in its original application, "nocebo" had a very specific meaning in the medical domains

of pharmacology, nosology, and etiology.

It was a subject-oriented adjective that was used to label the harmful, unpleasant, or undesirable
reactions (or responses) that a subject manifested (thus, "nocebo reactions" or "nocebo responses")
as a result of administering an inert dummy drug or placebo, where these responses had not been
chemically generated, and were entirely due to the subject's pessimistic belief and expectation that
the inert drug would produce harmful, injurious, unpleasant, or undesirable consequences.

In these cases, there is no "real" drug involved, but the actual harmful, unpleasant or undesirable
physiological, behavioural, emotional, and/or cognitive consequences of the administration of the inert
drug are very real.

[edit]Etymology

The term nocebo (Latin for "I will harm") was chosen by Walter Kennedy, in 1961, to denote the
counterpart of one of the more recent applications of the term placebo (Latin for "I will please");
namely, that of a placebo being a drug that produced a beneficial, healthy, pleasant, or desirable
consequence in a subject, as a direct result of that subject's beliefs and expectations.

[edit]Description

W.R.Houston may have been the first to have spoken of a doctor's deliberate application of harmful
"placebo" procedures, as distinct from the other, harmless sort of "placebo" procedures a doctor might
apply and whose "usefulness was in direct proportion to the faith that the doctor had and the faith that
he was able to inspire in his patients". Houston (1938,p.1418) wrote:

... [and while the  efficacy of the placebo procedure] is believed in by the doctor, [the placebo
procedure itself] is no longer harmless but harmful, sometimes very dangerous. It would
seem peculiarly contradictory to speak of the painful and dangerous placebo, yet men are so
constituted that they feel the need in dire extremity of resorting to dread measures. Nervous
patients in particular, feel that a certain standing and sanction is bestowed upon their
maladies when violent therapeutic measures are used."

Houston spoke of three significantly different categories of placebo (pp.1417-1418):

 the drug that the physician knows to be inert, but which the subject believes to be potent.
 the drug which is believed to be potent by both subject and physician, but which later
investigation proves to have been totally inert.
 the drug which is believed to be impotent by both subject and physician, but is actually
harmful and dangerous, rather than being inert and harmless.

The term "nocebo response" originally only meant an unpredictable unintentional belief-
generated injurious response to an inert procedure, but there is an emerging practice of labelling
drugs that produce unpleasant consequences as "nocebo drugs" meaning that the term "nocebo
response" may be used to label an intentional, entirely pharmacologically-generated and quite
predictably injurious outcome that has ensued from the administration of an active (nocebo)
drug.[citation needed]

Anthropologists use the term "nocebo ritual" to describe a procedure, treatment, or ritual that has
been performed (or a herbal remedy or medication that has been administered) with malicious
intent, by contrast with a placebo procedure or treatment or ritual that is performed with a
benevolent intent.

An example of nocebo effect would be someone who dies of fright after being bitten by a non-
venomous snake.

[edit]Response

In the strictest sense, a nocebo response occurs when a drug-trial's subject's symptoms are
worsened by the administration of an inert, sham,[1] or dummy (simulator) treatment, called
a placebo.

According to current pharmacological knowledge and the current understanding of cause and

effect, a placebo contains no chemical (or any other agent) that could possibly cause any of the
observed worsening in the subject's symptoms. Thus, any change for the worse must be due to
some subject-internal factor.

The worsening of the subject's symptoms is a direct consequence of their exposure to the
placebo, but those symptoms have not been chemically generated by the placebo. Because this
generation of symptoms entails a complex of "subject-internal" activities, in the strictest sense,
we can never speak in terms of simulator-centred "nocebo effects", but only in terms of subject-
centred "nocebo responses".

Although some attribute nocebo responses (or placebo responses) to a subject's gullibility, there
is no evidence that an individual who manifests a nocebo/placebo response to one treatment will
manifest a nocebo/placebo response to any other treatment; i.e., there is no fixed
nocebo/placebo-responding trait or propensity.

