are performed as part of clinical practice, delegation documentation may not be required.

The sponsor may help identify a suitable service provider, but the investigator keeps the final decision on whether a provider intended to support the investigator is appropriate, based on information the sponsor provides. Where the sponsor identifies or arranges a service provider for activities under the investigator's responsibility, such as home nursing, the sponsor should give the investigator information on that provider and ensure it is suitable, and the investigator remains responsible for those activities and for overseeing them. Agreements the investigator or institution makes with service providers for trial-related activities should be documented.

Where healthcare professionals perform trial-related activities that are part of usual clinical practice, the protocol should describe those activities. Where the activities do not require knowledge of the protocol, the investigator's brochure or other trial documents, arrangements should be in place for making the resulting information and records available to the investigator, defining how data are shared, how records are retained, for example as a certified copy, how data privacy is maintained and what mechanisms ensure data integrity. Where they do require such knowledge, appropriately trained delegated healthcare professionals should perform them. In either case the investigator's oversight should be proportionate to the criticality of the data to participant protection and to the reliability of the results, and whether the sponsor or the investigator arranged the healthcare professionals, that oversight should ensure the resulting records meet the relevant requirements of the protocol and thereby ensure reliable results, participant protection and appropriate decision making.

The investigator or institution should sign the protocol or an alternative contract to confirm agreement with the sponsor, and the investigator should comply with the protocol, GCP and applicable regulatory requirements. The investigator should follow the protocol and deviate from it only where necessary to eliminate an immediate hazard to participants, and should then inform the sponsor promptly and report the hazard, the change implemented and any proposed amendment that follows to the ethics committee and, where applicable, the regulatory authorities. A principal investigator may have a little trouble following the rules of the protocol, because their first reaction is to treat the patient as they would in practice rather than according to the study protocol. The investigator should document all protocol deviations, both those they identify and those the sponsor communicates to them, and should review them; for a deviation deemed important, the investigator should explain it and, where applicable, implement measures to prevent a recurrence. The sponsor should determine the trial-specific criteria for classifying deviations as important, important deviations being the subset that may significantly affect the completeness, accuracy or reliability of the data or a participant's rights, safety or well-being.

The investigator or institution should permit monitoring and auditing by the sponsor, inspection by the appropriate regulatory authorities and, in accordance with applicable requirements, review by ethics committees. An inspection is a regulatory authority's official review of documents, facilities, records and any other resources it deems related to the trial, whether at the investigator site, at the sponsor's or a service provider's facilities, or at other establishments the authority considers appropriate, and some aspects of it may be conducted remotely.

If a trial is terminated or suspended prematurely for any reason, the investigator or institution should promptly inform the participants and ensure appropriate therapy and follow-up for them. An investigator who terminates or suspends their own involvement without the sponsor's prior agreement should promptly inform the institution where applicable, the sponsor, the ethics committee and the regulatory authorities, and explain the reasons in detail. If the sponsor terminates or suspends the trial, the investigator or institution or the sponsor should promptly inform the committee and the authorities and give an appropriate explanation. If the committee terminates or suspends its approval, the investigator should inform the institution where applicable, and the investigator or institution should promptly notify the sponsor. For its part, the sponsor should promptly inform the investigators, institutions and regulatory authorities of a termination or suspension and its reasons; the committee should also be informed promptly, with the reasons, by the sponsor or the investigator; and where appropriate the sponsor should give the investigator information about potential subsequent therapies and follow-up for participants.

On completion of the trial, the investigator should inform the institution where applicable, and the investigator or institution should provide the ethics committee with a summary of the trial's outcome and, if applicable, the regulatory authorities with any required reports.

The sponsor's responsibility entails implementing risk-proportionate approaches to ensure participants' rights, safety and well-being and the reliability of results throughout the trial life cycle. Before initiating trial activities, the sponsor should determine the roles and allocate its trial-related activities accordingly, and it should ensure that sufficient resources are available to conduct the trial appropriately. It should use appropriately qualified individuals for the activities they are assigned, such as biostatisticians, clinical pharmacologists, physicians, data scientists and data managers, auditors and monitors, and should have medical personnel readily available to advise on trial-related medical questions or problems.

