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Surrogate Outcomes and Handling Multiple Endpoints in Clinical Trials. Benny Zee Centre for Clinical Trials The Chinese University of Hong Kong. Centre for Epidemiology and Biostatistics. Centre for Clinical Trials. Cochrane Centre. International Cooperative Group Studies.

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surrogate outcomes and handling multiple endpoints in clinical trials

Surrogate Outcomes and Handling Multiple Endpoints in Clinical Trials

Benny Zee

Centre for Clinical Trials

The Chinese University of Hong Kong

medical research support in cuhk

Centre for

Epidemiology

and Biostatistics

Centre for

Clinical Trials

Cochrane

Centre

International

Cooperative

Group Studies

Academic

Research

Industry

Studies

Medical Research Support in CUHK

Medical Research

Support Committee (MRSC)

missions statement for the centre for clinical trials cct
Missions Statement for the Centre for Clinical Trials (CCT)
  • Missions include:
    • Provide methodological advice in clinical trials
    • Regulatory submission assistance and contract negotiation with industry
    • Study and data management support
  • Act as a contract research organization (CRO) in the management of clinical trials
    • Academic single-institution trials
    • Multicentre cooperative group trials
    • Industry trials
any differences between a cro and cct
Any differences between a CRO and CCT?

Commercial

Benefits

Medicine &

Therapeutics

Obs & Gyn

Other

CRO’s

Comm &

Family Med

Pediatrics

Chem Path, ACP

Microbiology

Centre for

Clinical

Trials

Surgery

Benefit Community

Clinical Research

Multicentre Trials

Diagnostic

Radiology

…others

Clinical

Oncology

Big Pharma & Biotech

Companies, NCI US, etc.

services of cct
Services of CCT
  • Support Faculty with sound design methodology and analysis of clinical trials
  • Provide infrastructure for conducting clinical trials
  • Provide Good Clinical Practice (GCP) training for personnel from pharmaceutical and biotechnology companies, hospitals and clinical trials centers in Asia
  • Promote clinical trials methodology through research in biostatistics methodology, data management, bioinformatics, etc.
lunch time seminar series
Lunch Time Seminar Series
  • Surrogate Outcomes and Handling Multiple Endpoints in Clinical Trials
  • Repeated Measures in Randomized Controlled Trials (Oct 15)
  • Other suggestions of Topics, Speakers, Joint Events, etc?
    • Please contact me, Shirley Xu or Jennifer Mao
introduction to surrogate endpoint
Introduction to Surrogate Endpoint
  • Why do we use surrogate endpoint?
    • Can be measured earlier
    • Convenient or less invasive
    • Can be measured more frequently
    • Can accelerate the approval process
  • Advantages:
    • May reduce the size of clinical trials
    • May shorten the duration of clinical trials
    • May reduce the cost of clinical trials
endpoints inappropriately characterized as surrogates
Endpoints inappropriately characterized as surrogates
  • Quality of life
    • It is an outcome measure (not a surrogate endpoint)
  • Morbidity scale
    • It is a clinical benefit endpoint (not a surrogate endpoint)
endpoints for clinical trials
Endpoints For Clinical Trials
  • A surrogate endpoint does not directly measure any clinical benefit to patient, it only predicts the outcome
  • A mixed surrogate/clinical benefit endpoint directly measures significant benefit to patient and predicts an additional, more substantial benefit to patient
  • A clinical outcome directly measures substantial clinical benefit to patient
when is the use of surrogate endpoints justified
When is the use of surrogate endpoints justified?
  • Screening
    • For promising new therapies
    • Evaluation of biological activity in phase I/II trials
  • Caution in using surrogate endpoints:
    • Using biological markers as a surrogate endpoint, one may obtain misleading false positive or false negative conclusion when assessing treatment effects of longer term clinical outcome
  • Requirements:
    • Before a surrogate endpoint can replace a primary endpoint, it must be formally validated
ideal treatment surrogate and clinical outcome relationships

Surrogate

Marker

S

+

+

Clinical

Outcome

T

Treatment

Z

o

Other Biological

Processes

Ideal treatment, surrogate and clinical outcome relationships
  • + positive effect
  • negative effect
  • o no effect
problems in surrogate endpoint example in hiv

2. Surrogate marker may be

strongly predictive of

the clinical outcome

1. Treatments are chosen

based on their anticipated

effect on CD4 count

CD4

Lymphocyte

Count

AIDS

Event or

Death

AZT

vs

control

3. Treatments may

also affect other

biological processes

4. Clinical outcome

may be affected

by other biological

processes

Other Biological

Processes Affecting

Prognosis

Problems in Surrogate Endpoint: Example in HIV
example in hiv false positive case

