 Research
Issues Compendium Contents
Human Experimentation: An
Introduction to the Ethical Issues
In January 1944, a 17-year-old Navy seaman named Nathan
Schnurman volunteered to test protective clothing for the Navy.
Following orders, he donned a gas mask and special clothes and was
escorted into a 10-foot by 10-foot chamber, which was then locked
from the outside. Sulfur mustard and Lewisite, poisonous gasses
used in chemical weapons, were released into the chamber and, for
one hour each day for five days, the seaman sat in this noxious
vapor. On the final day, he became nauseous, his eyes and throat
began to burn, and he asked twice to leave the chamber. Both times
he was told he needed to remain until the experiment was complete.
Ultimately Schnurman collapsed into unconsciousness and went into
cardiac arrest. When he awoke, he had painful blisters on most of
his body. He was not given any medical treatment and was ordered
to never speak about what he experienced under the threat of being
tried for treason. For 49 years these experiments were unknown to
the public.
The Scandal Unfolds
In 1993, the National Academy of Sciences exposed
a series of chemical weapons experiments stretching from 1944 to 1975
which involved 60,000 American GIs. At least 4,000 were used in gas-chamber
experiments such as the one described above. In addition, more than
210,000 civilians and GIs were subjected to hundreds of radiation
tests from 1945 through 1962. Testimony delivered
to Congress detailed the studies, explaining that “these tests
and experiments often involved hazardous substances such as radiation,
blister and nerve agents, biological agents, and lysergic acid diethylamide
(LSD)....Although some participants suffered immediate acute injuries,
and some died, in other cases adverse health problems were not discovered
until many years later—often 20 to 30 years or longer.”1
These examples and others like them—such as the
infamous Tuskegee syphilis experiments (1932-72) and the continued
testing of unnecessary (and frequently risky) pharmaceuticals on
human volunteers—demonstrate the danger in assuming that adequate
measures are in place to ensure ethical behavior in research.
Tuskegee Studies
In 1932, the U.S. Public Health Service in conjunction
with the Tuskegee Institute began the now notorious “Tuskegee
Study of Untreated Syphilis in the Negro Male.” The study purported
to learn more about the treatment of syphilis and to justify treatment
programs for African Americans. Six hundred African American men,
399 of whom had syphilis, became participants. They were given free
medical exams, free meals, and burial insurance as recompense for
their participation and were told they would be treated for “bad
blood,” a term in use at the time referring to a number of ailments
including syphilis, when, in fact, they did not receive proper treatment
and were not informed that the study aimed to document the progression
of syphilis without treatment. Penicillin was considered the
standard treatment by 1947, but this treatment was never offered to
the men. Indeed, the researchers took steps to ensure that participants
would not receive proper treatment in order to advance the objectives
of the study. Although, the study was originally projected to last
only 6 months, it continued for 40 years. Following
a front-page New York Times article denouncing the studies
in 1972, the Assistant Secretary for Health and Scientific Affairs
appointed a committee to investigate the experiment. The committee
found the study ethically unjustified and within a month it was
ended. The following year, the National Association for the Advancement
of Colored People won a $9 million class action suit on behalf of
the Tuskegee participants. However, it was not until May 16, 1997,
when President Clinton addressed the eight surviving Tuskegee participants
and others active in keeping the memory of Tuskegee alive, that
a formal apology was issued by the government.
While Tuskegee and the discussed U.S. military experiments
stand out in their disregard for the well-being of human subjects,
more recent questionable research is usually devoid of obvious malevolent
intentions. However, when curiosity is not curbed with compassion,
the results can be tragic.
Unnecessary
Drugs Mean Unnecessary Experiments
A widespread ethical problem, although one that
has not yet received much attention, is raised by the development
of new pharmaceuticals. All new drugs are tested on human volunteers.
There is, of course, no way subjects can be fully apprised of the
risks in advance, as that is what the tests purport to determine.
This situation is generally considered acceptable, provided volunteers
give “informed” consent. Many of the drugs under development
today, however, offer little clinical benefit beyond those available
from existing treatments. Many are developed simply to create a patentable
variation on an existing drug. It is easy to justify asking informed,
consenting individuals to risk limited harm in order to develop new
drug therapies for a condition from which they are suffering or for
which existing treatments are inadequate. The same may not apply when
the drug being tested offers no new benefits to the subjects because
they are healthy volunteers, or when the drug offers no significant
benefits to anyone because it is essentially a copy of an existing
drug. Manufacturers, of course, hope that animal
tests will give an indication of how a given drug will affect humans.
