Clinical Trials

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Clinical Trials

• Importance in future therapies

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• 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.

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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

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Introduction to Clinical Trials

• Definition
• Keywords
• Randomized
• Placebo Controlled
• Blinded
• Phases of Clinical Trials
• Phase I
• Phase II
• Phase III
• Phase Iv

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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.

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Whats 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.

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• 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

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Must have comparability

• In a clinical trial, need comparability among
  study groups
• Best way to assure comparability is by
  randomization

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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.

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Assure comparability by randomization

• Best way to assure comparability is by
  randomization

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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.

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• 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

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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.
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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 stress-relieving effect of study
participation.
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Blinding, also called masking If the outcome
can conceivably be affected by patient or
investigator expectations, then blinding is
important.
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• 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.

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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
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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.
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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
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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.
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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.
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• 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.
• Surveillance
• Answer FDA inquiries
• 3. Cost effective analyses versus other
  treatments
• 4. Validation studies for rating scales
• 5. Large scale clinical Epidemiology (outcome)
  studies, usually sponsored by NIH

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Summary

• Clinical trials
• Controlled
• Randomized
• Placebo-controlled
• Blinded
• Phases of clinical trials
• Application/ethical approval
• Phase I-IV studies

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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

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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