Chapter 2 Research Ethics and
Informed Consent
Major Questions
Chapter 2 examines several important issues related to medical research:
(1) Medical research at some point requires tests on human subjects.
• Who is it ethical to perform tests on?
• To what extent does a test subject have to consent to or be informed about the
nature of the research in which they are participating?
(2) The goals of medical therapy and medical research are distinct and may conflict in
cases where a physician is engaged in both and some of the physician’s patients are
also actual or potential participants in research trials.
• Under what conditions, if any, is it morally acceptable for a physician to enroll a
patient of his in an research trial?
• In particular, since some clinical trials involve the use of placebos (medically
inactive substances), is it ethical for a physician to allow his patient to participate
in the trial knowing that the patient might receive a placebo rather than what he,
the physician believes, is the best treatment for his patient?
Major Questions
(3) A common view is that an experimental drug should only become
available to patients after they have been rigorously tested. But,
suppose a drug shows substantial promise before clinical trials are
complete.
• Why shouldn’t terminally ill patients have a right to try such drugs if
no other options exist?
• Aren’t we wrongly depriving patients of the benefits of the drug by
insisting that the trials be completed first?
(4) Animals are used extensively in biomedical research.
• Is animal experimentation ethically defensible?
• Often experiments performed on animals would be found
unacceptable if performed on human beings. What justifies treating
humans and animals differently?
Clinical trials
• The U.S. spends almost $100 billion per year on medical research,
and a large proportion of the money goes to fund randomized
clinical trials.
• A randomized clinical trial (RCT) is a form of research in which the
effectiveness and side effects of a treatment (for example, a drug,
surgical procedure, medical device) are tested by administering it to
human subjects. The discussion below uses drug testing as an
illustrative example.
• Trials have a preclinical and a clinical step. In the preclinical step, a
chemical thought to be potentially beneficial to humans is tested on
animals to determine its toxicity, more specifically, its therapeutic
index (the ratio of a dose producing toxic effects to a dose
producing desired effects).
Clinical trials
• If a drug shows promise
in animal testing and its
side effects are
acceptable, it is then
moves on to the clinical
step where it is tested
on humans in four
phases, as summarized
to the right
Clinical trials
• In the clinical part of testing, careful procedures are followed to attempt
to exclude bias in the results by making use of a “double-blind” design of
the experiment, which may also involve use of a placebo (from the Latin,
placebo, meaning “I shall please”), a medically inactive substance (such as
a sugar pill),.
•
• In the classic version of the double-blind design, a number of patients are
given the drug being tested and the remainder of the test group (the
control group) is given a placebo, or the currently best available, approved
treatment.
•
• Patients are assigned to the treatment group or the control group in a
random fashion (for example, by the flip of a coin).
•
• Neither the investigators nor the patients are allowed to know who is
receiving the drug and who is not—both are kept “blind.”
•
Clinical trials
• An important part of an ideal RCT is that the participants are faithful
representatives of the overall population for which the drug is intended.
• Using a placebo, or currently best medical treatment, in the control group
is important because of the potential bias resulting from the “placebo
effect”.
• The placebo effect refers to the fact that if a participant takes a substance
(for example, a sugar pill or the best current treatment) with the
possibility or expectation that it might help then, he may in fact show
improvement.
• This is possible because the participant’s hopes and expectations may
affect how his body responds and how he feel. (In a pain-relief study,
patients responded better to a placebo they were told cost $2.50 than to
one said to cost ten cents.)
Section 1: Consent and Experimentation
•
An experiment on human subjects requires that a suitable number of subjects be
available.
•
Nazi Germany and other tyrannical regimes, which have conducted medical
experiments, have met this need by forcing people, viewed by the regimes as
“undesirables” (for example, prisoners, certain ethnic minorities), to become test
subjects, without their informed consent.
•
Today, participant consent and understanding are widely recognized as a
fundamental to morally acceptable clinical trial, at least in most cases.
•
But, even with this general understanding, questions remain:
•
What exactly is meant by consent? What exactly is meant by understanding?
•
What kinds of individuals are ethically acceptable test subjects?
Section 1: Consent and Experimentation
The “Informed” Part of Informed Consent
• Consent to a research trial is more than simply saying yes to a
request to participate. The decision to participate must be based
on:
(a) adequate information about the trial and
(b) a clear understanding of that information.
• The information must include a description of the nature of the trial
as well as potential risks and benefits to the participants and
alternatives the participants have to participating in the trial.
Section 1: Consent and Experimentation
•
Additionally, the information must be presented to potential participants in a clear
and understandable way.
