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
Raccomandazioni per
la pratica clinica (LG)
Pratica Clinica
Utilizzo delle migliori evidenze disponibili,
compatibilmente con le condizioni e le attese del Paziente
Vi darò
TRE PAROLE…
Vi darò
TRE PAROLE…
PERCHE’ misurare (la PFS)
COME misurare (la PFS)
QUALE giudizio conclusivo
Survival Superiority Study
Offers Too Little, Too Late, For Too Much
Probability
1
0.9
=0.05
1-=0.80
2200 patients
4 years
$88M
Survival
0.8
0.7
0.6
19 mo
0.5
0.4
0.3
0.2
22 mo
0.1
0
0
6
12
18
Months
24
30
Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival)
36
L.L. Miller, 2003
Single Superiority Study Can Offer Highly
Robust PFS Assessment (=0.0025)
Probability
1
0.9
0.8
0.7
0.6
=0.05
1-=0.80
2200 patients
4 years
$88M
Survival
PFS
7 mo
0.5
0.4
0.3
0.2
10 mo 19 mo
22 mo
=0.0025
1-=0.90
800 patients
20 months
$32M
0.1
0
0
6
12
18
Months
24
Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival)
30
36
L.L. Miller, 2003
Single Superiority Study Can Offer Highly
Robust PFS Assessment (=0.0025)
Probability
1
0.9
0.8
0.7
0.6
=0.05
1-=0.80
2200 patients
4 years
$88M
Survival
PFS
7 mo
0.5
0.4
0.3
0.2
10 mo 19 mo
=0.0025
1-=0.90
800 patients
20 months
$32M
0.1
0
0
6
22 mo
… proprio quello che
vorrebbe l’Industria
Farmaceutica (?)
12
18
Months
24
Assumes accrual = 100 patients/mo; follow-up = largest median + 2 mo (TTP) or 4 mo (survival)
30
36
L.L. Miller, 2003
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics
Endpoint
Advantages
Disadvantages
Overall Survival (OS)
• 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
Endpoint
Advantages
Disadvantages
Progression-Free
Survival (PFS)
• Smaller sample size
and shorter follow-up
• Not affected by
crossover or subsequent therapies
• Subject to assessment
bias
• Frequent assessments
to be balanced among
treatment arms
• Blinded review recommended
Clinical benefit
for regular
approval
Surrogate for
accelerated
approval
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics
Endpoint
Advantages
Disadvantages
Overall Survival (OS)
• 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
Endpoint
Advantages
Disadvantages
Progression-Free
Survival (PFS)
• Smaller sample size
and shorter follow-up
• Not affected by
crossover or subsequent therapies
• Subject to assessment
bias
• Frequent assessments
to be balanced among
treatment arms
• Blinded review recommended
Clinical benefit
for regular
approval
Surrogate for
accelerated
approval
[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
Vi darò
TRE PAROLE…
PERCHE’ misurare (la PFS)
COME misurare (la PFS)
QUALE giudizio conclusivo
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics
Endpoint
Advantages
Disadvantages
Overall Survival (OS)
• 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
Endpoint
Advantages
Disadvantages
Progression-Free
Survival (PFS)
• Smaller sample size
and shorter follow-up
• Not affected by
crossover or subsequent therapies
• Subject to assessment
bias
• Frequent assessments
to be balanced among
treatment arms
• Blinded review recommended
Clinical benefit
for regular
approval
Surrogate for
accelerated
approval
ASCO 2011 Educational Book
ASCO 2011 Educational Book
FDA approval overview.
Discussion: P. Cortazar
Vi darò
TRE PAROLE…
PERCHE’ misurare (la PFS)
COME misurare (la PFS)
QUALE giudizio conclusivo
A. Stone & K. Carroll, ASCO 2008
NO!
A. Stone & K. Carroll, ASCO 2008
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
Raccomandazioni per
la pratica clinica (LG)
Pratica Clinica
Utilizzo delle migliori evidenze disponibili,
compatibilmente con le condizioni e le attese del Paziente