EVIDENCE-BASED MEDICINE AND GUIDELINES Giovanni L. Pappagallo Dipartimento di Scienze Mediche Azienda ULSS 13 – Mirano VE 2005/2006

Alessandro Liberati (1954-2012)

Le linee-guida dicono che…

RANDOM è SEMPRE "bello"?

- UNCERTAINTY +

Vediamolo in pratica… Criteria for assigning grade of evidence 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)

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%)

Aberdeen HTA Group, University of Aberdeen, September 2010 Pazopanib vs IFN: 0.36 (Pazopanib vs BSC) / 0.704 (IFN vs BSC) = 0.512

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

Nulla a che vedere con la rilevanza clinica dei risultati! Sunitinib QUALITA' GLOBALE DELLE EVIDENZE ALTA BILANCIO 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-α2a QUALITA' GLOBALE DELLE EVIDENZE MODERATA BILANCIO BENEFICIO/RISCHIO INCERTO 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. Pazopanib 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. 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 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%)

Balance of desirable and undesirable effects Favourable Uncertain Unfavourable

Bevacizumab+inteferon-α2a Sunitinib QUALITA' GLOBALE DELLE EVIDENZE ALTA BILANCIO 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-α2a QUALITA' GLOBALE DELLE EVIDENZE MODERATA BILANCIO 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. Pazopanib BILANCIO 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 danni e 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 danni e 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”.

The strenght of recommendation: STRONG FOR WEAK FOR WEAK AGAINST STRONG AGAINST

Bevacizumab+inteferon-α2a Sunitinib QUALITA' GLOBALE DELLE EVIDENZE ALTA BILANCIO 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-α2a QUALITA' GLOBALE DELLE EVIDENZE MODERATA BILANCIO 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. Pazopanib BILANCIO 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