Advice for non-commercial (academic) sponsors regarding GCP inspections
While the same inspection procedures and reference documents are used to determine compliance of all sponsors, irrespective of commercial status, the HPRA recognises that Chapter IV – Inspections of Volume 10 of the publication ‘The rules governing medicinal products in the European Union’, primarily concerns inspections performed in connection with marketing authorisation applications. Therefore, in order to assist non-commercial sponsors with inspection readiness, a description of the key systems that are typically examined during a non-commercial sponsor GCP inspection are outlined below:
- Organisation and personnel: Inspectors examine how the sponsor has distributed duties and tasks for the trial, and that roles and responsibilities are clearly defined, including in written agreements with third parties, where applicable. In the non-commercial setting, it is typically seen that the role of medical expert may be assigned to a principal investigator or a safety committee (as appropriate), and/or, other duties and tasks may be transferred or shared with other non-commercial entities as part of cooperative groups. All such arrangements are reviewed on inspection, including but not limited to verifying that the sponsor has considered the trial organisation as part of its quality risk management (ICH E6 (R2), Section 5), that a clear and timely record of roles and responsibilities was made, that the sponsor has qualified that the party undertaking a task can do so in a compliant manner, and that mechanisms are in place to maintain oversight.
- Facilities and equipment: Inspectors review the adequacy of facilities required for sponsor activities such as trial master file storage and archive. The validation status of any electronic equipment/computerised systems will also be confirmed. Non-commercial sponsors should ensure that electronic equipment/computerised systems, used to fulfil a trial purpose, have been validated taking into consideration the requirements of GCP.
- Quality risk management: The quality system is examined in detail, including compliance with ICH E6 (R2), Section 5. Activities including but not limited to the following are reviewed: quality risk management processes, document control, training, change control, compliance monitoring (e.g. deviations, auditing). The HPRA wish to highlight that when a risk-based approach to a GCP activity is taken, it is important that the sponsor retains a record of the rationale and approval for that approach, as such documentation may be requested on inspection. Records could include meeting minutes to completion of more formalised risk assessment tools.
- Implementation and termination of the trial: The availability of regulatory and ethics opinions, and that of any other statutory body are examined. The inspectee will be asked to demonstrate that it has adequate insurance coverage as a sponsor. Inspectors will also check that the sponsor has procedures to ensure compliance with the regulatory procedures outlined elsewhere in this guide (e.g. Section 5, 6, and 10) and to ensure the completeness and accuracy of documents submitted. For example, a key procedure examined during inspection is the process for preparation of the clinical trial protocol and amendments, including confirmation that input from relevant experts was sought and that quality control was applied to confirm internal consistency as well as consistency with other related documents (e.g. investigator brochure, case report form, patient information leaflet/consent form, monitoring plan).
- Monitoring: Monitoring procedures will be reviewed in detail, including plans for on-site monitoring, central monitoring and data committee monitoring, as applicable. The sponsor must be able to demonstrate that it has oversight of trial conduct and GCP compliance and has mechanisms in place to continuously monitor the benefit-risk balance. Documents requested may include risk assessment, monitoring plans, follow-up letters, GCP non-compliance escalations, data committee charters and meeting minutes.
- Investigational medicinal product: GCP inspections focus particularly on distribution and shipping of IMPs to the investigator site(s), labelling, and guidance provided to investigators. Where applicable, procedures for unblinding and randomisation will also be reviewed.
- Safety and adverse event (AEs) reporting: The pharmacovigilance system will be inspected, including but not limited to procedures for collecting and processing AEs/any other events specified in the clinical trial protocol, identifying and reporting SUSARs, managing reference safety information, communicating to HPRA/ethics committees/investigators and DSUR preparation and submission. It should be noted that assistance from the HPRA to academic sponsors with electronic report submission to EVCTM does not obviate sponsor obligations from other responsibilities under CT-3 ‘Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use’.
- Non-compliance: Sponsor procedures to deal with significant and/or persistent non-compliance, including processes for performing root cause analysis and implementing corrective and preventative actions, will be examined.
- Data handling and clinical trial report: Systems and procedures to collect clinical trial data and to process and report that data are examined, with a focus on data integrity and credibility. Key processes subject to inspection include the quality of the case report form, mechanism for entry of data into the clinical database, quality assurance/quality control of data (QA/QC, also known as data cleaning), audit trails, data locking and analysis/reporting.
- Documentation archiving: The sponsor system for maintaining the clinical trial master file (from before, during and after the trial) will be reviewed. The sponsor should also have a person appointed as responsible for trial archive.
The above areas are indicative of the types of areas examined during a GCP inspection of a non-commercial sponsor, however, additional areas may also be covered depending on the nature of the trial and the objectives of the inspection.