Placebo Surgery in Clinical Research

Trials for Parkinson Disease

Susan Rebecca Dunlop, MS, RN, and Margaret McCormick, MS, RN

ABSTRACT
Advances in the eld of neurology and neurosurgery have contributed to the
development of novel approaches in the treatment of motor symptoms of Parkinson
disease (PD). Comparative trials have been performed in PD to evaluate the efcacy of
implanted fetal tissue against the standard of care and placebo surgery. Placebo surgery
is when a research subject undergoes a surgical procedure that has the appearance of a
therapeutic intervention but during which the essential therapeutic maneuver is
omitted and is used as the control arm of the research trial. The purpose of this article
is to allow nurse practitioners to review the use of placebo surgery as a control arm in
the treatment of PD. The potential of transplantation surgeries to improve the lives of
those living with neurodegenerative conditions is a fascinating and promising avenue
of medical exploration. An overview of clinical trials in which placebo surgery is used
as a control is discussed in this article along with the Common Rule and ethical
principles to ensure the protection of human subjects in clinical research.

Keywords: Belmont Report, Common Rule, deep brain stimulator, equipoise, ethics,
fetal tissue transplantation, Parkinson disease, placebo surgery
2015 Elsevier, Inc. All rights reserved.

P
lacebo surgery is when a research subject
undergoes a surgical procedure that has the
appearance of a therapeutic intervention but
during which the essential therapeutic maneuver is
omitted and is used as the control arm of the research
trial.1,2 The history of placebo surgeries provides
a valuable perspective from which to initiate a
discussion of this topic. In his landmark article
supporting sham surgery, Beecher3 discusses the
internal ligation of the mammary artery as a
treatment for angina pectoris. This procedure,
which was developed in 1939 by Fieschi, resulted in
a signicant relief of angina, which was a spectacular
result at the time. The procedure became the
standard of care until the 1960s when 2 placebo
controlled trials concluded that the procedure was
no better than the placebo surgery.4
Beecher states, Bias in connection with a given
procedure on the part of the physician, or the patient,
is a complex and often misleading factor in the
treatment of disease.3(p88) He promoted the use of
placebo surgery on the grounds that surgery itself
can promote a positive effect. Beecher documented
the power of a placebo in multiple controlled studies
and made a case for controlled surgical intervention
trials. As a proponent of placebo controlled surgical
trials, Beecher questioned the ethics and morality of
conducting unnecessary surgical procedures that may
threaten the health and life of the participant while
costing both time and money.
Another historically relevant case in the discussion
of the value of placebo controlled surgery is the
example of arthroscopic knee surgery. Miller4 points
out that in a clinical trial of arthroscopic knee surgery
for osteoarthritis, those randomized to the 2 surgical
procedure arms of the study had no more improvement
than those receiving the placebo intervention. These
2 historically relevant scenarios provide the background
in support of the use of sham surgery to test cellular-
based implants in Parkinson disease (PD).
PD is the 2nd most common neurodegenerative
illness after Alzheimer disease.5 It is a progressive and

240 The Journal for Nurse Practitioners - JNP Volume 11, Issue 2, February 2015
complex disease characterized by slowness of
movement, tremor, and cogwheel rigidity.
Neurodegeneration of the dopamine-producing
cells occurs in the substantia nigra. Although there
have been tremendous advances in the pharmoco-
therapeutic options and neurosurgical options with-
in the past 5 decades, neuroscientists continue to
explore the neuropathologic processes occurring on
the cellular and biochemical levels. The pathogenesis
is considered to be the result of environmental fac-
tors, genetics, and aging. PD occurs as the result of
specic cell loss, which makes cell replacement a
therapeutic potential. The specicity of the cell loss,
the history of multiple neurosurgical interventions,
and the evolving knowledge of the neuropathology
provides a platform for a discussion of placebo
neurosurgery in PD clinical trials.
As of 1999, 18 centers worldwide had performed
open-label studies of tissue transplantation in PD.
