The International Conference on Harmonization/Good Clinical Practice E6 (ICH GCP) lays out clear expectations for both the sponsor and investigators for compliant trial conduct. These guidelines cover compliance with GCP and with the applicable regulatory requirements to ensure that procedures related to clinical trials are followed. The guidelines encompass data recording and processing to ascertain if essential documents are maintained in a way that permits events that occurred at the trial to be re-created. This oversight also serves to preserve the safety, wellbeing, and rights of trial participants, as well as the trustworthiness of the data collected.
It is an outstanding achievement for an organization to be inspection-ready according to Good Clinical Practices (GCP). All biopharma organizations strive for this outcome since it leads to a stronger opportunity for a successful inspection.
Certainly, the best way to maintain readiness for an inspection – whether a routine compliance check or a “for cause” visit triggered by regulatory concerns – is to establish an ongoing surveillance program. While we strongly recommend continuous monitoring to maintain compliant status, in practice, this often represents a challenge. Other priorities take precedence based on risk assessments that are not aligned with the inspection risk.
Understanding Readiness from a Regulatory Standpoint
What does “inspection-ready” mean to GCP inspectors? What does a GCP inspector expect from you to be considered inspection-ready?
In addition to producing a logistic inspection plan where all the main aspects are covered, starting with internal and external communications, gathering Subject Matters Experts, preparing storyboards, and conducting mock inspections, the confirmation that all processes, procedures, documents, and data collected from the beginning to the end of the study or, in a determined period, are GCP compliant is crucial.
Knowing How an Inspection Might Be Conducted
From the standpoint of a regulatory authority, organizations must be inspection-ready at any time. Inspections can be unannounced, and during their course, the objective is to verify that your processes and systems are compliant with regulatory obligations supporting the safety and wellbeing of trial participants and that the data is reliable.
GCP inspectors employ different approaches depending on the procedures of the regulatory authorities they represent. However, all of them will verify your compliance status on GCP and other applicable regulations during the inspection.
In an actual inspection scenario, GCP inspectors might look into the following processes, for example:
- Quality management system (QMS): Distribution of standard operating procedures (SOPs), control and training of clinical trial personnel and relevant vendors, policies, and quality manual.
- Contract management and outsourcing: Vendor selection process and oversight to ensure that all the delegated activities are aligned with the protocol and the QMS, including communication and escalation of events, and that actions have been appropriate.
- Clinical trial setup: Fundamentals from clinical trial operations, documentation, support, and oversight of the vendors used, in addition to any investigation on clinical trial site qualifications, insurance liabilities, protocol amendments, regulatory compliance, and training at clinical sites.
- Clinical monitoring: Documentation and processes from monitoring plan, selection, qualification, and training of monitors, issues escalation, and medical monitoring, including participation in committees for protocol deviations and assessments of potential serious breaches.
- Safety in clinical trials: Management of safety information, reconciliation of adverse events, case management, source documents, reporting of cases to regulatory authorities; implication on investigator brochure, as well as its distribution and reference safety information (RSI).
- Data management (DM): Database management, locks and unlocks, interim analysis, data traceability, non-CRF data importation, data transfer agreements, access, user privileges, and interaction with biostatistics.
- Statistics: Setup and statistical analysis, population, protocol deviations, and impact on the analysis.
- TMF: System functionalities, validation, data migration, quality and completeness of the documentation, audit trail, and oversight.
- This aspect represents a critical piece in inspections for European GCP inspectors.
- Investigational product: Manufacturing, shipment, handling, Interactive Voice/Web Response System (IXRS), administration to the trial participant, inventory and accountability, and special attention to any issue related to medication withdrawal, shortage, and temperature excursions.
- Data transfers to DM or biostatistics, depending on protocol design: Transfer of data from committees including the Independent Data Monitoring Committee (IDMC), Data & Safety Monitoring Board (DSMB), and International Data Review Center (IDRC).
- The medical writing function: The interaction between medical writing and relevant actors at the sponsor level.
- This is crucial for inspectors, especially if there have been inaccuracies in protocols or clinical study reports (CSR) due to an inadequate QA/QC process.
- Components used in a decentralized approach: All technology-related and patient-centric features.
- If the trial uses a hybrid approach, these relevant features will be of interest for inspection.
Of course, the inspection scope will differ depending on how it has been “generated.” If there is a concern regarding the assessment of the clinical trial or dossier (“for-cause” inspection), the inspection will be much different from surveillance of GCP compliance (routine inspection). Inspection readiness “status” is very much evident in a for-cause inspection when the actual trigger(s) is in the inspection focus.
Overcoming Challenges in Preparing for an Inspection
In summary, inspection readiness is more than a temporary or isolated effort to prepare for a pending inspection. On the contrary, it is a continuous, ongoing program that requires a commitment to steadily maintaining high-quality, GCP-compliant processes and deliverables.
For a small or midsize organization – or even for a larger enterprise with a sizable development pipeline and a registered product – the costs and time involved might be daunting. Using external resources with regulatory intelligence and insights can be a valid option. The ideal point to engage outside assistance is at the outset of the trial so that deficiencies can be corrected or prevented on an ongoing basis to ensure inspection readiness at any time.
When this is not possible and an inspection is imminent, a risk-based assessment tailored to your trial will show the areas where deficiencies are likely to be uncovered during the inspection. Needless to say, the latter scenario is not ideal, illustrating the importance of being prepared. However, a solid risk assessment will allow you to implement minimization measures in advance.
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