The sponsor is responsible for selecting the investigators and institutions, and for organising or selecting any coordinating committee or coordinating investigator in a multicentre trial, whose roles and responsibilities should be documented before they are involved. The sponsor should give the potential investigators and institutions the protocol and an up-to-date investigator's brochure, and enough time to review them.

Before initiating the trial, and in accordance with applicable requirements, the sponsor, or the sponsor and the investigator, should submit any required application to the appropriate regulatory authorities for review, acceptance or permission to begin; any submission should be dated and contain sufficient information to identify the protocol. The sponsor should also ensure that it obtains the name and address of the relevant ethics committee, with a statement that the committee is organised and operates according to GCP and applicable requirements, and the committee's documented initial and subsequent approval or favourable opinion as well as any termination of the trial or suspension of that approval. The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator or institution.

Where applicable requirements so require, the sponsor should provide insurance or indemnify the investigator and institution against claims arising from the trial, except claims arising from malpractice or negligence. Its policies and procedures should address the costs of treating participants for trial-related injuries, and its approach to compensating participants should comply with applicable requirements.

Agreements

An agreement, in the guideline's terms, is a document or set of documents describing any arrangements between two or more parties on the delegation or transfer, distribution or sharing of activities and, where appropriate, on financial matters; it may take the form of a contract, and the protocol may serve as its basis.

The sponsor's agreements with investigators and institutions, service providers and other parties, such as an independent data monitoring committee or an adjudication committee, should be documented before the activities begin and updated when necessary to reflect significant changes in the activities transferred. The sponsor should obtain the agreement of the investigator or institution and, where applicable, the service provider:

To conduct the trial in accordance with the approved protocol and in compliance with GCP and applicable requirements.
To comply with the procedures for recording and reporting data.
To retain the essential records for the required period or until the sponsor says they are no longer needed, whichever is longer.
To permit monitoring and auditing by sponsors, inspections by domestic and foreign regulatory authorities and, in accordance with applicable requirements, review by ethics committees, including direct access to source records and facilities, those of service providers included.

Any of the sponsor's activities transferred to and assumed by a service provider should be documented in an agreement, and any activity not specifically transferred and assumed stays with the sponsor. The sponsor is responsible for assessing the suitability of the service provider and selecting it, to ensure that the provider can adequately undertake the activities transferred; it should supply the protocol where necessary and any other documents the provider needs, have access to relevant information such as standard operating procedures and performance metrics for selecting and overseeing providers, and ensure appropriate oversight of important activities transferred, including activities the provider subcontracts further. A service provider's trial-related activities should be conducted in accordance with the relevant GCP requirements, and its existing quality management processes may fulfil them even where they were not designed specifically to be GCP-compliant, provided they are fit for purpose in the context of the trial. Any provider used should implement appropriate quality management and report to the sponsor any incident that might affect participant safety or the trial results.

The sponsor should implement an appropriate system to manage quality throughout all stages of the trial process, covering the design and implementation of efficient protocols, including the tools and procedures for conduct, data collection and management, so as to protect participants and ensure reliable results. The approach should be proportionate and risk-based: quality is incorporated into the design of the trial, which is quality by design, and the factors likely to have a meaningful impact on participants' rights, safety and well-being and on the reliability of the results, the critical to quality factors described in ICH E8(R1), are identified. The sponsor should describe the quality management approach implemented in the trial in the clinical trial report.

When planning a trial, the sponsor should ensure that sufficient safety and efficacy data, for example from nonclinical studies, clinical trials or real-world sources, are available to support human exposure by the route, at the dosages, for the duration and in the population to be studied. It should incorporate quality into the design by identifying the critical to quality factors and managing risks to them. It should consider inputs from a wide variety of interested parties, such as healthcare professionals and patients, both for the development plan and protocols and when developing consent materials and other participant-facing information. It should ensure that all aspects of the trial are operationally feasible and avoid unnecessary complexity, procedures and data collection; protocols, data acquisition tools and other operational documents should be fit for purpose, clear, concise and consistent, and the sponsor should place no unnecessary burden on participants and investigators.

