UK MHRA Guidance: Clinical Trials for Medicines: Good Clinical Practice Inspections
Good clinical practice (GCP) is an ethical and scientific quality guideline concerning the design, conduct, analysis and reporting of clinical trials of medicines. The Clinical trials for medicines: Good clinical practice inspections guidance provides information on GCP compliance, inspection processes, inspection findings, corrective actions and post-inspection activities.
Compliance with Good Clinical Practice
Organisations involved in clinical trials are required to comply with GCP requirements. These include pharmaceutical companies, organisations providing sponsor or investigator services, universities, NHS hospitals, charities, GP practices and laboratories analysing samples from clinical trials.
Serious breaches of GCP or the trial protocol must be notified. Inspections may be conducted where serious breaches are suspected, as part of routine risk-based compliance activities, or in relation to clinical trials supporting marketing authorisation applications.
Risk-Based GCP Inspections
The majority of GCP inspections are conducted under a risk-based compliance programme. These inspections may be systems-based or trial-specific.
Systems inspections examine the systems used by an organisation to conduct clinical trial research. Inspectors may select clinical trials to assess how trial procedures are applied, and investigator sites may also be inspected.
Trial-specific inspections assess an individual clinical trial and may involve any organisation involved in the trial. These inspections may be routine risk-based inspections or relate to a trial submitted as part of a marketing authorisation application.
The risk assessment uses information available to determine organisational risk, including clinical trial applications, marketing authorisation applications, previous compliance and inspection history, organisational changes and external intelligence.
Triggered Inspections
An organisation may be contacted for an inspection when there is a suspicion that the law has been broken. Information leading to a triggered inspection may come from a serious breach notification, a whistleblower, other regulatory departments, regulatory intelligence or the Health Research Authority.
In rare circumstances, triggered inspections may be conducted with little or no advance notice.
Pre-Inspection Documentation
When an organisation is being considered for inspection, it will normally receive a notification requesting information through a GCP inspection dossier and clinical trials spreadsheet. These documents must be provided within 30 days.
The information is used to assess clinical trial activities, determine whether an inspection is required and identify the areas that may need examination.
Specific templates are available for standard GCP inspection dossiers and for organisations providing computerised systems in support of clinical trials.
Following review of the submitted information, an inspection date is agreed and details of the inspection team and practical arrangements are provided. In some cases, the dossier review may indicate that an inspection is not required.
The Trial Master File
The trial master file (TMF) forms the basis for inspection. All records contained in the TMF must be made available to inspectors, including electronic records and emails.
Organisations must provide the equipment and software required to access electronic records. Where multiple electronic systems make up the complete TMF, direct access must be available to each system.
Where clinical trial activities have been subcontracted to a service provider, the organisation must provide access to the relevant TMF and other records.
Failure to provide the TMF can affect the results of the inspection.
Inspection Planning
The inspection plan is based on discussions with the organisation and information provided in the GCP inspection dossier. Appropriate personnel should be available for interviews, either in person or by teleconference.
Inspectors may request additional supporting documentation, such as line listings, database extracts and floor plans. Requested documentation should be provided within the agreed timeframe.
The inspection plan may be adjusted to accommodate working patterns and immediate issues that arise during the inspection.
During the Inspection
The inspection includes interviews with relevant personnel and review of documentation, including the TMF. Organisations should be prepared to provide additional documentation when requested.
During an on-site inspection, inspectors may visit relevant departments as necessary.
Inspection Findings
At the end of the inspection, the inspector provides a verbal summary of the inspection findings. The organisation is allowed to identify and correct any misunderstandings.
The grading provided at the end of the inspection is provisional and may change when the inspection report is prepared.
Grading of Inspection Findings
Inspection deficiencies are graded into three levels: critical, major and other.
Critical
A critical finding may involve significant and unjustified departures from applicable legislative requirements where the rights, safety or well-being of trial subjects have been or have significant potential to be jeopardised.
Critical findings may also involve unreliable clinical trial data, multiple major non-compliances indicating a systematic quality assurance failure, or inappropriate, insufficient or untimely corrective action for previously reported major non-compliances.
Failure to provide a readily available, accessible and sufficiently complete TMF may also result in a critical finding where this prevents inspectors from verifying compliance.
Major
A major finding may involve a significant and unjustified departure from applicable legislative requirements that has not developed into a critical issue but has the potential to do so if not addressed.
Major findings may also arise where multiple departures from legislative requirements or established GCP guidelines occur within a single area of responsibility and indicate a systematic quality assurance failure.
Other
Another finding involves a departure from applicable legislative requirements, established GCP guidelines, procedural requirements or good clinical practice that does not meet the criteria for a critical or major finding.
Inspection Report and CAPA
The inspection report is provided to the organisation, which must respond to the findings through a corrective action and preventative action (CAPA) plan.
Depending on the findings, the organisation may also be required to complete an impact assessment or provide periodic reports on the progress of proposed CAPA actions.
The lead inspector may request additional clarification regarding the responses. Once adequate responses have been received, a GCP inspection statement is provided by email.
Actions After the Inspection
Critical findings are referred to the GCP Inspection Action Group. This cross-agency group oversees critical findings and considers actions in addition to reviewing CAPA activities.
Depending on the critical finding and its impact on public safety and data integrity, possible post-inspection actions include periodic reporting, early re-inspection and referral to relevant stakeholders or regulatory organisations.
Other possible actions include suspension of clinical trial authorisations, an infringement notice or prosecution.
GCP Inspection Metrics and Infringement Notices
GCP inspection metrics are produced to help identify areas where inspectors have found compliance problems during GCP inspections in the UK.
An infringement notice may be issued when serious or serious and persistent non-compliance with GCP requirements has been identified.
The available infringement information includes the organisation or person involved, the date issued, the reason and the status of the regulatory action.
Oversight and Monitoring of Clinical Trials
The guidance on oversight and monitoring of clinical trials is currently under review, with updated guidance to be posted to the clinical trials hub in due course.
Guidance is also available on oversight and monitoring processes, including risk-based monitoring.
On-Site Access to Electronic Health Records
The guidance covering on-site access to electronic health records by sponsor representatives in clinical trials is currently under review.
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