People have debated the ethics of
clinical trials for as long as trials have been conducted. The
arguments have changed over the years and perhaps become more
sophisticated, but many of them involve issues such as the
physician’s obligations to the individual patient versus societal
good; clinical equipoise; study design considerations such as
randomization and the choice of control group, including use of
placebo; informed consent; conduct of trials in underdeveloped
areas and world regions; conflicts of interest; participant
confidentiality and sharing of data and specimens; lack of
publication; and publication bias.
A well-designed trial should answer
important public health questions without impairing the welfare of
participants. There may, at times, be conflicts between a
physician’s perception of what is good for his or her patient and
the design and conduct of the trial. In such instances, the needs
of the participant must predominate.
Ethical issues apply in all stages of a
clinical trial. In this chapter, we summarize some of the major
factors involving ethics in design, conduct, and reporting of
clinical trials. As will be noted, several of the issues are
unsettled and have no easy solution. We expect, however, that
investigators will at least consider these issues in the planning
stages of trials, so that high ethical standards can be applied to
all trials.
Emanuel et al. [1] listed seven criteria that they considered
essential to the ethical conduct of clinical research. These
criteria are value, scientific validity, fair selection of
participants, favorable benefit/risk balance, independent review,
informed consent, and respect for enrolled participants
(Table 2.1). Independent review is generally conducted
by ethics review committees specifically constituted for oversight
of research with human subjects. In the United States, such
committees are termed institutional review boards (IRBs). Other
names used outside the United States are research ethics
committees, ethics committees, or ethics review committees.
Although the role of ethics review committees is discussed later in
this chapter under Informed Consent, it must be emphasized that
independent review by these committees and others, such as data
monitoring boards, applies to several aspects of a trial.
Table
2.1
Requirements for an ethical clinical
trial
Requirement
|
Explanation
|
---|---|
Value
|
Evaluate an intervention that has the
potential to be of social or scientific value
|
Scientific validity
|
Use methods that will produce reliable
results
|
Fair selection of participants
|
Participant selection that avoids placing
the vulnerable at undue risk and avoids preferential access of
attractive interventions to the privileged
|
Favorable benefit/risk balance
|
Minimize risks and maximize potential
benefits, with an estimate that benefits will likely outweigh
risks
|
Independent review
|
Review of design by individuals not
directly affiliated with the research (for example, ethics review
committees)
|
Informed consent
|
Provide information about purpose of
research, procedures, and potential risks and benefits to enable
participants to make voluntary decisions in a way that respects
participant autonomy
|
Respect for enrolled participants
|
Protect the rights and wellbeing of
participants
|
We encourage the reader to seek out any
of the many books and journals devoted to ethical aspects of
clinical research. Those go into the issues, including ones we do
not address, in considerable depth. A particularly relevant book is
The Oxford Textbook of Clinical
Research Ethics, many chapters of which relate directly to
clinical trials [2]. The reader is
also referred to several key documents:
- 1.
Nuremberg Code. This was the first major international statement on the ethics of medical research, published in 1947 in response to unethical human experimentation on concentration camp prisoners in the Second World War [3]. This code outlined ethical standards for medical research with an emphasis on the requirement for voluntary consent to participation.
- 2.
Declaration of Helsinki. Issued by the World Medical Association in 1964, and periodically amended, the Declaration of Helsinki is a comprehensive statement of the ethics of human subject research [4].
- 3.
Belmont Report. Created by a United States federal commission in 1979, this report outlines ethical principles for clinical research [5]. The report is structured around three basic principles: respect for persons, beneficence, and justice.
- 4.
International Ethical Guidelines for Biomedical Research Involving Human Subjects, prepared by the Council for International Organizations of Medical Sciences in collaboration with the World Health Organization, first in 1982 and amended several times, including in 2002 [6]. This document includes 21 guidelines that address ethical responsibilities in human subject research, many of which apply to clinical trials.
Fundamental Point
Investigators and sponsors of clinical trials
have ethical obligations to trial participants and to science and
medicine.
Planning and Design
Ethics Training
All clinical trial investigators
should have training in research ethics. Understanding ethical
principles, and the related regulatory requirements (see Chap.
22), is essential for responsible
conduct of clinical trials. An important part of training in ethics
is a review of the history of abuses in clinical research that
prompted many of the guidelines and regulations that followed.
These include an experiment in Tuskegee, Alabama, when treatment
was withheld from around 400 African-American men with syphilis to
study the course of the disease as well as the abhorrent
experiments of concentration camp prisoners in the Second World
War. There are a number of resources for research ethics training,
including several National Institutes of Health (NIH) websites
[7–9].
Does the Question Require a Clinical Trial?
An early decision relates to whether a
clinical trial is even necessary. Not all questions need to be
answered, and not all of those that should be answered require
clinical trials. Sometimes, other kinds of clinical studies may be
able to address the question at least as well as, or even better
than, a clinical trial. Even if the answer may not be quite as
good, the added benefits from the trial may not be worth the added
risk.
Because clinical trials involve
administering something (a drug, device, biologic, or procedure) to
someone, or attempting to change someone’s behavior, there may be
adverse as well as positive results. Although some of the potential
adverse consequences may be known before the trial is started, and
therefore prevented or minimized, others may arise unexpectedly
during the trial or be more serious than anticipated. The question
being addressed by the clinical trial, therefore, must be important
enough to justify the possible adverse events. The question must
have relevant clinical, public health, and/or other scientific
value. A trivial question should not expose study participants to
risk of harm, either physical or emotional. Harm can be either a
direct result of the intervention or indirect, like from
withholding something beneficial. The study investigator, sponsor
or funder, and institutions where the study will be performed must
all ensure that the question is sufficiently important and the
trial is appropriately conducted to justify those risks.