In an effort to control the placebo effect, United
States investigators developed a National Institutes
of Healthesponsored double-blind trial of fetal tissue
transplantation, a cellular-based therapy, in patients
with PD. In a 1999 commentary published in The
New England Journal of Medicine, the scientists involved
in this trial provide their rationale for the pursuit of
what became a controversial use of placebo surgery.
Freeman et al6 argue that cellular-based surgeries are
less invasive, painful, burdensome, and risky than
traditional surgeries; are necessary to control bias;
and the risks to the few research subjects far
outweigh the risks to the many involved when per-
forming a potentially ineffective surgery(p988).
Three biotechnology companies, Amgen (Thou-
sand Oaks, CA), Titan (Delhi, India), and Ceregene
(San Diego, CA), have sponsored clinical trials of
dopamine replacement agents using sham surgery as
a control arm. Cohen et al7 provided a synopsis of
these results in a poster presented at the 2009 annual
meeting of the American Society of Experimental
Neuro Therapeutics. The treatments were benecial
to the subjects as recorded in the phase 1 results.
In the phase 2 study of these agents, the trials failed
to meet their primary end points, and, consequently,
the companies made the business decision to halt
development.
www.npjournal.org
Clinical researchers apply their discoveries to
humans and test new drugs, devices, or innovative
surgical therapies in the context of clinical trials.
According to the Food and Drug Administration,
phase 1 clinical studies are conducted in approxi-
mately 20 to 80 healthy volunteer subjects to deter-
mine the metabolic and pharmacologic actions and
side effects and, if possible, to gain early evidence on
effectiveness. During this phase, a clinical hold can
prohibit the study from proceeding or stop the trial
for safety reasons or if a sponsor fails to accurately
disclose the risk of study to investigators. During
phase 2 clinical studies, common short-term side
effects and risks associated with the drug are deter-
mined. This phase includes several hundred people
and is typically a well-controlled, closely monitored
study. Phase 3 studies, which can include several
hundred to several thousand people, are used to
evaluate the overall benet-risk relationship of the
drug. This phase of the studies provides data that
allow for extrapolating the results to the general
population and transmitting the labeling information.
In 1991, 16 federal agencies adopted the Com-
mon Rule (45CFR 46, subpart A), which governs
research that is conducted on human beings when
funded by 1 of the 18 federal agencies. It has 3 basic
requirements aimed at the protection of human
subjects: (1) a review of the proposed research by the
institutional review board (IRB), (2) informed con-
sent, and (3) documentation of institutional assur-
ances of compliance with regulations. The Common
Rule requires that the IRB examines the proposed
research activities and then decides to approve the
research, require modications, or disapprove the
research proposal based on a thorough review pro-
cess. The members of the IRB committee must
include at least 5 members with various backgrounds
including 1 in a scientic area, 1 in a nonscientic
area, and 1 member who is not afliated with the
institution. The researcher must obtain informed
consent, usually in writing, from a living person
or their legally authorized representative before
enrolling in a research trial. Critical elements of
the informed consent include the purpose of the
study, procedures, potential risks, and discomforts
to the subjects. It also should include the anticipated
The Journal for Nurse Practitioners - JNP 241
benets to both the subjects and society. Payment for
participation, possible commercial products, and new
ndings should be discussed. The informed consent
must describe an alternative to participation and in-
form the patient that he or she can withdraw at any
time. When a subject decides to terminate partici-
pation, Health Insurance Portability and Account-
ability Act privacy and condentiality rights of
research subjects as well as emergency care and
compensation for injury should be reviewed. To
receive federal funding for research covered under
the Common Rule, each institution is required to
provide written assurances promising regulatory
compliance to the head of the federal agency or
department from which they are receiving the
funding.8
The principle of equipoise is important to con-
sider in clinical trial design. Equipoise is a state
of genuine and credible doubt about the merits
of some set of interventions that target a specic
medical condition,9(p414) enabling the researcher to
ethically assign subjects to receive an intervention
of unproven effectiveness or safety. The success of
the new intervention depends on how well the
experimental group performs compared with the
control. In medical research, placebos constitute
an important methodological tool. They are used
with the intention of mimicking some experimental
intervention. Even negative clinical trials are scientic
successes even if they pose a commercial failure.
