RUOLO DELLA TERAPIA ANTI-ANGIOGENETICA NEL CARCINOMA MAMMARIO Il punto di vista del Metodologo Clinico Giovanni L. Pappagallo Uff. di Epidemiologia Clinica, Dipartim. Scienze Mediche, ULSS 13 Mirano VE

… tanto per non fare confusione Studio Registrativo Immissione in Commercio Altri studi prospettici Valutazione del rapporto beneficio / danno Pratica Clinica Utilizzo delle migliori evidenze disponibili, compatibilmente con le condizioni e le attese del Paziente Raccomandazioni per la pratica clinica (LG)

Vi darò TRE PAROLE…

PERCHE misurare (la PFS) COME misurare (la PFS) QUALE giudizio conclusivo Vi darò TRE PAROLE…

L.L. Miller, Months Probability =0.05 = = patients 4 years $88M 19 mo 22 mo 19 mo 22 mo Survival Superiority Study Offers Too Little, Too Late, For Too Much Survival Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival)

L.L. Miller, Months Probability = = = patients 20 months $32M Survival PFS =0.05 = = patients 4 years $88M Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival) Single Superiority Study Can Offer Highly Robust PFS Assessment ( =0.0025) 19 mo 22 mo 19 mo 22 mo 7 mo 10 mo

L.L. Miller, Months Probability = = = patients 20 months $32M Survival PFS =0.05 = = patients 4 years $88M Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival) Single Superiority Study Can Offer Highly Robust PFS Assessment ( =0.0025) 19 mo 22 mo 19 mo 22 mo 7 mo 10 mo … proprio quello che vorrebbe lIndustria Farmaceutica (?)

EndpointAdvantagesDisadvantages 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 EndpointAdvantagesDisadvantages 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

EndpointAdvantagesDisadvantages 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 EndpointAdvantagesDisadvantages 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

D. Sargent, ASCO 2011

[TITLE] LA Carey, Asco 2011

PERCHE misurare (la PFS) COME misurare (la PFS) QUALE giudizio conclusivo Vi darò TRE PAROLE…

EndpointAdvantagesDisadvantages 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 EndpointAdvantagesDisadvantages 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

FDA approval overview. Discussion: P. Cortazar

PERCHE misurare (la PFS) COME misurare (la PFS) QUALE giudizio conclusivo Vi darò TRE PAROLE…

A. Stone & K. Carroll, ASCO 2008

NO!

Si ritiene che il trattamento in esame A abbia le potenzialità per migliorare il trattamento standard B almeno di una quantità Δ

FDA approval overview. Discussion: P. Cortazar ?

… tanto per non fare confusione Studio Registrativo Immissione in Commercio Altri studi prospettici Valutazione del rapporto beneficio / danno Pratica Clinica Utilizzo delle migliori evidenze disponibili, compatibilmente con le condizioni e le attese del Paziente Raccomandazioni per la pratica clinica (LG)