Allan M. Green, MD,PhD,JD
Neil Steinmetz, MD, JD
Human clinical investigation plays a central role in contemporary fact-driven medicine. It is a complex expensive endeavor triggering multiple responsibilities not otherwise encountered by physicians in clinical practice. Clinical investigators, drug and device manufacturers, hospitals and universities, governmental agencies, research subjects, patient advocacy groups, and investors all have a legitimate interest in the conduct and the outcome of clinical research. Past abuses of research subjects in many countries have raised ethical concerns that are now addressed by overlapping laws, regulations, guidelines, and institutional policies that have evolved to guide the research enterprise. The policies underlying this legal and regulatory structure include protection of research subjects, protection of the integrity of research design and research data, and protection of the public and private purse. Socrates famously remarked that “Virtue is Knowledge.” Knowledge of these laws and regulations is essential for health care professionals participating in clinical investigations to protect their professional and personal interests.
Medicine, founded and conducted on firm scientific principles, derives much of its legitimacy from the results of human clinical investigations. The value of routine medical procedures and the routine prescription of lawfully available medications has been secured by rigorous testing and validation through well-conducted human clinical studies. The rapid development of new therapeutic targets as a result of the completion of the human genome map and the availability of computer-driven robotic laboratory tools has led to an increasing demand for human clinical studies. Many physicians who have focused on patient care find themselves in the position of an investigator in a clinical study, often for the first time. Noting this trend, the Food and Drug Administration (FDA) has placed a renewed emphasis on educating and training clinical investigators.
Research activity is conducted in a variety of settings including university hospitals and medical schools, community hospitals, private offices and freestanding outpatient facilities. Modern research is a complex and expensive enterprise involving research subjects, clinical investigators, local institutions, sponsors, monitors, and government agencies. It is not surprising that a complex and overlapping set of laws, regulations, guidelines, and local institutional policies has evolved to guide the research process and define the responsibilities of and the relationships among the various parties. The primary goals of this legal structure are to protect the research subject, to ensure the integrity of research data, and to protect the public and private purse. This section of the chapter will review legal issues of particular interest to investigators conducting human clinical studies in the United States, with an emphasis on studies intended to support FDA submissions.
Legal analysis of the rights and responsibilities of participants in the research process begins with what are called “threshold” issues; that is, what activities are defined as human clinical research, what rules apply to specific research activities, and which agencies have jurisdiction over a clinical study. Any such discussion begins with a definition of research. It is important to distinguish between biomedical research and the practice of medicine. Physicians are given great latitude to use lawfully available drugs and medical devices in a manner that they believe is in the best interest of any particular patient. For the most part, the term “medical practice” refers to the use of interventions that are designed solely to enhance the well-being of an individual patient and that have a reasonable expectation of success. By contrast, the term “research” designates an activity designed to test a hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizeable knowledge. Thus when a clinician departs from standard or accepted practice, the innovation does not, in and of itself, constitute research. Many clinicians believe that new surgical procedures should be made an object of formal research at an early stage, but there is no legal obligation to do so. In general, however, if there is any element of research in an activity, the activity is subject to research rules. The term “research subject” encompasses normal volunteers, patient volunteers without potential personal benefit from the intervention, and patient volunteers who may potentially benefit from participation in a clinical study.
The distinction between research and medical care activities is particularly important in the context of determining coverage of patient care by third-party payers. Although certain experimental drugs are covered by insurance, particularly anti-cancer drugs under late stage development by the National Cancer Institute, many medical insurance plans exclude research procedures or unapproved drugs or devices from coverage. Physicians should understand that a patient who is involved in a formal “investigational” or “experimental” study of a medical procedure for research purposes might still be considered to be receiving “acceptable standard medical care” for the purposes of insurance coverage. As one court found, “The fact that treatment is administered as part of an experimental protocol designed to facilitate the collection of data does not necessarily mean that the treatment is, by definition, experimental.” Under the law definitions can be flexible to meet the purposes of public policy.
Protection of Human Subjects of Research
Public policy toward human clinical experimentation is rooted in recent history. The Nuremberg “doctors' trial” at the conclusion of World War II, in which prominent Nazi physicians were convicted of murder, torture, and other atrocities committed in the name of medical science, shocked the world. These horrors and the less publicized biologic warfare experiments carried out by Japanese physicians during the war, led to renewed interest in the ethics of human experimentation. Concern about these events and about the abuse of psychiatric treatments and institutions for political purposes in the Soviet Union culminated in international agreement on standards for human clinical studies expressed in the Declaration of Helsinki.
Abuses of human experimentation were not confined, unfortunately, to activities outside North America. Recently the United States government apologized to the families of individuals participating in the Tuskegee experiments in which syphilis was left untreated for years, ostensibly for the purpose of scientific study. Of particular concern to the nuclear medicine community were a series of experiments conducted during and soon after World War II involving injection of plutonium and other radioactive substances without the knowledge or consent of the research subjects.
The extensive protections afforded human research subjects in the United States today are derived from a set of basic ethical principles laid down in a document known as the Belmont report. These principles include respect for persons, beneficence, and justice. Respect for persons requires acknowledgment of individual autonomy and protection of those with diminished autonomy such as prisoners, children, and the mentally handicapped. Beneficence encompasses an ethical duty not only to do no harm but also to make efforts to secure the well-being of others. Justice encompasses a fair distribution of the benefits and burdens of research.
On the basis of these common principles, 16 federal departments and agencies adopted a single general set of regulatory provisions governing human subjects protection (the Common Rule) in 1991. The Common Rule applies to all federally funded research conducted both intramurally and extramurally. The Department of Health and Human Services (DHSS) version of the Common Rule requires that institutions receiving DHSS support for research involving human subjects provide written assurances of compliance to the DHSS describing the means they will use to comply with the DHSS regulations. The Office for Protection from Research Risks negotiates and approves these assurances. A research institution providing such assurances must delegate to its institutional review board (IRB) the authority to preclude or halt the conduct of any federally funded research project that does not conform to federal human subject protections. Central to these protections is the requirement for informed consent by research subjects before involvement in clinical research projects.