•
These two requirements are the source of some controversy. Medical research is
highly technical.
•
Just how much does a subject need to be told?
•
How much can a patient reasonably be expected to understand?
•
Some researchers have argued that it is virtually useless to provide patients with
relevant scientific information because patients lack the proper scientific
background and therefore the patient’s interest is best served by allowing a
physician to make the decision.
•
Others claim that it is entirely possible to tailor the explanation of the trial to the
participants’ particular background. This may require an extra effort on the part of
researchers to ensure that understanding has been achieved but researcher have
an ethical obligation to make this effort.
Section 1: Consent and Experimentation
The “Consent” Part of Informed Consent
•
Legitimate consent requires that the individual consenting did so voluntarily or out
his “own free will”. This implies both that the person was competent to make the
decision and that he was not coerced or pressured into making it.
•
But it is not always clear what competence means or whether the person is
deciding under pressure which invalidates his consent.
•
For example, someone may volunteer to be a subject in a potentially hazardous
experiment because she believes the experiment holds out the promise of helping
countless others. In terms of self-interest alone, such an action would not be
reasonable. Is the person deciding competently in this case?
•
A person, in financially difficult circumstances, may agree to participate in trial,
because financial reward is offered for doing so. Was the decision freely made or
did the person’s circumstances constitute “pressure” or “coercion”?
Reading: The Willowbrook Letters: Criticism and
Defense
Stephen Goldby, Saul Krugman, M. H Pappworth, and Geoffrey
Edsall
•
This reading examines the moral legitimacy of a study of viral hepatitis that was
conducted on mentally disturbed children at the Willowbrook School by Krugman
and his associates from 1956 – 1970. As part of the experiment, children were
deliberately infected with the hepatitis virus (See the Case Presentation on
pages131-132 for more detail.).
•
Goldby charges that the study was “quite unjustifiable” because it was morally
wrong to infect children when no benefit to them could result.
•
Krugman defends himself by claiming that his results demonstrated a “therapeutic
effect” for the children involved, as well as for others. He presents several reasons
for holding that the infecting of the children was justified.
Pappworth claims that Krugman’s defense is presented only after the fact,
whereas an experiment is ethical or not in its inception. Moreover; he asserts,
consent was obtained through the use of coercion.
•
•
In the final letter, Edsall defends the Krugman study. The experiments, he asserts,
involved no greater risk to the children involved than they would have run in any
case. What is more, the results obtained were of general benefit.
Reading: Judgment on Willowbrook
Paul Ramsey
• Ramsey challenges the justifications offered for the Willowbrook
experiments and argues that:
• Children should not be subjects of risky experiments unless the
experiments are intended, by the researcher, to directly protect the
children’s health.
• This ethical obligation should be made a matter of law.
• The reason that such experiments should not be done (apart from the
exception noted) is because children are incapable of giving informed
consent.
• Risky experiments are morally off-limits even if parental consent is given
or even if the results of those experiments are likely to be highly beneficial
to others.
Reading : Principles of the Nuremberg
Code
• These principles emerged from the trials of
Nazi war criminals after the Second World
War conducted in Nuremberg, Germany..
• The principles define conditions under which
it is morally acceptable to perform medical
experiments on people. Among other things,
the principles emphasize the need for
voluntary consent.
Reading: Belmont Report
National Commission for the Protection of Human Subjects
• The 1974 National Research Act mandated that every institution receiving
federal funding and conducting research involving human subjects
establish an institutional review board (IRB) to oversee such research.
• The Act was prompted by public revelations about the United States
Public Health Service—sponsored Tuskegee syphilis study(see Chapter 4)
in which investigators enrolled patients without their consent and treated
them in ways that were condemned at the 1947 Nuremberg trials of Nazi
physicians and researchers.
• The act also established the National Commission for the Protection of
Human Subjects of Biomedical and Behavioral Research and charged it
with identifying the ethical principles basic to human research and
formulating guidelines to guarantee that are followed in its conduct. This
became the Belmont Report.
•
Among the principles it identified are those of respect for persons,
beneficence, and justice.
Reading: Philosophical Reflections on Experimenting with
Human Subjects
Hans Jonas
• Jonas argues that experiments on individuals, which expose them to
serious risks, can never be morally justified on the grounds that such
experiments provide benefits to society.
• Jonas asserts that an experiment on a human subject is only justified
when:
• The risk taken is voluntary
• Subjects must be recruited from those who are most knowledgeable
about the circumstances of research and who are intellectually most
capable of grasping its purposes and procedures
• The experiment must be undertaken for an adequate cause. Knowledge
for knowledge sake is insufficient. Progress which may come from
research is not necessarily worth our efforts or approval, and he reminds
us that there are moral values which we ought not to lose in the pursuit of
science.
