Ethics In Laboratory Medicine

Hippocratic Oath Today

The earliest codification of medical ethics in Western culture dates to the Hippocratic oath for physicians that originated in Greece in the fifth to third century BCE. The basic tenets of that oath are to treat patients appropriately and as best as can be done without harming them, to maintain patient confidentiality, and to teach the practice of medicine to ensuing generations of student physicians ( ; ). The original oath has been modernized, and some form of it is generally used in most medical schools. Schools of osteopathy have a similar osteopathic oath ( ). These oaths are highly relevant to ethics applied to the practice of laboratory medicine.

Regulations

Most individuals have an inherent sense of what constitutes ethical behavior, but to ensure that we operate at the appropriate and expected levels, the U.S. government has issued rules of such conduct. This discussion covers different regulations that are currently in effect for medical practice and human subjects research, with emphasis on issues that frequently arise in laboratory medicine.

Because these regulations are relatively new, having been produced in recent decades, they should be expected to evolve further, especially with regard to new therapies and their accompanying diagnostic procedures based on discoveries of molecular biology. Accordingly, medical practitioners should become familiar with current regulations and should be prepared to learn and follow new ones as they are enacted.

Human Subject Research

Modern ethics of research performed on human subjects came into being partly as a response to atrocities forced on prisoners by the Nazi regime of World War II. Revelations of these inhumane experiments occurred during the Nuremburg trials for war crimes.

The Helsinki Declaration adopted in 1964 by the World Medical Association and subsequently revised was an international effort to establish ethical principles for physicians performing medical research with human subjects or identifiable human material/data.

A comprehensive study by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research resulted in the Belmont Report (1978) that set the guidelines for ethical behavior in research. Three principles are elaborated in the Belmont Report ( Box 14.1 ):

• 1.

  Respect for persons. The principle of respect is embodied in obtaining informed consent from prospective subjects before they enter an experimental study. The informed consent document should be written in language appropriate for age and educational level. It should describe why the subject is being asked to participate in the research (e.g., if the subject has a particular disease which is being studied or if a subject is being recruited as a healthy control who does not have the disease) and what to expect in terms of experimental manipulations or treatments, known side effects of those actions, and what the subjects will be expected to do (e.g., time and effort to attend medical clinics for research purposes). It should be clear in the consent process that subjects are free to refuse participating and can leave the study at any time. Special provisions must be made for consent from children (including parental consent) and other vulnerable populations (e.g., pregnant women and their fetuses, mentally impaired persons, prisoners, or otherwise incapacitated individuals). Sometimes, an experimental design includes deception to study its effects. However, truthfulness is paramount to the informed consent process; thus, deception would be extremely unlikely to gain approval from a research review panel. Although written informed consent is the expected practice, oral consent with documentation can be used if keeping a record of the subject’s name could lead to embarrassment or other adverse consequences. Some research consists of potentially life-saving actions, such as at the onset of a heart attack, seizure, or trauma, in which a delay in treatment to fully explain the research to the subject (who might be unconscious) or relatives is not feasible because of the emergent medical condition. This type of research may be conducted as an Exempt From Informed Consent (EFIC) study without the usual written consent before initiating the experimental treatment, although written consent must be obtained subsequently from the subject or relative. EFIC studies should be extensively advertised and explained to the community where they will be conducted in advance of their approval.

• 2.

  Beneficence. Any experimentation performed on humans should carry the prospect of being good for the subjects. This principle excludes research that has the possibility of harm with no likelihood of good. Direct physical harm merely to study the result of that harm would be forbidden. Some research could potentially do harm to subjects, such as a trial of a new and unproven chemotherapy agent that has known toxicities but might have desirable antitumor effects based on preliminary research using animals or tissue culture models of the disease. Psychosocial research must build in safeguards when subjects could be frightened or alarmed by the research process, especially when deception might be part of the experimental design. Likewise, biomedical research should foresee probable or possible discomforts to subjects and take measures to minimize such effects.

• 3.

