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Surrogate
Endpoints
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The Surrogates Story3 Drug Trials
2 FDA Policy Issues
1. CAST TrialCardiac Arrhythmias
2. ConcordeAZT for AIDS
3. Erythropoietin for Dialysis Pts
1. Accelerated Approval (AA)
2. Patient-Reported Outcomes (PRO)
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PVCs
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Managing theWild Card of Cardiovascular Disease-
Sudden Cardiac Death
Up to half of the million cardiovascular
deaths are sudden deaths Known risk factors for sudden death
Cardiac ischemia (esp recent)
Poor ejection fraction fraction Ventricular arrhythmias
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Rigorous testing
of new anti-arrhythmics
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Antiarrthymics in the late 80s
Antiarrthymics for PVCs & V-Tach widely prescribed
Between - million patients/yr were taking
New antiarrthymic drugs more effective in
suppression arrthymias Scientific EPS selection of best therapies
Encainide Flecainide Moricizine
Placebo controlled trials considered unethical
Even tho no trails showing reduction of arrhythmias led toreduction of sudden death
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Cardiac Arrhythmia Suppression Trial
CAST-ingdoubt on the
dominant
pradigms
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High Risk Patients Require Treatment
Unethical not to treat such high risk
patients
Have to dosomething How would you feel if one of these
patients you ignored suffered sudden
death Plus legal ramifications
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Cardiac Arrhythmia Suppression Trial
CAST-ingdoubt on the
dominant
pradigms
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CAST trial 1987
Randomized, Double-Blind, Placebo Control
27 clinical centers, 4,400 patients
Open-label titration to select drug-responsivepatients:
1,727 randomized to Encainide, Flecainide or Moricizine
Trial is discontinued early Encainide and Flecainide 1989
Moricizine 1991
http://clinicaltrials.gov/ct/show/NCT00000526
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CAST Results
Sudden Death Total Death
Drug 43 63Placebo 9 23
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Cardiac Arrhythmia Suppression
Trial
CAST-ingdoubt on the
dominant
pradigms
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Surrogate Endpoints
Change in a clinical variablenot experienced directly by the patient
Blood pressure
Serum cholesterol
Serum Glucose
PVCs
Not itself a direct measure of clinical harm orbenefit
Patient does not necessarily feel better or worse
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Clinically Relevant Endpoints
Mortality or survival benefit
Clinically important change experienced
directly by the patient Reduced pain
Improved functional status
Improved quality of life Directly measures clinical benefit or
harm
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Hierarchy of endpoints
Level 1: True clinical-efficacy measure
Level 2: Validated surrogate endpoint
Level 3: Non-validated surrogate endpointsreasonably likely to predict clinical benefit
Level 4: A correlate that measures biologicalactivity but whose clinical relevance is not wellestablished
Fleming, T. Surrogate endpoints and FDAs accelerated approval process: the challenges are greater than they seem. Health Affairs (2005) 24(1) 67-78
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Why Use Surrogate Endpoints?
Reduction in sample size, duration of trialand cost
Easier to show benefits: weeks to mos vs.years
Assess benefits of drug wheremeasurement of clinical outcomes would
be unethical/invasive
Because death and other harder
outcomes are uncommon or delayed well
into future
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SurrogateReductio ad absurdum
Elevated WBC countsurrogate for severityof pneumonia
So, why not give cytotoxic agents to reducethe white count?!
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Limitations of Surrogate Endpoints
Surrogates may not be valid predictors of actualclinical outcomes
Rests upon physiologic assumptions
Persuasiveness of biologic plausibility May be statistically significant but not clinically
significant
Provide only partial picture of totality of drugs
effect
Lend themselves to manipulation by PhARMA
Many turn out to be misleading red herrings
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Fleming, T. R. et. al. Ann Intern Med 1996;125:605-613
Reasons for failure of surrogate end points
Surrogate is notinvolved in disease
pathway
Disease has multiple
pathways and
intervention effects
only one pathwaymediated through
surrogate
Surrogate is not
affected by/ insensitive
to interventions effect
Intervention has
mechanisms of action
independent of disease
process
Prostate Biopsy
Finasteride Trials
Ventricular Arrythmias
Encainide and Flecainide Tri
CD4 levels
HIV drugs
Ventricular Arrythmias
Encainide and Flecainide Tri
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Effective antimicrobial treatment
or Useless surrogate? 4,000 surgical patients
Treated patients for nasal staph carriage
Treated pts 4.6% vs. 21.3% control (p
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Zidovudine -- AZT
Thymidine Analogue
Synthesized 1964
Drug in the public domain
1984 scientists approachdrug companies to
expedite R&D
Got Burroughs Wellcometo patent (w/ difficulty)
Mitsuya, H. et al., 3'-Azido-3'-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virustype III/lymphadenopathy associated virus in vitro, Proc. Natl. Acad. Sci USA (82) 1985
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Pathophysiology of HIV
http://research.bidmc.harvard.edu/vptutorials/HIV/home.htm
AZT
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AZT surrogate endpoints:the context
No treatments for AIDSdesperation
Bribery to enter trials
Difficulties of obtaining accurate results Drug smuggling rings
Cook County: 100s of deaths per quarter
Regan administration largely ignores HIV
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AZT- The Hopes
New public private partnership
Burroughs Wellcome submits AZT
application in 3 stages over 7 months
Drug companies, scientists and regulatory
agency working together for good of thepublic
Sets stage for accelerated approval of otherdrugs
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AZT: The Doubts
The myth of public health altruism Burroughs Wellcome charges $10,000/year
Largely assumes credit for innovation Despite doing relatively little of R & D
Clinical trials on limited population
White, gay males
Difficult to adhere to regimen
Initially 6x/day
Controversies and questions about role of thedrug
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1994 CONCORDE Study
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Kaplan-Meier Plot for all causes of death
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Kaplan-Meier Plot for time to AIDS or Death
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Kaplan-Meier for time to ARC AIDS or death
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Kaplan-Meier for time to reduction in CD4 count lessthan half of baseline, AIDS or death
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The small but highly significant and persistentdifference in CD4 count between the groups
was not translated into a significant clinical
benefit. Thus, analyses of the time until certainconcentrations of CD4 were reached revealed
significantly shorter times in the Deferred AZT
treatment group. Had such analyses been
regarded as fundamental, the trial might have
been stopped early with a false-positive result.
