A

Abnormality
A sign, symptom, or laboratory
result not characteristic of normal
individuals.

Adverse event
The ICH defines an adverse event
as: “Any untoward medical
occurrence in a subject or clinical
investigation subject administered
a pharmaceutical product and
which does not necessarily have to
have a causal relationship with
this treatment” (see ICH Guideline:
Clinical safety data management:
definitions and standards for
expedited reporting). For non-
marketed drugs/product, or new
indications of marketed
drugs/product, an adverse event
is referred to as an adverse
reaction when there is a
reasonable possibility that it was
caused by the medicinal product,
i.e. a causal relationship cannot be
ruled out.

Adverse experience See adverse

event.
Adverse reaction
Unwanted effect(s) (i.e., physical
and psychological symptoms and
signs) resulting from treatment. A
less rigid definition of adverse
reaction includes the previous
definition plus any undesirable
effect or problem that is present
during the period of treatment and
may or may not be a well-known
or obvious complication of the
disease itself. Thus, many common
personality, physical,
psychological, and behavioral
characteristics that are observed
in medicine studies are sometimes
characterized as adverse reactions
even if they were present during
baseline.

Synonyms of adverse reactions

generally include adverse medical
effects, untoward effects, side
effects, adverse drug/product
experiences, and adverse
drug/product reactions. Specific
distinctions among some of these
terms may be defined
operationally. For example, the
term adverse reaction is used to
denote those signs and symptoms
at least possibly related to a
medicine, whereas the term
adverse experiences is used to
include nonmedicine-related
medical problems in a trial such as
those emanating from trauma or
concurrent illness. Distinctions
among side effects, adverse
events, and adverse reactions are
illustrated in the definitions of the
two former terms.

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 B

Bias
(1) A point of view that prevents
impartial judgment on issues
relating to that point of view.
Clinical trials attempt to control
this through double blinding. (2)
Any tendency for a value to
deviate in one direction from the
true value. Statisticians attempt to
prevent this type of bias by
various techniques, including
randomization.
Biomarker
A measure that is an indicator of a
normal physiologic process, or a
pathologic state or the response of
an organism to an intervention
that can be used in clinical
research. When a biomarker can
replace a clinical endpoint it is
called a surrogate endpoint.

Blind
The term “blind” refers to a lack of
knowledge of the identity of the
trial treatment. Subjects,
investigators, date review
committees, ancillary personnel,
statisticians, and monitors are the
major groups of individuals who
may be kept blind during a clinical
trial. Blinding is used to decrease
the biases that occur in a clinical
trial when subjects are evaluated
during treatment and to avoid a
placebo effect that often occurs in
open-label trials.

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C
Clinical Drug/ Product
Development Phase
This classification assumes a
sequential approach to
drug/product development.
However, the clinical
pharmacology programmed will
overlap the later phases with a
number of studies that are
required for registration (e.g.
interaction studies, or studies in
special populations – elderly,
renally or hepatically-impaired),
and are performed at the same
time as the Phase II/III studies.

Clinical Endpoint
A measure of how a subject feels
functions or survives.

Clinical Investigator’ s Brochure

An extensive summary of all that
is known about a research
compound with regard to pre-
clinical and clinical data.

Clinical significance
The quality of a study’s outcome
that convinces physicians to
modify or maintain their current
practice of medicine. The greater
the clinical significance, the
greater is the influence on the
practice of medicine. The
assessment of clinical significance
is usually based on the magnitude
of the effect observed, the quality
of the study that yielded the data,
and the probability that the effect
is a true one. Although this
operational definition is presented
from the physician’s perspective,
the term could operationally be
defined from the subject’s
perspective. Subjects are primarily
concerned with results that will
lead to an improved quality of life
or a lengthening of their life. In
addition, clinical significance may
be applied to either positive data
of efficacy or negative safety data
such as for adverse reactions.
Synonyms include clinical
importance, clinical relevance, and
clinical meaningfulness.

Clinical studies
The class of all scientific
approaches to evaluate medical
disease preventions, diagnostic
techniques, and treatments.
Investigational and marketed
prescription medicine
evaluations plus over-the-counter
medicines or other agents
(dietary supplements) are
included.

Clinical trials
A subset of those clinical studies
that evaluates investigational
medicines in Phases I, II, and III.
Phase IV evaluations of marketed
medicines in formal clinical trials
using the same or similar types of
protocols to those used in Phases I
and III are also referred to as
clinical trials.

