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Review Article

Usha Gupta, Menka Verma

Placebo in clinical trials
Nodal Corporate Resource for Clinical
Pharmacology and Medication
Management, Fortis Hospital, B‑22,
Sector‑ 62, Noida, Uttar Pradesh, India

Address for correspondence:

Dr. Usha Gupta,
Nodal Corporate Resource for Clinical
Pharmacology and Medication
Management, Fortis Hospital,
B‑22, Sector‑ 62,
Noida, Uttar Pradesh, India.
E‑mail: usha.gupta@
fortishealthcare.com

INTRODUCTION definition should be unable to elicit an effect, and therefore

placebos cannot elicit effects.This can be further confused
For many years, placebos have been conceptualized by their with terminology such as ‘active’, ‘true’, and ‘perceived’
inert content and their use as controls in clinical trials and placebos.[3‑6]
treatments in clinical practice. Recent research demonstrates
that placebo effects are genuine psychobiological A greater understanding of the placebo effect is the
phenomena attributable to the overall therapeutic recognition that there is not one placebo effect but
context, and that placebo effects can be robust in both many. These mechanisms can be broadly discussed from
laboratory and clinical settings. Evidence has also emerged psychological and neurobiological viewpoints.
that placebo effects can exist in clinical practice, even if
Psychological mechanisms
no placebo is given.[1] The use of the word ‘placebo’ in a
From the psychological viewpoint, a multitude of
medical context, meaning innocuous treatment to make
mechanisms contribute to placebo effects. These include
a patient comfortable, dates back to at least the end of
expectations, conditioning, learning, memory, motivation,
the 18th century.[2] The interest in placebo effects only began
somatic focus, reward and reduction of anxiety.[7,8]
with the widespread adoption of the randomized controlled
trial (RCT) after world war II. Since then several trials Neurobiological mechanisms
using placebo as a control group have been carried out. Research into the neurobiology of responsiveness to
However, its use in certain clinical trials remains one of placebo has addressed placebo analgesia; accordingly, the
the debated elements. neurobiology of placebo effects is commonly considered
in terms of opioid and non‑opioid mechanisms.[9,10] Several
MECHANISM OF ACTION OF THE PLACEBO studies have demonstrated that placebo effects can be
completely or partially reversed by the opioid antagonist
Generally, a placebo is seen as an inert substance or naloxone, supporting the involvement of endogenous
procedure and the placebo effect (or response) is something opioids in some analgesic effects of placebo. [11‑14]
that follows the administration of a placebo. The paradox in Furthermore, analgesic effects of placebo are likely to be
this statement lies with the fact that if something ‘inert’ by inhibited by the peptide cholecystokinin (CCK) for they
are potentiated when a CCK antagonist is administered.
Access this article online Considered together, these studies demonstrate that some
Quick Response Code:
Website: mechanisms of placebo operate by altering the activity of
www.picronline.org
both CCK and endogenous opioids.[12,15,16]

DOI: PLACEBO IN CLINICAL TRIALS

10.4103/2229-3485.106383
The placebo, a pharmaceutically inert substance (typically

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Gupta and Verma: Placebo in clinical trials

a sugar pill), is the clinical researcher’s analogue to the to placebo in RCTs may reflect the natural course of the
scientist’s control experiment. To prove a new treatment disease, fluctuations in symptoms, regression to the mean,
effective above and beyond the psychological results of a response bias with respect to the patient’s reporting of
simple belief in the ability of the drug to cure, a researcher subjective symptoms and other concurrent treatments.[3,4]
compares the results of the experimental treatment for
an illness with those obtained from the placebo. The Clinical equipoise in placebo‑controlled trials
placebo‑controlled trial “is widely regarded as the gold Another argument proposed against placebo‑controlled
standard for testing the efficacy of new treatments.”[17] trials is that they potentially violate the concept of clinical
equipoise when proven effective therapy is available.
Interest in placebo effects began only with the widespread Clinical equipoise refers to the state where clinicians are
adoption of the placebo‑controlled clinical trials after unsure whether the new treatment or intervention is as
World War II. The randomized clinical trial was a major good as the standard treatment. Those who reject the
methodological breakthrough in medicine and the best use of placebo‑controlled trials argue that they violate
evidence for new treatment came from randomized the therapeutic obligation of physicians to offer optimal
placebo‑controlled (RCT) double‑blind studies. It was medical care. In other words, they compromise the right of
noticed that patients improved, sometimes dramatically, the patient to receive the best care possible and violate the
in placebo control arms. Henry Beecher popularized this ethical principle of therapeutic beneficence. Furthermore,
observation in his famous proto‑meta‑analysis which these clinicians have argued that when proven therapy
claimed that about 35% of the patients responded exists, the use of a placebo‑controlled trial lacks both
positively to placebo treatment.[18,19] scientific and clinical merit.[21‑23]
The use of placebo is also questioned in vulnerable groups
ETHICS OF PLACEBO‑CONTROLLED TRIALS like children, psychiatric patients, and patients suffering
from cancer.
The use of a placebo in clinical research continues to be a
topic of debate in the medical community in recent times. Ethics of placebo in children
Some argue that the use of placebos is often unethical The use of placebo in children is more restricted than
because alternative study designs would produce similar in adults, because children cannot consent. Placebo
results with less risk to individual research participants. should not be used when it means withholding effective
Others argue that the use of placebos is essential to protect treatment, particularly for serious and life‑threatening
the society from the harm that could result from the conditions. The use of placebo is often needed for
widespread use of ineffective medical treatments. scientific reasons, including pediatric trials. The use of
placebo may be warranted in children as in adults when
Critics of placebo‑controlled trial or trials that include an evidence for any particular treatment is lacking or when
untreated control group cite Article 11.3 of the Declaration the placebo effect is known to be very variable (e.g., pain,
of Helsinki: “In any medical study, every patient including hay fever). As the level of evidence in favor of an effective
those of control group, if any should be assured of the treatment increases, the ethical justification for the use
best proven diagnostic and therapeutic methods and no of placebo decreases.[24]
patient should suffer from unnecessary pain.”[20]
Usefulness of placebo
In randomized clinical trials, for conditions having no The use of placebo is not equivalent to the absence of
effective treatment, the control regimen with which the treatment, for example, placebo could be used in addition
new treatment is compared, is warranted to establish the to standard care. In all cases, its use should be associated
evidence. However, when an effective treatment already with measures to minimize exposure and avoid irreversible
exists, it is unethical to create a placebo group that will harm, especially in serious or rapidly evolving diseases.
receive no treatment. In other words, patients are deprived As appropriate, rescue treatment and escape procedures
from an already existing effective therapy. The objective should be set up.
of testing such drugs to establish whether the new drug is
better in efficacy or safety when compared to the existing Other situations where the use of placebo should be
drug/s placebo controlled trial considered unethical. scrutinized and challenged include run‑in periods where a
protocol requires active treatment to be withheld.
The association of placebo effects with RCTs has caused
confusion because the response in the placebo arm is Situations in which placebo may be considered as a
not necessarily a genuine psychosocial response to the comparator, for example, might be when there is no
simulation of treatment. In fact, the observed response commonly accepted therapy for the condition and the