Though the question may be important,
the clinical trial may be infeasible or unethical. An obvious
example is cigarette smoking—providing non-smokers with cigarettes
to prove that smoking is harmful is clearly unethical.
Observational studies have given us sufficient evidence to answer
that question, since the relative risk is so great. The Cardiac
Arrhythmia Suppression Trial (CAST) [10] was designed to determine whether
suppression of ventricular arrhythmias with antiarrhythmic agents
in people with heart disease would lead to a reduction in sudden
cardiac death. After two of the three antiarrhythmic drugs were
found to be harmful and the trial was stopped, some asked whether
the study might be continued but reconfigured to demonstrate that
quinidine, a long-used drug with some properties similar to the two
discontinued agents, would also be harmful. The CAST investigators
quickly decided that designing a trial specifically to prove harm,
especially serious harm, would be unethical. Although the outcome
of a trial is uncertain, the primary response variable should
always be one where either benefit or noninferiority is potentially
achievable.
Two kinds of trials raise ethical
issues because of concerns about the balance between potential
benefits to society (and perhaps to participants) and the risks of
harm and discomfort to participants. In both, the likelihood of
immediate benefit to the study participants exists but is remote.
One involves “marketing” (also termed “seeding”) trials. Such
clinical trials are conducted to show that a new drug or new
version of an old drug is at least as good as (i.e., noninferior
to) a drug already proven to be beneficial. Other than enhancing
the financial status of the industry sponsor, there may be little
benefit from the new drug. Yet trial participants are being put at
risk from a drug with unknown adverse effects, some of which might
be serious. If the new drug has some potential improvement over the
existing one, the trial might be justified. Perhaps the new drug is
easier to take (e.g., once a day rather than twice a day
administration, or taking a pill rather than an injection), is
better tolerated, or causes fewer adverse events. One could also
argue that having more than one drug with similar benefits is good
for the economy, fostering lower medical care costs. But in the
end, those conducting such trials should show how the question is
important and how there will be meaningful benefits for
patients.
A second kind of trial, the ethics of
which have been debated, is the early phase study. If these studies
are performed in healthy volunteers, there is a nontrivial chance
that they will be harmed, but have little opportunity to benefit,
other than from whatever payment they receive as a result of their
participation and from the possible contribution they provide to
advancing treatment. Some people regularly enroll in such studies
for the payment [11]. It has been
argued that with proper attention to study design and safety
monitoring, appropriate evaluation by ethics review committees, and
true informed consent, these studies are ethical [12]. As always, risk must be kept to a minimum
and the payment must not be so great as to encourage participants
to do something that would place them at serious risk. The pros and
cons of various payment models for research participants are
discussed by Dickert and Grady [13]. As with other clinical research, early
phase studies are only ethical if investigators and sponsors do
whatever is necessary to minimize risk. Unfortunately, instances
when investigators may not have taken proper care have occurred and
received widespread attention [14–16].
Some early phase studies are conducted
with participants who have a disease or condition. Patients with
cancer that have not responded to other therapies may volunteer for
such trials, hoping that the experimental intervention will prove
beneficial. Given the small size of these studies and the
unfortunate fact that most interventions early in their development
do not prove beneficial, there may be only a small chance of
benefit. But even if there is only a slight possibility of
improvement, as long as there is adequate informed consent and the
expectation of benefit to society from the knowledge to be gained,
most would agree that these trials can be conducted in an ethical
manner [17, 18]. However, the strategy of commonly
subjecting participants to experimental therapies without the
ability to compare safety and harm to a control group in an
unbiased way raises its own ethical issues.
On the other hand, most treatments
used in medicine, including those recommended in clinical practice
guidelines [19], do not have the
clinical trial evidence to be certain that the benefit outweighs
the risk. This suggests that we have a responsibility, when
possible, to promote high-quality clinical trials to provide the
evidence to guide clinical decision-making. It is ironic that
consent is essential for a patient to be in a clinical trial
comparing two commonly used treatments, and yet assignment to those
treatments in clinical practice is routine and accepted without
consent and without gaining knowledge about whether there is
benefit or harm. If one accepts that randomized trials are the most
reliable way to define modest treatment effects, then increasing
the number and efficiency of trials should be a priority for the
broader health care system, a goal of the Patient-Centered Outcome
Research Institute (PCORI) [20].
Controversies in the approach to
informed consent in trials that compare treatments commonly used in
practice were highlighted by the Surfactant, Positive Pressure, and
Oxygenation Randomized Trial (SUPPORT) [21]. This trial randomly assigned premature
babies to supplemental oxygen to keep the arterial oxygen
saturation at the lower end versus the higher end of standard
recommendations. The six-page, single-spaced consent form included
standard elements of informed consent, including a statement that
lower levels of oxygen might reduce retinopathy, a known
complication of higher oxygen levels. The trial showed less
retinopathy with lower oxygen target, but unexpectedly higher
mortality, and the results have changed practice. Meanwhile, the
Office for Human Research Protections (OHRP) of the U.S. Department
of Health and Human Services investigated the consent process in
the trial and determined that institutional review boards failed to
have the consent state that mortality might be increased in one of
the treatment strategies [22].
This decision has caused concern among academic institutions about
the risk of conducting trials as well as undermining attempts to
streamline the consent process in pragmatic trials that are
comparing standard therapies [23].
