EVIDENCE-BASED MEDICINEAND GUIDELINES

Giovanni L. PappagalloDipartimento di Scienze Mediche

Azienda ULSS 13 – Mirano VE

2005/2006

Alessandro Liberati(1954-2012)

Le linee-guida dicono che…

RANDOMè SEMPRE "bello"?

-

UNCERTAINTY

+

Type of evidence Randomised trial = high Observational study = low Any other evidence = very low

Decrease grade if:

• Serious (−1) or very serious (−2) limitation in study design and/or execution

• Important inconsistency of results (−1)

• Some (−1) or major (−2) indirectness of evidence

• Imprecision of results (−1)

• High probability of reporting bias (−1)

Criteria for assigning grade of evidence

Vediamolo in pratica…

1st line Bevacizumab (plus IFN) in clear-cell, metastatic, RCC

Available studies Escudier B et al, Lancet 2007 + JCO 2010; Rini B et al, JCO 2008 + JCO 2010

Quality of Evidence

- Limitation in study design: primary endpoint OS → PFS (both studies); lack of placebo control and independent review of imaging (Rini)

- Inconsistency of results: NML- Indirectness of evidence: NML- Imprecision of results: NML- Reporting bias: NML

Benefit/Risk ratio

- HR(PFS) 0.63; 4.8-month improvement (Escudier); HR(PFS) 0.67; 3.3-month improvement (Rini); HR(OS) 0.86 (NS) (both studies);

- Hypertension (3-10%); proteinuria (7-15%)→ UNCERTAIN

1st line Sunitinib in clear-cell, metastatic, RCC

Available studies Motzer RJ et al, NEJM 2007 + JCO 2009; Cella D et al, JCO 2008;

Quality of Evidence

- Limitation in study design: NML- Inconsistency of results: NML- Indirectness of evidence: NML- Imprecision of results: NML- Reporting bias: NML

Benefit/Risk ratio

- HR(PFS) 0.54; 5.9-month improvement; HR(OS) 0.82 (P=.051); 4.6-month improvement;

- G3-5 SAEs:- RCT: hypertension (12%), fatigue (11%), diarrhea

(9%), hand-foot syndrome (9%); - OCS: hypertension (5%), fatigue (8%), diarrhea

(5%), hand-foot syndrome (6%);

1st line Pazopanib in clear-cell, metastatic, RCC

Available studies Sternberg CN et al, JCO 2010; NICE technology appraisal guidance #215, 2011; Cella D et al, EJC 2012

Quality of Evidence

- Limitation in study design: placebo as comparator; - Inconsistency of results: NML- Indirectness of evidence: indirect comparison to

estimate the relative effect vs active comparators- Imprecision of results: sparse data for OS - Reporting bias: NML

Benefit/Risk ratio

- HR(PFS) 0.40; 8.3-month improvement vs placebo; HR(PFS) 0.51 vs IFN (indirect comparison);HR(OS) 0.50, 95% CL 0.14-2.35 (RPSFT method) vs placebo;

- QoL: trend (NS) to less HRQoL deterioration- G3-5 SAEs: ↑ALT/AST (12%); diarrhea (4%); hyper-

tension (4%)

The choice of placebo as comparator in the pivotal trial was an initial

concern supported by two centralised scientific advices (initial and

clarification) given by the CHMP recommending the conduction of a

study with an active comparator.

Therefore, the CHMP was of the opinion that even though in the

specific case of pazopanib it has been shown that the product is

effective, an active comparator with other TKI inhibitors was necessary

in order to rule out that the use of pazopanib would mean a loss of

opportunity for the patients.

Analysis of historical data including a qualitative comparison and

discussion of biases has been provided by the applicant, however the

data itself were not considered to provide conclusive evidence.

