The Fundamentals of Clinical Research. P. Michael Dubinsky

FDA’s review process of applications for permission or authorization to conduct clinical trials does provide a somewhat generic blueprint for application review.

      First a trial sponsor submits an application which is assigned to one of the three FDA headquarters’ offices:

      1 Center For Drug Evaluation and Research (CDER) – INDs

      2 Center for Biologics Evaluation and Research (CBER) – INDs and IDEs

      3 Center for Devices and Radiological Health (CDRH) – IDEs

      Each of the FDA Centers has a scientific technical group assigned to receive, review, evaluate, and decide on acceptability of the applications submitted.

There are procedural aspects of the review process that must be followed including timeframes for decisions. It is the responsibility of the FDA and all regulatory agencies to determine whether there is adequate information from nonclinical as well as clinical information about an investigational product to support the plan for the proposed clinical trial. Information about the manufacturing aspects of the investigational product as well as details about the investigation plan and the ethics review process is also included in the application. Part of the authorization decision by the FDA is determining whether the ethics review process for the planned study is already completed or a commitment is made to do so before enrolling any subjects. If a proposed trial is approved the sponsor is advised and periodic reports will be required. The number of trial sites along with the proposed number of subjects is, or becomes part of the application file as the study progresses.

      In the European Union, the application from the sponsor is evaluated by the individual member state’s health authority. So if trials are to be conducted in five of the member states applications must be submitted to each. There is no common application forum as with the US FDA using the IND format. This lack of a central clinical trial authorization process is an issue that is being addressed by EU authorities and is expected to be resolved with the advent and full implementation of the European Clinical Trial regulation [5]. The European Medicines Agency (EMA) does play a role in facilitating coordination among the member states for clinical trial matters, e.g. inspections, but it does not serve as a central reviewer providing mutually accepted decisions. This text will not attempt to outline the regulatory review processes for all regulatory authorities/competent authorities but rather to point out that they exist and are the players in the regulatory environment.

2.7 Academic Medical Centers (AMCs)

      What is an AMC and why do they fit in this matrix? The answer in part is found in the definition developed by the University of Pennsylvania – At an academic medical center, education, research, and clinical care are combined to provide the best possible clinical care, that uses cutting‐edge technologies, resources and therapies other community hospitals may not have available [6]. AMCs are often affiliated with a college or university which pursues human clinical research through commercial sponsors via government agency grants or on their own as sponsors. Such institutions have established the infrastructure necessary to navigate the Federal, State and if needed foreign regulatory pathways to conduct human clinical trials in full compliance with national and local laws as well as meet all ethical expectations. A title for such a group at an AMC might be Office of Research Conduct and Compliance.

Since an AMC is a hospital environment patients receiving clinical care may also be recruited into clinical trials. Researchers, whether independent or affiliated directly with the AMC must abide by all applicable regulations, codes, and ethical review expectations in order to draw on the resources of the institution. In addition, the researcher must follow the internal procedures established by the institution many of which may be more rigorous above the baseline regulations imposed by the regulatory authority. AMCs also have a substantive measure of enforcement powers or sanctions which can be brought to bear swiftly if a researcher violates commitments made to the AMC and/or the regulator. For example revocation of medical privileges, economic sanctions, or being denied the ability to continue enrollment in a trial are the types of actions an AMC can take to address bad behavior by a clinical researcher.

      AMCs also coordinate and support local IRB services in many cases so a researcher seeking to undertake a study can be directed to that resource. AMCs can be either nongovernmental or government affiliated. They wield important authority and impact in terms of ensuring that the Regulatory environment or matrix prevents uncontrolled human research study activity from occurring.

2.8 Professional Organizations

      Not every medical practitioner belongs to a professional organization but most of those who are providing services in conformance with local licensing and professional credentialing requirements do belong to one or more professional organizations. Primary examples are medical associations who affiliate locally, nationally, and worldwide. Examples are the World Medical Association which developed and regularly updates the Declaration of Helsinki, and the, World Health Association which has its own set of Good Clinical Practices utilized throughout the globe. Those organizations promote and expect their members to comply with ethical and regulatory requirements. With their membership layered from global down through local states, regions and countries any transgressions in the conduct of human biomedical clinical trials or experimentation would be quickly identified and made visible to appropriate authorities. The reach of the international organizations is especially important in developing countries where the regulatory scheme is less mature.

2.9 Summary

      There is no doubt that the primary force in the regulatory environment is the regulatory or competent authority. They are provided under law with the necessary authority to affect control over most clinical trial activities including evaluating compliance with GCP through laws, regulations, directives, and other legal instruments. There is a layering of this authority in many countries and regions. For example in the USA there are Federal and State authorities which may have a role depending upon the nature of the research. In the European Union, it would be the Central Government Directorates and the health ministries for the member states. Supporting the authorities are AMCs which work to ensure that clinical trials are conducted in conformance with requirements and ethical standards through their infrastructure. Professional organizations complete the regulatory matrix.

The regulatory matrix may be more complete in some parts of the globe than others but as a concept it continues to expand providing protection to subjects in human clinical trials and further ensuring the quality of data supporting application decisions.

      Knowledge Check Questions

      1 The regulatory matrix outlined in this chapter includes: Select all that apply____________ Regulatory authorities____________ Local Law enforcement organizations____________ Organizations that license/credential medical professionals____________ Standard setting organizations, e.g. ANSI____________ Academic Medical Institutions

      2 Regulatory authorities create, publish, and enforce codes or requirements governing the conduct of clinical trials. True or False?

      3 If a physician in the United States or an European Union member state was advertising for subjects to participate in a clinical research trial of an unapproved product without the approval of the regulatory authority what scenario do you think might occur once the regulatory authority (FDA or EMA) was alerted to the situation? (Brief narrative)

      4 A physician practicing at an AMC decides to participate in a clinical trial. Do you think the trial protocol and/physician will need to obtain any internal approvals as well as external approvals for permission to participate? Who might be the first to act if it is found that the trial is being performed in nonconformance with GCP?

      5 ICH E6(R2) E6 is considered a Guideline. True or False?

References

      1 1 EMA Scientific Guidelines http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000043.jsp&mid=WC0b01ac05800240cb