+

+

Treatment

Effect Cancelled

-

+

Example in HIVFalse Positive Case

2. Surrogate marker may be

strongly predictive of

the clinical outcome

1. Treatments are chosen

based on their anticipated

effect on CD4 count

CD4

Lymphocyte

Count

AIDS

Event or

Death

AZT

vs

control

3. Treatments may

also affect other

biological processes

4. Clinical outcome

may be affected

by other biological

processes

Other Biological

Processes Affecting

Prognosis

example in hiv false negative case

Treatment effect

Not detected

+

+

Example in HIVFalse Negative Case

2. Surrogate marker may be

strongly predictive of

the clinical outcome

1. Treatments are chosen

based on their anticipated

effect on CD4 count

CD4

Lymphocyte

Count

AIDS

Event or

Death

o

AZT

vs

control

3. Treatments may

also affect other

biological processes

4. Clinical outcome

may be affected

by other biological

processes

Other Biological

Processes Affecting

Prognosis

cardiac arrhythmia suppression trial cast
Cardiac Arrhythmia Suppression Trial (CAST)
  • Patients with myocardial infarction
    • Ventricular arrhythmia is a risk factor for subsequent sudden death
    • Arrhythmia was considered a surrogate endpoint
  • Encainide and flecainide are known effective anti-arrhythmic drugs
    • Approved by FDA
    • Their effect on survival was not established
  • CAST randomized more than 2000 myocardial infarction patients to receive either anti-arrhythmic drug or placebo
cardiac arrhythmia suppression trial cast19
Cardiac Arrhythmia Suppression Trial (CAST)
  • Results
    • Death rates of the study treatment arm nearly tripled that of the placebo arm
  • Conclusion
    • This study had shown that a false positive conclusion can be made with a surrogate endpoint
    • FDA prematurely released antiarrhythmic drugs for patients with myocardial infarction due to the use of surrogate endpoint
chronic granulomatous disease cgd
Chronic Granulomatous Disease (CGD)
  • Background
    • Childhood disease, disorders in immune system
    • Phagocytes ingest microorganism but fail to kill them
  • International CGD Cooperative Group
    • Randomized patients between interferon- and placebo in a double-blind fashion
    • Superoxide measurements and bacterial killing can be used as surrogate endpoints
    • After a lengthy debate, rate of infection was finally used as primary endpoint
    • Individual follow-up extended from 1-month to 1-year
chronic granulomatous disease cgd21
Chronic Granulomatous Disease (CGD)
  • Results
    • Interferon- significantly reduced the rate of recurrent of serious infections at interim analysis using O’Brien-Fleming rule
    • FDA approved the use of Interferon- in CGD patients
    • There were no significant differences between treatment arms on surrogate biological markers, superoxide measurements and bacterial killing
  • Reliance on surrogate markers would have led to false negative conclusion
prentice s definition
Prentice’s Definition
  • A “surrogate” endpoint for which a test of the null hypothesis of no relationship to the treatment groups is also a valid test of the corresponding null hypothesis based on the true endpoint
  • Let T and S be random variables denote true and surrogate endpoints respectively, Z be indicator variable for treatment, and f(.) denotes p.d.f. such that S must satisfy:

f(S|Z) = f(S)  f(T|Z) = f(T)

validation
Validation
  • Criteria for checking if a triplet (T,S,Z) fulfills the definition are:

(1)f(S|Z)  f(S), Z is significant on S

(2)f(T|Z)  f(T), Z is significant on T

    • However, this validation is impossible since one may fail to detect differences due to lack of power
  • Other sufficient conditions:

(3) f(T|S)  f(T), S is informative about T

(4) f(T|S,Z) f(T|S), S fully captures the effect of Z on T

comments on validation
Comments on Validation
  • The condition f(T|S,Z) = f(T|S)
    • requiring the surrogate endpoint S fully capture the effect of treatment on the true endpoint T
    • so restrictive that this condition rarely holds in clinical application
    • even in a rare setting that data on treatment Z allow us to view S as a valid surrogate for T, we cannot extrapolate this to a new treatment Z*
  • Auxiliary variable
    • S provides additional information if it strongly correlates with outcome T
    • It can be used to increase efficiency
freedman s proportion explained pe
Freedman’s Proportion Explained (PE)
  • The Prentice’s criteria (1)-(3) are provided by tests of significance of parameters , , and 

Sj|Zj = S + Zj + Sj

Tj|Zj = T + Zj + Tj

Tj|Sj =  + Sj + j

  • PE = 1 – (S/)
    • where  is the estimate of the effect of Z on T
    • and S is the estimate of the effect of Z on T after adjustment for S