1st line Pazopanib in clear-cell, metastatic, RCC

Available studies Sternberg CN et al, JCO 2010; NICE technology appraisal guidance #215, 2011; Cella D et al, EJC 2012

Quality of Evidence

- Limitation in study design: placebo as comparator; - Inconsistency of results: NML- Indirectness of evidence: indirect comparison to

estimate the relative effect vs active comparators- Imprecision of results: sparse data for OS - Reporting bias: NML

Benefit/Risk ratio

- HR(PFS) 0.40; 8.3-month improvement vs placebo; HR(PFS) 0.51 vs IFN (indirect comparison);HR(OS) 0.50, 95% CL 0.14-2.35 (RPSFT method) vs placebo;

- QoL: trend (NS) to less HRQoL deterioration- G3-5 SAEs: ↑ALT/AST (12%); diarrhea (4%); hyper-

tension (4%)

Pazopanib vs IFN: 0.36 (Pazopanib vs BSC) / 0.704 (IFN vs BSC) = 0.512

Aberdeen HTA Group, University of Aberdeen, September 2010

1st line Pazopanib in clear-cell, metastatic, RCC

Available studies Sternberg CN et al, JCO 2010; NICE technology appraisal guidance #215, 2011; Cella D et al, EJC 2012

Quality of Evidence

- Limitation in study design: placebo as comparator; - Inconsistency of results: NML- Indirectness of evidence: indirect comparison to

estimate the relative effect vs active comparators- Imprecision of results: sparse data for OS - Reporting bias: NML

Benefit/Risk ratio

- HR(PFS) 0.40; 8.3-month improvement vs placebo; HR(PFS) 0.51 vs IFN (indirect comparison);HR(OS) 0.50, 95% CL 0.14-2.35 (RPSFT method) vs placebo;

- QoL: trend (NS) to less HRQoL deterioration- G3-5 SAEs: ↑ALT/AST (12%); diarrhea (4%); hyper-

tension (4%)

A single study with a small sample size yielding wide confidence intervals should be considered

as imprecise or sparse data

SunitinibQUALITA' GLOBALE DELLE EVIDENZE ALTABILANCIO BENEFICIO/RISCHIO FAVOREVOLE LA FORZA DELLA RACCOMANDAZIONE E' POSITIVA FORTE (16/5/0/0)

Si raccomanda di eseguire la chemioterapia di prima linea per la malattia metastatica con Sunitinib come prima opzione terapeutica.

Bevacizumab+inteferon-α2aQUALITA' GLOBALE DELLE EVIDENZE MODERATABILANCIO BENEFICIO/RISCHIO INCERTOLA FORZA DELLA RACCOMANDAZIONE E' POSITIVA DEBOLE (0/19/2/0)

La chemioterapia di prima linea per la malattia metastatica con Bevacizumab +inteferon-α2a è una opzione terapeutica proponibile (condizioni/attese del paziente) in prima linea metastatica.

PazopanibQUALITA' GLOBALE DELLE EVIDENZE MODERATABILANCIO BENEFICIO/RISCHIO INCERTOLA FORZA DELLA RACCOMANDAZIONE E' POSITIVA DEBOLE (0/14/6/0)

La chemioterapia di prima linea per la malattia metastatica con Pazopanib è una opzione terapeutica proponibile (condizioni/attese del paziente) in prima linea metastatica.

Nulla a che vedere con la rilevanza clinica dei risultati!

1st line Bevacizumab (plus IFN) in clear-cell, metastatic, RCC

Available studies Escudier B et al, Lancet 2007 + JCO 2010; Rini B et al, JCO 2008 + JCO 2010

Quality of Evidence

- Limitation in study design: primary endpoint OS → PFS (both studies); lack of placebo control and independent review of imaging (Rini)

- Inconsistency of results: NML- Indirectness of evidence: NML- Imprecision of results: NML- Reporting bias: NML

Benefit/Risk ratio

- HR(PFS) 0.63; 4.8-month improvement (Escudier); HR(PFS) 0.67; 3.3-month improvement (Rini); HR(OS) 0.86 (NS) (both studies);

