On 19 May 2023 the International Council for Harmonization (“ICH”) of technical requirements for pharmaceuticals for human use endorsed a draft version of Good Clinical Practice (“GCP”) Guidelines – E6(R3) – which is currently under public consultation.

Historically, the first version of GCP Guidelines was released for public consultation on 27 April 1995 and the latest version was adopted by the Regulatory Members of the ICH Assembly on 9 November 2016.

In a nutshell, these GCP Guidelines, in our opinion, are very comprehensive and cover a sufficiently wide range in terms of the specialized field of clinical trials. Of course, with the reservation that there is always room for improvement given the complexity, specificity, and remarkable relationship of clinical trials` domain with notions – abstract perhaps – such as ethics.

In this regard, we mention general aspects such as principles of ICH GCP, the purpose of developing such guidelines, but especially specific aspects such as, but not limited to procedures, responsibilities, compliance with both clinical trial protocol and legislation, records, trainings, resources, quality control, ethics – all the above are presented in relation to the actors involved in the study.

Concerning the sponsor and the investigator and the relationship between their roles.

Clarification of these actors` role definition.

The GCP Guidelines detail these steakholders` responsibilities marking a delimitation between these.

To this regard, we mention that it is expressly stated that the Investigator may delegate trial-specific activities to other persons or parties and, correspondingly, he may be supported by the sponsor to identify a suitable service provider. But delimitating, the GCP Guidelines further sets forth that the Investigator retains the final decision on whether the service provider intended to support the Investigator is appropriate based on information provided by the Sponsor.

Moreover, the GCP Guidelines stipulate that the Investigator retains the ultimate responsibility and maintains appropriate supervision of the persons or parties undertaking the activities delegated to ensure the rights, safety and well-being of the trial participants and data reliability.

Also relating to the above, correspondingly, the GCP Guidelines state as mandatory that 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.

Further it is stated as Sponsor`s responsibility that 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.

Ethical considerations – an extremely important element in the conduct of the clinical trial

Regarding Ethics in clinical studies, it is already known that this one of the most important components of this complex process, so we can affirm that a strong ethical foundation is the key to comply with requirements both legally and moral for the trial to succeed.

To this end, any, all, and every clinical trial that is conducted will have an Institutional Review Board/Independent Ethics Committee (“IRB” / “IEC”) attached to it.

According to the GCP Guideline, the IRB/IEC is responsible for the ethical review of the trial. Also, it is provided that the requirements for the IRB/IEC in the above-mentioned GCP Guideline should be read in conjunction with local regulatory requirements.

Therefore, in addition to the provisions of the GCP, any clinical trial must also comply with the provisions of the national legislation where the clinical trial is to be conducted – provisions which may not only be additional, but also more restrictive in terms of medical Ethics.

The IRB/IEC role and responsibilities are expressly provisioned by GCP Guidelines, mentioning that their purpose is to safeguard the rights, safety, and well-being of all trial participants. Therefore, it clearly states the best interests of the human being.

Among others, we mention that the IRB/IEC should review (where applicable) Protocol and any amendments; informed consent material(s), assent form(s), where applicable, and any updates, including the description of the process for how informed consent is to be obtained; Investigator’s Brochure or current scientific information, such as a basic product information brochure (e.g., Summary of Product Characteristics (SmPC), package leaflet or labelling), as appropriate, including their updates; any other information to be provided to the trial participant(s), including a description of the media through which such information will be provided; investigator’s current curriculum vitae and/or other documentation evidencing qualifications.

So, as a preliminary conclusion, it should be noted that among other things, correct and complete information of the patient (either about the medication and procedures, or about the doctor involved in the study) is among the essential requirements of ethics in clinical trials. Moreover, we must mention that in relation to the roles of each actor involved in the clinical trial (developed above), the Sponsor has the oversight obligation so should be ensured 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. Also, the GCP Guidelines state that 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.

About the guidance in record keeping – roles and standards

From the outset it is clear that the management of any data, whether related to the clinical study or personal data protection etc. must be carried out responsibly and its handling and storage must be thoroughly regulated.

To this end, also GCP Guidelines provide that clinical trials should incorporate efficient and well-controlled processes for managing records through appropriate management of data integrity, traceability, and protection of personal information, thereby allowing the accurate reporting, interpretation, and verification of the clinical trial-related information.

In relation to the above discussion about ethics in clinical trial, IRB/IEC, we must mention that according to GCP guidance, the IRB/IEC should retain all relevant records (e.g., documented procedures, membership lists, lists of occupations/affiliations of members, submitted documents, minutes of meetings and correspondence) in accordance with applicable regulatory requirements and make them available upon request from the regulatory authority(ies) – This is because state authorities have not only the right but also the obligation to ensure that the safety (lato sensu) of citizens is respected as a priority.

But, summarizing for the sake of brevity, who has the obligation of recording according to GCP Guidance? The IRB/IEC, the Investigator, and the Sponsor; mentioning also that the Protocol must include, among others, provisions describing the right to direct access to source records.

To this end, according to GCP Guidelines, the sponsor should ensure that it is specified in the protocol or other documented agreement that the investigator(s)/institution(s)/service provider(s) will permit trial-related monitoring, audits, institutional review board/independent ethics committee (IRB/IEC) review and regulatory inspection(s), providing direct access to source records.

Non-compliance and its effective management

The risk of non-compliance may occur in relation to both the study Protocol and the Good Clinical Practices or applicable legislation in the field. Thus, the sponsor’s oversight obligation includes the Quality Assurance and Quality Control obligation.

In other words, the GCP Guidelines provide that 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).

To this end, the GCP Guidelines provide that it is mandatory to have auditing procedures in place during the clinical study, which should ne carried out by individuals who are independent of the clinical trial being audited. It is also provisioned that the sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. Moreover, it is provisioned that the observations and findings of the auditor(s) should be documented.

With respect to all the above we also draw attention to the fact that both the risk of non-compliance and the obligation to keep records, as well as the obligation to respect ethical rules and the roles and responsibilities of each of the actors involved in a clinical trial are inextricably linked.

Thus, ICH felt the need to include in the GCP Guidelines the following: “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 during legal proceedings. When required by applicable regulatory requirements, the sponsor should provide an audit certificate”.

As a short conclusion, the draft Guidelines Good Clinical Practice represents a very valuable tool, pragmatic and oriented towards ethical values and effective risk management, which we look forward to seeing adopted.