McGlashan, Evans & Orne (1969, p.319) found no evidence of what they termed a "placebo
personality". Also, in a carefully designed study, Lasagna, Mosteller, von Felsinger & Beecher
(1954), found that there was no way that any observer could determine, by testing or by
interview, which subject would manifest a placebo reaction and which would not.

Experiments have shown that no relationship exists between an individual's

measured hypnotic susceptibility and his/her manifestation of nocebo or placebo
responses.[2]

[edit]Causes
The term "nocebo response" was coined in 1961 by Walter Kennedy (he actually spoke of
a "nocebo reaction").

He had observed that another, entirely different and unrelated, and far more recent
meaning of the term placebo was emerging into far more common usage in the technical
literature (seehomonym); namely that a "placebo response" (or "placebo reaction") was a
"pleasant" response to a real or sham/dummy treatment (this new and entirely different
usage was based on the Latin meaning of the word placebo, "I shall please").

Kennedy chose the Latin word nocebo ("I shall harm") because it was the opposite of the
Latin word placebo ("I shall please"), and used it to denote the counterpart of the placebo
response: namely, an "unpleasant" response to the application of real or sham treatment.

Kennedy very strongly emphasized that his specific usage of the term nocebo did not refer
to "the iatrogenic action of drugs":[3] in other words, according to Kennedy, there was no
such thing as a "nocebo effect", there was only a "nocebo response".

He insisted that a nocebo reaction was subject-centred, and he was emphatic that the
term nocebo reaction specifically referred to "a quality inherent in the patient rather than in
the remedy".[3]

Even more significantly, Kennedy also stated that whilst "nocebo reactions do occur [they
should never be confused] with true pharmaceutical effects, such as the ringing in the ears
caused by quinine".[3]

This is strong, clear and very persuasive evidence that Kennedy was precisely speaking of
an outcome that had been totally generated by a subject's negative expectation of a drug
or ritual's administration; which was the exact counterpart of a placebo response that would
have been generated by a subject's positive expectation.

And, finally, and most definitely, Kennedy was not speaking of an active drug's unwanted,
but pharmacologically predictable negative side-effects (something for which the
term nocebo is being increasingly used in current literature).

[edit]Ambiguity of medical usage

In a paper,[4] Stewart-Williams and Podd argue that using the contrasting terms "placebo"
and "nocebo" to label inert agents that produce pleasant, health-improving or desirable
outcomes, or unpleasant, health-diminishing, or undesirable outcomes (respectively), is
extremely counterproductive.

For example, precisely the same inert agents can produce analgesia and hyperalgesia, the
first of which, from this definition, would be a placebo, and the second a nocebo.
 A second problem is that precisely the same effect, such as immunosuppression, may be
quite desirable for a subject with an autoimmune disorder, but be quite undesirable for
most other subjects. Thus, in the first case, the effect would be a placebo, and in the
second, a nocebo.

A third problem is that the prescriber does not know whether the relevant subjects consider
the effects that they experience to be subjectively desirable or undesirable until some time
after the drugs have actually been administered.

A fourth problem is that, in cases such as this, precisely the same phenomena are being
generated in all of the subjects, and these are being generated by precisely the same drug,
which is acting in all of the subjects through precisely the same mechanism. Yet, just
because the phenomena in question have been subjectively considered to be desirable to
one group, but not the other, the phenomena are now being labelled in two mutually
exclusive ways (i.e., placebo and nocebo); and this is giving the false impression that the
drug in question has produced two entirely different phenomena.

These sorts of argument produce a strong case that — despite the fact that, in some of its
applications, the term "placebo" is used to denote something that pleases (compared with it
denoting an inert simulator) — the desirability (placeboic nature) or undesirability (noceboic
nature) of the phenomena that have been manifested by a subject, after a drug has been
administered, should never be part of the definition of what constitutes either "a placebo" or
"a placebo response".

