paper dels marcadors subrogats d’eficàcia · 2010. 4. 8. · paper dels marcadors subrogats...

Paper dels marcadors subrogats d’eficàcia

Miquel Àngel Seguí Palmer


The Effectiveness Standard

• 1962 amendments: “claimed effect”• Subsequent rulings: “Clinical meaning”• “Clinical meaning” in oncology

– 1970s: minimal activity– 1985 : survival or effect on “QOL”

(symptoms or function)– 1990s-2000s: use of some surrogates


Changing landscapeIn the past 15‐20 years:– Better molecular understanding of diseases– Earlier, more precise diagnosis– New targeted, improved therapies

Impact on clinical trials– Assessment of improvements in clinically meaningful endpoints

require enrolling many patients and then following them for a long time.

Emerging need– Develop strategies for reducing the time and cost of drug

development.– Use of surrogate endpoints either in proof‐of‐concept or label‐

enabling trials. Defined in clinical practice and used by clinicians to monitor and treat patientsNew mechanism‐driven biomarkers


Surrogates in Oncology• Surrogate endpoint definition*:

– Substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives.

– Changes are expected to reflect changes in a clinically meaningful endpoint.

*Temple RJ, Clinical Measurement in Drug Evaluation. Nimmo and Tucker. John Wiley & Sons Ltd, 1995.


Why do we need surrogates?

• Practicality of studies: – Shorter duration– Smaller sample size (?)

• Availability of biomarkers:– Tissue, cellular, hormonal factors, etc. – Imaging techniques– Genomics, proteomics, other-ics

Ref: Schatzkin and Gail, Nature Reviews (Cancer) 2001, 3.


Definitions• Clinical endpoint: a characteristic or variable that

reflects how a patient feels, functions, or survives • Biomarker: a characteristic that is objectively

measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeuticintervention

• Surrogate endpoint: a biomarker that is intended to substitute for a clinical endpoint. A surrogateendpoint is expected to predict clinical benefit (or harm or lack of benefit or harm)

Ref: Temple, JAMA 1999;282:790.


Established Surrogates Supporting Regular Approval

• Blood pressure• Blood sugar• Blood cholesterol

The Ideal:Prentice’s Sufficient Conditions

The surrogate endpoint must be correlated with the clinical outcome

The surrogate endpoint must fully capture the net effect of treatment on the clinical outcome



Reasons to Use Early Endpoints Instead of Survival as the Primary Endpoint of Randomized Clinical Trials


A surrogate (S) is acceptable if the surrogate and the clinical endpoint (C) are correlated (individual-level surrogacy) and if the effects of treatment (Trt) on the

surrogate and the clinical endpoints are correlated (trial-level surrogacy).


PFS AS A SURROGATE FOR SURVIVAL


Attributes of Overall Survival


PFS as an Endpoint

Survival versus TTP

Survival TTP -100% Accurate Event -Less Accurate -100% Accurate Time -Less Accurate -Assessed Daily -Assessed every 2-6 mo -Importance Unquestioned -Uncertain -Both Safety & Efficacy -Only Efficacy -Takes Longer -Faster -Might be Obscured by Secondary Rx

-Not Obscured


Which Events Count?Time to Tumor Progression (TTP)

• TTP event = progression– Measures tumor effects

– Deaths are censored at last visit• Non‐informative censoring assumption


Which Events Count?Progression Free Survival (PFS)

• PFS events = progression + death

• Better surrogate for CB?

• Poor follow‐up causes prolongation of progression time – Need careful follow‐up

– Need analysis rules for deaths after loss to follow‐up?


Which Events Count?Time to Treatment Failure (TTF)

• TTF events = death, progression, toxicity, etc. – Does not isolate efficacy

– Not adequate as the primary regulatory endpoint

• Drug must be safe and effective

• Demonstrating less toxicity is not adequate


Visit 1 Visit 2Randomization

= Date of Death or actual tumor progression

Survival Event Date

Visit 1 Visit 2Randomization

TTP Event Date

Survival Analysis

TTP Analysis

Determining Event Dates



Prediction of true endpoint from surrogate endpoint

True

End

poin

t

Surrogate Endpoint

Endpoints observed onindividual patients

R² indicates qualityof regression


For a marker to be used as a surrogate, we need “repeated demonstrations of a strong correlation between the marker and the clinical outcome”

Ref: Holland, 9th EUFEPS Conference on “Optimising DrugDevelopment: Use of Biomarkers”, Basel, 2001.