Section 2: The Ethics of Randomized Clinical Trials
(RCTs)
• The goals of medical therapy and medical research are
distinct and may conflict in cases where a physician is
engaged in both and some of the physician’s patients are
also actual or potential participants in research trials.
• A physician, in his capacity as a physician is concerned to
provide the best possible care for each of his patients.
For example, if one of them has a heart condition, he will
propose treatments he believes are best for improving
that condition in this particular patient.
Section 2: The Ethics of Randomized Clinical Trials
(RCTs)
• But suppose the physician is also involved in a research trial of a
drug intended to help people with the same condition as his
patient, A. A could be a likely test subject in the trial.
• Should he try to encourage A’s enrollment in the program or
discourage it if the patient proposes participation on his own? Or, if
A is already in the trial, could his obligation to give A the best
treatment the physician thinks possible require him to breach trial
protocol and recommend a possibly different treatment?
• The question becomes even more acute if the trial in which patient
A might participate involves the use of a placebo. Is it ethical for the
physician to allow patient A to participate in the trial knowing that
A might receive a placebo rather than what he, the physician
believes, is the best treatment for him?
Reading: How to Resolve an Ethical Dilemma Concerning
Randomized Clinical Trials
Don Marquis
•
Marquis addresses the dilemma a physician faces when she believes that one of the two
treatments in a clinical trial is better for her patient. Should she advise the patient to choose the
treatment she thinks best or let him enter the trial and have to accept the randomly assigned
treatment?
•
If she keeps quiet she won’t be giving the patient the benefit of her judgment but if she doesn’t
advise him, she will hinder the clinical trial.
•
Marquis rejects two attempts at resolving the dilemma.
•
The first holds that she doesn’t really know which treatment is better (“equipoise”), because, in the
absence of the results of the RCT, she lacks the best evidence. This approach is in error because it
wrongly assumes that only evidence from an RCT can support a view.
•
The second approach holds that because the professional community has not decided which
treatment is best she need not express her view about the matter. But this is wrong because we
expect the best advice from our physician.
•
Resolving the dilemma requires that the physician explains her views to the patient, informs the
patient of the alternatives (explaining also that in the clinical trial the patient may not get the
experimental treatment), then allows the patient to make the decision.
Reading: Clinical Trials: Are They Ethical?
Eugene Passamani
•
The author argues that randomized clinical trials (RCTs) are the most reliable
means of evaluating new therapies. Without RCTs, chance and bias may affect our
conclusions.
•
Passamani rejects the argument that the physician–patient relationship demands
that physicians recommend the “best” therapy for patients, no matter how poor
the data on which the recommendation is based.
•
He acknowledges that RCTs pose ethical problems for physician–researchers but
believes the difficulties can be overcome by:
(a)
Requiring that all participants give their informed consent.
(a)
Clinical equipoise must exist. [Equipoise exists when competent physicians are
genuinely uncertain about which of the alternative therapies in the trial is
superior and content to allow their patients to be treated with any of them]
(c)
The trial must be a critical test of the therapeutic alternatives.
Reading: How Necessary Are Randomized Controlled
Trials?
Robert Northcott
• The author argues that although RCTs are usually considered the “gold
standard” for testing a new treatment, they are not always the preferred
way.
• Historical studies, which assess the effectiveness of treatments on the
basis of data drawn from experiences using them, are sometimes
preferable to RCTs.
• Northcott uses the case of extracorporeal membranous oxygenation
(ECMO) to argue that when the treatment was introduced, it was so
successful in saving the lives of newborns with underdeveloped lungs that
no RCT was needed to prove its superiority to conventional treatment.
• The belief that an RCT was required. Northcott claims, led to deaths that
were not only tragic, but unnecessary
Section 3: Access to Experimental Drugs
• A common view is that an experimental drug
should only become available to patients after
they have been rigorously tested. But,
suppose a drug shows substantial promise
before clinical trials are complete.
• Why shouldn’t terminally ill patients have a
right to try such drugs if no other options
exist?
Section 3: Access to Experimental Drugs
• Aren’t we wrongly depriving patients of the
benefits of the drug by insisting that the trials be
completed first?
• The case of Abigail Burroughs illustrates some
ethical and legal issues involved in trying to
decide whether clinically unproven drugs should
be available to people who are in medically
desperate circumstances and where existing
medical treatments have failed them.
