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Research on Human Subjects – Part 1 (Paul Raymont, August 2009)

The Kantian concern to avoid the instrumentalization of persons is evident in the ethical
protocols for research involving human subjects. The upshot of these protocols is that
even in the context of a research program, healthcare professionals must continue to work
primarily for the benefit of the human subjects in the study and must not think of human
research subjects as if they were mere objects to be manipulated and used for some
scientific purpose.

Ethical guidelines for research involving human subjects were developed in the wake of
World War II in response to the atrocities committed by the Nazis and by the Imperial
Japanese. Both parties had conducted obviously unethical research during the war (and
before it in the case of Japan) which involved deliberately producing illness in human
subjects and even killing people. Clearly, in these studies, researchers instrumentalized
the human research subjects; that is, they treated these subjects as mere means to some
desired research outcome. For example, in Japan Dr. Shiro Ishii was in charge of Unit
731, which committed atrocities while carrying out research on germ warfare and
chemical weapons in China (which Japan had invaded before WWII). These atrocities
included deliberately exposing Chinese people to the bubonic plague, cholera and
anthrax, dissecting people while they were alive, spinning people in a centrifuge until
they died, etc. After the war, some of Dr. Ishii’s researchers were convicted of war crimes
by the Soviet Union. Dr. Ishii himself was never brought to justice. Instead, the American
General MacArthur granted Ishii immunity in exchange for data from the Japanese
research. (The Japanese government finally acknowledged the existence of Unit 731 in
1998, although – as the linked article indicates – Japanese courts didn’t acknowledge its
existence until 2002.)

As a result of German and Japanese atrocities, the Nuremberg Code was instituted in
1948. This code included such directives as the following for research on humans:

1. voluntary, informed consent from the research subjects is required;

2. avoid unnecessary physical and mental suffering;
3. no experiment should be conducted where there is reason to expect death or
disabling injury;
4. scientists must terminate a study if they have probable cause to believe that it
will result in injury, disability or death.

The emphasis in the Nuremberg Code is on the duty of non-maleficence. This is a

negative duty – specifically, it is the general duty not to harm people.

Unfortunately, even after these guidelines were formulated many unethical studies
involving human subjects were carried out in various countries, including Canada and the
USA. For example, there was the case of Dr. Ewen Cameron, a prominent psychiatrist
who treated patients in Montreal. He received funding from a CIA program called MK-
ULTRA, the purpose of which was to develop mind-control techniques (‘brainwashing’).
Between 1950 and 1964, Cameron experimented with the methods that he called ‘de-
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patterning’ and ‘psychic driving’, by means of which he attempted to erase large portions
of a patient’s personality and replace them with ‘healthier’ character traits and attitudes.
Cameron’s methods included the use of sleep deprivation, sensory deprivation, massive
and repeated electric shock treatments (beyond what was then considered to be normal in
treating depression), LSD and other experimental drugs, and drug-induced comas. In
1988, the CIA gave Cameron’s victims $67000 each in compensation for this abuse. In
1994, the Canadian government (which knew of and also funded Cameron’s work) gave
$100 000 to seventy-seven of Cameron’s victims. These people were deemed to have
suffered the most since Cameron had reduced them to a ‘childlike state’. (Our
government denied compensation to more than 250 other patients of Cameron’s, although
one, Janine Huard, who had been ‘treated’ by Cameron for post-partum depression, won
an out-of-court settlement from the Canadian government in June, 2007.)

In the USA, there was the Tuskegee study. Between 1932 and 1972 a government agency
funded the Tuskegee study of untreated syphilis in Alabama. In this research, 399 poor,
rural, African-American men who had syphilis were not informed of their condition by
their physicians. Their physicians compared them with a control group of 204 men who
were receiving treatment for syphilis. The study continued even after 1947, when
penicillin had been adopted as the standard treatment for syphilis – the men were still not
informed of their diagnosis and so were not offered penicillin. Chillingly, one of the
administrators of the study in the 1940’s was quoted by James Jones as saying, “The
men’s status did not warrant ethical debate. They were subjects, not patients; clinical
material, not sick people.”

In the Tuskegee case, the researchers claimed that they had done nothing unethical on the
basis that they hadn’t actually harmed any of the men with syphilis. In short, went their
argument, those men still would have suffered from syphilis even if the research trial had
not been conducted.