LITERATURE REVIEW
In recent years, new medications, combination
therapies, and surgical interventions such as deep
brain stimulation have been introduced as vehicles
to reduce the debilitating motor symptoms of PD.
In 1999, a federally funded phase 2 randomized
control trial was performed to study the effect of
fetal dopaminergic cell transplantation on patients
with PD.6 This investigator initiated a trial using a
double-blind design that included 2 arms: the rst
consisting of subjects with PD who would receive
fetal tissue transplantation and a second arm consist-
ing of subjects with PD who would undergo a pla-
cebo procedure, involving anesthesia, intraoperative
stabilization of the head to a stereotactic frame, and
242 The Journal for Nurse Practitioners - JNP
partial-thickness burr holes but without the fetal tis-
sue transplantation. All subjects underwent magnetic
resonance imaging and positron emission tomogra-
phy scanning before study intervention. Both groups
received standard medical therapy for PD. Intrave-
nous antibiotics and cyclosporine were administered
for 6 months after their surgery. Similar trials inves-
tigating fetal cell transplantation were conducted,
but the control group received local anesthesia rather
than general anesthesia. Subjects did not require
immunosuppression but still were tted for a ste-
reotactic frame and received scans and a partial burr
hole drilled into their skull.10 The goal of the double-
blind design is to control for bias in assessing the
effect of the intervention.
Frank et al11 reviewed 4 studies that used a placebo
surgery methodology and found that harm occurred
more frequently in those subjects receiving the
experimental intervention. They concluded that
placebo surgery procedures in PD had an acceptable
risk/benet ratio. Kieburtz12 discussed the clinical
design methodology used in the studies of experimental
cellular-based therapies and provided ample support
of a placebo surgery group as a control group in the
design of these trials. In his endorsement of placebo
surgery, he emphasized that the engrafted group was
exposed to greater risks in all trials. Kieburtz states,
the ethical commentators have been surprisingly
quiet on this ironic twist of their prior concerns.12(p72)
Albin13 defends placebo surgery controls as necessary
to ensure that false positive trial results do not occur
and endanger public safety. Albin justies placebo
surgery controls if the trial meets the standards of
ethical conduct, there is no alternative research design,
the risk/benet ratio is minimized, the enrollments
reect the minimum needed to address the question,
and the safety monitoring board is exceptionally
vigilant.(p324) Horng and Miller14 determined that
placebo surgery is ethically justied if the following
criteria are met: (1) there is a valuable, clinically
relevant question to be answered by the research; (2)
the placebo control is methodologically necessary to
test the study hypothesis; (3) the risk of the placebo
control itself has been minimized; (4) the risk of
a placebo control does not exceed a threshold of
acceptable research risk; (5) the risk of the placebo
Volume 11, Issue 2, February 2015
control is justied by valuable knowledge to be
gained; and (6) using a placebo control is adequately
disclosed and authorized during the informed consent
process.(p126)
CONFLICTS OR CONFUSION
Ethical concerns about performing placebo surgeries
on subjects are important to consider, but there are
also major ethical implications in not using placebo
controls. Without controls, misleading data could
result in harm to future subjects. Without an ap-
propriate control group, scientists cannot make
accurate estimates of the benets and risks. On the
other hand, with appropriate controls, interventions
could be developed that could benet subjects and
limit the risk to participants.
