- Posted By: Joanna Black
Objectives for the day were to provide feedback on the QA Sub-groups activity since Nov 2013 especially GCP for laboratories undertaking analysis on samples; to understand the scope and nature of audit activity across the Network; to learn about audit programmes within CTUs and training for staff who perform audits. Jason Wakelin-Smith, a MHRA GCP Inspector joined the group to give an update on the implementation of the CT Regulation and talked about Laboratory specific Inspections and provided feedback of specific CTU MHRA Inspections findings. This blog will focus on the laboratories and MHRA update.
Guidance on CTU Oversight of Laboratories (by Simon Kerridge from Oxford Vaccine CTU):
Training should be proportionate to role for pathology laboratories performing standard tests, there should be no requirement to provide CVs or evidence of GCP training to CTUs for all laboratory staff; study specific training should be provided (using the study laboratory manual where available) for processes that are not standard laboratory practice (e.g. sample identification, reporting or study specific assays); the laboratory ‘research champion’ should receive detailed GCP training; laboratory staff performing assays for primary and secondary endpoints should receive laboratory GCP training and study specific training.
NHS laboratories performing standard assays may only require demonstration of functional quality management systems via evidence of accreditation PLUS triggered audit/monitoring following incidents. Where laboratories are making significant contributions to primary and secondary objectives further evidence to support the quality of results will be required (e.g. monitoring, self evaluation questionnaire, audit).
Jason Wakelin-Smith observed that there is a significant push by non-commercial organisations to use a CTU if sponsorship is to be undertaken; there is a difference in the quality of trials conducted by CTUs when compared to individual investigator led trials; there is a push by organisations to become ‘national centres of excellence’. He also commented that CTUs are becoming more like specialist CROs and working in partnership with a number of organisations.
The MHRA have implemented a Clinical Laboratories project to identify laboratories which are performing analysis of samples in support of clinical trials. Their purpose is to identify and collate data on the laboratories involved in the analysis of samples from human clinical trials with the aim of giving the MHRA a more comprehensive understanding of these laboratories. This information will be incorporated into the Risk Based Inspection system and laboratories will be inspected on a risk based approach. Laboratories performing routine safety analysis of blood samples will not be inspected but the MHRA will inspect laboratories that perform end point analysis including: Pharmacodynamics; Pharmacokinetics; Histology; Immunology; Bioanalysis; Biomarkers. A request for information letter is going to be sent to an initial group of organisations involved in clinical trials that use laboratories for sample analysis or if you organisation don’t receive such a letter they are required to complete the information on-line.
Recent Inspection findings from CTUs:
Topic - Data Integrity:
On a particular study there was a change of measure of response published so trial data was amended to include this new criteria. Response was re-assessed by the CTU (rather than a physician) but inconsistencies were found between the publication and the assessment. Findings were associated with: No SOPs; No peer review or QC ; No training (despite complex re-assessment); Queries not always raised when unsure; Responses from queries not always reviewed; Poor documentation of work undertaken.
Topic - Computer Systems Validation:
Historic processes for computer system development, testing and release failed to ensure that databases were adequately tested and released prior to use despite systems continuing to be used. The database had not been validated prior to use despite the SOP in place at the time. It was noted that financial reasons may have impacted on the selection and validation of this system. There was no documentation to support the validation, testing and release of systems.
Topic -Data Management:
There were no formalised QC processes associated with data management activities. It was noted that QC was carried out in an ad-hoc manner but varied between trials and were generally not documented. CRFs could be emailed or faxed to the trial offices in the event of short timelines being in operation but there was no process to ensure that the email copies were checked against the hard copy when received to ensure that there were no discrepancies. There was no process or requirement for supporting documentation to support data management activities undertaken leading up to an interim data analysis snapshot being taken.
Topic –Monitoring:
Monitoring activities appeared to be determined by available finance rather than risk. General lack of monitoring. Frequency and timing of visits. Visit reports (timeliness of reporting, review and close out). Oversight of outsourced monitoring. Issue escalation. What does ‘Central Monitoring’ mean and how is it executed?
Other Common Topics: Quality Systems -Insufficient for the work undertaken. Pharmacovigilance - General lack of understanding of Expectedness assessments and inconsistency; timeliness of reporting; Time zero and Reference safety information. Insurance - Doesn’t cover the trial being undertaken (e.g. drug being used, countries used, protocol compliance exclusion); duration. Lack of Contracts; timeliness and vendor oversight.
A lot of food for thought.