[edit]Ambiguity of anthropological usage

Some people maintain that belief kills (e.g., "voodoo death": Cannon (1942) describes a
number of "voodoo deaths" from a variety of different cultures) and belief heals (e.g., faith
healing).

A "self-willed" death (due to voodoo hex, evil eye, pointing the bone procedure,[5] etc.) is an

extreme form of a culture-specific syndrome or sociogenic illness, that produces a
particular form of psychosomatic or psychophysiological disorder, which results in a
psychogenic death.

There are many recorded instances of self-willed psychogenic death. [citation needed]
Rubel (1964) spoke of "culture bound" syndromes, which were those "from which members of
a particular group claim to suffer and for which their culture provides an etiology, diagnosis,
preventive measures, and regimens of healing” (p.268).

It is important to distinguish these "self-willed deaths" from other "self-imposed"

sorts of death, such as:
 the "self-inflicted deaths" of suicide, voluntary euthanasia, or the refusal of
life-extending treatment;
 the "heroic" "self-inflicted death" of a soldier who throws himself on a hand
grenade to save his mates, or that of the Antarctic explorer
Captain Lawrence Oates (“I am just going outside and may be some time”);
or
 the "religious self-inflicted death"' of the self-immolating suttee, or the mors
voluntaria religiosa (= "voluntary religious death") of the aged person, who
religious elders have permitted to voluntarily, peacefully, and slowly die
by fasting.

Certain anthropologists, such as Robert Hahn and Arthur Kleinman have

extended the placebo/nocebo distinction into this realm in order to allow a
distinction to be made between rituals, like faith healing, that are performed in
order to heal, cure, or bring benefit (placebo rituals) and others, like "pointing
the bone", that are performed in order to kill, injure or bring harm (nocebo
rituals).

As the meaning of the two inter-related and opposing terms has extended, we
now find anthropologists speaking, in various contexts, of nocebo or placebo
(harmful or helpful) rituals:

 that might entail nocebo or placebo (unpleasant or pleasant) procedures,

 about which subjects might have nocebo or placebo (harmful or beneficial)
beliefs,
 that are delivered by operators that might have nocebo or placebo
(pathogenic, disease-generating or salutogenic, health-promoting)
expectations,
 that are delivered to subjects that might have nocebo or placebo (negative,
fearful, despairing or positive, hopeful, confident) expectations about the
ritual,
 which are delivered by operators who might have nocebo or placebo
(malevolent or benevolent) intentions, in the hope that the rituals will
generate nocebo or placebo (lethal, injurious, harmful or restorative,
curative, healthy) outcomes;

and, that all of this depends upon the operator's overall beliefs in the harmful
nature of the nocebo ritual or the beneficial nature of the placebo ritual.
Phase 0
Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the
United States Food and Drug Administration's (FDA) 2006 Guidance on ExploratoryInvestigational
New Drug (IND) Studies.[21] Phase 0 trials are also known as human microdosing studies and are
designed to speed up the development of promising drugs or imaging agents by establishing very
early on whether the drug or agent behaves in human subjects as was expected from preclinical
studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses
of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the
agent's pharmacokinetics (how the body processes the drug) and pharmacodynamics (how the drug
works in the body).[22]

A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any
therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates in
order to decide which has the best pharmacokinetic parameters in humans to take forward into further
development. They enable go/no-go decisions to be based on relevant human models instead of
relying on sometimes inconsistent animal data.

Questions have been raised by experts about whether Phase 0 trials are useful, ethically acceptable,
feasible, speed up the drug development process or save money, and whether there is room for
improvement.[23]
As per GCP section 4.8.13, "a non-therapeutic trial (i.e. a trial in which there is
no anticipated direct clinical benefit to the subject), should be conducted in
subjects who personally give consent and who sign and date the written informed
consent form." 

An investigator  is conducting BA-BE study (non-therapeutic) in healthy

postmenopusal female subjects who are illitrate and can not sign the informed
consent form but can put their thumb impression. Investigator does the ICF
presentation in presence of impartial witness as per GCP.