  Justice. This principle states that the subjects who are being experimented on should represent the population that is expected to benefit from products or treatments that might be developed based on experimental findings. Thus, it would be unethical to recruit subjects solely from low socioeconomic levels if the intended new treatment could be afforded only by wealthy people.

The Belmont Report and its principles form the basis for modern human subjects research, although it is not the actual law.

Development Of Federal Regulations For Human Subjects Research

The U.S. Public Health Service (USPHS) conducted observational experimentation on African-American males diagnosed with syphilis from 1932 to 1972. Termed the Tuskegee Health Survey, this study consisted of monitoring these men with regular physical examinations plus laboratory evaluation of blood and cerebrospinal fluid specimens to document the natural progression of syphilis, which was untreated in the study. This experimental design violated all three principles of the Belmont Report:

• 1.

  Whatever informed consent used was inadequate, as participants were deceived into thinking that their visits and the collection of specimens was therapeutic.

• 2.

  There was no beneficence, as the disease was not treated.

• 3.

  Surely, there was no justice in the study, as subjects with clearly diagnosed disease were denied standard-of-care treatment that would have cured them simply to study the progression of untreated syphilis.

When the nature of the Tuskegee study was made known publicly, the USPHS was in an indefensible position, which led to a complete overhaul of human subjects research and the development of a code of ethical behavior that is now in effect for approval and conduct of the research. These regulations are published in the code of federal regulations 45 CFR 46 and are referred to as the Common Rule, which is mandatory for human subjects research supported by the U.S. Department of Health and Human Services and has been adopted by other research entities as well.

This presentation will focus on guidelines for human subjects research in which laboratory professionals are likely to be engaged. The federal guidelines deal with some additional categories of research, such as taste testing and opinion surveys, that will not be considered here.

The definition of human subjects research is crucial to decisions about what studies require review and approval by a panel such as an institutional review board (IRB). All human subjects research receiving federal funding either directly or indirectly must have institutional review. IRBs at individual institutions are regulated, in turn, by the Office for Human Research Protection (OHRP) of the Department of Health and Human Services under Title 45 Code of Federal Regulations Part 46 (45 CFR 46).

Research consists of (1) a systematic investigation with (2) the intent of contributing to generalizable knowledge (45 CFR 46.102). Human subjects research meeting these two criteria requires IRB review of a study proposal before it is initiated. By federal code, each IRB has at least five members, with at least one member who works in scientific areas, at least one member whose primary concerns are in nonscientific areas, and at least one member not otherwise affiliated with the institution. Efforts should be made to avoid an IRB that is all men or all women. No IRB member may be part of the review of a project for which that member has a conflict of interest. IRB members must maintain current knowledge and certification with continuing education in human subjects research regulations.

Routine and usual laboratory practices—such as method validation for establishing standard procedures (e.g., when changing instrumentation to upgraded equipment), quality assurance (QA), and quality improvement (QI) studies—are not considered research (they are not intended to contribute new generalizable knowledge). Thus, they do not fall under IRB review. It is important to note here that the intent to publish, as stated in OHRP policy, is “an insufficient criterion for determining whether a project involves research.” Therefore, since QA and QI studies are not considered research, the results may be published without the need for IRB approval provided that all patient identifiers are removed so that results cannot be traced to any particular patients (see later discussion). Included in these QA studies would be results concerning mass analysis of patient values, such as running averages for specific analytes, in which there is no patient identification.

Waived and Expedited IRB Reviews: Discarded Specimens. There are situations in which it is desired to perform research studies on patient samples that would normally be discarded after a fixed period (usually 1 week for serum samples). These are so-called “discarded samples.” These studies must be submitted to an IRB. However, if the studies involve deidentification of all patient samples and fulfill other requirements of the IRB, special (or short) forms are given to the investigators to complete. The Chief Officer of the IRB and other senior IRB officials then evaluate the investigators’ filled out special forms. If these officials conclude that the forms are acceptable, one of two actions can then be taken. A waiver can be issued by the IRB exempting the study from any further IRB review or an expedited review can be performed. In case of the latter, approval is issued for 1 year for the study. For continuance of the study, the investigators must submit an annual review of their study and, if desired, request renewed IRB approval for another year.