However, a full 70 to 75 percent of drugs approved by the Food and
Drug Administration for clinical trials based on promising results
in animal tests, ultimately prove unsafe or ineffective for humans.2
Even limited clinical trials cannot reveal the full range of drug
risks. A U.S. General Accounting Office (GAO) study reports that
of the 198 new drugs which entered the market between 1976 and 1985,
102 (52 percent) caused adverse reactions that premarket tests failed
to predict.3 Even in the brief period between January
and August 1997, at least 53 drugs currently on the market were
relabeled due to unexpected adverse effects.4
In the GAO study, no fewer than eight of the drugs
in question were benzodiazepines, similar to Valium, Librium, and
numerous other sedatives of this class. Two were heterocyclic antidepressants,
adding little or nothing to the numerous existing drugs of this
type. Several others were variations of cephalosporin antibiotics,
antihypertensives, and fertility drugs. These are not needed drugs.
The risks taken to develop these drugs by trial participants, and
to a certain extent by consumers, were not in the name of science,
but in the name of market share.
As physicians, we necessarily have a relationship
with the pharmaceutical companies that produce, develop, and market
drugs involved in medical treatment. A reflective, perhaps critical
posture towards some of the standard practices of these companies—such
as the routine development of unnecessary drugs—may help to
ensure higher ethical standards in research.
Unnecessary
Experimentation on Children
Unnecessary
and questionable human experimentation is not limited to pharmaceutical
development. In experiments at the National Institutes of Health
(NIH), a genetically engineered human growth hormone (hGH) is injected
into healthy short children. Consent is obtained from parents and
affirmed by the children themselves. The children receive 156 injections
each year in the hope of becoming taller.
Growth hormone is clearly indicated for hormone-deficient
children who would otherwise remain extremely short. Until the early
1980s, they were the only ones eligible to receive it; because it
was harvested from human cadavers, supplies were limited. But genetic
engineering changed that, and the hormone can now be manufactured
in mass quantities. This has led pharmaceutical houses to eye a
huge potential market: healthy children who are simply shorter than
average.
Short stature, of course, is not a disease. The problems
short children face relate only to how others react to their height
and their own feelings about it. The hGH injection, on the other
hand, poses significant risks, both physical and psychological.
These injections are linked in some studies to a potential
for increased cancer risk,5-8 are painful, and may aggravate,
rather than reduce, the stigma of short stature.9,10
Moreover, while growth rate is increased in the short term, it is
unclear that the final net height of the child is significantly
increased by the treatment.
The Physicians Committee for Responsible Medicine
worked to halt these experiments and recommended that the biological
and psychological effects of hGH treatment be studied in hormone-deficient
children who already receive hGH, and that non-pharmacologic interventions
to counteract the stigma of short stature also be investigated.
Unfortunately, the hGH studies have continued without modification,
putting healthy short children at risk.
Use of Placebo in Clinical
Research
Whooping cough, also known as pertussis, is a serious
threat to infants, with dangerous and sometimes fatal complications.
Vaccination has nearly wiped out pertussis in the U.S. Uncertainties
remain, however, over the relative merits and safety of traditional
whole-cell vaccines versus newer, acellular versions, prompting the
NIH to propose an experiment testing various vaccines on children.
The controversial part of the 1993 experiment was
the inclusion of a placebo group of more than 500 infants who get
no protection at all, an estimated 5 percent of whom were expected
to develop whooping cough, compared to the 1.4 percent estimated
risk for the study group as a whole. Because of these risks, this
study would not be permissible in the U.S. The NIH, however, insisted
on the inclusion of a placebo control and therefore initiated the
study in Italy where there are fewer restrictions on human research
trials. Originally, Italian health officials recoiled from these
studies on ethical as well as practical grounds, but persistent
pressure from the NIH ensured that the study was conducted with
the placebo group.
The use of double-blind placebo-controlled studies
is the “gold standard” in the research community, usually
for good reason. However, when a well-accepted treatment is available,
the use of a placebo control group is not always acceptable and
is sometimes unethical.11 In such cases, it is often
appropriate to conduct research using the standard treatment as
an active control. The pertussis experiments on Italian children
were an example of dogmatic adherence to a research protocol which
trumped ethical concerns.