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Gupta and Verma: Placebo in clinical trials

investigational medicinal product is the first one that may ‘add‑on’ method, keeping the subjects on identical
modify the course of the disease process. maintenance treatments and then adding on the active
treatment to one arm and the placebo to the other. This
It is useful when the commonly used therapy for the design is especially applicable when the available treatment
condition is of questionable efficacy or carries with it a is known to decrease mortality or morbidity.
high frequency of undesirable adverse reactions and the
risks may be significantly greater than the benefits.[24] Shortened treatment periods reduce the risks associated
with delayed treatment. In situations in which long‑term
Guidelines of the office for human research protection on placebo treatment would not be acceptable, the use of a
placebo placebo group for a short period at the beginning of a trial
The Office for Human Research Protection (OHRP) could establish short‑term effects. The trial could then
published guidelines in 2008 for the use of placebo and continue without the placebo group.
methods to minimize the risk associated with it.[25]
Unblinded data review by a data safety monitoring board
The guidelines state, “Placebos may be used in clinical trials with interim analysis of study results and safety issues is
where there is no known or available (i.e., FDA‑approved) desirable. This is especially important for multicenter site
alternative therapy that can be tolerated by subjects.” The studies.
use of placebos in controlled clinical trials must be justified
by a positive risk‑benefit analysis, and the subjects must If a placebo is used in a study, the informed consent
be fully informed of the risks involved in the assignment form must include all of the following information: The
to the placebo group. Continued assignment of subjects subjects must be informed that they may be given a placebo.
to placebo is unethical, once there is good evidence to A clear lay definition of the term ‘placebo’ must be given
support the efficacy of the trial therapy. Some drug trials to the subjects. The rationale for using a placebo must be
involve a period during which all participants receive only explained to the subjects. If applicable, the subjects must
a placebo prior to the initiation of the study. This period be informed of any viable medical alternatives to being
is called a ‘placebo washout’. The purposes of a washout placed on placebo. The duration of time that a subject
period include: will be on a placebo, degree of discomfort, and potential
• Terminating the effects of any drug the subject may effects of not receiving medication must all be explained.
have been taking before entering the clinical trial, so Any consequences of delayed active treatment must be
that the effects of the trial drug‑and only the trial explained to the subjects.
drug‑may be observed.
• Understanding whether the subjects co‑operate with A statement in the risk section of the consent that the
instructions to take drugs. condition of the subject may worsen while on placebo
• Understanding which subjects are ‘placebo responders’, should be included.
in that they experience a high degree of placebo effect.
A discussion in the benefits section that subjects who
• In some protocols, the investigators plan to exclude
receive placebo will not receive the same benefit as those
those subjects they find either poorly compliant or
who receive active treatment if that treatment is effective
highly responsive to the placebo.
should also be included.
Methods that can be used to minimize risks associated with
the use of placebo. Subjects with an increased risk of harm SUMMARY
from non‑response may be excluded.
There are valid scientific and ethical considerations for
Increased monitoring for deterioration of subjects and the using a control group in a clinical trial. Placebo‑controlled
use of rescue medications may be included in the protocol. trials are justifiable when they are supported by sound
methodologic consideration and when their use
‘Early escape’ mechanisms and explicit withdrawal criteria does not expose research participants to excessive
may be built in so that subjects will not undergo prolonged risk of harm. Consideration should be given to the
placebo treatment if they are not doing well. ‘best‑available therapy’ control groups in the evaluation
of a new therapy or intervention over an existing
The size of the population placed on placebo may be kept therapy. Investigators should bear in mind that one
smaller than the number in the active treatment arms. should not sacrifice the scientific merit of a trial to
include the best‑available therapy control group as long
Placebo and active treatment may be compared in an as the placebo control group poses little harm to the

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Gupta and Verma: Placebo in clinical trials

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verbal expectancy in the placebo response. Pain 1990;43:121‑8.
14. Siegel S. Explanatory mechanisms for placebo effects: Pavlovian
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2003;105:17‑25. Source of Support: Nil. Conflict of Interest: None declared.

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