Combination of blinds
(a) In part 1 of a clinical trial, one
type of blind may be used (e.g.,
single blind), and in part 2 of the
same trial, another blind (e.g.,
double blind) may be used. A third
part of the same trial may utilize
the same blind as part 1 or use an
entirely different type of blind. (b)
Some subjects may follow a
protocol under one type of blind
and others follow the same
protocol under a different type of
blind. (c) The blind used may be
changed during the course of the
clinical trial according to certain
criteria (e.g., when study is done
with medical patients, the double
blind may be broken, and they
may continue their treatment on
open-label medication).

Compliance
1. Adherence of subjects to
following medical advice and
prescriptions. Primarily applied
to taking medicine as directed,
but also applies to following
advice on diet, exercise, or
other aspects of a subject’s life.
2.Adherence of investigators to
following a protocol and related
administrative and regulatory
responsibilities.
3.Adherence of sponsors to
following regulatory, legal, and
other responsibilities and
 requirements relating to a
clinical trial.

Compound
A chemical synthesized or
prepared from natural sources that
is evaluated for its biological
activities in preclinical tests.

Control Group
A group of clinical trial participants
that receives the placebo or
standard therapy for a condition
while another group is given the
experimental treatment. The
control group serves as a
measuring stick to gauge the
effectiveness of the experimental
treatment.

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Development of Medicines
The term development as applied
to medicines is used in several
different contexts, even within the
pharmaceutical industry. This often
leads to confusion and
misunderstanding. No single
definition is preferred, but the
particular meaning intended
should be made clear by all people
using the term. Three operational
definitions are presented, from the
broadest to the narrowest.

1. All stages and processes

involved in discovering,
evaluating, and formulating a
new medicine, until it reaches
the market (i.e., commercial
sale).
2.All stages involving the
evaluation and formulation of a
new medicine (after the
 medicine has been discovered
and has gone through
preclinical testing), until it
reaches the market.
3.Those stages after the
preclinical discovery and
evaluation that involve
technical development. These
processes include formulation
work, stability testing, scaling-
up the compound for larger-
scale synthesis, and providing
analytical support. Clinical trials
 are not included in this
definition.

Disease
Disorders (e.g., anxiety disorders,
seizure disorders), conditions (e.g.,
obesity, menopause), syndromes,
specific illnesses, and other
medical problems that are an
acquired morbid change in a
tissue, organ, or organism.
Synonyms are illness and sickness.

Dosage regimen
(1) The number of doses per given
time period (usually days), (2) the
time that elapses between doses
(e.g., dose to be given every six
hours) or the time that the doses
are to be given (e.g., dose to be
given at 8 a.m., noon, and 4 p.m.
each day) or (3) the quantity of a
medicine (e.g., number of tablets,
capsules, etc.) that are given at
each specific time of dosing.

Double Blind
Neither the subject nor
the investigator is aware
of which treatment the
subject is receiving. A
 double-blind design is
generally considered to
provide the most reliable
data from a clinical trial.
This type of clinical trial,
however, is usually more
complicated to initiate
and conduct than single-
blind or open-label trails.

Drug
A drug is defined as:

o A substance recognized by an
official pharmacopoeia or
formulary.
o A substance intended for use in
the diagnosis, cure, mitigation,
treatment, or prevention of
disease.
o A substance (other than food)
intended to affect the structure
or any function of the body.
o A substance intended for use as
a component of of a medicine
but not a device or a
component, part or accessory
of a device.
o Biologic products are included
within this definition and are
 generally covered by the same
laws and regulations, but
differences exist regarding their
manufacturing processes
(chemical process vs. biological
process.)

Drug Product
The finished dosage form
that contains a drug
substance, generally, but
not necessarily in
association with other
active or inactive
ingredients.
Drug/ product
A licit or illicit substance that is
abused. Medicines should be
described as drugs/product when
they are being purposely abused.

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Efficacy
A relative concept referring to the
ability of a medicine to elicit a
beneficial clinical effect. This may
be measured or evaluated using
objective or subjective parameters,
and in terms ranging from global
impressions, to highly precise
measurements. Efficacy is
assessed at one or more levels of
organization (e.g.-subcellular,
cellular, tissue, organ, whole body)
and may be extrapolated to other
levels.

Endpoint
An indicator measured in a subject
or biological sample to assess
safety, efficacy, or another trial
objective. Some endpoints are
derived from primary endpoints
(e.g., cardiac output is derived
from stroke volume and heart
rate). Synonyms include outcome,
variable, parameter, marker, and
measure. See surrogate endpoint
in the text. Also defined as the
final trial objective by some
authors.