There are ethical considerations of placebo sur-
gery for the participants and society. This is a com-
plex issue involving principles including respect for
persons, benecence, and justice. Autonomy ac-
knowledges the right of patients to determine what
will be done with his or her own person. It allows
them to decide their own course of treatment and
follow through on a plan in which they agree. It
is from this principle that informed consent is de-
rived. Burris15 in his editorial comments states that
preventing subjects from deciding what risks they
are willing to take is a direct violation of the principle
of autonomy.(p353) Research should not be declared
unethical because the process of informed consent is
imperfect. Instead, many believe that the informed
consent process should be improved.
The American Medical Association (AMA) states
that the use of surgical placebo controls should only
be applied when there is no other trial design that can
give the requisite data needed for the research study.2
In order to protect the rights of patients, the AMA
advocates that safeguards are put in place. These
include particular attention to the informed consent
process, especially during the enrollment process, and
a careful explanation of the use of placebos along
with the description of the differences between the
trial arms emphasizing the essential procedure that
will or will not be performed. In addition, the AMA
recommends that a neutral third party provide
information and obtain the consent. The AMA
has stated that the use of surgical placebo controls
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must be justied when an existing accepted surgical
procedure is being tested for efcacy. However, they
do not feel it is justied if only minor modications
of an existing accepted surgical procedure.8
The ethical principles of benecence and non-
malecence are also important to consider in the case
of placebo surgery. The ethical principle of bene-
cence means to promote good.16 It actively contributes
to the health and well-being of a person and is
concerned with issues such as quality of life. PD is a
neurodegenerative disease and is complex because it
involves motor and nonmotor symptoms that affect
the quality of life of patients and their families.
A consideration of the viewpoint of patients and
their families is an integral component of the dis-
cussion. A qualitative research study in the United
Kingdom was conducted by Swift17 and examined
the perspectives of patients living with PD and their
families. This study found that a small majority of
interviewees felt that placebo controls were ethically
acceptable. However, the hypothetical participation
in the surgery was driven by disease severity, age, and
lack of standard treatment options. Patients attitudes
toward research in general inuenced their desire to
participate in placebo surgery. In Swifts article, it was
reported that patients had a preference for receiving
the real surgery over the placebo surgery (Table 1).
One patient, when asked about reservations for sham
surgery, stated that without research people wouldnt
get the treatment I am getting now, so someone had
to take the risk somewhere along the line. Another
patient commented, I dont disagree with it, they
need to know what works and what doesnt, dont
they? If this is their best method of trying to nd
out what works, then Id have to go with it.17(p10)
Those who disagreed with the idea of sham surgery
stated that they would be disappointed or upset if
they were assigned to the placebo control group. A
relative of a patient living with PD commented that
I dont believe in the pretend group, I think it is
upsetting for people.(p10)
The Parkinsons Pipeline Project is a grassroots
effort founded and led by Dr Perry Cohen that
provides a knowledgeable patient advocate perspec-
tive on this issue as well other issues surrounding the
development of new treatments. Cohen et al18 ask
how, in good conscience, we can sell our peers on
The Journal for Nurse Practitioners - JNP 243
Table 1. Advantages and Disadvantages of Placebo Surgery
1. Age and disease severity
2. Attitude toward research
3. General attitudes to surgery
and medical environment
4. Individual attitude toward
opportunity and risk taking
5. Trial group preference
Adapted from Swift T, 2012.16
Pro
Advanced Stages of Parkinson
disease, poor quality of life
Strong support to research in general
and methodological rationale behind
trial design
Altruistic nature
Research is valuable and necessary
(self-interest and benecial for future
generations)
Gratitude to others who participated in
research
Rationally accept randomization
Potential benet from placebo effect
Want autonomy and right to make
own decision
Ultimate benet for patient
Strong desire to improve quality of life
General positive attitude toward new
opportunities
Chance to avoid risk of real treatment
if in placebo group
Advantage of receiving real treatment
after trial tested
Prefer to receive real treatment
Con
Early Stages of Parkinson disease
Unhappiness if allocated to sham surgery
group-stress without benet
Time wasted between sham and real
operation
Burden of sham operation without direct
benet gained
Risk related to hospital environment and
brain surgery
Risk of iatrogenic illness
Personal tendency against risk taking, feel
like guinea pig
Dont like being the pretend group
Considerable burden of going through 2
operations
Risk of real group
Sense of unfairness if in sham group
Burden if in placebo group without direct
benet

placebo control and sham surgery in particular.(p539)
Cohen19 presented the patient activist perspective at
a symposium titled Sham Neurosurgical Procedures
in Clinical Trials for Neurodegenerative Diseases
and Ethical Considerations hosted by the National
Institutes of Health. Cohen concluded his talk with
several points, but 2 are particularly relevant to this
discussion. First, if assumptions are made about the
relationships among variables, it needs to be veried.