Several trials


Prediction of treatment effect: several trials

Trea

tmen

t Effe

ct o

nTr

ueE

ndpo

int

Treatment Effect on Surrogate Endpoint-1 0 1

-1

-.5

.5

1

0

Treatment effects observedin all trials

R² indicates quality of regression


R2 = 0.30


R2 = 0.48


R2 = 0.79


Stage II patients

Stage III patients


Surrogate Endpoints in Practice

The surrogate must be in the causal pathway of the disease processAn intervention’s entire effect on the clinical outcome of interest should be fully captured by the surrogateWe need to assess more than a single study to decide on the adequacy of a surrogate

Is TTP a Clinical Benefit Measure?

• Does TTP have clinical meaning?– Cancer growth leads to suffering and death

– Delaying cancer growth is good


Is TTP a Clinical Benefit Measure?

• The critical issues:– Can you measure TTP reliably?

– How much progression delay is worth how much toxicity?

– What is the relative meaning of a TTP benefit to other benefits such as survival?


Acceptance of Clinical Benefit Based on Tumor Effects (RR or TTP), Examples

• Hormonal drugs for metastatic breast cancer – Primary endpoint: response rate (RR)

– Secondary endpoints: TTP and Survival

– Regulatory acceptance• long experience with tamoxifen

• no proven survival benefit for drugs in this setting

• low drug toxicity


What is TTP?

• Complex: Check the protocol,case report form, & statistical analysis plan!

• Time from randomization to first evidence of progression. RECIST:– 20% increase in sum of marker lesions

– New lesions

– Unequivocal increase in non‐marker lesions


• Measured in all patients

• Measures cytostatic activity

• Oncologists usually change therapy at progression

• Assessed before crossover

• Requires smaller studies

• Face validity?

TTP: Advantages


• Doesn’t always “correlate” with survival(vs. inadequate data to assess relationship?)

• Indirect measure of patient benefit

• Unclear meaning of small difference

• Reliability in unblinded setting?

• Unknown reliability of small TTP difference with usual trial monitoring

• Expensive to measure, difficult to verify

TTP: Problems


• Data are usually inadequate to assess– Many different cancer settings

– Large survival benefits are rare

– Cited “lack of correlation” usually invalid• Greater statistical power for TTP than survival

• Studies cannot rule out survival effect

• Significant TTP analysis and non‐significant survival analysis would be expected

• Crossover may obscure survival effect

The Relationship between TTP and Survival


Problem #2:TTP is Indirect measure of benefit

TTP would be more persuasive benefit measure when:– When symptoms frequently occur at or soon after progression time

– When TTP increment is large

– When treatment toxicity is low

– When benefit of available drugs is less


Incorporate symptoms into TTP:“time to symptomatic progression”

• Represents full clinical benefit

• Potential bias in symptom data

• Symptom data needed beyond tumor progression time

• Confounding effects of additional treatments


Verifying TTP: Difficulties for Sponsors and for FDA

• What if:– Not all lesions are followed?

– Measurements occur at non‐standard times?

– Some measurements are missing from a visit?

• How do you:– Assure equal screening for new lesions?

– Evaluate bias from lack of blinding?

– Verify progression of “evaluable disease?”


A case study in early colorectal cancer:the trials

• Fifteen collaborative group trials for patients after resection of colorectal tumor (12,915 patients)

• Unit of analysis for treatment effects: 18 comparisons between 33 treatment arms

• Patients randomized between various 5-FU regimens and/or control

A case study in early colorectal cancer:the endpoints

Potential surrogate endpoint:• 3-year disease-free survivalTrue endpoint:• 5-year overall survival

Ref: Sargent et al, Proceedings ASCO (Abstract # 3502), 2004.

Most recurrences occur before 3 years

0

3.5

7.26.9

5.6

4

3.2

2.2 2

1.3 1.20.9 0.8

0.5 0.5 0.4 0.3

0

1

2

3

4

5

6

7

8

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8

Years after randomization

Rec

urre

nce

Rat

e (%

)

Strong association between endpoints

0.5

0.55

0.6

0.65

0.7

0.75

0.8

0.5 0.55 0.6 0.65 0.7 0.75 0.8

Disease Free Survival

Ove

rall

Surv

ival

R2=0.86

Strong association between treatment effects

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3

Disease Free Survival Hazard Ratio

Ove

rall

Surv

ival

Haz

ard

Rat

io

R2=0.87

paper dels marcadors subrogats d’eficàcia · 2010. 4. 8. · paper dels marcadors subrogats...

Documents