Surrogate End Points Presentation

8/12/2019 Surrogate End Points Presentation

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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


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


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



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Kaplan-Meier Estimates of the Probability of the Primary Composite End Point



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Kaplan-Meier Estimates of Secondary Endpoint of Death



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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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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


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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Surrogate End Points Presentation

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