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2 Regulatory Environment

       P. Michael Dubinsky

      GCP Key Point

       Regulatory authorities along with medical institutions and professional groups form a network of controls which set the boundaries for human biomedical clinical trials thereby ensuring that GCP is followed.

2.1 Introduction

      Is it idealistic to think that all clinical research whether commercial, academic, governmental or otherwise will be conducted under ethical guidelines and according to best scientific and professional practices such as GCP? Unfortunately idealism has not always been the guiding force in human biomedical research and along the way governmental and professional oversight has been implemented to ensure that abuses are avoided. This chapter explores the regulatory environment that has evolved to oversee human biomedical clinical trials.

2.2 Objective

      To describe the nature and scope of controls that are in place to ensure that human biomedical clinical trials are conducted in a manner which ensures the protection of human subjects participating in them and the scientific integrity of the trial plan. Understanding the nature, scope and reach of the regulatory controls as well as their enforceability is essential to applying the GCP principles.

2.3 Regulatory Matrix

      The regulatory environment within which human biomedical clinical trials are conducted is a matrix composed of: (i) the policies, laws, and regulations which describe the requirements and guidance; (ii) the governmental jurisdictions (Federal, State, Country, Region e.g. EU) which are responsible for implementing the requirements through regulatory authorities; (iii) nongovernmental organizations, e.g. Academic Medical Centers (AMCs), which both sponsor clinical trials and set their own internal standards for how clinical trials will be conducted; and (iv) the professional organizations (e.g. WHO, WMA) which support, define, and interpret the requirements, standards, and guidelines for their professional members.

      It is not always clear whether this matrix works together under a planned scenario but the end result is that if a commercial sponsor, medical establishment, or individual practitioner wishes to conduct experimental biomedical studies in humans, that activity receives considerable oversight and review. There are complexities which the regulatory environment matrix introduces to the conduct of clinical trials; therefore it is important to understand the makeup of the regulatory environment. For example conducting trials in conformance with ICH E6(R2) does not guarantee that a trial meets all of the applicable regulatory standards called for by the country or region where the study is performed but it is probable that the use of the those guidelines would ensure that 90% or more of applicable requirements will be met.

Let us begin the examination of the regulatory environment by reviewing each of the four part matrix as depicted in Figure 2.1.

2.4 Laws, Regulations, and Policies

The enforceable requirements governing human biomedical clinical trials are found in the written laws (statutes) and implementing regulations. These laws and regulations, which are based on governmental policies provide the societal backbone for the authorities to regulate and affect control over human biomedical clinical trial activities. The laws are written by the elected legislatures which in the United States is the Congress. Congress is composed of the Senate and House of Representatives. The laws are passed by the Legislature, i.e. Congress and approved by the President and as needed interpreted by the US Supreme Court. Laws however are very high level statements and call for implementing details. Once in place, USA laws are implemented by the executive departments who report to the President. In the United States, the Federal Food Drug and Cosmetic Act (FFDCA) is a primary governing statute and the implementing regulations are developed/written by staff in the Food and Drug Administration (FDA) which is part of the Department of Health and Human Services (DHHS). The regulations are memorialized in the US Code of Federal Regulations (CFR). Regulations are developed according to the Administrative Procedures Act of 1946 (APA) which calls for agencies such as the FDA/DHHS to (i) keep the public informed of their organization, procedures and rules; (ii) provide for public participation in the rulemaking process; (iii) to establish uniform standards for the conduct of formal rulemaking and adjudication; (iv) to define the scope of judicial review. The rules developed pursuant to the APA have the force and effect of law, i.e. they are enforceable. There are sanctions and penalties if the rules are not followed.