In fact, it has been argued that the participant risks involved
with random assignment to commonly used standard treatments are not
different than standard practice and that this should be
acknowledged in the regulations [24].
It appears that most people are
willing to volunteer for clinical trials, but most people are not
approached to participate in trials [25]. Some have suggested that there should be a
greater sense of social responsibility to participate in clinical
research since current treatments are available only due to
previous patients participating, and future advances will likewise
depend on this participation [26].
This places the burden on clinical researchers to be responsible in
designing trials that will provide reliable guidance for future
care. In fact, most trials are too small to provide reliable
information and many results of trials are never published
[27]. Even if our current complex
approach to conducting trials were simplified, the costs are still
a major barrier. Moreover, relatively little funding is allocated
to answering the questions that would have the greatest impact on
improving public health.
Randomization
In the typical “superiority trial”
described in Chap. 5, randomization is usually done on
top of standard or usual therapy, which all participants should
receive. The special issues related to noninferiority trials are
discussed in Chap. 5. Randomization can be a problem for
physicians and other clinicians who feel pressure to be able to
choose the treatment that has the greatest likelihood of benefit.
The investigator, however, must acknowledge uncertainty when it
exists. Therefore, an objection to random assignment should only
apply if the investigator believes that there is reasonable
certainty that a superior therapy exists. If that is the case, he
or she should not participate in a trial that randomizes
participants to a therapy other than the believed superior therapy.
On the other hand, if he or she truly cannot say that one treatment
is better than another, there should be no ethical problem with
randomization. Such judgments regarding efficacy may vary among
investigators, such that there is uncertainty for some but not
others. Because it is unreasonable to expect that an individual
investigator should have no preference, not only at the start of a
trial but during its conduct, the concept of “clinical equipoise”
among the expert clinical community has been proposed
[28]. Some have maintained that
until an intervention has been proven beneficial, randomization is
the most ethical approach and one that will provide the correct
answer soonest [29–32]. It may be that “equipoise” will change over
the course of a trial, as was the case in the Second International
Study of Infarct Survival (ISIS-2) trial testing streptokinase for
myocardial infarction. During the period of recruitment, the data
monitoring committee found that there was “proof beyond reasonable
doubt” that streptokinase reduced mortality for patients 0–4 h
after onset of pain, and this information was shared with
investigators [33]. They were told
that “patients can be randomized if the responsible physician
remains, in the light of this and other evidence, uncertain as to
whether streptokinase is indicated” [33]. However, is it ethically justifiable for a
data monitoring committee to allow participants to be randomly
assigned to an arm (in this case, placebo) for which there is
“proof” of higher mortality? Many would argue that the committee
should have recommended a change in the protocol with no further
enrollment in this subset.
There are other situations in which
consent is not possible in the traditional sense, including certain
situations in which the patient is unable to provide consent (for
example in the setting of cardiac arrest) and when the unit of
randomization is not the patient (cluster randomized studies). An
example of such a cluster randomized study is the Randomized
Evaluation of Decolonization versus Universal Clearance to
Eliminate MRSA (REDUCE MRSA) trial [34]. Forty-three hospitals were randomly
assigned to 1 of 3 strategies of MRSA screening and patient
isolation, targeted decolonization, or universal decolonization (of
all patients without screening), to reduce rates of MRSA infection.
Most hospitals used a central IRB. Since all regimens were standard
of care and participation in the trial was anticipated to have a
favorable benefit-risk balance, the requirement for patient consent
was waived. Patients were given information sheets explaining the
trial.
Control Group
Choice of the control group is a major
design issue in clinical trials. If there is a known best therapy,
one would generally expect the new intervention to be compared with
that therapy, or added to it. But the optimal therapy may not be
widely used for various reasons. These could include cost,
unavailability of the therapy or lack of sufficient clinicians
competent to administer it, lack of acceptance by the practicing
clinical community, socioeconomic and cultural differences, or
other factors. Depending on these circumstances, some trials may
not use the best known therapy or standard of care as the control.
They may rely on what the practicing communities typically do, or
usual therapy [35]. Investigators
and ethics review committees need to judge whether the usual
therapy deprives participants of a proven better treatment that
they would otherwise receive. If so, serious ethical concerns
arise. A major area of disagreement has been the degree of
responsibility of investigators to ensure that all participants
receive the best proven therapy as a control or background care,
even if usual care in the community in which the trial is being
conducted is not up to that standard [36]. The appropriate control and background
therapy depends, in part, on the purpose of the trial. (See also
the section below, “Trials in Low- and Middle-Income
Countries.”)
Considerable confusion has arisen when
people talk about placebo-controlled trials, as they may refer to
different kinds of designs. Often, a new intervention is added to
usual care or standard care and compared against that care plus
placebo. Sometimes, a new intervention is seen as a possible
replacement for an existing therapy, yet for various reasons, it is
not thought appropriate to compare the new intervention against the
existing therapy. The commonly used therapy, for example, may not
have been proven to be beneficial, or it may be poorly tolerated.
Therefore, a placebo comparator is used instead of the existing
therapy. Often, a blinded placebo control provides the most
complete information about the risks and benefits of a new therapy
as an inert placebo is the best approximation of a neutral control.
The SYMPLICITY HTN-3 (Renal Denervation in Patients With
Uncontrolled Hypertension-3) trial of renal denervation for control
of severe refractory hypertension is a good example of the
importance of a placebo (in this case a sham procedure)
[37]. Earlier randomized trials of
renal denervation compared with no renal denervation, on top of
optimal medical therapy, showed a major (22–32 mmHg) reduction
in systolic blood pressure with renal denervation that led to
widespread enthusiasm and adoption of this treatment in Europe,
where the device to perform the procedure was approved based on
those results. However, the sham-controlled trial found similar
12–14 mmHg reductions in systolic blood pressure with renal
denervation and with the sham procedure.
