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Allan M. Green, MD,PhD,JD Neil Steinmetz, MD, JD |
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Original Business Thinking for the Life Sciences |
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Allan M. Green, MD, PhD, JD, LLC Attorney at Law |
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FDA Regulations for Clinical Investigators: A Summary |
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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.”18 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.19 These horrors and the less publicized biologic warfare experiments carried out by Japanese physicians during the war,20 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.21
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.22
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.23 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 1991.24 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 Rule25 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.
Although technically the Common Rule applies only to federally funded research, in practice it sweeps much more broadly. Institutions, such as hospitals, universities, and medical schools, are rightfully reluctant to accept the administrative overhead and moral and legal uncertainty related to having one set of ethical norms and procedures for federally funded research and another for privately funded research. Further, institutions filing written assurances with the DHSS must include a statement of principles governing the institution in the discharge of its responsibilities for protecting the rights and welfare of human subjects of research conducted at or sponsored by the institution, regardless of whether the research is subject to federal regulation.26
FDA jurisdiction over clinical investigation depends on the status and intended use of the product being studied and the intended use of the research results. The FDA regulates clinical studies of drugs under the investigational new drug (IND) process.”27 The agency regulates medical device studies under a more complex set of guidelines and regulations that may involve clinical data collection under IRB oversight alone or may add more formal FDA review under the investigational device exemption (IDE) requirements of the medical device amendments.28
Most clinical trials subject to FDA jurisdiction are privately funded and thus are not covered by the Common Rule; therefore the FDA has adopted its own rules for the protection of human subjects.29 Because the substance of the FDA regulations and the Common Rule overlap, they will be discussed together, with emphasis on the FDA version. Investigators and institutions receiving federal funds and conducting investigations subject to FDA regulation need to comply with both the FDA rule and the Common Rule.
The FDA and the pharmaceutical and medical device industries have coined the term “good clinical practice” to describe the federal regulations and the general principles of good scientific practice in the design of studies, the fair treatment of study subjects, the accurate recording of data, and the fair and complete analysis of data that govern clinical trials on humans conducted to support FDA applications.30 Good clinical practice implies that any procedures or assays performed during the course of clinical studies are validated and periodically checked for accuracy. In a real sense good clinical practice regulations impose the requirements of honesty, accuracy, and fair dealing on clinical investigators.
The FDA regulations create numerous specific obligations for sponsors, IRBs, and clinical investigators. FDA regulations on the “General responsibilities of sponsors” including physician-investigators sponsoring their own clinical studies note the responsibility of sponsors to select qualified investigators and to provide them with information needed to properly conduct the clinical trial.31 They also require the sponsor to monitor the study to ensure that the investigation is conducted in accordance with the general clinical investigational plan and protocols filed with the FDA. Finally, the regulations require the sponsor to notify the investigators and the FDA promptly of any significant new adverse events or risks associated with the study drug or device.
FDA regulations impose specific responsibilities on investigators.32 Studies must be conducted in accordance with relevant current protocols. Changes in the protocols may be made only after the sponsor and the IRB are notified, except where necessary to protect the safety, rights, or welfare of investigational subjects. The named investigator is expected to personally conduct or supervise the investigations. The named investigator also has the personal responsibility to ensure that appropriate (usually written) informed consent is obtained from study subjects in accordance with IRB requirements. Finally, the named investigator is obligated to ensure that all associates, colleagues, and employees are informed of their responsibilities with respect to the study.
The FDA also exerts jurisdiction over the use of radioisotopes in basic research, as distinguished from clinical trials, involving human subjects. Radioactive chemicals for research are recognized as safe and effective, and therefore exempt from IND requirements, only when they are used in accordance with regulations promulgated by the FDA.33 Prominent among these requirements is review of the research by a Radioactive Drug Research Committee composed and functioning in accordance with FDA requirements. Recently a major research university was threatened with loss of the right to use radioisotopes in research studies because of deficiencies of its Radioactive Drug Research Committee.34
IRBs
Responsibility for overseeing protection of research subjects centers on the IRB. An IRB is an appropriately constituted group that has been formally designated to review and monitor biomedical research involving human subjects. It has the authority to approve, require modifications to, or disapprove research. The purpose of IRB review is to ensure that appropriate steps are taken to protect the rights and welfare of research subjects. It must ensure that studies minimize risks to subjects by using procedures that are consistent with sound research design and that they do not unnecessarily expose subjects to risk. Risks to subjects must be reasonable in relation to anticipated benefits, if any, to the subject, and to the importance of the knowledge that may result. The selection of subjects must be equitable. Informed consent must be obtained from each subject or the subject’s legally authorized representative. There must be adequate provisions to protect the privacy of subjects and appropriate additional safeguards for vulnerable groups.
Most commonly the IRB is associated with the investigator’s institution, but this is not a requirement. Thus investigators in private outpatient practice may function under the umbrella of an IRB at a local hospital. An IRB may also be associated with a medical society, government agency, or commercial enterprise. In any case the IRB must be properly constituted, independent, and cognizant of local community norms.