Tj|Zj,Sj = T + SZj + ZSj + Tj

hiv infection aids
HIV Infection & AIDS
  • Early stages HIV infection
    • Used progression of disease rather than survival as endpoint
    • A decline of CD4+ cells count to less than 0.5 x 109/L has been used as endpoint
  • Advanced disease
    • Mortality remained as primary endpoint
  • Biological markers
    • e.g. CD4+
how can we assess the validity of a potential surrogate marker for trials of aids treatment
How can we assess the validity of a potential surrogate marker for trials of AIDS treatment?
  • A strong biological rationale
  • The marker value at a given time is strongly predictive of ultimate survival
  • The effect of treatment on the surrogate endpoint will reliably predict the effect of treatment on survival
example concorde trial
Example: Concorde Trial
  • Double-blind randomized trial for asymptomatic HIV-infected individuals:
    • Imm: immediate zidovudine (AZT)
    • Def: deferred AZT until AIDS-related complex
  • Targeted sample size = 2000
  • Endpoints:
    • Progression, haemoglobin, total white cells, total and CD4+ lymphocytes, CD4 percentage, CD4/CD8 ratio, CD8 cells, CD8 percentage, CD3+ cells, neutrophils, monocytes, platelets, p24 antigen, 2 microglobulin and weight
concorde trial summary
Concorde Trial: Summary
  • Final Results on Primary Clinical Endpoint
    • No significant difference between arms with respect to time-to-progression and survival
    • More toxicity in the Immediate arm
    • Do not encourage early use of AZT in symptom-free HIV infected adults
  • Results on immunological markers
    • In favor of Immediate arm:
      • CD4 cells, CD4 percentage, CD4/CD8, CD3 percentage, platelets
    • It would have been a false positive conclusion if based on surrogate endpoint
advanced colorectal cancer meta analysis
Advanced Colorectal Cancer Meta-analysis
  • A Meta-analysis of 3791 patients
    • First-line treatment with standard bolus intravenous fluoropyrimidines versus experimental treatment
      • 5FU+LV
      • 5FU+methotrexate
      • 5FU continuous infusion
      • Hepatic-arterial infusion of floxuridine
  • To evaluate the relationship between tumor response and survival
advanced colorectal cancer meta analysis39
Advanced Colorectal Cancer Meta-analysis
  • Tumor response
    • CR: disappearance of all detectable tumor
    • PR: decrease of 50% or more in the tumor surface area without new lesion
    • SD: decrease of less than 50% or increase of less than 25%
    • PD: increase of more than 25%
      • Tumor surface area is calculated by sum of the products of the largest perpendicular diameters
  • Best overall response for each patient was used as surrogate endpoint
slide40

Response odds ratios for Experimental vs Bolus fluoropyrimidines

N=# patients; O=observed # of response; E=expected # response; V=variance

slide41

Survival hazards ratios

N=# patients; O=observed # of response; E=expected # response; V=variance

summary
Summary
  • Increase response rate  increase survival?
    • The benefits of experimental treatment are more obvious in tumor response than survival
    • No survival benefit from treatment within any tumor response categories
      • The survival benefit in favor of experimental arm was due to higher tumor response rates
    • Treatment effect on survival associated with treatment effect on tumor response, but with a low coefficient of determination 0.38, i.e., only 38% variation was explained
  • Benefit in tumor response does not imply survival benefit
final remarks
Final Remarks
  • FDA review of first-line therapy for advance colorectal cancer
    • Required evidence of survival advantage
    • Control arm using 5-FU & leucovorin (LV) has response rate of 15-20%
  • Experiences of two new agents reviewed by FDA
    • Regarding the use of surrogate endpoint
irinotecan example
Irinotecan Example
  • Irinotecan vs best supportive care as second-line treatment
    • Induced partial responses in 10-15% of patients who had not responded to 5FU/LV
    • Demonstrated survival advantages as second-line therapy in an European trial
    • FDA approved for use as second-line after 5FU/LV
slide48

Irinotecan Example

  • USA and Europe done studies on first-line treatment
    • comparing Irinotecan/5FU/LV versus 5FU/LV
    • Both studies showed significant improvement in response rate (35% and 39% for irinotecan-containing regimen vs. 21% and 22% for control)
    • Modest but significant improvement in survival
    • Irinotecan/5FU/LV was approved by FDA in Apr 2000
oxaliplatin example
Oxaliplatin Example
  • First-line therapy studied in Europe
    • Response rate (51% for oxaliplatin/5FU/LV vs 23% for 5FU/LV)
    • Did not show significant improvement in survival
    • Not approved by FDA
  • Is effective new drug being withheld unnecessarily since FDA exclusively relies on improvement in survival?
    • Survival may not be significant since patients may benefit from second-line treatment
    • Can response be used as surrogate endpoint?
surrogate endpoints in practice
Surrogate Endpoints in Practice
  • The surrogate must be in the causal pathway of the disease process
  • An intervention’s entire effect on the clinical outcome of interest should be fully captured by the surrogate
  • We need to assess more than a single study to decide on the adequacy of a surrogate
guideline in reviewing medical literature on surrogate endpoint
Guideline in reviewing medical literature on surrogate endpoint
  • Is there a strong, independent, consistent association between the surrogate and clinical endpoint
  • Is there evidence from randomized trials in other drug classes that improvement in the surrogate has consistently led to improvement in the outcome?
  • Is there evidence from randomized trials in the same drug classes that improvement in the surrogate has consistently led to improvement in the outcome?
  • What were the results? How large, precise, and lasting was the treatment effect?