Reading: Abigail Alliance V. FDA Majority Opinion:
Patients Have a Right to Have Access to Experimental Drugs
Judith W. Rogers
•
(a)
Circuit Judge Rogers argues that terminally ill adult patients should have access to
investigational drugs if
they have no better treatment options
(b) the drugs have completed Phase I trials and been found safe enough for
additional human testing.
•
Her argument rests on two primary two claims:
First, that for most of US history, “the government has not blocked access to new
drugs”.
Second, the right to access lifesaving drugs can be inferred from the Cruzan decision,
in which the Supreme Court found a right to refuse lifesaving treatment. (For the
Cruzan case, see pp. 591–593 of the text.)
Reading: Abigail Alliance V. FDA Dissenting Opinion:
Patients Have No Right to Experimental Drugs
Thomas B. Griffith
• Circuit Judge Griffith argues that Rogers’ opinion is based on a
series of faulty inferences:
(1) The fact that government has not always regulated drugs does not
imply a recognition of a constitutional right to be free of such
regulation;
(2) The traditions of the necessity defense and the prohibition of
forced medication do not imply a right of access to medication;
(3) That a drug has completed Phase I testing does not imply that it has
a medical benefit and a minimal risk. In fact, the government has
regulated drugs for a long time through the executive and legislative
bodies.
Reading: Abigail Alliance V. FDA Dissenting Opinion:
Patients Have No Right to Experimental Drugs
Thomas B. Griffith
• To ignore this and give the judicial branch the role
of deciding which drugs are safe and beneficial
enough for use would burden the courts with a
task both practically and logically impossible to
carry out.
• Griffith concludes by agreeing with the lower
court decision that even terminally ill patients
have no right to get access to drugs that are still
in the testing stage.
Section 4: Animal Experimentation
Animals are used in virtually all basic biomedical research because of their physiological resemblance to
human being in various respects. Experimentation on animals often involves:
•
Subjecting them to extreme pain or
•
Severely disabling them or
•
killing them.
It is of course obvious that animal subjects do not consent to the experiments nor understand the
possible harm to their welfare.
All of the above circumstances were true of the inmates of Nazi concentration camps and are
condemned in by the Nuremberg Code when applied to humans. So, why doesn’t the Nuremberg Code
apply to animals as well?
The usual answer is that humans are morally superior to non-human animals and because of this fact it
is morally acceptable to use animals in experiments in a way that we would not condone if a human
subject were involved. Is this a rationally defensible view?
The two readings in this section explore this question.
Reading: Animal Experimentation
Peter Singer
• Singer argues that most animal experiments cannot be
justified because they cause great animal suffering,
while producing little or no knowledge.
• Singer provides multiple examples of painful, pointless
experiments leading to the death of animal subjects.
• He argues that our willingness to tolerate such
experiments reflects an attitude of “speciesism”—the
notion that the interests of nonhuman animals need
not be considered.
Reading: Animal Experimentation
Peter Singer
•
Speciesism, Singer holds, is analogous to racism and is just as indefensible.
•
Singer argues that the fundamental issue in determining how we may treat
animals is whether they suffer and that the pains of animals and humans deserve
equal consideration.
•
Many animals are more intelligent than severely retarded or infant humans, so
that if lack of intelligence would justify painful animal experiments, it would also
justify the same experiments on retarded and infant humans.
•
Because it is immoral to subject humans to such experiments, we have good
reason to believe it is also wrong to subject animals to them.
•
Singer holds that researchers should be required to demonstrate that the benefits
of their research will outweigh the suffering of the animals involved. He
recommends that ethics committees, with members representing the welfare of
animals, be established to oversee experiments.
Reading: The Case for the Use of Animals in Biomedical Research
Carl Cohen
•
The author argues that we have a strong duty to conduct experiments on animals for the benefit of
human.
•
He rejects the claim that animals have rights, as humans do.
•
To have a right, a being must have the capacity to comprehend rules of duty (autonomy). Humans
have this capacity, animals do not.
•
Because animals lack autonomy, Cohen rejects Peter Singer’s argument that the pleasures and
pains of animals deserve consideration equal to those of humans in calculating the overall benefits
of animal experiments.
•
Having autonomy makes the pleasures and pains of humans morally more important than those of
animals (an attitude Singer stigmatizes as “specieism”).
•
Cohen believes that we should be specieists. Speciesism is “essential to right conduct,” because
those who fail to make the relevant distinctions between humans and nonhumans will fail to
recognize their moral duties.
•
Cohen concludes that a proper analysis of animal experimentation shows “that contrary to Singer;
instead of having a duty to decrease the use of animal experimentation, we have a duty to increase
it.