Even if a proven therapy exists,
whether short-term discontinuation of that therapy for the purpose
of conducting a placebo-controlled trial is harmful depends on the
condition being studied. Exposing participants to serious harm by
withholding beneficial treatment is unethical even in the short
term. For conditions causing only mild to moderate discomfort, it
may be acceptable. For example, investigators evaluating new
analgesic agents might choose to use a placebo control, as long as
any pain or discomfort is treated promptly. As always, there will
be borderline cases that require discussion and review by ethics
review committees [38].
Freedman et al. [39, 40]
acknowledged that many factors are considered in deciding whether
to use a placebo control. They argued that if an accepted treatment
exists, much of the time a placebo control is unethical and,
indeed, unnecessary. Rothman and Michels [41, 42] also
maintained that in many cases a placebo, in lieu of the proven
therapy, has been used inappropriately because a proven therapy
existed. This debate occurred with the Enhanced Suppression of the
Platelet IIb/IIIa Receptor with Integrilin (ESPRIT) trial
[43–45]. The decision to use a placebo control,
rather than another proven IIb/IIIa receptor inhibitor, was only
allowed after it was shown that many cardiologists were not
persuaded by the prior evidence, and even then only with
declaration by the investigators that they were uncertain as to the
benefits of IIb/IIIa inhibitors. We think that this is a valid
argument as the participating investigators were informed about the
current evidence and made the decision to conduct another
placebo-controlled trial because they questioned the applicability
of that evidence. History has supported their decision, since
IIb/IIIa inhibitors are no longer strongly recommended in
guidelines nor used as a standard in practice. Ethics review
committees must have full knowledge and informed consent must
contain the relevant information.
Before an investigator uses a placebo
control, which will often be the best design, he or she should
assess whether it will provide the basis for a better assessment of
the active therapy and should determine that its use will not cause
serious harm (due to withholding a proven effective alternative).
Importantly, all participants must be told that there is a
specified probability (e.g., 50%) of their receiving placebo. The
World Medical Association Declaration of Helsinki (as amended in
2013) [4], the Council for
International Organizations of Medical Sciences (CIOMS)
[6], regulatory bodies
[46], and others have guidelines
for use of placebo. Miller summarizes the issues that should be
considered by investigators [47].
If life-saving treatment is available, patients should not be
assigned to placebo versus an active treatment. For example, once
streptokinase was shown to save lives of patients with myocardial
infarction, it would no longer be ethical to compare a new
fibrinolytic agent, like alteplase, with placebo. Likewise, if
assignment to placebo (versus available active therapy) would
likely result in any significant pain or harm, then a placebo would
be unethical. A placebo control is particularly important when
studying conditions with a variable course and/or frequent
spontaneous remissions, when existing therapies are inconsistently
effective or have serious side effects, or when frequency of the
condition is so low that an equivalence trial would be impractical
[47].
Protection from Conflicts of Interest
A widely expressed concern in clinical
research is the potential for conflicts of interest on the part of
the investigators. In the context of ethical issues, conflicts of
interest can lead to bias in design, conduct, data analysis,
interpretation, and reporting of findings. Conflicts of interest
are generally considered in the financial context, but intellectual
or other conflicts also exist [48]. Ideally, no investigator should have any
interests other than the well-being of the study participants and
the generation of new knowledge that will improve clinical care and
public health. That is unrealistic, however, given that
investigators must receive research funding to conduct research,
and this funding may come from government, industry, research
foundations, private investors, or others who have considerable
interest in the outcome of the study. Many investigators have also
spent a career attempting to advance the science, and could be
disappointed if or fail to accept that their theory is incorrect.
Therefore, most clinical trials find it more realistic to manage
conflicts of interest rather than to avoid them completely.
The practice of disclosing financial
relationships to participants and others has been reviewed and
recommendations have been proposed [49]. Among these recommendations, it was noted
that because many participants may not fully appreciate the impact
that financial relationships might have on research design,
conduct, and analysis, in addition to disclosure, IRBs and others
should “play a significant role in determining the acceptability of
these relationships” [49]. We
think that disclosure and IRB or other oversight may be sufficient
for early phase studies. It may not be sufficient, however, for
late phase trials—those that are designed to have major
implications for clinical practice. Most late phase clinical trials
are sponsored by industry, and although the investigators enrolling
and following participants may not stand to gain financially from
the results of the trial, the sponsors clearly do. Therefore,
analysis should be conducted, or at least validated, by groups
independent of the industry sponsor. Ideally, this should also
occur in trials sponsored by others. Any investigators who have
significant economic interests in the outcome either should not
participate or should not have opportunities to affect and publish
the trial results. This may mean that the lead investigator in
multi-investigator studies or the investigator in
single-investigator studies should have no major financial
conflicts if the study is one likely to change practice and
increase sales. Financial conflicts may also contribute to the
problem of “negative” trials being less likely to be published or
having their publication delayed (see Chap. 20). Trials with positive results are
published more often (see Chap. 20). Other key investigators with
major conflicts should also be barred from such trials. If the
investigators have limited roles or only small financial
investments, it may be acceptable for them to participate. We
recognize that the situation is more complicated when those
designing and overseeing, and perhaps co-authoring publications,
are employees of the company sponsoring the trial. Nevertheless,
complete openness and data analysis by an independent group remain
important. The use of external independent oversight bodies and
clear lines of authority may mitigate conflicts of interest. In the
end, however, clinical trial results must be believed and accepted
by the clinical communities. To the extent that conflicts of
interest (real or perceived) lessen that acceptance, the study is
impaired. Therefore, all appropriate ways of minimizing and
managing conflicts should be used.