We can see why this response fails to exonerate the researchers when we consider the
professional obligation of healthcare professionals (including physicians) to help their
patients as best they can. This brings us to another important duty, this time a positive
obligation called the duty of beneficence, which is the general duty to bring aid and
assistance to those in need. In the context of healthcare, this becomes the duty to provide
the best known treatments and care to one’s patients; in other words, one must not
provide known inferior treatments.

Beneficence is more prominent in a newer set of international guidelines for research

ethics, the Declaration of Helsinki (1964). Among its guidelines are the following:

1. the interests of science and society should never take precedence over
considerations of the well-being of a human research subject;

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2. every patient (inc. those in a control group) should be assured of the best
proven diagnostic and therapeutic method.

In short, researchers must not compromise their human subjects’ care for the sake of
some perceived greater good. Put this way, the Nuremberg and Helsinki codes seem to be
anti-utilitarian, since they prohibit the sacrifice of human individuals for a (perceived)
greater good such as a new cure for a disease. Thus, even if we could cure cancer by
running research trials that involved harming (or at least not helping) some cancer
patients, we still should not do so.

The duty of beneficence underlies an important ethical principle that applies specifically
to research on human subjects, the principle of clinical equipoise. According to
equipoise, we may give experimental treatment X to some patients and compare it to
treatment Q (either a placebo or a currently accepted standard treatment) only if there is
no consensus in the relevant community of experts to the effect that one of these
treatments is better than the other. If there were such a consensus favouring, say, X, then
it would be unethical to give Q to anybody in the research trial; for to give people Q
would be to give them a known inferior treatment, thereby failing to uphold the duty of
beneficence. Roughly, then, we can go ahead and give X and Q to various participants in
the study only if the experts are poised equidistant between X and Q (in the sense that
they are neutral between the two treatments, seeing neither of them as being superior to
the other).

New drugs are tested against either a placebo or the current standard treatment for the
illness in question. The people in the ‘control group’ receive the placebo or (if there is
one) the current standard treatment.

It is because of beneficence that it is increasingly difficult to use a placebo in research in

wealthy nations if the research is to meet the standards of ethics review boards. To wit,
since we have developed treatments that are at least somewhat effective for a wide range
of conditions, it would be unethical to give people in the control group a placebo instead
of one such effective treatment (since to do so would be to give a known inferior
treatment).

Given the difficulty of using placebos in wealthy nations, in which patients generally
have access to whatever effective treatments have been developed, pharmaceutical
companies have tried to conduct more drug trials in poorer nations. The idea is that it’s
easier to justify the use of a placebo in a nation where many people receive little, if any,
medical attention, since the standard treatments that are available in richer countries are
unlikely to be accessible to people in poorer nations.

Guidelines for such studies were introduced in 1992 by the Council for International
Organizations of Medical Sciences (CIOMS). Of the extensive CIOMS guidelines,
Guideline 11 addresses exceptions to the rule that human research subjects should not
generally be given known inferior treatments. In its discussion of Guideline 11, the
CIOMS panel leaves it open that agencies from wealthy nations may give known inferior
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treatment to research subjects in a poor nation if the superior treatments are not generally
available in that poor nation and if the purpose of the research is to develop an effective,
relatively cheap treatment that can be made ‘reasonably available’ to the people in that
country.

This is relevant to the research into zidovudine as a means of reducing the likelihood of
transmission of HIV from an infected pregnant woman to the fetus. It was known that an
$800 zidovudine treatment reduced maternal-fetal transmission by approximately two-
thirds. Since this treatment is too expensive to be widely available in poor nations, the
National Institutes of Health (USA) and the UN wanted to see if a cheaper dose regimen
would also reduce the likelihood of transmission. The research was conducted in
Thailand, Dominican Republic and five African nations. Early in the study some of the
researchers expressed ethical misgivings about the research, since women in the control
group were not given any zidovudine – they received only a placebo. Thus, these women
were being given a known inferior treatment. Others disagreed, arguing that the purpose
of the research was to help people in the poorer nations, and not to develop a treatment
that would then be used in richer nations (which were already using the $800 regimen).

In view of the CIOMS rules, this research was perhaps ethical in some of the
participating nations but not in others. This is because some of the countries (e.g.,
Thailand) pledged before the study began that if the cheaper zidovudine treatment
worked, it would be made widely available to the people in that nation. However, the
African governments did not make this pledge. So, if we stick to the CIOMS guidelines,
it looks like the research was ethical in Thailand but not in the African nations.