Clinical research is a complex, multidisciplinary industry that integrates science, business, law, ethics, and health care. It is regulated by multiple government agencies and is conducted for a variety of purposes. As such, the roles of individuals within the industry are diverse and multifaceted. However, overall, the clinical research environment is divided into four areas that have distinct but overlapping responsibilities and goals. These areas or roles include regulatory agencies, sponsors, investigators, and ethical/institutional review boards (IRBs). Each encompasses a scope of responsibilities intertwined with regulations, ethics, best practices, and professional standards.
This book focuses on the operational conduct of clinical trials at the research site for the purpose of collecting data on the safety and efficacy of new investigational products, which will, in turn, be submitted to the Food and Drug Administration (FDA) by a sponsor for marketing approval. These clinical trials are often referred to as industry-sponsored studies because pharmaceutical or device companies “sponsor” research to prove the safety and effectiveness of their products in anticipation of marketing the product to the public. The purpose of this chapter is to review the rules, standards, regulations, and best practices that are part of good clinical practices (GCPs), then to explore the roles and responsibilities of sponsors, investigators, and ethical review boards (or IRBs) as they relate to the conduct and operations of industry-sponsored clinical trials.
Good clinical practice, or GCP, is a combination of standards, regulations, guidance documents, and best practices that, when combined, ensure the ethical and scientific conduct of clinical trials. In this book, we focus on FDA regulations and guidance documents, Office for Human Research Protections (OHRP) regulations and guidance documents, and International Conference on Harmonisation (ICH) guidelines, as we discuss GCP related to conducting clinical research.
Although the U.S. FDA’s regulatory functions began with the passage of the 1906 Pure Food and Drugs Act, its current name and regulatory functions were officially established under the Federal Food, Drug, and Cosmetic Act of 1938. The Act was passed as a direct reaction to the Elixir Sulfonamide Tragedy in which more than 100 children and adults ingested a sweet-tasting elixir that had been sold as a drug but which also contained antifreeze. Their deaths spurred legislation toward the oversight of various drugs. Besides bringing cosmetics and medical devices under its control, the Act required premarket approval of all new drugs, mandating that a manufacturer would have to prove to the FDA that a drug was safe before it could be sold. Section 505(i) of the Act gives the FDA authority for oversight of clinical investigations to test for safety and effectiveness of investigational products.
Today, the FDA regulates food, drugs, biologics, medical devices, electronic products that emit radiation, cosmetics, veterinary products, and tobacco. Of specific relevance to this book is the FDA oversight of drugs, biologics, and medical devices in issuing regulations that permit and govern the investigational use of drugs and devices to determine their safety and effectiveness before approval or clearance. Title 21 of the Code of Federal Regulations focuses on the FDA regulations relevant to market approval. These regulations include the following:
21 C.F.R. Part 312: Investigational New Drug Application
21 C.F.R. Part 812: Investigational Device Exemptions
21 C.F.R. Part 50: Protection of Human Subjects
21 C.F.R. Part 11: Electronic Records, Electronic Signatures
21 C.F.R. Part 54: Financial Disclosure by Clinical Investigators
21 C.F.R. Part 56: Institutional Review Boards
As part of its approval of medical products, the FDA regularly performs inspections of research sites to ensure compliance to GCP. At these inspections, the FDA inspector reviews and discusses his/her findings with the investigator and the research team. If deficiencies are found, they are summarized on a form entitled “Inspectional Observations,” otherwise known as a Form 483
). Inspections are conducted through the FDA’s Bioresearch Monitoring Program (BIMO) for the following reasons:
To verify the accuracy and reliability of data that have been submitted to the agency;
As a result of a complaint to the agency about the conduct of the clinical trial at a particular research site;
In response to sponsor concerns;
Upon termination of the research site;
During ongoing clinical trials to provide real-time assessment of the investigator’s conduct of the trial and protection of human subjects;
At the request of an FDA review division; and
Related to certain classes of investigational products that the FDA has identified as products of special interest in its current work plan (i.e., targeted inspections based on current public health concerns) (U.S. Department of Health and Human Services [HHS], FDA, 2010a, p. 3).
Inspections, audits, monitoring visits, and corrective action plans will be explored further throughout the book but will be emphasized in Chapter 6
The OHRP is part of the Office of the Assistant Secretary for Health within the U.S. Department of HHS. It is tasked with overseeing compliance related to the rights of human subjects of research conducted or supported by HHS under Section 289 of the Public Health Service Act. Specifically, OHRP oversees the regulations codified in 45 C.F.R. Part 46, Protection of Human Subjects, informally known as the “Common Rule,” and research that is conducted or supported by various government agencies or departments that have adopted the Common Rule.
The Common Rule applies to all research involving human subjects that is conducted or supported by HHS (grants or other funding mechanisms) or is conducted in an institution that has agreed to assume responsibility for the research in accordance with HHS regulations, regardless of the source of funding. It was published in 1991 and adopted by 15 Federal departments and agencies. These agencies have adopted section numbers and language that are identical to those found in the HHS regulations, codified as 45 C.F.R. Part 46, subpart A (U.S. HHS, n.d.). This section outlines the basic provisions for IRBs, informed consent, and Assurances of Compliance. An example of a clinical trial that OHRP would oversee might include a human subject clinical trial comparing the nutritional benefit of carrots versus broccoli, sponsored by funding through the Department of Agriculture (as a department that has adopted the Common Rule).
The Common Rule is based on the “Ethical Principles and Guidelines for the Protection of Human Subjects of Research,” otherwise known as the Belmont Report (Appendix A
). The ethical principles of respect for persons, beneficence, and justice found in the Belmont Report underpin the concepts of informed consent, subject benefit and risk, and fair distribution found within the regulations. The Common Rule is found in the following regulatory citation:
Although the regulations found in 45 C.F.R. Part 46 are very similar to those found in 21 C.F.R. Part 50, the OHRP and the FDA each has different scopes and oversight. The FDA’s scope is aligned with the purpose of medical product approval for marketing, and the OHRP oversees research conducted or sponsored by government agencies or departments that have adopted the Common Rule. However, there may be times when a clinical trial may fall under both 45 C.F.R. Part 46 and 21 C.F.R. Part 50. As an example, the National Cancer Institute may sponsor a clinical trial in collaboration with a pharmaceutical company that is in the midst of conducting studies under an Investigational New Drug (IND) application for the drug. In this case, the research site is obligated to follow both sets of regulations.
Similar to FDA inspections, the OHRP conducts inspections through its Division of Compliance Oversight. The OHRP will conduct a for-cause inspection in response to receipt of “substantive written allegations or indications of noncompliance with HHS regulations” from research subjects, institutional officials, or others who may have concerns in regard to compliance with Title 45 regulations under the OHRP jurisdiction (U.S. OHRP, 2009).
The ICH evolved from a meeting held in 1990 to explore the possibility of “harmonizing” pharmaceutical regulations throughout Europe, Japan, and the United States. The objective of the resulting E6 Guideline for Good Clinical Practice is to provide a “unified standard for the European Union (EU), Japan a...