The relationships among the research sponsor (drug or device manufacturer), the clinical investigator, and the IRB are complex. The sponsor and the clinical investigator are responsible for ensuring that a duly constituted IRB approves and oversees the research. The clinical investigator assures the sponsor in writing (on form FDA- 1572 for drugs and in the investigator agreement for devices) that the study will be reviewed by the IRB. The sponsor, in turn, assures the FDA of compliance by including the investigator’s assurance with its IND or investigational device exemption submission. A clinical investigator may serve as an IRB member but may not participate in the IRB’s initial or continuing review of any study in which the member has a conflicting interest except to provide information requested by the IRB.
INFORMED CONSENT
Informed consent has been famously described in legal prose as “the knowing consent of an individual, so situated as to be able to exercise free power of choice without undue inducement by any element of force, fraud, deceit, duress, or other forms of constraint or coercion.”35 The legal doctrine of informed consent has developed from the basic moral principal that it is wrong to force another to act against his or her will and from strong judicial deference toward individual autonomy in our society.36 This principle was articulated in the medical context by Justice Cardozo: “Every human being of adult years and sound mind has a right to determine what shall be done with his own body.”37
The consent doctrine was applied in the research context through the concept of the normal volunteer but has only recently been extended to the patient volunteer. The 1946 Nuremberg code stated that the voluntary consent of the human subject is absolutely essential to the fair and ethical conduct of human clinical studies. The code further states that the duty and responsibility to ascertain the quality of the consent rests on each individual who initiates, directs, or engages in the experiment. That formal responsibility typically resides with the physician responsible for the conduct of a clinical study.
Consent is more than just a signature on a paper; it is a process of information exchange that includes recruitment materials, written materials, verbal instructions, question and answer sessions, and measures of subject understanding. The signed consent form provides documentary evidence of this process. This distinction is important. For example, where research presents no more than minimal risk of harm to subjects and involves only procedures for which written consent is not normally required outside the research context, FDA requirements permit a waiver of written documentation of consent. Nonetheless, both FDA requirements and general principles of tort law-the body of law that covers issues related to negligence and its consequent damages in Anglo-American practice-require that each of the elements of informed consent be satisfied. When obtained, the written consent form should stand alone in the sense that it must be a comprehensive account of the dialog that has occurred.
Each principal physician investigator is responsible for the content of the consent form at his or her institution, although a commercial sponsor commonly develops a sample form for submission to the IRB. The consent form must be reviewed and approved by the IRB before commencement of a study. FDA regulations generally require use of a written consent form. When the study presents no significant safety risk and the IRB agrees, the elements of informed consent may be presented orally and patient consent obtained orally. If this oral form is used, the oral presentation must be witnessed, and the IRB must review and approve a written summary of the information to be presented.38
Consent documents for FDA-regulated studies must meet specific requirements.39 The consent form should be in language understandable to the subject. For non-English-speaking subjects either written or oral translation should be provided. Technical and scientific terms must be avoided or explained. The consent form must not include any exculpatory language requiring the subject to waive or appear to waive any legal rights or to release the investigator, sponsor, or institution from liability for negligence.40
Subjects are not in a position to determine whether they have been fully informed and thus should not be required to certify completeness of disclosure. Consent documents must not contain claims of effectiveness or overly optimistic representations that may unduly influence potential subjects. The consent form must neither claim nor imply that the FDA has officially approved the study or that an IRB has approved solicitation of subjects to participate in the research.
At a minimum, the consent form must cover each of the eight basic elements required by FDA regulation.41 It must inform the subject that the study involves research, provide an explanation of the purposes of the research, and include a description of procedures involved in the research. Any procedures relating solely to research such as randomization and placebo controls should be explained in terms understandable to a lay individual. Everything relative to a subject’s participation in the study including duration of the study, anticipated procedures, and required study visits should be explained. If a purpose of the study includes determination of the safety of the test article, this should be stated.
The reasonably foreseeable risks or discomfort of the study must be presented to the subject. Any previous adverse experience with the test article or similar articles should be mentioned. Risks associated with the administration of approved drugs used in a research study should also be noted. The explanation of risks should not minimize reported adverse effects. The risks of tests required in the study protocol should be explained, especially for tests that carry significant risk. However, it may be important to note even rare adverse events if they could be so serious as to enter into the judgment of a reasonable person as to the wisdom of participating in a study. The tragic death of a young volunteer in a seemingly benign study from an extremely rare allergic reaction to the fluorescein dye commonly used in ophthalmologic vascular exams was rendered more traumatic for the lack of inclusion of this risk on the informed consent she was given for review. Thus, the consent form for investigation of a proposed myocardial imaging agent requiring stress imaging during the early post-myocardial infarction period should describe the procedure and list both the risks of the imaging agent |
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