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

2. 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

3. Objectives and Endpoints by Phase
Efficacy/Endpoint
Phase I
Safety evaluation
Patient tolerance
None
Phase II
Identify efficacy endpoints and doses for Phase III
“Exploratory”
Primary
Secondary
Phase III
Efficacy & Safety
Evaluate for general use
Primary- Indication
Secondary- may be described in label
Phase IV
Expand efficacy & safety
Expand patient reported outcomes

4. Endpoint Definition
“Results, condition or events associated with individual study patients that are used to assess study treatments”

5. 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

6. Characteristics of Endpoint Measures
Clinically relevant
Influence Rx choices by physicians and patients
“How” and “When” to prescribe the drug

7. 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

8. “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.”

9. 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

10. Example Epilepsy “Event” of interest: Seizures
Maintain seizure diary for study
Video EEG in infants for accurate counts
Global Impression of Change
QOL scales 10

11. 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)

12. Example Multiple Sclerosis – Relapsing Remitting
“Result” of interest: Neurological Disability
“Episodes” of focal Neuro signs and symptoms
Disability rating scales
MRI changes
CSF changes

13. Example Diabetic Neuropathy
“Event” of Interest: Foot ulcers, foot injuries
Nerve conduction velocity changes
Surrogate measurement
Sensory changes
Rating scales

14. Conclusions - Endpoints
Critical and challenging study design decision
Consider
Phase of development
Disease under study
Characteristics of measure
Question to be answered by trial