Ethics Committee
An independent group of
professionals often complimented
by a non-scientific member of the
public responsible for approval of
study protocols before a study is
actually carried out. Subject safety
and scientific integrity of the
protocol are the main concerns.

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Good Clinical Practice

A standard to ensure protection of
research subjects and data
integrity in clinical studies of new
drugs/product.

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I
Incidence rate
The rate of occurrence of new
cases of a disease, adverse
reaction, or other event in a given
population at risk (e.g., the
incidence of disease X is Y
subjects per year per 100,000
population).

International Conference on
Harmonization
The International Conference on
Harmonization (ICH) has produced
guidelines on Good Clinical
Practice (GCP) encompassing the
requirements of the European
Union (EU), Japan and the United
States (US) as well as those of the
World Health Organization (WHO),
Australia, New Zealand and the
Nordic countries (ICH Topic E6,
Guidelines on Good Clinical
Practice).

Interpretation
The processes whereby one
determines the clinical meaning or
significance of data after the
relevant statistical analyses have
been performed. These processes
often involve developing an
explanation of the data that are
being evaluated.

Investigator
A suitably trained scientist (often
medically qualified) involved in the
execution of a clinical
drug/product study. The person
with ultimate responsibility for this
is called principle or responsible
investigator.

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 M

Medicine
When a compound or substance is
tested for biological and clinical
activity in humans, it is considered
to be a medicine. Some individuals
prefer to define a medicine as a
compound that has demonstrated
clinically useful properties in
subjects. This definition, however,
would restrict the term to use
sometime during or after phase II.
Others use the term loosely and
apply it to compounds with
biological properties during the
preclinical period that suggest
medical usefulness in humans. The
author has adopted the first
definition for use in this book.

Med Watch ( FDA- AER’ s)

The Adverse Event Reporting
System (AERS) is a computerized
information database designed to
support the FDA's post-marketing
safety surveillance program for all
approved drug and therapeutic
biologic products. The ultimate
goal of AERS is to improve the
public health by providing the best
available tools for storing and
analyzing safety reports.

The FDA receives adverse drug

reaction reports from
manufacturers as required by
regulation. Health care
professionals and consumers send
reports voluntarily through the
MedWatch program. These reports
become part of a database. The
structure of this database is in
compliance with the international
safety reporting guidance
(www. fda. gov/ medwatch/ repo
rt/ iche2 b. pdf) issued by the
International Conference on
Harmonisation. The guidance
describes the content and format
for the electronic submission of
reports from manufacturers. FDA
codes all reported adverse events
using a standardized international
terminology, MedDRA (the Medical
Dictionary for Regulatory
Activities). Among AERS system
features are: the on-screen review
of reports; searching tools; and
various output reports. FDA
staff use reports from AERS in
conducting postmarketing drug
surveillance and compliance
activities and in responding to
outside requests for information.

The reports in AERS are evaluated

by clinical reviewers in the Center
for Drug Evaluation and Research
(CDER) and the Center for
Biologics Evaluation and Research
(CBER) to detect safety signals
and to monitor drug safety. They
form the basis for further
epidemiological studies when
appropriate. As a result, the FDA
may take regulatory actions to
improve product safety and
protect the public health, such as
updating a product’s labeling
information, sending out a "Dear
Health Care Professional" letter, or
re-evaluating an approval decision.

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O
Open- Label Study
No blind is used. Both investigator
and subject know the identity of
the medicine.

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Pharmaco- Dynamics
The scientific discipline involved in
the study of drug/product action
on molecular or cellular targets or
on the whole organism.

Pharmaco- kinetics
The study of the time course of
the concentration of a substance
and its metabolites in body fluids
like blood and urine.

Phases of clinical trials and

medicine development
Four phases of clinical trials and
medicine development exist and
are defined below. Each of these
definitions is a functional one and
the terms are not defined on a
strict chronological basis. An
investigational medicine is often
evaluated in two or more phases
simultaneously in different clinical
trials. Also, some clinical trials may
overlap two different phases.

Phase I
Clinical Pharmacology Studies in
healthy volunteers (sometimes
subjects) to determine the safety
and tolerability of the
drug/product, other dynamic
effects and the pharmacokinetic
profile (absorption. distribution,
metabolism and excretion –
ADME). Evidence of efficacy may
be gained if subjects, disease
models or biomarkers are used.
Phase II
Clinical Investigation studies in
subjects with the target disease, to
determine efficacy, safety and
tolerability in carefully controlled
dose-ranging studies.