- Hypertension (3-10%); proteinuria (7-15%)

1st line Sunitinib in clear-cell, metastatic, RCC

Available studies Motzer RJ et al, NEJM 2007 + JCO 2009; Cella D et al, JCO 2008;

Quality of Evidence

- Limitation in study design: NML- Inconsistency of results: NML- Indirectness of evidence: NML- Imprecision of results: NML- Reporting bias: NML

Benefit/Risk ratio

- HR(PFS) 0.54; 5.9-month improvement; HR(OS) 0.82 (P=.051); 4.6-month improvement;

- ↑QoL: FKSI-15, FKSI-DRS, FACT-G, EQ-VAS, EQ5D- G3-5 SAEs:

- RCT: hypertension (12%), fatigue (11%), diarrhea (9%), hand-foot syndrome (9%); 32% ↓ dose

- OCS: hypertension (5%), fatigue (8%), diarrhea (5%), hand-foot syndrome (6%);

1st line Sunitinib in clear-cell, metastatic, RCC

Available studies Motzer RJ et al, NEJM 2007 + JCO 2009; Cella D et al, JCO 2008; Gore ME, Lancet Oncol 2009

Quality of Evidence

- Limitation in study design: NML- Inconsistency of results: NML- Indirectness of evidence: NML- Imprecision of results: NML- Reporting bias: NML

Benefit/Risk ratio

- HR(PFS) 0.54; 5.9-month improvement; HR(OS) 0.82 (P=.051); 4.6-month improvement;

- ↑QoL: FKSI-15, FKSI-DRS, FACT-G, EQ-VAS, EQ5D- G3-5 SAEs:

- RCT: hypertension (12%), fatigue (11%), diarrhea (9%), hand-foot syndrome (9%); 32% ↓ dose

- OCS: hypertension (5%), fatigue (8%), diarrhea (5%), hand-foot syndrome (6%); 40% ↓ dose

1st line Pazopanib in clear-cell, metastatic, RCC

Available studies Sternberg CN et al, JCO 2010; NICE technology appraisal guidance #215, 2011; Cella D et al, EJC 2012

Quality of Evidence

- Limitation in study design: placebo as comparator; - Inconsistency of results: NML- Indirectness of evidence: indirect comparison to

estimate the relative effect vs active comparators- Imprecision of results: sparse data for OS - Reporting bias: NML

Benefit/Risk ratio

- HR(PFS) 0.40; 8.3-month improvement vs placebo; HR(PFS) 0.51 vs IFN (indirect comparison);HR(OS) 0.50, 95% CL 0.14-2.35 (RPSFT method) vs placebo;

- QoL: trend (NS) to less HRQoL deterioration- G3-5 SAEs:↑ALT/AST (12%); diarrhea (4%); hyper-

tension (4%)

Aberdeen HTA Group, University of Aberdeen, September 2010

Risultati fortemente dipendenti dal modello scelto e dalle assunzioni iniziali

1st line Pazopanib in clear-cell, metastatic, RCC

Available studies Sternberg CN et al, JCO 2010; NICE technology appraisal guidance #215, 2011; Cella D et al, EJC 2012

Quality of Evidence

- Limitation in study design: placebo as comparator; - Inconsistency of results: NML- Indirectness of evidence: indirect comparison to

estimate the relative effect vs active comparators- Imprecision of results: sparse data for OS - Reporting bias: NML

Benefit/Risk ratio

- HR(PFS) 0.40; 8.3-month improvement vs placebo; HR(PFS) 0.51 vs IFN (indirect comparison);HR(OS) 0.50, 95% CL 0.14-2.35 (RPSFT method) vs placebo;

- QoL: trend (NS) to less HRQoL deterioration- G3-5 SAEs: ↑ALT/AST (12%); diarrhea (4%); hyper-

tension (4%)

Balance of desirable and undesirable effects

Favourable

Uncertain

Unfavourable

SunitinibQUALITA' GLOBALE DELLE EVIDENZE ALTABILANCIO BENEFICIO/RISCHIO FAVOREVOLE (F:18/I:3/S:0)LA FORZA DELLA RACCOMANDAZIONE E' POSITIVA FORTE (FP:16/DP:5/DN:0/FN:0)

Si raccomanda di eseguire la chemioterapia di prima linea per la malattia metastatica con Sunitinib come prima opzione terapeutica.