ICH E6(R3) describes a proportionate approach to the identification and management of risk:

Identification. The sponsor should identify risks that may have a meaningful impact on the critical to quality factors, before initiation and throughout conduct, considering them across the processes and systems used, computerised systems included, such as trial design, participant selection, the informed consent process, randomisation, blinding, investigational product administration, data handling and service provider activities.
Evaluation. The sponsor should evaluate identified risks and the existing controls in place to mitigate them by considering the likelihood of the harm or hazard occurring, the extent to which it would be detectable, and its impact on participant protection and on the reliability of results.
Control. Risk control should be proportionate to the importance of the risk to participants' rights, safety and well-being and to the reliability of results, and mitigation may be built into, for example, protocol design and implementation, monitoring plans, agreements between parties defining roles and responsibilities, and training. Where relevant, the sponsor should set pre-specified acceptable ranges, such as quality tolerance limits at trial level, to support the control of risks to critical to quality factors; these reflect limits that when exceeded have the potential to affect participant safety or the reliability of results, and where a deviation beyond them is detected, an evaluation should determine whether there is a possible systemic issue and whether action is needed.
Communication. The sponsor should document and communicate the identified risks and mitigating activities, if applicable, to those involved in taking action or affected by them; communication also facilitates risk review and continual improvement during conduct.
Review. The sponsor should periodically review the risk control measures to ascertain whether the implemented quality management activities remain effective and relevant, taking into account emerging knowledge and experience; additional risk control measures may be implemented as needed.
Reporting. The sponsor should summarise and report important quality issues, including instances in which the acceptable ranges are exceeded, and the remedial actions taken, and document them in the clinical trial report.

The sponsor should ensure that the design, conduct, processes and generated information and data are of sufficient quality for reliable results, participant safety and appropriate decision making, and that trial processes comply with the protocol and related documents, applicable requirements and ethical standards. Decisions related to the trial should be assessed for their impact on participants and on the reliability of results, and the risks those decisions carry should be managed through planning, conduct and reporting. The range and extent of oversight measures should be fit for purpose and tailored to the trial's complexity and risks; the selection and oversight of investigators and service providers are fundamental features of the oversight process, and it includes quality assurance and quality control of their activities. The sponsor should ensure appropriate and timely escalation and follow-up of issues so that appropriate action can be taken in time. Sponsor oversight may be more complex depending on the range of methodological approaches to design and conduct and on the number of service providers involved. The sponsor should ensure that processes are in place, including clear lines of communication, to provide an appropriate level of oversight, such that participants' rights, safety and well-being are protected and the reliability of the results is ensured. Sponsor oversight involves, among other things, quality control and assurance measures customised to the trial and its critical to quality factors and identified risks, implemented in proportion to the potential impact on participant protection or the reliability of results. The sponsor should maintain appropriate oversight of service providers, including ensuring the maintenance of their essential records.

The sponsor may consider establishing an independent data monitoring committee, such as a data safety monitoring board, to assess the progress of a trial at intervals, including the safety data and the efficacy endpoints, and to recommend whether to continue, modify or stop it. Where appropriate, the sponsor may also establish an endpoint assessment or adjudication committee to review whether endpoints reported by investigators meet protocol-specified criteria; to minimise bias, such a committee should typically be blinded to the assigned treatments, whether or not the trial itself is blinded. Any committee established for purposes that could affect participant safety or the reliability of results should include members with relevant expertise and managed conflicts of interest, have written operating procedures such as a charter, and document its decisions.

Noncompliance

Noncompliance with the protocol, standard operating procedures, GCP or applicable requirements, whether by an investigator or institution or by the sponsor's own staff, should lead the sponsor to take appropriate and proportionate action to secure compliance.

If the sponsor discovers noncompliance that significantly affects, or could significantly affect, participants' rights, safety or well-being or the reliability of results, it should perform a root cause analysis, implement appropriate corrective and preventive actions and confirm their adequacy, unless otherwise justified. Where the issues it identifies are likely to have that significant impact, which is serious noncompliance, the sponsor should notify the regulatory authority, the ethics committee or the investigator as appropriate and in accordance with applicable requirements.

If significant noncompliance by an investigator, institution or service provider persists despite efforts at remediation, the sponsor should consider terminating that party's participation in the trial. In that case it should promptly notify the regulatory authorities and the ethics committee of the serious noncompliance, as appropriate, and act to minimise the impact on the participants and on the reliability of the results.

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