Questions: As the subjects can not sign and date (as per 4.8.13 mentioned
above) they should not be enrolled into the  non-therapeutic trial? Thumb
impression of subject is sufficient? Does it mean that only littrate subjects can
participate in non-therapeutic trials?

I wouls be very thankful to have your precise opinion as per GCP.

Yes only literate patients should participate in a non therapeutic study as per 4.8.13,
however if all criteria of 4.8.14 are getting fulfilled then, the subject may put a thumb
impression and a literate legal representative may sign and date. If legal representative
is also illiterate then subject and legal representative will put thumb impression +
impartial witness will sign and date.
Favorable risk-benefit ratio

Every medical research project involving human subjects should be

preceded by careful assessment of predictable risks and burdens in
comparison with foreseeable benefits to the subject or to others.

Declaration of Helsinki. Principle 16

Research in the form of controlled clinical trials involves components that

offer the prospect of direct health-related benefits (therapeutic components),
and components that are included solely to answer the research question
(non-therapeutic components). The research question is typically framed in
the form of a null hypothesis that states that there is no difference between
the trial arms with respect to the outcomes measured. These non-
therapeutic components may take the form of invasive or non-invasive
diagnostic and prognostic testing procedures, not ordinarily performed in the
course of clinical care; accumulation of additional clinical and biochemical
parameters; performance of investigational genetic tests on blood or tissue
samples as ancillary research studies; and a greater intensity or duration of
follow-up monitoring after the completion of the therapeutic interventions.

As with other forms of research, the design of the research protocol should
maximize benefits and minimize risks to research participants. Research
ethics committees should engage in a systematic, non-arbitrary assessment
of risks and benefits associated with the clinical protocol insofar as possible
(1). To this end, a systematic, component-based approach to risk-benefit
assessment proposed by Weijer (2) is recommended for this section. This
approach makes a clear distinction between the research components
described above, and emphasizes that the associated risks and benefits
should be considered separately -- risks associated with non-therapeutic
components cannot be justified on the basis of the potential benefits
derivative of the therapeutic components. This notion is discussed further in
the sections that follow.

Interventions offering the prospect of health-related benefits

The therapeutic components are directed towards the participant as a

patient. Risks associated with therapeutic components are justified by the
prospect of health-related benefits (a risk-benefit calculus). Such risks are
assumed by patients receiving therapeutic interventions outside of the trial
setting, and this concept is generally well understood by doctors and
patients. In general, it is recognized that informed patients may assume
greater risks (considering both probability and magnitude) in return for the
prospect of benefits they judge worthwhile. In the trial setting (assuming the
presence of clinical equipoise as discussed below), the situation is
conceptually analogous. The patient-subject, fully apprised of the possible
risks and benefits associated with the therapeutic interventions in both arms,
may then make a personal judgment with respect to trial participation.

Interventions and evaluations performed solely to answer the

research question

The non-therapeutic components are experienced by the participant as a

research volunteer. Risks associated with non-therapeutic components (also
referred to as "demarcated research risk") are justified by the prospect of
acquiring valuable and relevant knowledge (a risk-knowledge calculus). The
knowledge gained is intended primarily to benefit future patients. Research
ethics committees, comprising members with the necessary scientific and
non-scientific expertise to evaluate the proposed trial, should make a
determination that the inclusion of such interventions is scientifically
necessary in relation to the methodologic and statistical aspects of the trial
design, and justified in relation to the value and relevance of the knowledge
to be gained.

When research involves vulnerable participants such as children or

individuals with impaired decisional capacity, regulations or guidelines may
specify that the risks associated with research participation be limited
to minimal risk (3) or a minor increase over minimal risk. An example of this
is the regulatory prescription of permissible categories of research involving
children in the U.S. as codified in Subpart D of the Common Rule (4), and
also formally adopted by the F.D.A. Considering the component-based
approach to risk analysis, these risk limitations should be applied to the non-
therapeutic research components. Thus, the need to identify and distinguish
between therapeutic and non-therapeutic components is evident, and
should be delineated as such in the application for research.