Informed Consent
Proper informed consent is essential
to ethical trial conduct. Partly as a result of terrible things
done in the name of clinical research, various bodies developed
guidelines such as the Nuremberg Code [3], Declaration of Helsinki [4], Belmont Report [5], and International Ethical Guidelines for
Biomedical Research Involving Human Subjects [6]. These guidelines lay out standards for
informed consent that are commonly followed internationally. In
parallel to the Belmont Report, the United States Congress passed
laws that require adherence to informed consent regulations by
those receiving government support—the so-called Common Rule, or
Title 45 of the Code of Federal Regulations, part 46 (45 CFR 46)
[50]—and those evaluating agents
under the auspices of the U.S. Food and Drug Administration
[51]. These regulations require
that clinical research studies be reviewed by IRBs, and establish
the membership and other procedures that IRBs must follow.
One of the primary roles of the IRB is
to ensure that there is true, voluntary informed consent. The
Common Rule and 21 CFR 50 [52]
require consent forms to contain basic elements.
Table 2.2
lists these as well as other elements that may be added as
appropriate. Simply adhering to legal requirements does not ensure
adequate informed consent [53–55].
Informed consent is a process that can take considerable time and
effort; it is not simply a matter of getting a form signed. In
many, perhaps most, clinical trial settings, true informed consent
can be obtained. Potential participants have the capacity to
understand what is being requested of them, they have adequate time
to consider the implications of joining a trial, ask questions, and
take information home to review and discuss with their families and
personal physicians, and they are familiar with the concepts of
research and voluntary consent. As discussed in the “Privacy and
Confidentiality” section below, investigators may share data and
biospecimens with other researchers, while following federal
guidelines. If such sharing is planned or required by the sponsor,
the informed consent material must make it clear that sharing will
occur and that the data may be used for purposes other than those
of the trial for which the person is volunteering.
Table
2.2
Informed consent checklist—basic and
additional elements
Basic elements
|
A statement that the study involves
research
|
An explanation of the purposes of the
research
|
The expected duration of the subject’s
participation
|
A description of the procedures to be
followed
|
Identification of any procedures that are
experimental
|
A description of any reasonably
foreseeable risks or discomforts to the subject
|
A description of any benefits to the
subject or to others that may reasonably be expected from the
research
|
A disclosure of appropriate alternative
procedures or courses of treatment, if any, that might be
advantageous to the subject
|
A statement describing the extent, if any,
to which confidentiality of records identifying the subject will be
maintained
|
For research involving more than minimal
risk, an explanation as to whether any compensation and any medical
treatments are available if injury occurs and, if so, what they
consist of, or where further information may be obtained
|
An explanation of whom to contact for
answers to pertinent questions about the research and research
subjects’ rights, and whom to contact in the event of a
research-related injury to the subject
|
A statement that participation is
voluntary, refusal to participate will involve no penalty or loss
of benefits to which the subject is otherwise entitled, and the
subject may discontinue participation at any time without penalty
or loss of benefits to which the subject is otherwise
entitled
|
Additional elements, as appropriate
|
A statement that the particular treatment
or procedure may involve risks to the subject (or to the embryo or
fetus, if the subject is or may become pregnant), which are
currently unforeseeable
|
Anticipated circumstances under which the
subject’s participation may be terminated by the investigator
without regard to the subject’s consent
|
Any additional costs to the subject that
may result from participation in the research
|
The consequences of a subject’s decision
to withdraw from the research and procedures for orderly
termination of participation by the subject
|
A statement that significant new findings
developed during the course of the research, which may relate to
the subject’s willingness to continue participation, will be
provided to the subject
|
The approximate number of subjects
involved in the study
|
Sometimes people may not understand
that a clinical trial is a research endeavor. They may believe that
they are receiving therapy for their condition. This may happen in
early phase trials of new drugs that are being developed for
serious, untreatable diseases, or in any clinical trial testing a
promising intervention for a serious or chronic condition. Patients
may view the trial as the last or best possibility for cure.
Sometimes clinicians are also researchers and may seek to enroll
their own patients into clinical trials. These situations can lead
to what has been termed “therapeutic misconception” [56]. The distinction between research, an
experiment in essence, and clinical care may blur. Extra effort
must be made to provide patients with the information needed to
judge the merits of volunteering for research, separate from their
clinical care.
The situations where participant
enrollment must be done immediately, in comatose patients, or in
highly stressful circumstances and where the prospective
participants are minors or not fully competent to understand the
study are more complicated and may not have optimal solutions. In
the United States, FDA [57] and
Department of Health and Human Services [58] guidelines allow for research in emergency
situations, when informed consent is not possible. Under these
regulations, IRBs may approve the study without informed consent as
long as a series of special conditions has been met, including that
there has been community consultation and a safety committee is
formed to monitor accumulating data. Similar research is also
allowed in Canada [59] and under
the European Medicines Agency (EMA) Guidelines for Good Clinical
Practice [60]. A trial of
fibrinolytic therapy versus placebo in the context of resuscitation
for cardiac arrest was successfully conducted under the EMA
guidelines [61] and a trial of
therapeutic hypothermia for patients with out-of-hospital cardiac
arrest was conducted under Department of Health and Human Services
guidelines [62]. In these trials,
local ethics committees agreed that the trial could be done without
informed consent prior to enrollment. Instead, consent was later
given by surviving participants or their family members or
others.
