The Fundamentals of Clinical Research. P. Michael Dubinsky

Inspections are a mechanism of oversight that regulators use to aid in ensuring that clinical trial activities being conducted in their jurisdiction are performed in compliance with the investigational plan, the regulations, and GCP. Inspections can have a number of outcomes but it is important to keep in perspective that unlike audits conducted by a sponsor’s quality assurance staff, an inspection which documents significant noncompliance can result in legal/administrative penalties or sanctions being applied. The regulatory authorities have a responsibility to act on significant noncompliance in part to punish and in part to demonstrate that such behavior will not be tolerated.

      Regulatory authority inspections of clinical trial activities are not mandated in all global regions or countries. For example, GCP inspections became a responsibility for EU member states when the EU Clinical Trial Directive 2001/20/EC became effective in 2004. In the United States, GCP inspections are authorized but not mandated by law or regulation. Whether mandated or not, inspections are a key role performed by regulators as part of their oversight activities. Inspections which are GCP in nature include inspections of trial sponsors, investigational sites, and institutional review boards. Inspections of the manufacturing of investigational articles may also be conducted but they would be categorized as GMP inspections. Inspections of animal and in‐vitro studies supporting CTAs are inspected but are categorized as Good Laboratory Practice (GLP) and are not addressed in this text.

      With regard to investigator sites, regulators depend in large measure upon sponsors to serve as the primary go‐between with sites during the course of a study unless it becomes apparent that the sponsor is not exercising control over the site(s). If the application involves an investigator‐sponsor, then the situation is different; however, most of the discussion points above would apply since that person is also the sponsor. The one area of difference would be the matter of inspections. Regulators recognize that the investigator sites are where all of the key steps associated with the trial occur. Drug is administered, adverse reactions are recorded and reported, records are made and maintained, and subjects are given informed consent. Therefore, it is the inspections of sites where regulators spend the bulk of their available inspectional time when it comes to GCP compliance. Regulators will want to interact directly with the principal investigator at a site if they are aware of, or document noncompliances at the site. Clinical investigators are viewed as having a direct responsibility to ensure conformance with the protocol, the applicable regulations, and GCP at their site. Admittedly, they work through the sponsor on critical items such as reporting serious unexpected adverse reactions; however, the regulators usually have some administrative or legal mechanism available to bring to bear against noncompliant investigators. Administrative provisions granting regulators the ability to put clinical holds in place, disqualify clinical investigators, terminate sites, or limit enrollment are tools that regulators have available if serious noncompliance is documented during inspections.

11.7 Summary

      In this topic area, we have outlined the roles and responsibilities of the regulatory authority within the context of the GCP Guidelines. It is meaningful to keep in perspective that while the regulatory authority is a player in the clinical trial process, as defined in GCP and has roles and responsibilities, it (the regulator) is not in large measure the focus of the GCP requirements.

      The responsibilities of the regulatory authority are founded in law, regulations, and directives and are carried out by governmental agencies or their designees. It is the role of the regulatory authority to act as a gatekeeper, overseer, and evaluator using the legally mandated requirements including GCP.

      The regulatory authority has a responsibility to be accountable for its actions through documentation, transparency, and clear communications with sponsors, investigators when appropriate, and IRBs/IECs.

      Knowledge Check Questions

      1 A primary role/responsibility of the regulatory authority is to review clinical trial applications and then advise the independent ethics Committee whether the trial can begin. True _____ or False____?

      2 Regulatory Authorities are called upon to inspect the ICH as well as sponsors and clinical trial sites. True_____ or False______?

      3 Unlike the quality assurance audits conducted by clinical trial sponsors, the inspections conducted by regulators can result in enforcement action if: 1) the inspection uncovers significant noncompliance:_____; 2) The sponsor or site refuses to allow inspection______; or 3) The sponsor or site has made significant changes to the study plan without notifying the regulator____; 4) all three situations apply.

      4 Communication between the sponsor and the regulator is essential. The regulator will therefore provide the sponsor with several – up to five – points of contact (POCs) within their organization who can be contacted about important changes to the clinical trial plan. Correct? If not how many are considered acceptable?

      5 You have recently been hired by a large pharmaceutical drug manufacturer to oversee several of their clinical trial projects. Upon reviewing your assigned projects, you determine that the annual reports to regulators are overdue for every one of the trials. What steps should you be taking on an immediate basis? Prepare a brief plan to serve as an agenda for your meeting with your supervisor and/or the regulatory authority.

Part IV Individual Clinical Trial