The United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) is renowned and feared for its high expectations regarding the Trial Master File (TMF). MHRA expects your TMF to be “the story of how the trial was conducted and managed.” Given the MHRA’s expectations, it is no surprise that the TMF is well represented among the findings outlined in their GCP Inspections Metrics Report for 88 GCP inspections conducted between April 2017 and March 2018. At LMK, we have reviewed the findings and summarized what we have identified as this year’s most critical TMF conclusions.
MHRA defines a critical finding as one where “evidence exists that significant and unjustified departure(s) from applicable legislative requirements has occurred with evidence that the rights, safety or well-being of trial subjects either has been or has significant potential to be jeopardized, and/or the clinical trial data are unreliable and/or there are a number of Major non-compliances….across areas of responsibility, indicating a systematic quality assurance failure, and/or where inappropriate, insufficient or untimely corrective action has taken place regarding previously reported Major non-compliances…. or where provision of the TMF does not comply with Regulation 31A 1-3, as the TMF is not readily available or accessible, or the TMF is incomplete to such an extent that it cannot form the basis of inspection and therefore impedes or obstructs inspectors carrying out their duties in verifying compliance with the Regulations.”
Three out of twelve commercial sponsors had at least one critical finding falling under pharmacovigilance, false and misleading information, and/or data integrity. A total of 12 non-commercial organizations were inspected, and of the 12 inspections, 3 had at least one critical finding. Critical findings include investigational medicinal products, clinical trial authorization, and GCP Compliance. Seventeen investigator sites were inspected and oversight of the sites by the sponsor/CRO was the main focus for these inspections. Of the 17 inspections, 1 had data integrity critical findings. On the other hand, CRO’s and Phase 1 Units/Clinical Research Units had no critical findings.
MHRA defines a major finding as “a non-critical finding where evidence exists that a significant and unjustified departure from applicable legislative requirements has occurred that may not have developed into a critical issue, but may have the potential to do so unless addressed, and/or where evidence exists that a number of departures from applicable legislative requirements and/or established GCP guidelines have occurred within a single area of responsibility, indicating a systematic quality assurance failure.” Other findings are defined as “Where evidence exists that a departure from applicable legislative requirements and/or established GCP guidelines and/or procedural requirement and/or good clinical practice has occurred, but it is neither Critical nor Major.”
One hundred percent of both Commercial Sponsors and Non-Commercial Organizations had major/other findings. The 2 top major inspection findings for commercial sponsors included record keeping/essential documents and quality system (including SOPs and document control). Non-Commercial Organizations’ major findings included the organizations’ oversight of clinical trials leading, quality assurance, and pharmacovigilance.
A total of 10 CROs had systems inspections conducted. Vendors of electronic systems and niche providers of services used in clinical trials (aside from clinical conduct of a trial) are included in this category. 80% of CROs had major findings and the top 3 major findings included record-keeping/essential documents, data integrity control processes, and computer validation. Of the nine Phase 1 Units/Clinical Research Units inspections, half had at least one major finding. Major findings included recording keeping/essential documents, quality system (including SOPs and document control), and quality assurance. Lastly, over 60% of Investigator Sites had at least one major finding. Over 55% of Investigator Site inspections reported CRF data/source data stood out as a major finding. Other findings included staff delegation and responsibilities, protocol compliance, medical oversight by the principal investigator, IMP management/pharmacy, and data integrity.
Overall, the MHRA report shows a general improvement following the introduction of statutory GCP inspections. This current report presents a downward trend for Commercial Sponsors and CROs, as far as the severity of findings. Investigator sites trended in the opposite direction, with a significant increase in findings, which is thought to be the result of increased use of electronic medical records and other sponsor provided electronic source data/CRF systems. MHRA’s focus on the TMF is not meant to place a greater burden on those who conduct clinical research but stems from a clear truth: a healthy TMF is the basis of a compliant trial.
Read the GCP Inspections Metrics Report Here: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/884154/GCP_INSPECTIONS_METRICS_2017-2018_final_04-05-20.pdf