Some have questioned research in
emergency settings because of the lack of prior informed consent,
and several such clinical trials have been quite controversial. An
example is a trial of a product intended to be used as a blood
substitute in trauma patients [63]. Because patients were unconscious at the
time of administration of the blood substitute, consent could not
be obtained. Therefore, community consultation was obtained before
local IRBs approved the study. However, there were allegations that
safety problems noted in earlier trials of the agent were not
published or otherwise disclosed to those bodies. We do not take a
position on the merits of this particular trial, and we support the
concept of being able to conduct important research in settings
where full informed consent before enrollment is not possible. The
sponsors and investigators, though, must be completely open about
all data relevant to the conduct of such studies and must follow
all local regulations [64].
Failure to do so harms not only the unwitting participants, but the
entire field of research in emergency settings.
For pragmatic, simple trials that are
comparing treatments that are each standard of care, a streamlined
approach to consent has been proposed [65]. Just as a “learning health care system”
integrates clinical research with care, a simple consent process
could be integrated into patient care with an explanation of the
research, of the fact that either treatment is approved and
standard, and that it is uncertain which is better.
Research on prisoners is restricted
[66] due to a history of violation
of ethical principals in the population and since informed consent
free of the appearance of possible coercion is difficult to
establish.
Also contentious is the practice of
obtaining consent from participant surrogates when the study
participant is unable to provide fully informed consent. This
typically happens with research in minors, when parents or other
guardians make the decision. Special review is required for
pediatric research; requirements vary depending on the expected
risks from the study [50]. Other
situations, such as research in emotionally or mentally impaired
individuals, also have generated discussion and guidelines
regarding use of surrogate consent [67, 68]. Less
clear is the use of surrogate consent for potential study
participants who are temporarily unable to understand the nature of
the study and give consent. This issue arose in research in people
with acute respiratory distress syndrome [69]. Suggestions for accommodating research in
such situations include risk assessment, determination of patient
capacity, and reconsent [70]. As
in all such situations, judgment on the part of investigators,
sponsors, IRBs, and others will be required and second-guessing
will inevitably occur.
The right to withdraw consent to
continue in a trial, including withdrawing consent to continue to
receive study interventions and undergo study procedures, is
another important ethics principle. Less clear is to what extent
participants have the right or option to refuse to have any type of
follow-up, since determining major outcomes as well as serious
adverse outcomes, including death, is essential in many trials to
interpret the results and entails minimal risk to participants. If
the initial consent declares that participants may withdraw from
intervention and all study procedures but that vital status will be
obtained at the end of the study regardless, this may be an
appropriate compromise. This can protect the contributions of
others who have placed themselves at some risk with the
understanding that their participation may help future patients,
while minimizing risk and discomfort to those who wish to
withdraw.
Conduct
Trials in Low- and Middle-Income Countries
Many large multicenter clinical
outcome trials are international, and they are becoming more so
[71] (see Chap. 21). Most diseases are global. The
ability to enroll and follow participants in more than one country
assists in enrollment and may help in generating results that are
generalizable to different populations and settings. However,
trials that are conducted in low- and middle-income countries can
raise ethical issues. Are they conducted in those regions because
the disease of interest is prevalent there, and the results
relevant to the region? Or are the countries or regions selected
primarily for convenience, low cost, or fewer administrative and
regulatory burdens? The control group may be receiving less than
optimal care, and thus may have a higher event rate, permitting a
smaller, shorter, and less expensive trial. If the trial is
conducted for those reasons, it may be unethical. Some have said
that the investigators are obligated to ensure that all
participants receive optimal care without regard to usual practice
in the country where the trial is being conducted. Others have
maintained that it is sufficient if the participants receive care
at least as good as what they would receive had they not been in
the trial, or care that is better than standard care for their
setting. This was the argument of the investigators in a tamoxifen
trial of adjuvant oophorectomy and tamoxifen in the treatment of
breast cancer in Vietnamese and Chinese women. State-of-the-art
treatment by United States standards (including radiation) was not
available and not likely to be available. What was being tested was
whether a simple and affordable treatment like tamoxifen would be
better than what was available [72].
Extrapolation of study results from
less developed regions to highly developed countries with very
different health care systems and standards of care, and vice
versa, has also been questioned. While it is clear that risk and
event rates tend to be higher in low-income countries
[73], some studies have suggested
that the treatment effects may indeed be different [74, 75].
After the trial ends, what is the
obligation of the investigators to provide an intervention shown to
be beneficial, both to the study participants and to the broader
population in a low-income country? This and other similar issues
have no easy answers. We believe, however, that trials should only
be conducted in places and with participants likely to benefit from
the results and with informed consent procedures that clearly
describe what will be done at the end of the trial. The results
from the trial must be able to be applied to clinical practice in
the population from which the participants came [76].
Recruitment
Recruitment of trial participants is
often one of the more challenging aspects of conducting a clinical
trial (see Chap. 10). Unless an adequate number of
participants are enrolled to generate the number of outcomes
needed, the trial will not be able to answer the questions about
benefit and harm. Therefore, there is great pressure to recruit an
adequate number of participants and to do so as quickly as
possible. The use of some financial incentives, such as “finder’s
fees” (i.e. payment to physicians for referring participants to a
clinical trial investigator), is inappropriate in that it might
lead to undue pressure on a prospective participant [77]. This differs from the common and accepted
practice of paying investigators a certain amount for the cost and
effort of recruiting each enrolled participant. Even this practice
becomes questionable if the amount of payment is so great as to
induce the investigator to enroll inappropriate participants
[13].
