MULTIPLE TREATMENT CHOICES:
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MULTIPLE TREATMENT CHOICES: ARE THEY EQUALLY ( cost ) EFFECTIVE?. Giovanni L. Pappagallo ([email protected]). Azienda ULSS 13 – Mirano VE. Dipartimento di Scienze Mediche U.O.C. di Oncologia & Ematologia Oncologica. Ufficio di Epidemiologia & Sperimentazioni Cliniche.

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MULTIPLE TREATMENT CHOICES:

ARE THEY EQUALLY

(cost) EFFECTIVE?

Giovanni L. Pappagallo

([email protected])

Azienda ULSS 13 – Mirano VE

Dipartimento di Scienze Mediche

U.O.C. di Oncologia & Ematologia Oncologica

Ufficio di Epidemiologia & Sperimentazioni Cliniche


YOUR TREATMENT CHOICE…

Statistical Significance

vs

Clinical Significance

Registrative Studies

vs

Therapeutic Strategies

Controlling

the Cost of Innovative

Cancer Therapeutics


YOUR TREATMENT CHOICE…

Statistical Significance

vs

Clinical Significance

RegistrativeStudies

vs

TherapeuticStrategies

Controlling

the Costof Innovative

CancerTherapeutics


A. Stone & K. Carroll, ASCO 2008


A. Stone & K. Carroll, ASCO 2008


PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection


RL Schilsky, ASCO 2005


RL Schilsky, ASCO 2005


J Slutsman, ASCO 2005


J Slutsman, ASCO 2005


target Δ of

HERA trial:

RRR 23%

HR 0.54

(95%CL 0.43-0.67)

Trastuzumab

better

Control

better

J Slutsman, ASCO 2005


HR 0.62

(95%CL

0.41-0.95)

target Δ of

CALGB 9633:

RRR 33%

CarboTaxol

better

Control

better

J Slutsman, ASCO 2005


PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection


Target Δ: HR erlotinib:placebo = 0.75 (2 months OS improvement)

Analysis after 381 events (450 patients; α 5%, power 80%)

Analysis after 486 events (569 patients)

Actual difference:

0.33 months (10 days)


Target Δ: HR cetuximab:placebo = 0.80 (2.5 months OS improvement)

Analysis after 845 events (1100 patients; α 5%, power 90%)

Analysis after ??? events (1125 patients)

Actual difference:

1.2 months


PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection


“Standard” therapy?

Equipoise?


Equipoise?

“Standard” therapy?


Equipoise?

New “standard”?

“Standard” therapy?


S.D. Averbuch, ASCO 2008


PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection


F. Pignatti, ESMO 2008


VALIDATION OF SURROGATE ENDPOINTS:“FULL CAPTURE OF EFFECT”

Effect of treatment on surrogate

Effect of surrogate on true endpoint

S

T

Trt

Effect of treatment on trueendpoint

must befullycaptured by surrogate

Prentice, Statist Med 1989;8:431.


VALIDATION OF SURROGATE ENDPOINTS:“FULL CAPTURE OF EFFECT”

Effect of treatment on surrogate

Effect of surrogate on true endpoint

S

T

Trt

Effect of treatment on trueendpoint

must befullycaptured by surrogate

Prentice, Statist Med 1989;8:431.


PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis


AO Sartor


A. Gennari, 2008


S.L. George


F. Cappuzzo, WCLC 2009


PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection


PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection


E. Winer, St. Gallen 2009


Breast-cancer deaths

Other deaths

Competing causes of mortality

Age ≥50 years and ER+

Probability

0.4

0.3

0.2

0.1

0.0

0

5

10

15

Time from diagnosis (years)

ER+, oestrogen receptor-positive

Hanrahan et al. J Clin Oncol 2007; 25: 4952-60


E. Winer, St. Gallen 2009


YOUR TREATMENT CHOICE…

StatisticalSignificance

vs

ClinicalSignificance

Registrative Studies

vs

Therapeutic Strategies

Controlling

the Cost of Innovative

Cancer Therapeutics


MAINTENANCE THERAPY IN ADVANCED NSCLC: PROOF OF PRINCIPLEOR READY-TO-USE STRATEGY?

Only 19% of placebo ptsreceivedPemetrexed at anytime

Only 16% of placebo ptsreceivedErlotinib at anytime

C. Belani, ASCO 2009

F. Cappuzzo, WCLC 2009


The Best 2ndLine

(one of)The Best 1st Line


YOUR TREATMENT CHOICE…

StatisticalSignificance

vs

ClinicalSignificance

RegistrativeStudies

vs

TherapeuticStrategies

Controlling

the Cost of Innovative

Cancer Therapeutics


YOUR TREATMENT CHOICE…

StatisticalSignificance

vs

ClinicalSignificance

RegistrativeStudies

vs

TherapeuticStrategies

Controlling

the Cost of Innovative

Cancer Therapeutics


YOUR TREATMENT CHOICE…

StatisticalSignificance

vs

ClinicalSignificance

RegistrativeStudies

vs

TherapeuticStrategies

Controlling

the Costof Innovative

CancerTherapeutics


ThankYouforYourAttention!


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