Clinical trials regulatory inspections

Regulatory authorities play an important and active role to ensure regulatory compliance in the conduct of a clinical trial. Agencies such as the FDA inspect clinical studies. An inspection of a trial may reveal that the protocol is not being followed strictly, the Investigator may not be involved with the project as much as is expected, there may be a lack of patient care, changes to the protocol may not have been relayed to the IRB, and so on. In such cases, corrective actions have to be implemented immediately and the FDA must be satished before the trial can continue. Deficiencies found are reported on Form 583. 

Most clinical trials have problems, sometimes detected by inspection and audit. These can usually be resolved and, if so, the regulatory submission must include a full explanation of how they were dealt with. Therefore, an audit trail with all the data should be available, accompanied by a statement by QA confirming that the procedures have been audited. 

The closing down of the clinical trial at the site after the last visit of the last study subject has finished and all the CRFs are completed is an important part of the clinical trial. The process of archiving the documentation, both at the site and at the sponsor office, needs to take place -ideally as soon as possible after the end of the clinical phase of the study. The effort required to do this well is very much less than that which will be required if deficiencies are identified later -particularly if that occurs during a regulatory authority inspection ... 

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. 

But DSHEA is very different then the standard approval process for drugs and medical devices, and emphasizes the regulatory enforcement of label claims and advertising and marketing issues rather than the efficacy and quality of the supplements themselves. Unlike new drug and medical device applications, controlled clinical trials aren t part of the supplement review process, nor is any FDA inspection of a company s manufacturing facilities or quality control systems. 

Every batch of clinical trial material is not necessarily included in stability studies however, because so many factors that can affect stability (e.g., formulation, manufacturing, container-closure) change during product development, many if not most clinical trial materials are included in some form of stability study. The results of the stability studies and the rationale for not conducting stability studies should be documented and organized appropriately in anticipation of regulatory review during pre-approval inspections (PAIs). 

This chapter will focus on some, but not all, of the areas in which the U.S. Food and Drug Administration (FDA) and the European Union (EU) regulatory authorities have attempted to coordinate their efforts to provide uniform rules and standards for the pharmaceutical industry. Specifically, we will review the efforts to harmonize approaches relating to inspections (including public disclosure of confidential information) and product approval or authorization (including clinical trials). While space limitations do not provide sufficient opportunity to describe each regulatory authority s system or the harmonization attempts in detail, it is our hope to provide some background of where the efforts are now, where the efforts are intended to go, and what we believe will be the results of these efforts. In addition, the author is much more familiar with the U.S. system than the EU system because of his experience and daily exposure with FDA, this chapter will focus more on the U.S. structure. 

The Clinical Trials Directive requires the integration of the GCP guidelines into the national law of all MS (which had not been the case in some MS before May 2004). Local regulatory authorities now carry the burden of inspecting for compliance with both GCP and the GMP guidelines for investigational drugs. Inspections take place at both sponsor s facilities and clinical trial sites. 

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 . 

The CA in whose territory the CT takes place enters the details into a new European Drug Regulatory Affairs Clinical Trial (EUDRACT) database. It allocates a unique EUDRACT number that cannot be reallocated to another trial if the original one does not proceed if an International Standard Randomized Controlled Trial Number (ISRCTN) is available, this detail is also entered. These EUDRACT entry data are accessible only to the CA, the EMEA, and the Commission and details the request for authorization, the protocol, any proposed protocol amendments, approvals by the CA and IEC, any suspension, the declaration at the end, and reference to any GCP inspections. 

Internal Audits (Self Inspection), Contract Manufacturers and Agents, Brokers, Traders, Distributors, Repackers and Relabelers. The section on APIs for Use in Clinical Trials clarifies the regulatory authorities expectations for drugs designated for clinical trials, as opposed to approved drugs manufactured on a routine production basis. 

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