Study participants may (and at times
should) be paid for their involvement in clinical trials.
Typically, payment is meant to compensate them for the time,
effort, and expense of attending clinic visits. Studies that enroll
healthy volunteers (usually phase I studies) will often provide
payment beyond reimbursement for expenses. The amount generally
depends on the time required and the amount of pain and risks
involved in any procedures. As with paying investigators, when the
amount is such that people, whether they are healthy volunteers or
patients, might make unwise or dangerous decisions, it becomes
excessive. Participants should not be paid more for taking on more
risk. Ethics review committees often have guidelines as to
appropriate payment amounts for various kinds of studies and
procedures and must ensure that the amount provided does not create
an undue influence.
As discussed in Chap. 9, many potentially eligible trial
participants may be on medication. This treatment may be for the
condition that will be studied or some other reason. In order to
assess the participant’s condition at baseline, the investigator
may be tempted to withdraw medication, at least temporarily. For
example, one might be interested in enrolling people at high risk
of cardiovascular disease, and thus try to accrue those with
hypertension. But an accurate baseline blood pressure might not be
obtainable in those already on treatment. It might not even be
clear that the participant already on antihypertensive drugs would
have met the eligibility criteria if not on medication. Should one
withdraw the drug or simply accept that those on treatment probably
truly had hypertension, especially if while on treatment they still
have high normal blood pressures? Usually, the latter is the better
course of action.
Safety and Efficacy Monitoring
Occasionally, during a trial,
important information relevant to informed consent derives either
from other studies or from the trial being conducted. In such
cases, the investigator is obligated to update the consent form and
notify current participants in an appropriate manner. A trial of
antioxidants in Finnish male smokers (the Alpha-Tocopherol Beta
Carotene Cancer Prevention Study) indicated that beta carotene and
vitamin E may have been harmful with respect to cancer or
cardiovascular diseases, which was contrary to earlier
observational studies [78].
Because of those findings, investigators of the ongoing Carotene
and Retinol Efficacy Trial (CARET) informed the participants of the
results and the possible risks [79]. CARET was subsequently stopped earlier than
planned because of adverse events similar to those seen in the
Finnish trial. The investigator of a third trial of antioxidants,
the Age-Related Eye Disease Study (AREDS), then notified
participants (with a focus on the smokers) of the findings from
both the Finnish study and CARET [80, 81].
Five trials of warfarin in patients
with atrial fibrillation were being conducted at approximately the
same time [82] in the late 1980s.
After the first three ended, showing clear benefit from warfarin in
the reduction of strokes, the remaining two found it difficult
ethically to continue. Interim results from the Heart and
Estrogen/progestin Replacement Study (HERS) [83] and a Women’s Health Initiative (WHI)
[84] evaluation of estrogen
suggested that thromboembolic adverse events that had not been
clearly presented in the informed consent were occurring. In both
studies, the data and safety monitoring boards debated whether the
studies should stop or continue with additional actions taken. The
trials continued, but participants in those trials and medical
communities were notified of these interim findings of embolic risk
[85, 86]. Not only is such a practice an ethical
stance, but a well-informed participant is usually a better trial
participant. How much data should be provided to study participants
and when, and the role of independent safety monitoring groups in
this decision, are still areas of debate [87].
The issue of how to handle
accumulating data from an ongoing trial is a difficult one, and is
further discussed in Chap. 16. With advance understanding by
both participants and investigators that they will not be told
interim results unless they show conclusive benefit or harm, and
that there is a responsible safety monitoring group, ethical
concerns should be lessened if not totally alleviated.
Early Termination for Other Than Scientific or Safety Reasons
Clinical trials are only ethical if
there are adequate resources to conduct them and see them to
completion. Trials may (and should) be stopped early if there are
safety concerns or if there are scientific reasons to do so (see
Chap. 16). It is inappropriate, however, to
stop a trial early because the sponsor changes its mind about
research agendas or marketing priorities, or failed to adequately
plan for sufficient resources. In such cases, participants who
enrolled did so with the understanding that they would be helping
to advance medical knowledge. In the process, they put themselves
at possibly considerable risk based, in part, on that
understanding. To fail to complete the study is a serious breach of
ethics. An example of when this happened is the Controlled Onset
Verapamil Investigation of Cardiovascular End Points (CONVINCE)
trial [88]. Partway through
follow-up, the sponsor ended the study for reasons other than
scientific or safety concerns. As noted in an editorial by Psaty
and Rennie [89], “the responsible
conduct of medical research involves a social duty and a moral
responsibility that transcends quarterly business plans….”
In another situation, an investigator
with inadequate funds to complete his trial solicited money from
participants in the trial so that he could continue purchasing the
experimental drug [90]. Because
the trial was being conducted in patients with a fatal condition,
amyotrophic lateral sclerosis, the study participants viewed the
trial as a last hope and were therefore under considerable pressure
to donate. We view such actions as completely unethical. Plans for
conducting the trial, including obtaining experimental agents, must
be in place before the trial begins.
With all trials, investigators need to
plan in advance how they will handle end-of-study issues such as
whether participants will have continued access to the intervention
and transition to appropriate medical care.