CONCORDE Conclusions
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This discrepancy in the differences between
Immediate and Deferred AZT treatment
groups in terms of changes in CD4 count and
of long-term clinical response casts doubt on
the uncritical use of CD4 counts as "surrogate
endpoints" in trials, although their value as a
prognostic marker for disease progression incohorts and trials is beyond dispute. The
reason for this discrepancy is unclear.
CONCORDE Conclusions II
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History of Erythropoietin
U of C scientist Eugene Goldwasser startsresearch on erythropoietin 1960s
Purified in 1970s
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Erythropoietin and Biotech Revolution
Amgen works with Goldwasser tosequence and clone erythropoietin
1985 Amgen files patent Orphan Drug
1989 approved for marketing
Decade later $5b in profits
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Erythropoietin
Bloods Life-Blood
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Policy Context: Not that simple
Natl Kidney Foundation guidelines
Progressively raised Hb level w/out clinical
evidence of benefit Strong conflicts of interest
10/18 panel members w/significant financial interest
57% of NKF funding from industry
Medicare reimbursementssource ofprofit for dialysis centers
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CHOIR: Enrollment and Outcomes
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Singh A et al. N Engl J Med 2006;355:2085-2098
CHOIR: Enrollment and Outcomes
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Mean Monthly Hemoglobin Levels
Singh A et al. N Engl J Med 2006;355:2085-2098
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Kaplan-Meier Estimates of the Probability of the Primary Composite End Point
Singh A et al. N Engl J Med 2006;355:2085-2098
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Kaplan-Meier Estimates of Secondary Endpoint of Death
Singh A et al. N Engl J Med 2006;355:2085-2098
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Drueke T et al. N Engl J Med 2006;355:2071-2084
CREATE: Enrollment, Randomization, and Study Completion
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Drueke T et al. N Engl J Med2006;355:2071-2084
Median Hemoglobin Levels in the Intention-to-Treat Population during the Study
Ch f B li t Y 1 i SF 36 Q lit f Lif S
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Drueke T et al. N Engl J Med 2006;355:2071-2084
Changes from Baseline to Year 1 in SF-36 Quality-of-Life Scores
Changes from baseline to Year 1 in Time to Dialysis during the Study
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Changes from baseline to Year 1 in Time to Dialysis during the Study
Drueke T et al. N Engl J Med 2006;355:2071-2084
Lower Hb Groupremains off dialysislonger
C t FDA i ith
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Current FDA issues withRegulation of Surrogate Endpoints
Accelerated approval (1992) Formal acceptance of surrogates
Endpoints reasonably likely to predict clinicalbenefit
Early marketing approval contingent upon post-marketing studies confirming clinical benefit
Patient-Centered Outcomes
Lancet commentary, controversies
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Pressures for Accelerated Approval (AA)
1962 Kefauver-Harris Amendments requiredemonstration of efficacy
Alleged drug lag Drug industry and free market economists
want less regulation
Patient groups demand more availabletreatments for AIDS and cancer
ACT UP Demonstrations
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ACT UP Demonstrations
http://aidshistory.nih.gov/search_for_treatments/demonstration.html
http://www.actupny.org/documents/FDAhandbook1.html
1988 FDA Headquarters
1990 NIH Headquarters
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Accelerated Approval --Issues
More lenient criteria-slipping intosurrogates
Lack of urgency to complete post-marketing study commitments
No teeth
Unwillingness and lack of power to pulldrugs off the market
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Accelerated Approval, Animal Efficacy Rule and
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cce e a ed pp o a , a cacy u e a dPediatric Research Equity Act
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How to handle cases where validationstudies dont conclusively support the
drug? What to do if no tangible benefit in face
of well documented toxicities or safety
risks
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CAST-ingabout for
better pradigms
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Patient-Reported Outcomes (PRO)
Attempt to weigh patient-centered qualityof life outcomes
Step forward: care about more than just death
Want to value and measure quality of life (QOL) Respect and weight for how patients are feeling
True valued outcomes
.or back door surrogates? Susceptible to manipulation
How to achieve validated measures/scales?
Revicki, Lancet 2/17/2007
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Take Home Points
Misconception that if an outcome is acorrelate it is a valid surrogate end point
A correlate does not a surrogate make
Lowering risk marker: ? masking or killing themessenger
Multiple other unintended effects to drugs
besides putative neat mechanisms of action Even best surrogates, risk misleading in various
ways
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2 Criteria for Valid Surrogate
Biologic marker must be correlated withthe clinical endpoint
Marker must fully capture the net effectof the intervention on the clinical-efficacyendpoint
Fleming, Health Affairs 2005
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