Fundamentals of Clinical Trials

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• Fundamentals of Clinical Trials
• Endpoints
• Betsy Garofalo MD
• Michigan Technology and Research Institute

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Clinical Trial Features

• Study objective hypothesis testing
• Type of study comparisons
• Primary and secondary endpoints
• Measures taken to minimizing bias
• Treatment groups (drug control),
• dosage and dose regimen

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Objectives and Endpoints by Phase
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Endpoint Definition

• Results, condition or events associated with
  individual study patients that are used to assess
  study treatments

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Characteristics of Endpoint Measures

• Easy to diagnose
• Easy to identify no evaluator judgment needed
• Free of measurement error
• Reliable with repeated measure
• Internal validity
• Directly linked to property of interest
• External validity
• Ability to generalize to a wider population

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Characteristics of Endpoint Measures

• Clinically relevant
• Influence Rx choices by physicians and patients
• How and When to prescribe the drug

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Surrogate Endpoint

• Surrogate endpoint used instead of direct
  endpoint ex BP or Cholesterol LDL
• Reduction as 1 endpoint as opposed to a
  reduction in CV morbidity or mortality

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• The difference between a surrogate and a true
  endpoint is like the difference between a check
  and cash. You often get the check earlier but
  then, of course, it may bounce.

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Primary, Secondary, Tertiary..

• Primary single (may be co-endpoint) endpoint
  parameter for rejection of the null hypothesis
  regulatory implication in PhIII
• Secondary- other endpoints pre-specified, may be
  powered for hypothesis testing
• Tertiary exploratory and all other

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Example

• Epilepsy
• Event of interest Seizures
• Maintain seizure diary for study
• Video EEG in infants for accurate counts
• Global Impression of Change
• QOL scales

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Example

• Depression/Anxiety
• Result of Interest Functional improvement/
  symptom relief
• Hamilton Scale for Depression (HAM-D)
• Hamilton Scale for Anxiety (HAM-A)
• Global Impression of Change
• Suicide rates (small numbers of events, efficacy
  and safety issue)

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Example

• Multiple Sclerosis Relapsing Remitting
• Result of interest Neurological Disability
• Episodes of focal Neuro signs and symptoms
• Disability rating scales
• MRI changes
• CSF changes

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Example

• Diabetic Neuropathy
• Event of Interest Foot ulcers, foot injuries
• Nerve conduction velocity changes
• Surrogate measurement
• Sensory changes
• Rating scales

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Conclusions - Endpoints

• Critical and challenging study design decision
• Consider
• Phase of development
• Disease under study
• Characteristics of measure
• Question to be answered by trial