Transcript Clinical Trials

Clinical Trials
Importance in future therapies
What are the Requirements to
Produce New Drugs?
• Drug must work significantly better than a control
treatment
• Indicated by at least two double-blind
randomized controlled clinical trials with 95%
power or by three double (triple) -blind
randomized controlled clinical trials with 90%
power.
Causal Hierarchy
• Epidemiologists evaluate evidence
to determine whether an exposure
is directly responsible for an
outcome
• Studies follow a hierarchy in terms
of the quality of evidence that they
can provide
• Strongest study is the randomized
clinical trial
Introduction to Clinical Trials
 Definition
 Keywords
 Randomized
 Placebo Controlled
 Blinded
 Phases of Clinical Trials
 Phase I
 Phase II
 Phase III
 Phase Iv
Definition
All clinical trials are prospective
studies in which individuals are
exposed (or not) and followed
for an outcome (or a few
different outcomes). The
outcomes must be clearly
defined.
What’s involved in a clinical trial?
1. Internal Review Board (IRB). Forms
need to be filed with the IRB. A
committee determines whether the
study is ethical. The committee must
include some lay people as well as
scientists. It should contain an "ethics
expert," such as a clergy-person.
2. Protocol. Before conducting a clinical
trial, a protocol must be written,
describing exactly what you are going to
do
3. On site Patient Monitoring and Data
collection
4. Data analysis, write results and
conclusions
5. Written report: includes clinical and
statistical sections
Must have comparability
• In a clinical trial, need comparability
among study groups
• Best way to assure comparability is
by randomization
Examples of confounding
• Food outbreak: suspect the ham salad,
but everyone who ate the ham salad
(and only those who ate the ham salad)
also ate ice cream. Problem: ham or
ice-cream?
• Observe lower death rate in Alaska
than in Florida; conclude sunlight is
bad. Problem: people in Florida are
older.
Assure comparability by
randomization
• Best way to assure comparability is
by randomization
What does randomization do?
• 1. It forms the basis for the derivation of
statistical tests
• 2. It prevents selection bias by not
allowing the physician to decide who to
enroll/treat.
• 3. It minimizes confounding – e.g.: It
minimizes the possibility that the
observed association between the
exposure and the outcome is really
caused by a third factor.
Placebo Effects
• “Inert” substitute for a treatment or
intervention
• “Inert” means the compound has no known
activity that would be expected to affect the
outcome
Placebo Effects
In actuality, a placebo effect is a psychosomatic effect
brought about by relief of fears, anxiety or stress
because of study participation.
It's not just the little white pill that brings about the effect;
it's the additional attention and the belief that your
condition might be being treated with a superior new
treatment.
All outcomes affected by psychosomatics are prone to
placebo effects.
A component of every specific treatment
effect can be attributed to the placebo
response.
The question that a study should be
asking is whether the treatment has any
effect on outcome aside from the stressrelieving effect of study participation.
Blinding, also called masking
If the outcome can conceivably be
affected by patient or investigator
expectations, then blinding is important.
Types of Blinding
• Single Blind: The patient is blind
• Double Blind: The patient and the
investigator are blind
• Triple Blind: The patient, investigator and
data-cleanup people are blind. The statistician
can only be partially blinded since he/she has
to know which patients are in the same
treatment group.
IND: Investigational new drug
(device) application
Filed prior to beginning clinical trials
NDA: New drug application
Filed after pivotal trials to get drug
(device) approval
1992, 1997 Food and Drug
Administration Modernization Act
Major drug companies pay a fee of
$350,000 when an NDA is submitted.
The money is spent to hire a qualified
person to review the NDA. Drugs are
now approved in less than a year.
Phase 1: Small studies conducted in
healthy volunteers. These studies are
usually uncontrolled and open labeled.
1. Initial tolerability and safety
2. Pharmacodynamics
3. Dose-finding
4. Pharmacokinetics
5. Bioequivalence studies (these are
usually double-blind crossover studies)
6. Food interaction/drug interaction
studies
Phase 2. Small to moderate sized trials
(usually controlled double or triple
blinded) studies in patients.
1. Safety and tolerability
2. Preliminary efficacy. These trials are
done with 80% power.
3. Dose-ranging. Find the dose that
produces the optimal outcome.
Phase 3. Pivotal clinical trials
Two trials with sample size adequate to determine a
clinically important difference with 95% power or three
trials with sample size adequate to determine a clinically
important difference with 90% power are required.
For things like blood pressure or cholesterol, sample
sizes most often are in the vicinity of 300-600 per trial
(150 to 300 per treatment group).
For a drug (does not apply to vaccines), if all trials show
a significantly greater effect then placebo, the drug is
considered efficacious. The magnitude of the effect does
not matter.
Phase IV Post marketing studies:
Another hodgepodge of studies, of which clinical trials
are a minority. By and large these are descriptive,
case-control or cohort studies.
1.
2.
3.
4.
5.
Surveillance
Answer FDA inquiries
Cost effective analyses versus other treatments
Validation studies for rating scales
Large scale clinical Epidemiology (outcome) studies,
usually sponsored by NIH
Summary
• Clinical trials
– Controlled
– Randomized
– Placebo-controlled
– Blinded
• Phases of clinical trials
– Application/ethical approval
– Phase I-IV studies
Why participate in a
clinical trial?
• Clinical trials provide opportunity to
contribute to development of future
therapies
• Opportunity to test new therapies
before they are publicly available
Clinical Trial Opportunities
• Studies for patients who have never
taken PD medication
• Patients who are advanced and
have dyskinesia
• Patients who are in need of
medication