held responsible for the study being conducted in conformance with regulatory requirements including GCP.
Figure 11.1 Regulatory Authority’s interaction with other players.
11.5 Communication, Reporting, and Oversight
Communication is a key role for the regulator as well as the sponsor in terms of a successful CTA application and the regulators generally accommodate, in a reasonable manner, a variety of lines of communication including telephone conversations, letters, facsimile, online message, or meetings. Obviously, such communication will be consistent with the available technology as long as appropriate confidentiality is maintained. It is useful to remember that there is one regulatory authority serving a large number of sponsors/applicants so at times a queue may form. The responsibility for effective lines of communication is a shared one with the sponsor. The regulator must maintain a full and complete administrative record of their interactions with a sponsor if they are to be accountable for making decisions about such matters as starting a clinical trial in humans with a new investigational drug product or other investigational article. The content of the administrative records documenting communication may well be reviewed and evaluated by others and by panels of experts who might be called upon to assist the regulator at some point in making a decision impacting the application.
The regulator will usually identify one central point of contact (POC) for the applicant/sponsor. That POC will be organizationally located in a group which is responsible for such applications or in a group whose responsibilities are grounded in the area of therapeutic treatment being researched. That POC person or office serves as the gateway, either electronically or physically, for communications with the regulator. Regulators almost always enforce the use of a central POC or the potential for miscommunications and misunderstandings is magnified. The POC is not, however, the only person with whom the applicant’s staff will communicate. The regulator’s professional experts in topics such as chemistry, statistical analysis, safety evaluations, etc., will interact as needed with the sponsor’s counterparts but always working through or with the central POC. This approach ensures that the lines of communication remain centralized, complete, and up to date.
By ensuring the centralization of submissions and communications, the regulatory authority has in one place the body of information needed to conduct overall reviews and evaluations should it be necessary. Such evaluations might be needed if a safety issue arose or if a report, e.g. complaint of noncompliance with the protocol were received. ICH E6(R2) speaks to the regulatory authorities’ role in receiving and evaluating such reports especially as it relates to safety information. Most regulators have rules specifying the timing of serious and unexpected safety and adverse drug reaction reports. Such reports may generate additional communications between the regulator and the sponsor/applicant. It is essential that the regulator obtain and review the full body of information concerning adverse reactions which are serious and unexpected so they can weigh, along with the sponsor/applicant, whether the risks associated with the trial have changed and if that change warrants enrollment being halted.
There is a continuous and viable line of communication about the conduct of a clinical trial for which the regulator shares responsibility. This is not to imply that communication is daily or weekly, although that might occur from time to time, but the communication must be timely for the topic or issue at hand.
The regulatory authorities have through regulation and policy a responsibility to ensure that appropriate periodic reports are received from sponsors/applicants about the status of the clinical trial endeavor. These reports are usually termed progress reports and the review and evaluation of them is a role that the regulator is expected to perform. Depending upon the content, or lack thereof the regulator may need to consider some follow‐up action regarding the application. Progress reports must be adequate and complete since they represent a key component of the regulator’s oversight role in clinical trials. Such reports are usually required on an annual basis unless they are specified at different times. If required reports are not received or are found to be inaccurate or incomplete, the regulator may take steps to terminate the study or penalize the sponsor. In most such situations, the regulator, through its POC, will attempt to resolve such matters through communications both informal and formal and documented in the regulator’s file on the study.
Taking and documenting actions on an application throughout its lifecycle is expected of the regulator.
11.6 Inspections and Oversight
Most regulatory authorities will be performing inspections as part of their clinical trial oversight role. Some regulators have a defined responsibility for conducting inspections of clinical trial related, i.e. GCP activities during the time period that the study is underway and some do not.
Clinical trial activities can be inspected at any time; however, such inspections are usually not conducted on a routine or programmatic basis but generally are driven by events. One such event is the successful completion of the overall clinical study which results in the submission of a marketing application. Another is to follow‐up on reports of noncompliance or complaints which are received either from the sponsor or some other source knowledgeable about the study. The nature and scope of such inspections are covered in Chapter 34 Regulatory Authority Inspections in some detail but suffice it to say that if inspections are scheduled and conducted, they will be rigorous and demanding.
Regulators, having the decision‐making responsibility for applications, want to ensure they make valid, supportable, and accountable decisions. 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