Bevacizumab+inteferon-α2aQUALITA' GLOBALE DELLE EVIDENZE MODERATABILANCIO BENEFICIO/RISCHIO INCERTO (F:1/I:19/S:1)LA FORZA DELLA RACCOMANDAZIONE E' POSITIVA DEBOLE (0/19/2/0)

La chemioterapia di prima linea per la malattia metastatica con Bevacizumab +inteferon-α2a è una opzione terapeutica proponibile (condizioni/attese del paziente) in prima linea metastatica.

PazopanibQUALITA' GLOBALE DELLE EVIDENZE MODERATABILANCIO BENEFICIO/RISCHIO INCERTO (F:0/I:18/S:3)LA FORZA DELLA RACCOMANDAZIONE E' POSITIVA DEBOLE (0/14/6/0)

La chemioterapia di prima linea per la malattia metastatica con Pazopanib è una opzione terapeutica proponibile (condizioni/attese del paziente) in prima linea metastatica.

Bilancio tra benefici e dannie direzione della raccomandazione

• La direzione a favore o contro l’uso del trattamento si dovrebbe basare sul bilancio tra gli effetti positivi (benefici) e negativi (effetti dannosi) dell’intervento.

• In linea di principio, se gli effetti positivi vengono considerati prevalenti rispetto a quelli negativi, la raccomandazione dovrebbe essere a favore dell’intervento, viceversa dovrebbe essere contro.

Bilancio tra benefici e dannie forza della raccomandazione

• Una raccomandazione “forte” dovrebbe essere riservata a situazioni nelle quali si è molto convinti che la maggioranza dei soggetti che ricevono l’inter-vento ottengano un beneficio.

• Quando vi è incertezza sul rapporto beneficio/danno, si dovrebbe optare per una raccomandazione “debole”.

STRONG FOR

WEAK FOR

WEAK AGAINST

STRONG AGAINST

The strenght of recommendation:

SunitinibQUALITA' GLOBALE DELLE EVIDENZE ALTABILANCIO BENEFICIO/RISCHIO FAVOREVOLE (F:18/I:3/S:0)LA FORZA DELLA RACCOMANDAZIONE E' POSITIVA FORTE (FP:16/DP:5/DN:0/FN:0)

Si raccomanda di eseguire la chemioterapia di prima linea per la malattia metastatica con Sunitinib come prima opzione terapeutica.

Bevacizumab+inteferon-α2aQUALITA' GLOBALE DELLE EVIDENZE MODERATABILANCIO BENEFICIO/RISCHIO INCERTO (F:1/I:19/S:1)LA FORZA DELLA RACCOMANDAZIONE E' POSITIVA DEBOLE (FP:0/DP:19/DN:2/FN:0)

La chemioterapia di prima linea per la malattia metastatica con Bevacizumab +inteferon-α2a è una opzione terapeutica proponibile (condizioni/attese del paziente) in prima linea metastatica.

PazopanibQUALITA' GLOBALE DELLE EVIDENZE MODERATABILANCIO BENEFICIO/RISCHIO INCERTO (F:0/I:18/S:3)LA FORZA DELLA RACCOMANDAZIONE E' POSITIVA DEBOLE (FP:0/DP:14/DN:6/FN:0)

La chemioterapia di prima linea per la malattia metastatica con Pazopanib è una opzione terapeutica proponibile (condizioni/attese del paziente) in prima linea metastatica.

Clinical Expertise

GRAZIE PER L’ATTENZIONE