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Slide 1: Lessons Learned: Surrogates & Intermediate Outcomes
David L. DeMets, Ph.D.
Department of Biostatistics and Medical
Informatics
University of Wisconsin-Madison
Slide 2: Definition of Surrogate & Intermediate Outcome
- A physiologic or biological measurement that is used instead of a
clinical outcome (e.g. live longer, feel good, function better)
- Surrogate may be used to
- Develop a new intervention
- Assess biological or mechanical activity
- Assess clinical efficacy
-
Slide 3: Appeal of Surrogates/Intermediate Outcomes
- Criticism of clinical trials
- Too long
- Too large
- Too expensive
- May allow for studies to be
- Smaller
- Shorter and faster
- Less expensive
Slide 4: Response Variables
- Cancer
- Death or disease recurrence
- Tumor shrinkage
- Cardiology
- Death, non fatal MI or hospitalization
- Blood pressure, lipid levels, PVCs, cardiac output
Slide 5: Response Variables
- AIDS
- Death or progression to AIDS
- T4 Cells, viral load
- Diabetes
- Death, visual impairment, kidney failure
- Microaneurysms, clearance
-
Slide 6: Use of Surrogates
- Phase I Trials
- Maximum Dose/Dose Response
- Phase II Trials
- Measures of Activity
- Phase III Trials
- Supporting Evidence/Secondary Outcomes
- e.g., Cholesterol Changes
- Primary Outcome?
Slide 7: Time Chart (1)
The setting that provides the greatest potential for the surrogage
endpoint to be valid. Reprinted from Ann Intern Med 1996: 125:605-13
Slide 8: Time Chart (2)
Slide 9: Concerns About Surrogates
- Relationship between surrogate and true endpoint may not be causal,
but coincidental to a third factor
- Other unfavorable effects of the drug
- Effect on surrogate may correlate with one clinical endpoint, but not
others
Slide 10: Intermediate/Surrogate Outcomes
- Reliance on intermediate outcome might lead to incorrect conclusion
about benefit or harm
- Consider a few examples
Slide 11: Nocturnal Oxygen Therapy Trial (NOTT)
- Hypothesis
- Is continuous oxygen therapy better than nocturnal oxygen therapy in
chronic obstructive lung disease patients?
- Surrogates
- Survival
- Design
- 203 patients
- Two-sided 0.05 Type I error
- Powered for several intermediate outcomes
- Randomized, multicenter
Slide 12: Possible NOTT Surrogates
- PaO2
- Hematocrit
- FEV1 % Predicted
- FVC % Predicted
- Maximum Workload
- Heart Rate
- Mean Pulmonary Artery Pressure
- Cardiac Index
- Pulmonary Vascular Resistance
- Neuropsychiatric Impairment
- Quality of Life
Slide 13: The Nocturnal Oxygen Therapy Trial (Line chart)
Slide 14: Cardiac Arrhythmias
- Cardiac arrhythmias associated with sudden death
- Class of drugs developed to suppress arrhythmias
- Drugs approved for high risk patients
- "Off-label" use increased
Slide 15: Cardiac Arrhythmia Suppression Trial
Hypothesis
s suppression of arrhythmia following an MI reduce incidence of:
- Sudden death
- Total mortality
Slide 16: Cardiac Arrhythmia Suppression Trial
- Three Drug Arms vs. Placebo
- Double blind placebo control
- One Sided (0.025 Type I Error) for Benefit
- Advisory One Sided (0.025) for Harm
- Sequential monitoring plan
o
Slide 17: Cardiac Arrhythmia Suppression Trial
Early Termination in Two Drug Arms
Drugs Placebo
Sudden Death 33 9
Total Mortality 56 22
Slide 18: Chronic Heart Failure
- A major problem in heart disease
- Increased mortality, decreased quality of life
- Drugs developed to improve cardiac function
- Not known if survival or quality of life improved
Slide 19: PROFILE
(Prospective Randomized Flosequinan Longevity Evaluation)
- Flosequinan is primarily a vasodilator
- Approved for CHF
- improved exercise tolerance
- reduced symptoms
- slight adverse mortality
- PROFILE Design
- randomized double blind multicenter
- Mortality outcome
- placebo vs. 75 mg vs. 100 mg
- Class III or IV CHF
Slide 20: PROFILE Results
Flosequinan Dose
75 mg 100 mg Combined Total
Flosequinan 40/206 201/964 241/1170
Mortality (19.4%) (20.9%) (20.6%)
Placebo 43/238 138/937 181/1175
Mortality (18.1%) (14.7%) (15.4%)
Relative Risk 1.05 1.48 1.39
P-value .83 .0004 .0009
Slide 21: SURROGATES
- Can delay use of effective treatments
- Example: Beta blockers in congestive heart failure; betablockers
known to
- ower blood pressure
- slow heart rate
- Beta blocker drugs not used for heart failure for a decade or
more
Slide 22: Beta-Blockers in Heart Failure
- Metoprolol in MERIT [JAMA 283(10):1295-1302, 2000]
- Bisoprolol in CIBIS-II [Lancet 353: 9-13, 1999]
- Carvedilol in COPERNICUS [New Engl J Med 334(22):1651-58, 2001]
- Bucindolol in BEST [Am J Cardiol 1995;75:1220-3]
- Class II-IV heart failure, low ejection fraction patients
- Demonstrated beneficial effects
Slide 23: MERIT
Total Mortality (Chart)
Slide 24: Intermediate/Surrogate Outcomes
- Reliance on an intermediate outcome might lead to concluding harm
when in fact intervention is beneficial
Slide 25: Diabetes
- Diabetes affects several organ systems (heart, kidney, eyes)
- Long duration causes visual impairment (diabetic retinopathy)
- Clinical Outcome
- Blindness
- Severe visual loss
- Surrogate
- Microaneurysm (retinal small vessel deformity filled with blood)
Slide 26: DCCT
(Diabetes Complication and Control Trial) (NEJM, 1994)
Does tight control of glucose reduce visual impairment compared to
normal control?
- Design
- Tight control achieved by intense monitoring of an insulin pump
- Randomized multicenter trial
- 1441 diabetic patients
- Followed for average of 6 years
Slide 27: DCCT
(Diabetes Complication and Control Trial)
- Results
- Early trends for microaneurysm were in negative direction, could
perhaps have led to termination if the primary outcome
- Longer term follow-up showed definite reduction in visual
impairment
- Trial terminated early for benefit
Slide 28: Concluding Remarks on Surrogates
- Surrogates play an important role in the development of Phase I, II,
and pilot Phase III studies
- Treatments may affect more than one mechanism
- "Surrogates" do not reliably predict treatment on clinical
outcome
- Problems seen in many disease areas
- Continued success in a given field is not even guaranteed
Slide 29: References
- Prentice RL: Surrogate endpoints in clinical trials: Definition and
operational criteria. Statistics in Medicine 8:431-440, 1989
- Temple RJ: A regulatory authority's opinion about surrogate
endpoints. In: "Clinical Measurement in Drug Evaluation" (Ed. WS Nimmo, GT
Tucker). John Wiley & Sons Ltd., 1996.
- Fleming TR and DeMets DL: Surrogate endpoints in clinical trials: Are
we being misled? Annals of Int Med 125(7):605-613, 1996
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