Download Intro to Clinical Research

CLINICAL RESEARCH
CONTENTS
 Drug
Development Process
 Pre – Clinical Studies
 Clinical Trials
 Phase I
 Phase II
 Phase III
 Phase IV
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DRUG DEVELOPMENT
 Drug
development is a term used to
define the entire process of bringing a
new drug or device to the market.
It includes:
 drug discovery
 product development
 pre-clinical research
(microorganisms/animals)
 clinical trials (on humans)
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STEPS OF DRUG DEVELOPMENT
NCE
Preclinical
Studies
INDA
APPROVAL
NDA
Clinical
Trials
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NEW CHEMICAL ENTITIES (NCE’s)
 New
Chemical Entities are compounds
which emerge from the process of drug
discovery.
 Little will be known about the safety, toxicity,
pharmacokinetics and metabolism of this
NCE in humans.
 It becomes necessary to assess all of these
parameters before conducting human
clinical trials.
 Pre- Clinical studies are performed
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INVESTIGATIONAL NEW DRUG
APPLICATION (INDA)
 Application
filed with the FDA after completion of
pre-clinical and prior to human testing.
 The IND application contains: Preclinical data: Animal Pharmacology and
Toxicology Studies
 Chemistry and Manufacturing Information
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INVESTIGATIONAL NEW DRUG
APPLICATION (INDA)
 Clinical
Trial Protocols & Investigator Information:
Detailed protocols for proposed clinical studies to
assess whether the initial-phase trials will expose
subjects to unnecessary risks.
 Unless the FDA specifically objects, the IND is
automatically allowed after 30 days and clinical
trials can begin.
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NEW DRUG APPLICATION (NDA)
 Submitted
after completion of Phase I, Phase II,
Phase III studies of Clinical Trials
 Application
filed with the FDA for sale and
marketing of the drug product.
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NEW DRUG APPLICATION (NDA)
 Following
information is reviewed through NDA:
1. Is
the drug safe and effective in its proposed
use(s) when used as directed, and do the
benefits of the drug outweigh the risks?
2. Is
the drug’s proposed labeling (package insert)
appropriate, and what should it contain?
3. Are
the methods used in manufacturing (GMP)
the drug and the controls used to maintain the
drug’s quality adequate to preserve the drug’s
identity, strength, quality, and purity?
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OVERVIEW
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PRE- CLINICAL STUDIES
 Drugs
that pass the initial screening and
profiling procedures are carefully evaluated
for potential risks before and during clinical
testing.
 Pre-clinical studies include Safety and
Toxicity testing.
 Generally conducted on animals,
microorganisms or tissue cultures.
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PRE- CLINICAL STUDIES
Toxicity studies:
 acute toxicity - effects of large single doses
up to the lethal level. Usually two species,
two routes, single dose.
 subacute and chronic toxicity- effects of
multiple doses, especially for drug that is
intended for prolonged use in humans
 effects on reproductive functions, including
teratogenicity and postnatal development
 Carcinogenicity: Two years, two species.
 Mutagenicity, Investigative toxicology
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PRE- CLINICAL STUDIES
 In
addition to toxicity studies:
 "no-effect" dose—the maximum dose at
which a specified toxic effect is not seen
 minimum lethal dose—the smallest dose
that is observed to kill any animal
 LD50 – Lethal Dose at 50%
 ED50 – Effective Dose at 50%
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PRE- CLINICAL STUDIES
ED
LD
100
% subjects 50
0
0
• Relatively safe
DRUG DOSE
X
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PRE-CLINICAL STUDIES
ED
LD
100
% subjects 50
0
0
• Less safe drug
DRUG DOSE
X
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LIMITATIONS
•
•
•
•
•
Toxicity testing is time-consuming and
expensive.
Large numbers of animals are needed to
obtain valid preclinical data.
Cell and tissue culture in vitro methods are
increasingly being used, but their predictive
value is still severely limited.
Extrapolation of toxicity data from animals to
humans is not completely reliable.
For statistical reasons, rare adverse effects
are unlikely to be detected.
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CLINICAL TRIALS
•
•
Clinical trials are conducted on human
volunteers to allow safety and efficacy data
to be collected for health interventions
The most commonly performed clinical trials
evaluate new drugs, medical devices,
biologics, psychological therapies or other
interventions.
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WHY ARE CLINICAL STUDIES
PERFORMED?
 No
chemical can be certified as completely
"safe". Every chemical is toxic at some
dosage
 It is important to estimate the risk
associated with exposure to the chemical
under specified conditions by performing
appropriate tests.
 Clinical trials may be required before the
national regulatory authority approves
marketing of the drug or device, or a new
dose of the drug, for use on patients.
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WHEN IS CLINICAL TRIAL
NECESSARY?
1.
2.
3.
4.
Assess safety and efficacy of New
Chemical Entity
Assess safety and effectiveness of a
different dose
(e.g., 10 mg dose instead of 5 mg dose)
Assess safety and efficacy of an already
marketed medication or device for a new
indication i.e. a disease for which the drug
is not specifically approved
To compare the effectiveness in patients
with a specific disease of two or more
already approved or common interventions
for that disease
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CLINICAL TRIALS
I.
II.
III.
IV.
