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

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.

Definition

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 stress-relieving 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 safety2. Pharmacodynamics3. Dose-finding 4. Pharmacokinetics5. 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. Surveillance2. Answer FDA inquiries3. Cost effective analyses versus other treatments 4. Validation studies for rating scales 5. 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