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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Azienda ulss 13 mirano ve

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

YOUR TREATMENT CHOICE…

Statistical Significance

vs

Clinical Significance

Registrative Studies

vs

Therapeutic Strategies

Controlling

the Cost of Innovative

Cancer Therapeutics


Your treatment choice1

YOUR TREATMENT CHOICE…

Statistical Significance

vs

Clinical Significance

RegistrativeStudies

vs

TherapeuticStrategies

Controlling

the Costof Innovative

CancerTherapeutics


Azienda ulss 13 mirano ve

A. Stone & K. Carroll, ASCO 2008


Azienda ulss 13 mirano ve

A. Stone & K. Carroll, ASCO 2008


Poor clinical significance when

PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection


Azienda ulss 13 mirano ve

RL Schilsky, ASCO 2005


Azienda ulss 13 mirano ve

RL Schilsky, ASCO 2005


Azienda ulss 13 mirano ve

J Slutsman, ASCO 2005


Azienda ulss 13 mirano ve

J Slutsman, ASCO 2005


Azienda ulss 13 mirano ve

target Δ of

HERA trial:

RRR 23%

HR 0.54

(95%CL 0.43-0.67)

Trastuzumab

better

Control

better

J Slutsman, ASCO 2005


Azienda ulss 13 mirano ve

HR 0.62

(95%CL

0.41-0.95)

target Δ of

CALGB 9633:

RRR 33%

CarboTaxol

better

Control

better

J Slutsman, ASCO 2005


Poor clinical significance when1

PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection


Azienda ulss 13 mirano ve

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)


Azienda ulss 13 mirano ve

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


Poor clinical significance when2

PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection


Azienda ulss 13 mirano ve

“Standard” therapy?

Equipoise?


Azienda ulss 13 mirano ve

Equipoise?

“Standard” therapy?


Azienda ulss 13 mirano ve

Equipoise?

New “standard”?

“Standard” therapy?


Azienda ulss 13 mirano ve

S.D. Averbuch, ASCO 2008


Poor clinical significance when3

PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection


Azienda ulss 13 mirano ve

F. Pignatti, ESMO 2008


Azienda ulss 13 mirano ve

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.


Azienda ulss 13 mirano ve

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.


Poor clinical significance when4

PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis


Azienda ulss 13 mirano ve

AO Sartor


Azienda ulss 13 mirano ve

A. Gennari, 2008


Azienda ulss 13 mirano ve

S.L. George


Azienda ulss 13 mirano ve

F. Cappuzzo, WCLC 2009


Poor clinical significance when5

PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection


Poor clinical significance when6

PoorClinicalSignificancewhen

PossibleClinicalSignificancealsowhen

P<0.05

  • Earlytermination

  • Overpowering

  • Inadequatecontrolgroup

  • Inadequate (?) primaryendpoint

  • Subgroupanalysis

  • P≥0.05

  • Underpowering

  • Inadequate(?) patientselection


Azienda ulss 13 mirano ve

E. Winer, St. Gallen 2009


Competing causes of mortality

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


Azienda ulss 13 mirano ve

E. Winer, St. Gallen 2009


Your treatment choice2

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 principle or ready to use strategy

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


One of the best 1 st line

The Best 2ndLine

(one of)The Best 1st Line


Your treatment choice3

YOUR TREATMENT CHOICE…

StatisticalSignificance

vs

ClinicalSignificance

RegistrativeStudies

vs

TherapeuticStrategies

Controlling

the Cost of Innovative

Cancer Therapeutics


Your treatment choice4

YOUR TREATMENT CHOICE…

StatisticalSignificance

vs

ClinicalSignificance

RegistrativeStudies

vs

TherapeuticStrategies

Controlling

the Cost of Innovative

Cancer Therapeutics


Your treatment choice5

YOUR TREATMENT CHOICE…

StatisticalSignificance

vs

ClinicalSignificance

RegistrativeStudies

vs

TherapeuticStrategies

Controlling

the Costof Innovative

CancerTherapeutics


Thank you for your attention

ThankYouforYourAttention!


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