Transcript IN THE NAME OF GOD

Treatment should be given “ not because they ought
to work, but because they do work.”
L.H. Opie
 Once
the nature of a patient's illness has
been established and its expected course
predicted, the next question is, what can
be done about it? Is there a treatment
that improves the outcome of disease?
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Ideas about what might be a useful treatment arise
from virtually any activity within medicine. Ideas
are called hypotheses to the extent that are
assertions about the natural world made for the
purposes of empiric testing.
 Other hypotheses about treatments have come
from astute observations by clinicians.These
observations are shared with their colleagues in
case reports,which are detailed descriptions of a
single case or just a few cases.

Example:
Amantadine
 Minoxidil
 Tamoxifen
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Ideas about treatment, but more often
prevention, have also come from
epidemiologic studies of populations.
Example:
-High-fiber diets
-Fluoride
Some treatment effects are so prompt and powerful
that their value is self-evident even without formal
testing.
 In contrast, many diseases, including most chronic
diseases, involve treatments that
are considerably less dramatic.
It is then necessary to put ideas about treatments to
a formal test, through clinical research, because a
variety of circumstances, such as coincidence,
faulty comparisons, spontaneous changes in the
course of disease, or wishful thinking, can obscure
the true relationship between treatment and
outcomes.

 When
knowledge of the pathogenesis of
disease, based on work with laboratory
models or physiologic studies in humans,
has become extensive, it is tempting to
predict effects in humans on this basis
alone. However, relying solely on current
understanding of mechanisms without
testing ideas using strong clinical research
on intact humans can lead to unpleasant
surprises.
Example:
Some strokes are caused by…
Clinical experience and tradition also need to
be put to a test.
Therefore,It is almost always necessary to test
therapeutic hypotheses by means of clinical
research.
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Treatment is any intervention, which may
include prescribing drugs, performing
surgery, or counseling, that is intended to
improve the course of disease once it is
established. Treatment is a special case of
interventions in general that might be at any
point in the natural history of disease ,from
disease prevention to palliative care at the
end of life.
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In observational studies of interventions,
investigators simply observe what happens to
patients who for various reasons do or do not
get exposed to an intervention
Experimental studies are a special kind of cohort
study in which the conditions of study-that is,
selection of treatment groups, nature of
interventions, management during follow-up, and
measurement of outcomes are specified by the
investigator for the purpose of making unbiased
comparisons
 The
patients to be studied are first selected
from a larger number of patients with the
condition of interest. They are then divided,
using randomization, into two groups (or
more) of comparable Prognosis.one
group,called the experimental group and
other group,called a control group or
comparison group.
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The main reason for structuring clinical trials in
this way is to avoid bias (systematic error)
The validity of clinical trials depends on how well
they have created equal distribution of all
determinants of prognosis, other than the one
being tested, in treated and control patients.
 Clinical
trials typically require patients to
meet rigorous inclusion and exclusion
criteria.
 The usual inclusion criterion is that patients
really do have the condition being studied.
 patients in clinical trials are usually a highly
selected, biased sample of all patients with
the condition of interest.
 Because
of the high degree of selection in
trials, it may require considerable faith to
generalize the results of clinical trials to
ordinary practice settings
 Large, simple trials are a way of overcoming
the generalizability problem.
The intervention itself can be described in
relation to three general characteristics:
generalizability, complexity, and strength.
 First, is the intervention one that is likely to
be implemented in usual clinical practice?
 Second, does the- intervention reflect a
complexity that is normal for real-world
treatment plans?
 Third, is the intervention in question
sufficiently different from alternative
managements that it is reasonable to expect
that the outcome will be affected?