Establishment of clinical equipoise

The benefits, risks, burdens, and effectiveness of a new method should be

tested against those of the best current prophylactic, diagnostic, and
therapeutic methods.

Declaration of Helsinki. Principle 29

Randomized controlled trials are performed to accomplish this purpose, and

may also be used to evaluate the comparative efficacy of currently available
and utilized treatments. Stated differently, a randomized trial is performed to
resolve uncertainty about the efficacy of an intervention, particularly when
considered in relation to other available treatments, if any (5). At the
inception of a randomized trial, there should be genuine uncertainty
concerning which arm of the trial may be superior, when both benefits and
risks associated with the interventions are taken into account. This notion
has been termed the uncertainty principle, and may be present at three
levels as described by Rolleston (6) and Sackett (7). The latter's elaboration
is adapted and summarized in the table below.
 Levels of uncertainty relevant to the conduct of, and
participation in, a randomized controlled clinical trial

Community uncertainty -- reflecting the collective judgment of

the community of expert practitioners in the pertinent field,
and derivative of a systematic assessment of existent evidence
in the medical literature

Individual clinician uncertainty -- reflected in the opinion of an

individual practitioner who needs to decide whether to
recommend participation to a particular patient

Patient uncertainty -- as expressed through the patient-

physician relationship, and representing a patient's values
derivative of an informed consideration of purported benefits
and risks of available treatments

The notion of community uncertainty is particularly relevant to research

ethics committees which must decide whether to approve the proposed trial
and thus make it available to potential participants. This level of uncertainty
represents the moral underpinning of randomized clinical trials, and is the
state of clinical equipoise as originally conceived by Freedman
(8). Equipoise implies that the expected size and probability of improvement
balance the size and probability of side effects (perceived risks) of
comparator treatments (9). This concept is perhaps less ambiguous than the
notion of uncertainty. More recently, Weijer and colleagues (10) have again
emphasized the relevance of clinical equipoise over the uncertainty
experienced by the individual clinician as a precondition for trial inception.
The presence of clinical equipoise permits the simultaneous
accomplishment of two objectives: offering the patient-participant the best
bet (in the presence of uncertainty) of getting the best treatment through the
process of randomization, and acquiring valuable and relevant medical
knowledge.

Investigators proposing a trial should provide the committee with

relevant background information in support of a claim of equipoise,
including reference to a pertinent Systematic Review (11) whenever
feasible. If a Systematic Review is not available for the subject under
investigation, the investigator should provide the committee with
details concerning the literature review conducted in support of the
conduct of a randomized controlled trial. These details should include
a full description of the methods and search strategy utilized to
acquire and synthesize the relevant medical literature. Guidance in this
regard is available from the Cochrane Collaboration (12).
A systematic literature review will also serve to accumulate evidence in
support the choice of a control arm, particularly when new therapies are
being evaluated. It has been demonstrated in analysis of reported trials that
inappropriate choices have been made, particularly when trials are
supported by commercial sponsors (13). Analogously, the use of placebo
controls must be carefully appraised to ensure that clinical equipoise is
present. If equipoise is not present, the use of a placebo control must be
explicitly justified. The use of placebo controls is a contentious issue (14),
and a full discussion is beyond the scope of this document.

With respect to a particular trial, a physician may or may not be in equipoise.

In recognition of his fiduciary status derivative of the physician-patient
relationship, he may be uncertain whether to offer participation to his
patient. Even if he is not in equipoise, he should inform his patient of the
availability of a trial, thus fulfilling the obligation to provide information
concerning alternatives to any proposed treatments. Indeed, it has been
proposed that this is a moral requirement (15). Analogously, the potential
participant should be provided all the necessary information about the trial
so that the patient, expressive of his personal medical goals and values,
may determine whether he is in equipoise and thus willing to undergo
randomization.

The concept of component-based risk analysis, and the application of

clinical equipoise to the analysis of a clinical research protocol
is summarized in this figurefrom Weijer, which is reproduced with the
permission of the author.