Phase IIa
Pilot clinical trials to evaluate
efficacy (and safety) in selected
populations of subjects with the
disease or condition to be treated,
diagnosed, or prevented.
Objectives may focus on dose-
response, type of subject,
frequency of dosing, or numerous
other characteristics of safety and
efficacy.

Phase IIb
Well-controlled trials to evaluate
efficacy (and safety) in subjects
with the disease or condition to be
treated, diagnosed, or prevented.
These clinical trials usually
represent the most rigorous
demonstration of a medicine’s
efficacy.

Phase III
Formal clinical trials. Large-scale
placebo controlled and active
comparator studies in subjects to
confirm efficacy, and provide
further information on the safety
and tolerability of the
drug/product.

Phase IIIa
Trials conducted after efficacy of
the medicine is demonstrated, but
prior to regulatory submission of a
New Drug/product Application
(NDA) or other dossier. These
clinical trials are conducted in
subjects’ populations for which the
medicine is eventually intended.
Phase IIIa clinical trials generate
additional data on both safety and
efficacy in relatively large numbers
of subjects in both controlled and
uncontrolled trials. Clinical trials
are also conducted in special
groups of subjects (e.g. renal
failure subjects), or under special
conditions dictated by the nature
of the medicine and disease.
These trials often provide much of
the information needed for the
package insert and labeling of the
medicine.

Phase IIIb
Clinical trials conducted after
regulatory submission of an NDA
or other dossier, but prior to the
medicine’s approval and launch.
These trials may supplement
earlier trials, complete earlier
trials, or may be directed towards
new types of trials (e.g., quality of
life, marketing) or phase IV
evaluations. This is the period
between submission and approval
of a regulatory dossier for
marketing authorization.

Phase IV
Post-marketing surveillance to
expand safety and efficacy data in
a large population, including
further formal therapeutic trials
and comparisons with other active
comparators.

Pilot Study
A pilot trial is used to obtain
information, and work out the
logistics and management,
deemed necessary for further
clinical trials. Although pilot trials
are often unblind and use open-
label medicines, they may also be
single or double blind and may
include tight control on all
appropriate variables. The term
“pilot” refers to the purpose of the
trial (2).

Placebo
Means “I shall please” in Latin; it
is a term applied to a remedy that
does not affect the “specific
mechanisms” of the disease in
question, or to the favorable
response that the treatment often
elicits.

Pre- clinical Drug/ product

Development
The studies done in cells, tissues
and whole animals as well as the
chemical and pharmaceutical
investigations to obtain adequate
Assurance that a new
drug/product may safely be given
to man in clinical studies.

Prevalence
The total number of people in a
population that are affected with a
particular disease at a given time.
This term is expressed as the rate
of all cases (e.g., the prevalence of
disease X is Y subjects per 100,000
population) at a given point or
period of time.

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Quality Assurance
The procedures ad control systems
in place during a clinical trial to
ensure integrity of the data and
protection of the subjects.
Quality Control
The checks performed to ensure
that the quality control system is
adhered to.

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Randomization
Each subject has a known chance,
usually equal chance, of being
given each treatment, but the
treatment to be given cannot be
predicted. The idea of randomness
accords with our intuitive ideas of
chance and probability, but it is
distinct from those of haphazard
or arbitrary allocation.

Research( on medicines)
Numerous definitions of research
are used both in the literature and
among scientists. In the broadest
sense, research in the
pharmaceutical industry includes
all processes of medicine
discovery, preclinical and clinical
evaluation, and technical
development. In a more restricted
sense, research concentrates on
the preclinical discovery phase,
where the basic characteristics of
a new medicine are determined.
Once a decision is reached to
study the medicine in humans to
evaluate its therapeutic potential,
the compound passes from the
research to the development
phase.

Research and development

When research and development
are used together, it refers to the
broadest definition for research
(see above). Some people use the
term research colloquially to
include most or all of the scientific
and medical areas (discovery,
evaluation, and development)
covered by the single term
research and development.
Medicine development has several
definitions and, in its broadest
definition, is exactly the same as
the broad definition of research.

Risk
A measure of (1) the probability of
occurrence of harm to human
health or (2) the severity of harm
that may occur. Such a measure
includes the judgment of the
acceptability of risk. Assessment of
safety involves judgment, and
there are numerous perspectives
(e.g., subjects, physicians,
company, regulatory authorities)
used for judging it.