The value of a treatment can only be judged by
comparing its results to those of some
alternative course of action.
 No intervention. Do patients who are offered
the experimental treatment end up better off
than those offered nothing at all?
 Observation. Do treated patients do better
than other patients who are simply observed?
Placebo Treatment. Do treated patients do
better than similar patients given a placebo
an intervention intended to be
indistinguishable from the active treatment
(whether in physical appearance, color, taste,
or smell) but which does not have a specific,
known mechanism of action?
 Usual Care. Do patients given the
experimental treatment do better than those
receiving usual care?
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To study the effects of a clinical intervention free of
other effects, the best way to allocate patients to
treatment groups is by means of random allocation
(randomization).
Random allocation of patients is preferable to other
methods of allocation because only randomization
has the ability to create truly comparable groups.
All factors related to prognosis, whether or not
they are known before the study takes place or
have been measured, tend to be equally distributed
in the comparison groups.
 To
assess whether this kind of "bad luck"
has occurred, authors of randomized
controlled trials often present a table
comparing the frequency of a variety of
characteristics in the treated and control
groups, especially those known to be
related to outcome. These are called
baseline characteristics because they are
present before randomization and so
should be equally distributed in the
treatment groups.
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Patients are gathered into groups (strata) having
similar levels of a prognostic factor (such as age
for most chronic disease) and are randomized
separately within each stratum. This is a process
called stratified randomization.
Some investigators do not favor stratified
randomization
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Not all patients in a clinical trial participate as
originally planned.There are several reasons:
Patients Do Not Have the Disease Under Study
It is sometimes necessary (both in clinical trials
and in practice) to begin treatment before it
is certain whether the patient actually has the
disease for which the treatment is designed.
When patients are enrolled in a study and later turn
out not to have the index disease, there is a price
to pay. The main disadvantage of this approach
is the inefficiency of enrolling and gathering data
on patients who do not contribute to the study’s
results.
Compliance
Compliance is the extent to which patients follow
medical advice. The term adherence may be
preferable because it connotes a less subservient
relationship between patient and doctor.
In clinical trials, patients are typically selected
for their compliance. During a run-in period,
in which placebo is given and compliance
monitored, noncompliant patients can be
detected and excluded before randomization.
Co-interventions
After randomization, patients may receive a
variety of interventions other than the ones
being studied
In some clinical trials, particularly those
involving cancer, the outcomes of patients
who initially improve after treatment
(responders) are compared with outcomes in
those who do not (nonresponders).
Participants in a trial may change their
behavior or reporting of outcomes in a
systematic way if they are aware of which
patients receive which treatment. One way to
minimize this effect is by blinding
 Masking is a more appropriate metaphor, but
blinding is the time-honored term.
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First, those responsible for allocating patients
to treatment groups should not know which
treatment will be assigned next so that the
knowledge does not allow them to break the
randomization plan. Allocation concealment
is a common term for this form of blinding.
Second, patients should be unaware of which
treatment they are taking so that they cannot
change their compliance or reporting of
symptoms because of their knowledge of this
information
Third, physicians who take care of patients in
the study should not know which treatment
each patient is on
 The terms single-blind (patients) and double
blind are sometimes used, but their meanings
are ambiguous .
 A trial in which there is no attempt at
blinding is called an open or in the case of
drug trials, an open label trial.

In some trials, patients and doctors are asked
whether they believe the patient is taking an active
drug or placebo. Their answers provide objective
evidence of whether efforts to mask patients were
successful.

Assessment of outcome and how it can be
affected by measurement bias has been
discussed,as have the dangers of substituting
intermediate outcomes for clinically
important ones
 The
results of a randomized controlled trial
can be analyzed and presented in two
general ways: according to the treatment to
which the patients were randomized or
according to the one they actually received.
 Trials analyzed in this way are called
explanatory trials because they assess
whether actually taking the treatments, rather
than just being offered them,makes the
difference.
Clinical trials are also classified according to
whether they describe the results of an
intervention in ideal or real-world situations.
First, can treatment work under ideal
circumstances? trials that answer this
question are called efficacy trials.
Second, does treatment work under ordinary
circumstances? Trials designed to answer this
kind of question are called effectiveness
trials.

Clinical trial, involve pooling the experience
of many patients who may be dissimilar, both
to one another and to the patients to whom
the trial results will be generalized.
Subgroups
Patients in clinical trials can be sorted into
subgroups, each with a specific combination
of characteristics, such as age, severity of
disease, and comorbidity, that might affect
outcome
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Trials of N=1
Rigorous clinical trials, with proper attention to
bias and chance, can be done with individual
patients, one at a time. The method-called
trials of N = 1 - is an improvement over the
more informal process of trial and error that
is time-honored in clinical practice.
 This method is useful when activity of disease
is unpredictable, response to treatment is
prom pt, and there is no carryover effect from
period to period.
 N of 1 trials can be useful for guiding clinical
decision making.
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A treatment that is effective on the average may
not work on an individual patient.
When managing an individual patient,it is useful to
ask the following series of questions;
Is the treatment known (by randomized controlled
trial) to be efficacious for any patients?
Is the treatment known to be effective, on the
average, in patients like mine?
Is the treatment working in my patient?
Are the benefits worth the discomforts and risks
(according to the patient's values and preferences)?
Randomized controlled trials are the gold
standard of intervention studies.
 There may not be enough patients with the
disease of interest, at one time and place, to
carry out a scientifically sound trial. This can
be overcome by multicenter trials.
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 Comparisons
Across Time and Place
Experimental and control patients can be
assembled from different time and places.

The results of current treatment are
sometimes compared to experience with
similar patients in the past,called historical
controls or nonconcurrent controls
 Uncontrolled
trials describe the course of
disease in a single group of patients before
and after exposure to an intervention.
Another name for this design is a beforeafter study.
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The assumption of this approach is that any
improvement observed after treatment is the result
of treatment.This assumption may be unwarranted
for the reasons described below.
Unpredictable Clinical Course
Nonspecific Effects
Regression to the Mean
Predictable Improvement

Especially troubling is confounding by
indication,which occurs,in the case of a
drug,when whatever has made the dr
prescribe a drug(the”indications”)is the cause
of the observed outcome,not the drug itself.
 phase
1 trials are intended to identify a
dose range that is well tolerated and
safe(at least for high-frequency,severe side
effects)and include very small numbers of
patients(perhaps a dosen), without a control
group.
phase 2 trials provide preliminary
information on whether the drug is
efficacious and the relationship between
dose and efficacy
 phase 3 trials are randomized trials and
can provide definitive evidence of efficacy
and rates of common side effects.
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