The interactions between the treatment and the very
powerful placebo response to brain surgery are not
known. Second, if placebo responses are reliable,
stable, and durable, they should not be treated as bias
to be eliminated but rather as an important part of the
therapeutic process.
Nonmalecence is a term that means to do no
harm, indicating that medical personnel must avoid
harming patients and actively prevent harm when-
ever possible. All placebo surgeries expose a patient
to risk of anesthesia and infection, and there is post-
operative pain after surgery. Subjects need to be
carefully monitored for signs and symptoms of
infection at the operative site and receive appropriate
pain management. Cohen19 hypothesized that the
agreement to participate in placebo surgery trials may
relate to desperation and a lack of treatment options.
Murray and Stoessi20 describe the placebo effect in
patients with PD linked to the expectation of reward.
The principle of justice involves the fair distri-
bution of care. Rising health care costs coupled with

244 The Journal for Nurse Practitioners - JNP Volume 11, Issue 2, February 2015
the decreased availability of care makes this principle
an important one. The balance needs to be found
between expenses and revenue available to pay for
them. A realistic concern is that patients are being
invited to undergo higher than minimal risks in
the placebo group without any chance for direct
benet. A poor research design is one that has no
control and may produce data that are not clinically
helpful. It may leave subjects without the best
possible therapy.
ARGUMENTS IN FAVOR OF PLACEBO SURGERY AS A
CONTROL
Freeman et al8 supported the use of placebo
cellular-based surgery in PD because the placebo
surgical procedures were similar to the gold standard
of a placebo-controlled study design used in other
pharmacologic clinical trials. Frank et al11 and
Miller4 agree with this. It is interesting to note that
Freeman et al formulated, designed, and conducted
the placebo surgical trials and are invested in the
success of these trials. Frank et al conducted an
analysis of the trials in order to determine the safety
of placebo surgery. The cohort studied was small,
and there was no reference made to the statistical
power used to draw these conclusions except to say
that the sample size is small.(p1103) Kieburtz,
who is a well-known neurologist and clinical trial
design expert, stated that perhaps this situation is
not right, but this is the current environment in
which clinical trials of surgical procedures will be
conducted.12(p67)
ARGUMENTS AGAINST THE USE OF PLACEBO
SURGERY
Macklin21 voiced ethical concerns in opposition to
the use of placebo surgery in human research trials.
Macklins commentary delineates the following
questions: When the highest research design and
highest ethics standards are in direct conict, which
standard is the most important? When there exists
a disagreement of the risk/benet ratio within a
research protocol, which is the correct one to
consider? Does the subject determine the risks
they are asked to assume? and Does the subject
require protection by someone more knowledgeable
of the risks? Macklin concluded that fetal cell
www.npjournal.org
transplantation placebo surgeries in PD were
ethically unacceptable because nonmalecence
provides the ethical standard for any research design
and accordingly is the most important standard; the
risk/benet ratio was uncertain and unfavorable
and, therefore, not minimal; and the informed
consent led to therapeutic misconception.
Therapeutic misconception means that when a
participant enrolls in a research study, they misinterpret
and or even distort information about the research
so that they believe that some aspect of the research
will directly benet them. They may hear only what
they want to hear, be confused about the role of
the physician and/or researcher, or be confused
about the methods of randomization in a research
protocol.22 Dekkers and Boer23 stated that placebo
surgery was morally unacceptable and favored
alternatives to the use of a placebo surgery
control. London and Kadane9 also opposed the
use of placebo surgery based on ethical and
methodological considerations that fail to meet the
equipoise condition for the pursuit of a clinical trial.