Privacy and Confidentiality
The issues of privacy and
confidentiality have received considerable attention. The
widespread uses of electronic media have made many people concerned
about the privacy of their medical records, including research
records. Electronic medical records have simplified the tasks of
finding potentially eligible participants for trials, conducting
international multicenter studies, following up on participants
during and after the studies, and sharing data with other
researchers. They have also led to laws restricting what kinds of
medical records can be shared and with whom, in the absence of
clear permission from the patients. In the United States, the
Health Insurance Portability and Accountability Act (HIPAA)
primarily addresses privacy issues in clinical practice
[91]. However, there are clinical
research provisions that affect how investigators identify,
contact, and obtain informed consent from prospective participants,
and how study data are maintained and provided to others
[91] (see also Chap. 10). These laws, in turn, have
generated articles pointing out the increased difficulty in
conducting clinical research. Policies encouraging or mandating
sharing of data and biospecimens from research studies
[92–94] may conflict with the objectives of
maintaining confidentiality. If data are shared with other
researchers for unspecified purposes, might participants who
volunteered for a trial object to their data being used for goals
of which they might not approve? If the original informed consent
does not allow for use of the biospecimens by others or for
purposes different from the stated ones, either the biospecimens
cannot be shared or new informed consents must be obtained. The
increasing availability and use of genetic material adds to this
conflict. Fear of employment or health insurance discrimination
based on genetic information may make some people unwilling to
participate in trials if complete confidentiality cannot be
ensured. It is probably not possible to share data and specimens
that are useful to the recipient investigator while also completely
removing all participant identifiers. Some compromises are
inevitable. At the current time, there are no clear solutions to
these issues, but trial participants must have a right to make
informed choices. Clinical trial investigators need to be aware of
the concerns, and to the extent possible, plan to address them
before the study starts.
Data Falsification
There has been concern about
falsification of data and entry of ineligible, or even phantom,
participants in clinical trials (see Chap. 10). A case of possible falsification
that gained considerable attention was a trial of bone
morphogenetic protein-2 in the management of fractures due to
combat injuries [95]. An editorial
in the journal that published the article, which had purported to
show benefit from treatment, said that “much of the paper was
essentially false” and announced the article’s withdrawal
[96]. A trial of lumpectomy and
radiation therapy for breast cancer was severely harmed because of
falsified data on a small number of participants at one of many
enrolling sites. The overall results were unchanged when the
participants with the falsified data were not included
[97, 98]. Nevertheless, the harm done to the study
and to clinical trials in general was considerable. We condemn all
data fabrication. It is important to emphasize that confidence in
the integrity of the trial and its results is essential to every
trial. If, through intentional or inadvertent actions, that
confidence is impaired, not only have the participants and
potentially others in the community been harmed, the trial loses
its rationale and ability to influence science and medical
practice. Chapter 11 reviews issues of ensuring data
quality.
Reporting
Publication Bias, Suppression, and Delays
All investigators have the obligation
to report trial results fully and in a timely fashion. As discussed
in Chap. 20, it is well known that publication
bias exists. Positive or exciting findings are more likely to be
published than null results. In one survey of 74 trials of
antidepressant agents, 38 were considered to have results favorable
to the intervention. All but one of these were published. Of the 36
studies considered not to have favorable results, 22 were not
published. Eleven others were published in ways that obscured the
lack of favorable results [99].
Heres and colleagues examined trials of head-to-head comparisons of
second-generation antipsychotic agents [100]. Ninety percent of the trials sponsored by
industry were reported in favor of the sponsor’s drug.
Interestingly, this occurred even with trials that compared the
same drugs, but the outcome changed when the sponsor was a
different company. Clearly bias and conflicts of interest can have
important effects on publication and interpretation of
results.
It is more probable that large, late
phase trials will be published regardless of the results than will
small, early stage trials. There are exceptions, however. As
discussed in Chap. 5, the results of the second
Prospective Randomized Amlodipine Survival Evaluation 2 (PRAISE-2)
trial [101], although presented
in 2000, were only published 13 years after the trial was completed
[102]. The problem of delayed or
absent publication is undoubtedly true of other trials with
disappointing outcomes.
An important advance in ensuring
publication is that many journals [103], sponsors such as the NIH [104], and the FDA [105] require that trials be registered at
initiation in one of several accepted registration sites. Although
it is not a complete solution to the problem of failure to make
public the results of all trials, registration allows for easier
tracking of trials that are initiated but perhaps never completed
or never published. An analysis of trials registered on
ClinicalTrials.gov [106] showed
from a sample cohort that only 78 of 150 (52%) had associated
publications within 2 years after results posting.
We take the position that the results
of all clinical trials should be published in a timely way
regardless of the findings. It is important that the totality of
the information, pro and con, be available so that those designing
other studies and clinicians can make informed decisions. If the
study results are not published, it is also unfair to the
participants who volunteered for a trial with the understanding
that they would be helping medical research. So-called “gag
clauses” in industry-sponsored trials [107] are both antithetical to academic freedom
and contrary to ethical practice.
Conflicts of Interest and Publication
All researchers have biases of some
sort. It is understandable that an investigator’s perspective will
enter into a publication, even though best efforts are made to be
objective in reporting and interpreting study results. For this
reason, many journals, and most high-profile ones, require that
authors disclose their potential conflicts of interest
[108]. In addition, many
multi-investigator studies have publication policies that exclude
from authorship those with major conflicts of interest.
More extreme is “ghost authorship,”
where the papers are written by employees of the sponsors, who are
not listed as authors, and the academic-based investigators, who
may have had little or no role in drafting the manuscript, are
given authorship credit. We deplore this practice. We also deplore
the practice of listing as authors anyone who did not truly
contribute to the research. In response to concerns about “ghost
authorship,” many journals now ask for the contribution of each
listed author when the manuscript is submitted for publication (see
Chap. 19 for further discussion of these
issues).
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