Phase I – Healthy Volunteers
Phase II – Target Patient Volunteers
Phase III – Larger Number of
Patients
Phase IV – After marketing
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PHASE I
•
•
•
In phase I, the effects of the drug is checked
in a small number of healthy volunteers.
If the drug is expected to have significant
toxicity, as is often the case in cancer and
AIDS therapy, volunteer patients with the
disease are used in phase I rather than
normal volunteers.
Phase I trials are done to determine whether
humans and animals show significantly
different responses to the drug and to
establish safe clinical dosage range.
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PHASE I
•
•
•
These trials are non-blind or "open," i.e,
both the investigators and the subjects know
what is being given.
Many predictable toxicities are detected in
this phase.
This phase includes trials designed to
assess the safety (pharmacovigilance),
tolerability, pharmacokinetics, and
pharmacodynamics of a drug.
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PHASE I
 These
trials are often conducted in an
inpatient clinic, where the subject can be
observed by full-time staff.
 The subject who receives the drug is usually
observed until several half-lives of the drug
have passed.
 Phase I trials also include dose-ranging,
also called dose escalation, studies so that
the appropriate dose for therapeutic use can
be found.
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PHASE I
 SAD
: Single Ascending Dose
 small groups of subjects are given a single
dose of the drug while they are observed
and tested for a period of time.
 If they do not exhibit any adverse side
effects, and the pharmacokinetic data is
roughly in line with predicted safe values,
the dose is escalated, and a new group of
subjects is then given a higher dose.
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PHASE I
 SAD
: Single Ascending Dose
 This is continued until pre-calculated
pharmacokinetic safety levels are reached,
or intolerable side effects start showing up
 At this point the drug is said to have
reached the Maximum tolerated dose
(MTD).
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PHASE I
 MAD:
Multiple Ascending Dose studies
 In these studies, a group of patients receives
multiple low doses of the drug
 Samples of blood and other fluids are
collected at various time points and analyzed
to understand how the drug is processed
within the body.
 The dose is subsequently escalated for
further groups, up to a predetermined level.
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PHASE I
 Food
effect
 A short trial designed to investigate any
differences in absorption of the drug by the
body, caused by eating before the drug is
given.
 These studies are usually run as
a crossover study, with volunteers being
given two identical doses of the drug on
different occasions; one while fasted, and
one after being fed.
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PHASE II
•
•
•
In phase II, the drug is studied for the first
time in patients with the target disease to
determine its efficacy.
A small number of patients (100–200) are
studied in great detail.
When the development process for a new
drug fails, this usually occurs during Phase
II trials when the drug is discovered not to
work as planned, or to have toxic effects.
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PHASE II
 Phase
II studies are sometimes divided into
Phase IIA and Phase IIB.
 Phase IIA:
designed to assess dosing requirements
(how much drug should be given).
 Phase IIB:
designed to study efficacy (how well the
drug works at the prescribed dose(s)).
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PHASE II
A
single-blind design is often used, with an
inert placebo medication and an older active
drug (positive control) in addition to the
investigational agent.
 Phase II trials are usually done in special
clinical centers (ex: university hospitals).
 A broader range of toxicities may be
detected in this phase.
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PHASE III
•
•
•
In phase III, the drug is evaluated in much
larger numbers of patients—sometimes
thousands—to further establish safety and
efficacy.
Using information gathered in phases I and
II, phase III trials are designed to minimize
errors caused by placebo effects, variable
course of the disease, etc.
Therefore, double-blind and crossover
techniques are frequently used.
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PHASE III
•
•
•
Phase III studies can be difficult to design
and execute and are usually expensive
because of the large numbers of patients
involved and the masses of data that must
be collected and analyzed.
The investigators are usually specialists in
the disease being treated.
Certain toxic effects—especially those
caused by immunologic processes—may
first become apparent in phase III.
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PHASE IV
•
•
1.
2.
3.
Phase IV trial is also known as Post
Marketing Surveillance Trial.
Phase IV studies may be required by
regulatory authorities or may be undertaken by
the sponsoring company for
competitive (finding a new market for the drug)
To check for drug interactions with other drugs
certain population groups such as pregnant
women, who are unlikely to subject
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themselves to trials
PHASE IV
•
•
•
This constitutes monitoring the safety of the
new drug under actual conditions of use in
large numbers of patients.
The sample size required to disclose druginduced events or toxicities is very large for
such rare events.
For example, several hundred thousand
patients may have to be exposed before the
first case is observed of a toxicity that
occurs with an average incidence of 1 in
10,000.
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PHASE IV
•
•
•
•
Careful and complete reporting of toxicity by
physicians after marketing begins is very
important.
Low incidence drug effects will not generally
be detected before phase 4 no matter how
carefully the studies are executed.
Phase 4 has no fixed duration.
Adverse effects detected by Phase IV trials
may result in withdrawal or restriction of a
drug.
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Comparison
Phase I
Phase II
Phase III
Phase IV
Healthy
Volunteers
Target
disease
Patients
Target
disease
Patients
Mixed
Sample Size 20 – 80
200 – 300
100 – 1000
1000 <
Duration
1 month
Several
Months
Several
Years
Ongoing
Design
Non blind
Single blind Double
blind
Population
Uncontrolled
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