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Safety
A relative concept referring to the
freedom from harm or damage
resulting from adverse reactions or
physical, psychological, or
behavioral abnormalities that
occur as a result of medicine or
nonmedicine use. Safety is usually
measured with one or more of the
following: physical examination
(e.g., vital signs, neurological,
opthalmological, general physical),
laboratory evaluations of biological
samples (e.g., hematology, clinical
chemistry, urinalysis), special tests
and procedures (e.g.,
electrocardiogram, pulmonary
function tests), psychiatric tests
and evaluations, and
determination of clinical signs and
symptoms.

Satellite site
A secondary site at which subjects
in a clinical trial are seen, usually
by the same investigator who sees
subjects at the primary site. A
satellite site may be the same
type of site (e.g., private office,
hospital) or a different type from
the primary site.
Serious Adverse Event ( SAE)
An adverse event that leads to
death, permanent disability or
(prolongation of) hospital
admission. These events are of
obvious importance to authorities
and fellow researchers working on
the same drug/product and have
to be reported to the local and
international authorities with the
greatest possible urgency. The
details of the reporting are given
in the study protocol.
Serious adverse reaction
Multiple definitions are possible
and no single one is correct in all
situations. In general usage
referring to subjects in clinical
trials, a serious adverse reaction
may be (1) any bad adverse
reaction that is observed, (2) any
bad adverse reaction that one
does not expect to observe, (3)
any bad adverse reaction that one
does not expect to observe and is
not in the label, or (4) any bad
adverse reaction that has not been
reported with standard therapy.
Definitions may also be based on
the degree to which an adverse
reaction compromises a subject’s
function or requires treatment.

A common used definition is “an

adverse event that leads to death,
permanent disability or
(prolongation of) hospital
admission”. The details of
reporting these events are often
given in the study protocol.

Side effect
Any effect other than the primary
intended effect(s) resulting from
medicine or non-medicine
treatment or intervention. Side
effects may be negative (i.e., an
adverse reaction), neutral, or
positive (i.e., a beneficial effect)
for the subject. This term,
therefore, includes all adverse
reactions plus other effects of
treatment. See definition of
adverse reaction.

Single blind
The subject is unaware of which
treatment is being received, but
the investigator has this
information. In unusual cases, the
investigator and not the subject
may be kept blind to the identity
of the treatment.

Site
This refers to the place where a
clinical trial is conducted. A
physician who has offices and sees
subjects in three separate
locations is viewed as having one
site. A physician who is on the
staff of four hospitals could be
viewed as having one or four sites,
depending on how similar or
different the subject populations
are and whether the data from
these four locations will be pooled
and considered a single site. For
example, a single physician who
enrolls groups of subjects at a
university hospital, private clinic,
community hospital, and Veterans
Administration Hospital should
generally be viewed as having four
sites, since the subject populations
would be expected to differ at
each site. See satellite site.
Sponsor
An organization (often a
pharmaceutical company) funding
a trial of a new drug/product or
other intervention for registration
purposes.

Standard Operating Procedure

( SOP)
A detailed description of a certain
activity or organizing principle in a
clinical trial. Such procedures must
be adhered to when performing a
trial under the Good Clinical
Practice standards.
Statistical
This term relates to the probability
that an event or difference
significanceoccurred by chance
alone. Thus, it is a measure of
whether a difference is likely to be
real, but it does not indicate
whether the difference is small or
large, important or trivial. The
level of statistical significance
depends on the number of
subjects studied or observations
made, as well as that magnitude
of difference observed.
Study Protocol
The document describing the
rationale, the subject population,
the drugs/product to be used and
the full time schedule of a clinical
study as well as the endpoints to
be evaluated. The study protocol
for independent evaluation.

Surrogate endpoint
A biomarker that has been
extensively studied to be
sufficiently confident that it can
replace a clinical endpoint for
registration purposes.
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Therapeutic window
This term is applied to the
difference between the minimum
and maximum doses that may be
given subjects to obtain an
adequate clinical response and
avoid intolerable toxic effects. The
greater the value calculated for
the therapeutic window, the
greater a medicine’s margin of
safety. Synonyms are therapeutic
ratio and therapeutic index.

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Volunteer
A normal individual who
participates in a clinical trial for
reasons other than medical need
and who does not receive any
direct medical benefit from
participating in the trial.