Dagli aspetti regolatori alle linee guida Pierfranco Conte
Approval, reimbursement, guidelines, recommendations a hurdle race to access: madness or method?
Efficacia, efficienza, sostenibilità e umanizzazione Un equazione impossibile? Medici SSR Dirigenti medici Pazienti SSN SOCIETA Cittadini
End points of efficacy from approval to access: madness or method? Goal Players End Point Parameters Development Scientists Pharma Go/no go testing Proof of principle Approval Regulators (FDA,EMA) Efficacy (risk/benefit) Survival PFS QoL Reimbursement Payers (AIFA) Cost effectiveness Value for money(qaly) Access Scientific societies Local boards Comparative effectiveness GRADE of recommendation Use Physicians(and patients) Benefit for the patient Cure Survival Symptom control
«there is a method to the madness» Drug reimbursement : AIFA Cost-effectiveness (costx unitof outcomeor valuefor money) Elements of the cost-effectiveness analysis Severity of the disease Absolute risk reduction Safety Price policy (risk-sharing, PbR)
From EBM to «good medicine» for all the patients
From «average» to «individual» patients: why doctors need options BENEFIT - Predictive factors - Life expectancy - Individual prognosis estimate: will the relative benefit translatein a clinically meaningful absolute improvement? RISK - Pre-existing comorbidities - Pre-existing risk conditions - Impact of potentialtoxicityfor the individualpatients(job, lifestyle, expectations)
HER2+ EBC Main patient characteristics in adjuvant trials vs Real World T<2cm % N neg % HRpos % Age Median (yrs) adjuvant trials 35-40 0-32 34-60 48-50 Real World Pooled data from 4 Italian Tumor Registries 61 43 64 58-60
From «average» to «individual» patients: why doctors need options BENEFIT - Predictive factors RISK - Life expectancy - Pre-existing comorbidities - Individualprognosisestimate: - Pre-existing risk conditions Lower will the risk relative = less benefit benefit translate - More Impact frail of potentialtoxicityfor & elderly = in a clinically meaningful absolute more the individualpatients(job, toxicity improvement? lifestyle, expectations)
Innovation, effectiveness and affordability RWE (Prospectivepost-marketing Registries) Investigator-driven& patient-oriented research Recommendations PDTA
Guidelines or Recommendations? Drug accessibility : recommendations Comparative-effectiveness Comparative effectiveness depends from: Risk-benefit ratio Availability of other therapeutic options Efficacy& tolerability in subgroups of patients
Classificazione dei livelli di evidenza Livelli di evidenze/forza delle raccomandazioni SIGN Scottish Intercollegiate Guidelines Network 1++ High quality meta-analyses, systematic reviews of RCTs or RCTs with a very low risk of bias 1 + Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1 - Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias 2++ 2 + 2 - High quality systematic reviews of case control or cohort studies High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal. Well conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal 3 Non-analytic studies, eg case reports, case series 4 Expert opinion
Tumore dell Ovaio: Terapia Medica * *.. Stadio IIIb-IV Bevacizumab in combinazione a CT e successivo mantenimento (15 mesi) Linee Guida, Edizione 2015
Tumore dell Ovaio: Terapia Medica Qualità dell evidenza SIGN Raccomadanzione clinica Forza della Raccomandazione clinica A Nelle pazienti in stadio III senza residuo macroscopico e residuo < 1 cm dopo chirurgia primaria è indicata la chemioterapia intraperitoneale Positiva*.. Pazienti sottoposte a chirurgia primaria ottimale o con residuo < 1 cm Linee Guida, Edizione 2015
RCTs with Bevacizumab in EOC trial setting # ORR % PFSmo. OS mo. Ctr Beva Ctr Beva HR* Ctr Beva HR GOG218 III-IV 1873 nr nr 10.3 14.1 0.71 39.3 39.7 0.91 ICON 7 I-IV 1528 48 67 17.4 19.8 0.87 NR NR 0.85 Oceans relapsed 484 57.4 78.5 8.4 12.4 0.48 29.9 35.5 0.75 Aurelia Pt-resistant 361 12.6 30.9 3.4 6.7 0.48 13.3 16.6 0.85 * All significant Burger RA, N Engl J Med 2011;Perren TJ, N Engl J Med 2011;C Aghajanian, JCO 2012; E Pujade-Lauraine JCO 2014
Hazard Ratios for Progression or Death Intraperitoneal vs Intravenous Therapy PFS OS Jaaback K et al, Cochrane Database Syst Rev. 2011
Long-TermSurvivalAdvantageand PrognosticFactorsAssociatedwith Intraperitoneal Chemotherapy Treatment in Advanced OC: A GOG Study Retrospectiveanalysison 876 ptswith a medianf.u.of 10.7 yearsfrom GOG 114 and 172. Cox proportional hazards regression models were used for statistical analyses HR 0.77 IP therapy enhanced mos from 51.4 to 61.8 months. Survival improved with increasing number of IP cycles. TewariD, JCO 2015
Intraperitoneal Chemotherapy for Ovarian Cancer- Real World Data Toxicities and Number of IP Chemotherapy Cycles Delivered Off Trial from 2006 to 2012 3-yr OS: IP was81% (95%CI, 73% to 86%) IV was 71% (95%CI, 62% to 78%) OS with propensity score matched sample for NCCN pts with optimally cytoreduced, stage III OC by first-line IP or IV chemotherapy administration, 2006 to 2012. Wright A, JCO 2015
Innovation, effectiveness and affordability RWE (Prospective post-marketing Registries) Investigator-driven & patient-oriented research Recommendations PDTA
Rete Oncologica Veneta (ROV) 1. Piattaforma informatica della ROV (accesso aperto) 2. Cartella clinica informatizzata (accesso limitato) 3. Gruppo di lavoro sui farmaci innovativi Metodologia Raccomandazioni di utilizzo Individuazione dei centri di Riferimento 4. Gruppo di lavoro : Rete di Biobanche 5. Gruppo di lavoro: Diagnostica Molecolare 6. Gruppi di lavoro: PDTA 7. Consulta del Volontariato
Gruppo di Lavoro sui Farmaci Innovativi Decreto n. 199/2014: Istituzione del Gruppo di Lavoro sui Farmaci Innovativi nell ambito del Coordinamento della Rete Oncologica Veneta (CROV) Elaborare raccomandazioni basate sull evidenza in merito a farmaci innovativi in ambito oncologico e di alto impatto economico indicandone la forza e gli indicatori d uso atteso attraverso specifici quesiti clinici. Metodologia di elaborazione delle Raccomandazioni Oncologi (8) Farmacologi (1) Farmacisti (5) Associazioni di pazienti/volontariato (2) Esperti di economia e HTA (2) Epidemiologo (1) MMG (1) Direzione sanitaria (1) Rilevanza clinica dei risultati Profilo di tollerabilità Qualità degli studi clinici Alternative terapeutiche Costi rispetto alle alternative