Placebos,
Ethics, and Poorer Nations
The ethical problems that placebo-controlled trials
raise are especially complicated in research conducted in economically
disadvantaged countries. Recently, attention has been brought to studies
conducted in Africa on preventing the transmission of HIV from mothers
to newborns. Standard treatment for HIV-infected pregnant women in
the U.S. is a costly regimen of AZT. This treatment can save the life
of one in seven infants born to women with AIDS.12 Sadly,
the cost of AZT treatment is well beyond the means of most of the
world’s population. This troubling situation has motivated studies
to find a cost-effective treatment that can confer at least some benefit
in poorer countries where the current standard of care is no treatment
at all. A variety of these studies is now underway in which a control
group of HIV-positive pregnant women receives no antiretroviral treatment.
Such studies would clearly be unethical in the U.S.
where AZT treatment is the standard of care for all HIV-positive
mothers. Peter Lurie, M.D., M.P.H., and Sidney Wolfe, M.D., in an
editorial in the New England Journal of Medicine, hold that
such use of placebo controls in research trials in poor nations
is unethical as well. They contend that, by using placebo control
groups, researchers adopt a double standard leading to “an
incentive to use as research subjects those with the least access
to health care.”13 Lurie and Wolfe argue that an
active control receiving the standard regimen of AZT can and should
be compared with promising alternative therapies (such as a reduced
dosage of AZT) to develop an effective, affordable treatment for
poor countries.
Control Groups and
Nutrition
Similar ethical problems are also emerging in nutrition
research. In the past, it was ethical for prevention trials in heart
disease or other serious conditions to include a control group which
received weak nutritional guidelines or no dietary intervention at
all. However, that was before diet and lifestyle changes—particularly
those using very low fat, vegetarian diets—were shown to reverse
existing heart disease, push adult-onset diabetes into remission,
significantly lower blood pressure, and reduce the risk of some forms
of cancer. Perhaps in the not-too-distant future, such comparison
groups will no longer be permissible. The
Ethical Landscape
Ethical issues in human research generally arise
in relation to population groups that are vulnerable to abuse. For
example, much of the ethically dubious research conducted in poor
countries would not occur were the level of medical care not so
limited. Similarly, the cruelty of the Tuskegee experiments clearly
reflected racial prejudice. The NIH experiments on short children
were motivated to counter a fundamentally social problem, the stigma
of short stature, with a profitable pharmacologic solution. The
unethical military experiments during the Cold War would have been
impossible if GIs had had the right to abort assignments or raise
complaints. As we address the ethical issues of human experimentation,
we often find ourselves traversing complex ethical terrain. Vigilance
is most essential when vulnerable populations are involved.
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References
1. Frank C. Conahan of the National Security and International
Affairs Division of the General Accounting Office, reporting to
the Subcommittee of the House Committee on Government Operations.
2. Flieger K. Testing drugs in people. U.S. Food and Drug Administration
Home Page; http://www.fda.gov/fdac/special/newdrug/testing.html
(10 Sept 1997).
3. U.S. General Accounting Office. FDA Drug Review: Postapproval
Risks 1976-85. U.S. General Accounting Office, Washington, D.C.,
1990.
4. MedWatch, U.S. Food and Drug Administration. Labeling changes
related to drug safety. U.S. Food and Drug Administration Home Page;
http://www.fda.gov/medwatch/safety.htm (10 Sept 1997).
5. Arteaga CL, Osborne CK. Growth inhibition of human breast cancer
cells in vitro with an antibody against the type I somatomedin receptor.
Cancer Research 1989;49:6237-41.
6. Pollak M, Costantino J, Polychronakos C, et al. Effect of tamoxifen
on serum insulin-like growth factor I levels in stage I breast cancer
patients. J Natl Cancer Inst 1990;82:1693-7.
7. Stoll BA. Growth hormone and breast cancer. Clinical Oncology
1992;4:4-5.
8. Stoll BA. Does extra height justify a higher risk of breast cancer?
Ann Oncology 1992;3:29-30.
9. Kusalic M, Fortin C. Growth hormone treatment in hypopituitary
dwarfs: longitudinal psychological effects. Canad Psychiatric Asso
J 1975;20:325-31.
10. Grew RS, Stabler B, Williams RW, Underwood LE. Facilitating
patient understanding in the treatment of growth delay. Clin Pediatrics
1983;22:685-90.
11. For a more extensive discussion of the ethical status of placebo-controlled
trials see especially: Freedman B, Glass KC, Weijer C. Placebo orthodoxy
in clinical research II: ethical, legal and regulatory myths. J
Law, Medicine & Ethics 1996;24:252-9.
12. Lurie P, Wolfe SM. Unethical trials of interventions to reduce
perinatal transmission of the human immunnodeficiency virus in developing
countries. N Engl J Med 1997:337:12:853.
13. Ibid, 855.
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