Macklin,21 London and Kadane,9 and Dekkers and
Boer23 oppose placebo surgery in PD. They are
bioethicists not neurosurgeons.
CONCLUSION/DISCUSSION
Horisberger24 recommends that the participants in a
randomized study with a placebo procedure group
should be offered the possibility of receiving the new
experimental treatment without participating in the
randomized study. When possible outcomes are
presented to a research subject in a realistic way,
including the uncertainties about the outcome of a
new treatment, some people may choose to participate
just for altruistic reasons. Horisberger states that more
subjects may want to participate if all the subjects are
offered the possibility of receiving the new treatment
later if proved to be effective.24(p354) Cohen19 stated
that a knowledgeable patient perspective must be a
key component of the dialogue. Cohen et al7 provided
evidence of type 2 errors (false negatives) in placebo
surgery trials. In a discussion of the risk/benet ratio,
Cohen et al18 stated that patients living with a
chronic debilitating illness are more concerned of the
possibility of type 2 errors as opposed to a type 1 error
(false positives). A type 2 error means that effective
The Journal for Nurse Practitioners - JNP 245
treatments do not make it to the market. A type 1
error exposes patients to an ineffective or harmful
treatment.
Opinion is divided among researchers, ethicists,
patients, and other stakeholders on the ethical
acceptability of placebo surgery. Nursing pro-
fessionals must be aware of the controversy in order
to provide sound knowledge and guidance to pa-
tients. A key nursing advocacy role is one of unbiased
resource as patients and families struggle to under-
stand the options in the setting of a chronic pro-
gressive illness. Individuals living with a progressive
neurodegenerative condition such as PD represent
a vulnerable group. Patients are often willing to pay
for cell replacement therapies and often travel out of
the United States for these therapeutic interventions,
which have not been tested in well-controlled clin-
ical trials. Nursing professionals are in a position to
provide education to patients and families by explaining
the rationale for well-conducted placebo-controlled
clinical trials. Nursing professionals can also be
advocates for these vulnerable individuals by providing
a knowledgeable unbiased sounding board as patients
consider their options. It is important that those who
fully understand the risk and benets be enrolled in
the experiments. The assessment of subject compre-
hension and independent verication of compre-
hension are 2 methods of limiting investigator or
study staff bias in the consenting process for high-risk
research.25
Neuroscientists are continuing to seek an un-
derstanding of the pathology of PD. Neurode-
generative diseases and traumatic brain injury are
devastating conditions. The hope in future treat-
ments lie in the hopes of coaxing the remaining
brain cells and nervous system to repair and replace
injured or damaged cells.26 As a result, novel
treatments will need to be tested on human subjects.
Cellular-based implants involving sham surgery
certainly have promise once neuroscientists have
unraveled the cellular pathology of PD. Although
there is no cure available for PD at this time, it is
incumbent on the research community to uphold
the highest ethical standards when studying new
therapies so that society as a whole will benet
from discoveries. At the same time, care needs
to be taken to ensure that patients will be offered
246 The Journal for Nurse Practitioners - JNP
the best treatment that medical science has
available. Nursing professionals are key members
of the neurology team who will provide educa-
tion and advocacy to the patients seeking these
therapies.
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engineering/research_programs/neuroregeneration.html. Accessed
June 14, 2014.

Susan Rebecca Dunlop, MS, RN, is an associate director at Johns 1555-4155/14/$ see front matter
2015 Elsevier, Inc. All rights reserved.
Hopkins Parkinsons Disease and Movement Disorders Center in http://dx.doi.org/10.1016/j.nurpra.2014.07.022

www.npjournal.org The Journal for Nurse Practitioners - JNP 247