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2 Human Subjects and Diagnostic Genetic Testing - Learn Science at Scitable PDF
2 Human Subjects and Diagnostic Genetic Testing - Learn Science at Scitable PDF
There is a vital need for human subjects in research related to drug development, but can we
properly balance the welfare of human research subjects with the need for experimental
data?
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Medical and psychological studies involving human subjects remain a critical factor in advancing our scientific knowledge. Despite historical episodes of
tragically unethical treatment of humans in the name of medical science, such as the Tuskegee study, the need for human subjects in biomedical
research is vital for the development of any new drug. But how can we balance the welfare of human research subjects with the need for valuable data
from human experimentation? Several solutions to this conundrum have been proposed, but none is without its flaws.
The initial aim of the Tuskegee Study of Untreated Syphilis in the Negro Male, as it was known, was perfectly legitimate: to gather medical knowledge.
However, during the mid-1940s, when penicillin had been shown to be a highly safe and effective cure for syphilis infection, the researchers did not
abandon the study, but continued to subject their unwitting participants to painful complications and death due to syphilis infection until 1972, when a
story about the study appeared in the national press. Public outcry caused an abrupt end to this research, followed by the filing of a class action lawsuit
against the U.S. government on behalf of the survivors.
Of course, a great deal of research and testing occur before drugs are subject
to clinical trial. First, after basic research and screening, promising
substances are moved into the development stage. While in development, the
drugs are tested in vitro. The next step involves preclinical trials, in which a
drug's effectiveness and toxicology are established in animal models, like
mice. Following successful animal studies, the substance is moved through
three phases of clinical testing that involve human subjects. The first phase
establishes the metabolism and the side effects of the drug treatment; the
second phase gauges the efficacy of the treatment; and the final stage
evaluates the overall risk-benefit ratio.
Figure Detail
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When the tragic ethical misconduct of the Tuskegee study came to light in the 1970s, it highlighted the importance of clearly defined regulations on
human testing. Thus, on July 12, 1974, the National Research Act was signed into law, thereby creating the National Commission for the Protection of
Human Subjects of Biomedical and Behavioral Research. The Belmont Report of 1979 is a summary of the Commission's recommendations. This
report is a statement of basic principles and guidelines to assist in resolving the ethical problems that surround the conduct of research with human
subjects. One of the major outcomes of this document was the mandate of institutional review boards (IRBs) for any federally funded research program
involving human subjects.
As previously mentioned, the purpose of an IRB is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the
rights and welfare of humans participating as subjects in a research study. Every institution intending to carry out research involving human subjects
must establish a committee of at least five members with expertise in science, ethics, and other nonscientific areas to serve as an IRB. IRBs evaluate
proposed research protocols to verify that they are scientifically sound and meet all legal and ethical standards. These boards can approve, disapprove,
or modify any research protocol and must conduct reviews of approved research protocols at least yearly (U.S. Department of Health and Human
Services, 2004). All IRBs must be registered with the Office for Human Research Protections (OHRP) within the U.S. Department of Health and Human
Services (HHS).
Informed Consent
A key requirement for IRB approval of human research is to obtain informed consent from all study participants. Informed consent is not just a form; it is
a process. Information must be presented to the participation candidates to aid their voluntary decision of whether or not to take part in the research
(U.S. Department of Health and Human Services). At a minimum, consent documents should include the following:
Providing such thorough background and guidelines to study participants ensures mutual collaboration and minimizes the risks associated with
uninformed consent.
The FDA recognizes that there are individuals with serious or life-threatening diseases or conditions who lack any alternative treatments. In an effort to
help such individuals while still maintaining the integrity of the scientific process that brings new drugs to the market, the FDA has made significant
regulatory changes to its policy in recent years to make investigational therapies more widely available (U.S. Food and Drug Administration, 2008).
Proposed in 2006, these changes attempt to increase awareness in the health care setting of the availability of investigational drugs, and to encourage
drug companies to make the products available to patients by allowing recompense for the provision of the drugs to such programs.
An alternative to this scenario is one in which full disclosure of all test information is permitted by the study subject. An example of this is the
Personal Genome Project (Harvard University), an open-ended research study that aims to improve our understanding of genetic and environmental
contributions to human traits. To that end, this study recruits volunteers who agree to the collection of full genomic sequence data and other personal
information to be shared with the scientific community and the general public. One goal of the project is to improve the understanding of
personal genomics and its potential use in the management of human health and disease.
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More recently, the question of financial interests influencing risky research protocols has come to the forefront with the death of 18-year-old gene
therapy study volunteer Jesse Gelsinger in 1999 (News Weekly, 2000). Gelsinger was involved in a trial that aimed to demonstrate the use of a
viral vector in replacing a defective ornithine transcarbamylase gene. Unfortunately, he died of major organ failure due to a massive immune response
to the viral vector. Amid accusations of undisclosed risks and possible side effects that might have stopped the study before Gelsinger's death, the FDA
temporarily halted all such studies while the NIH conducted thorough reviews of all adverse reactions and deaths associated with gene therapy trials.
Future scientific experiments will test medical treatments that are outside the scope of modern testing standards; therefore, these experiments will
undoubtedly prompt further modifications to the current regulations that ensure the well-being of human research subjects. Throughout this process of
evolution, however, the protocol for using human subjects in medical trials will most certainly continue to be tightly regulated.
Lee, M., & Clark, C. California Lawmakers want to stop human pesticide testing. SignOnSanDiego.com (2005) (accessed on September 29, 2008)
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: Ethical principles and
guidelines for the protection of human subjects of research. (National Institutes of Health Office of Human Subjects Research, 1979) (accessed on
September 29, 2008)
News Weekly. Bioethics: Gene therapy business: The tragic case of Jesse Gelsinger. (2000) (accessed on September 29, 2008)
Office of Human Subjects Research. Directives for human experimentation: Nuremberg Code. Reprinted from Trials of War Criminals before the
Nuremberg Military Tribunals under Control Council Law 10(2), 181–182. (U.S. Government Printing Office, Washington, D.C., 1949) (accessed on
September 29, 2008)
Pritchard, J. F., et al. Making better drugs: Decision gates in non-clinical drug development. Nature Reviews Drug Discovery 2, 542–553 (2003) (link to
article)
U.S. Department of Health and Human Services. U.S. Office for Human Research Protections. (accessed on September 29, 2008)
———. Guidelines for the conduct of research involving human subjects at the National Institutes of Health. (2004) (accessed on September 29, 2008)
U.S. Food and Drug Administration. Recruiting study subjects. (1998) (accessed on September 29, 2008)
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