Clinical studies/trials audits

Quality assurance activities actually begin early in the drug development process—in the analytical phase. United States requirements5 are established as early as non-clinical laboratory studies. At this early phase, the audit program concentrates on in vivo and in vitro experiments, focusing on early drug entities. These drug entities are tested under laboratory conditions to determine their potential safety risk. At this phase, human subjects (e.g., clinical studies) or field trials in animals are not involved. 

In contrast to GLP regulations, GCP does not require an audit for all trial reports. The number of report audits may depend on the audit plan, the importance of the trial for a regulatory submission and the confidence in the procedures followed for evaluating clinical study data and writing reports, just to name a few. 

The FDA plays a major part in the prevention and detection of research fraud and misconduct. The FDA carries out two different types of reviews. Study-orientated audits are conducted on clinical trial data itself, in order to ensure patient eligibility, and investigator-orientated inspections can be carried out either routinely or because a sponsor has concerns. If the inspectors have reason to believe that a site has not complied with regulatory requirements or has engaged in fraudulent activity - for which the definition in the Federal Code is very similar to that of the Wellcome Trust - they have the power to disqualify the investigator from taking part in further research, or severely restrict his activities. Such findings are widely publicized both within and outside the United States on the so-called Black List . 

Most centers or offices have access to a wide network of inspectors. These inspectors operate worldwide, and audit both animal and clinical studies, as well as manufacturing processes and premises. Such audits can be for cause , e.g. a complaint from the public or an emergent safety issue, or routine . Pivotal clinical trials in a submitted NDA or BLA will usually garner an inspection of the clinical trials sites and statutory documentation. 

CRAs achieve these tasks through frequent visits to the clinical trial site. During these visits, the monitor will verify source data, audit regulatory documents for accuracy and completion, perform drug accountability assessments, and communicate any concerns, problems, or new information with the study staff. 

The new European Directive (2001/20/EC) has reinforced the need for European agencies, as well as those of the United States and Japan, to conduct inspections of clinical trials. Sponsors, mindful of the implications of failed inspections, are carrying out audits by their QA units to try to ensure that standards at a particular site meet the regulatory requirements of GCP, and of any future regulatory inspection. Frequently, the inspections will occur 2 or more years after the end of the study. 

The new GCP requires that sponsors shall compile plan and operating procedures on auditing and implement auditing in conformity with the plan and the procedures, thus auditors audit not only the sponsor s in-house process but also processes at study sites. Within the sponsoring company, usually aU CRFs and study reports are subject to the audit. Study sites are selected for audit based on auditors SOP, usually based on sampling methodology. Audit certificate for each clinical trial is required to be incorporated into new drug submission dossier. 

Before 1990, clinical trials conducted in Russia were characterized by a number of peculiarities. Many trials had no protocol and were carried out following the recommendations of the MOH. No ethics committees existed. There was no communication between the sponsor and the investigator, and the latter had no idea about the monitoring or audits, as if no such things existed. Moreover, the clinical data (study reports) would go directly to the Pharmacological Committee without being circulated to the sponsor. 

Post-marketing surveillance studies, pharmacoeconomic studies, non-interventional trials, clinical audit programmes and the like, which have been commissioned, undertaken or provided by companies, must never be promotional in nature and must be conducted primarily with a scientific or educational purpose. This clause does not preclude the use of the data generated from such studies to support claims in promotion. 

For example, first-in-man studies and pivotal trials are more likely to be audited than phase IV trials, and external providers selected for the first time who are responsible for key areas in clinical trials should be audited with a higher priority than CROs with a long history and reliable performance. 

Trial-related audits focus on a particular trial to assess compliance with the protocol, with related SOPs and applicable GCP regulations. Of particular interest is how trial participants are informed of the trial, the study activities conducted at the investigator sites and the procedures of clinical data handling, recording, processing, analysis and reporting. 

Complete, consistent and accurate trial documentation is the basis for any inspection by regulatory authorities or sponsor/client audit and is a proof that the study was conducted according to GCP regulations, the trial protocol and SOPs. The TMF plays a vital role in providing confidence to auditors and inspectors that the clinical data are valid and that the trial was conducted properly. 

The study report is the essence of the clinical trial and summarizes trial data and their interpretation. Since trial reports are part of the package submitted to regulatory authorities for obtaining marketing authorization, the contents must be valid, complete and accurate. Trial report audits verify that all necessary components and attachments are included in the report. Ideally, the last draft version is subject to audit, thus avoiding rework which may be necessary after audits of early drafts which are substantially changed until they are considered final. In addition, all QC checks and activities should have been completed prior to the audit. 

Systems audits in this late phase in clinical trials aim at assessing related procedures to ensure that capable procedures exist for managing and cleaning clinical trial data, for conducting statistical analyses and for preparing the final study report which represents properly the data collected and reported in the clinical trial. Such systems audits are performed across functional boundaries. Such systems audit can be combined with a database audit and/or an audit of the final study report. 

For this reason, it is remarkable that, in many cases, clinical pharmacists lead the follow-up process for the clinical trials. It was in a pharmacy-promoted audit that a serious deviation in GCP recommendations was detected. In this study, it was concluded that compliance was adequate in 50% of protocols, so-so in 25% of cases, and poor in the remaining 25%. Surprisingly, in 13% of the patients, the informed consent document was not signed in 15% of the cases, the patient s clinical records did not reflect that the patients were included in a clinical trial. 

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