RUOLO DELLA TERAPIA ANTI-ANGIOGENETICANEL CARCINOMA MAMMARIO

Il punto di vista delMetodologo ClinicoGiovanni L. PappagalloUff. di Epidemiologia Clinica, Dipartim. Scienze Mediche,ULSS 13 Mirano VE

… tanto per non fare confusione

Studio Registrativo

Immissionein Commercio

Altri studi prospettici

Valutazione del rapportobeneficio / danno

Pratica ClinicaUtilizzo delle migliori evidenze disponibili,

compatibilmente con le condizioni e le attese del Paziente

Raccomandazioni perla pratica clinica (LG)

Vi daròTRE PAROLE…

PERCHE’ misurare (la PFS)

COME misurare (la PFS)

QUALE giudizio conclusivo

Vi daròTRE PAROLE…

L.L. Miller, 2003L.L. Miller, 2003

000.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.9

11

00 66 1212 1818 2424 3030 3636MonthsMonths

Prob

abili

tyPr

obab

ility

=0.05=0.051-1-=0.80=0.80

2200 patients2200 patients4 years4 years$88M$88M

19 mo 22 mo19 mo 22 mo

Survival Superiority Study Survival Superiority Study Offers Too Little, Too Late, For Too MuchOffers Too Little, Too Late, For Too Much

SurvivalSurvival

Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival)Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival)

L.L. Miller, 2003L.L. Miller, 2003

000.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.9

11

00 66 1212 1818 2424 3030 3636MonthsMonths

Prob

abili

tyPr

obab

ility

=0.0025=0.00251-1-=0.90=0.90

800 patients800 patients20 months20 months

$32M$32M

SurvivalSurvival

PFSPFS

=0.05=0.051-1-=0.80=0.80

2200 patients2200 patients4 years4 years$88M$88M

Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival)Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival)

Single Superiority Study Can Offer Highly Single Superiority Study Can Offer Highly Robust PFS Assessment (Robust PFS Assessment (=0.0025) =0.0025)

19 mo 22 mo19 mo 22 mo7 mo 10 mo7 mo 10 mo

L.L. Miller, 2003L.L. Miller, 2003

000.10.10.20.20.30.30.40.40.50.50.60.60.70.70.80.80.90.9

11

00 66 1212 1818 2424 3030 3636MonthsMonths

Prob

abili

tyPr

obab

ility

=0.0025=0.00251-1-=0.90=0.90

800 patients800 patients20 months20 months

$32M$32M

SurvivalSurvival

PFSPFS

=0.05=0.051-1-=0.80=0.80

2200 patients2200 patients4 years4 years$88M$88M

Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival)Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival)

Single Superiority Study Can Offer Highly Single Superiority Study Can Offer Highly Robust PFS Assessment (Robust PFS Assessment (=0.0025) =0.0025)

19 mo 22 mo19 mo 22 mo7 mo 10 mo7 mo 10 mo

… proprio quello che vorrebbe l’Industria

Farmaceutica (?)

Endpoint Advantages Disadvantages

Progression-Free Survival (PFS)

Surrogate for accelerated approval

• Smaller sample size and shorter follow-up

• Not affected by crossover or sub-sequent therapies

• Subject to assessment bias

• Frequent assessments to be balanced among treatment arms

• Blinded review recom-mended

Endpoint Advantages Disadvantages

Overall Survival (OS)

Clinical benefit for regular approval

• Universally accepted• Direct measure of

benefit • Easily measured • Precisely measured• Blinding not essential

• May involve larger studies

• May be affected by crossover therapy and sequential therapy

Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics

Endpoint Advantages Disadvantages

Progression-Free Survival (PFS)

Surrogate for accelerated approval

• Smaller sample size and shorter follow-up

• Not affected by crossover or sub-sequent therapies

• Subject to assessment bias

• Frequent assessments to be balanced among treatment arms

• Blinded review recom-mended

Endpoint Advantages Disadvantages

Overall Survival (OS)

Clinical benefit for regular approval

• Universally accepted• Direct measure of

benefit • Easily measured • Precisely measured• Blinding not essential

• May involve larger studies

• May be affected by crossover therapy and sequential therapy

Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics

[TITLE]

D. Sargent, ASCO 2011

Dr. Patricia Keegan, director of the Division of Biologic Oncology Products in CDER

Dr. Patricia Keegan, director of the Division of Biologic Oncology Products in CDER

D. Sargent, ASCO 2011

D. Sargent, ASCO 2011

[TITLE]

LA Carey, Asco 2011

PERCHE’ misurare (la PFS)

COME misurare (la PFS)

QUALE giudizio conclusivo

Vi daròTRE PAROLE…

Endpoint Advantages Disadvantages

Progression-Free Survival (PFS)

Surrogate for accelerated approval

• Smaller sample size and shorter follow-up

• Not affected by crossover or sub-sequent therapies

• Subject to assessment bias

• Frequent assessments to be balanced among treatment arms

• Blinded review recom-mended

Endpoint Advantages Disadvantages

Overall Survival (OS)

Clinical benefit for regular approval

• Universally accepted• Direct measure of

benefit • Easily measured • Precisely measured• Blinding not essential

• May involve larger studies

• May be affected by crossover therapy and sequential therapy

Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics

ASCO 2011 Educational Book

ASCO 2011 Educational Book

FDA approval overview.Discussion: P. Cortazar

PERCHE’ misurare (la PFS)

COME misurare (la PFS)

QUALE giudizio conclusivo

Vi daròTRE PAROLE…

A. Stone & K. Carroll, ASCO 2008

A. Stone & K. Carroll, ASCO 2008NO!NO!

Si ritiene che il trattamento Si ritiene che il trattamento in esame “A” abbia le in esame “A” abbia le

potenzialità per migliorare il potenzialità per migliorare il trattamento standard “B” trattamento standard “B” almeno di una almeno di una quantità quantità ΔΔ

FDA approval overview.Discussion: P. Cortazar

?

… tanto per non fare confusione

Studio Registrativo

Immissionein Commercio

Altri studi prospettici

Valutazione del rapportobeneficio / danno

Pratica ClinicaUtilizzo delle migliori evidenze disponibili,

compatibilmente con le condizioni e le attese del Paziente

Raccomandazioni perla pratica clinica (LG)