DALLA EBM ALL’HTA: LE NUOVE TECNOLOGIE AL
SERVIZIO DEL MALATO
Maurizio Koch
Unità Complessa
Gastroenterologia ed Epatologia
Azienda San Filippo Neri
e
Scuola di Specializzazione in Gastroenterologia
Policlinico S .Andrea, Università La Sapienza
Roma
ROAD MAP:
1. LO SCENARIO
2. EFFICACIA VS EFFECTIVENESS
3. BUDGET IMPACT
4.MODELLO FARMACO ECONOMICO TRASPARENTE
CON:
INCLUSIONE DEI COSTI DIRETTI ED INDIRETTI
DROP OUT PER EFFETTI COLL. SEVERI
5. PERCORSO DIAGNOSTICO TERAPEUTICO:
Quale sottogruppo di pazienti naïve ed experience
ammettere alla nuova tripla
(Who Can Wait and Who Can’t)
Who can we treat : data base, file regionale
6. DISINCENTIVI
Gaps in Care Resulting in Low Overall Effectiveness of
HCV Treatment in Veterans with Chronic HCV
SVR
Completed HCV treatment
Received Peg-IFN and ribavirin
No controindications to HCV treatment
Tested for genotype
4%
6%
12%
36%
60%
Patients with Chronic HCV
100%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
% of HCV infected Veterans (n=99,166)
Kramer JR et al, J Hepatol 2011
milioni
Actual number of patients treated with antiviral therapy for
hepatitis C per year between 2002 and 2007, and fitted line
projecting future treatment rates.
Treatment of HCV genotype 1 in Italy
Italy::
the current situation
• ∼ 7000 patients HCV Gt 1 patients treated each year (20082011) with a 10% yearly trend to decrease (2010-2011):
– Spontaneous change due to disease epidemiology
– Warehousing effect (
triple therapy IFN-free)
• ∼ ¼ of Gt 1 patients treated yearly (2008-2010) were retreatments. This figure has decreased markedly in 2011
(warehousing for triple therapy)
• Yearly expenditure (2011) for P/R: 165,000,000 Euros
• Aging population of naives (mean age at tx 48 years) with 2530% of F3/F4 fibrosis
• At least 20,000 patients with previous P/R failures (usually
unclassified) with a mean age > 55 years and at least 40% of
F3/F4 fibrosis
Peso della malattia
Spesa HCV in percentuale della
spesa SSN – Italia4,5
Costi Totali (diretti e non) per farmaci e complicazioni relativi a HCV – Italia1
Costo farmaci
HCV
Costo di gestione delle complicazioni per HCV
26%
74%
0,8%
99,2%
Spesa SSN
Spesa HCV
In Italia, circa
In Italia, circa
In Italia, circa
In Italia, circa
230.000
3.500
1.100
7.000
Pazienti con cirrosi dovuta
a HCV1,2
Casi annuali di HCC dovuti
a HCV2
Casi annuali di trapianti di
fegato dovuti a HCV1,3
Casi annuali di morti HCV
dipendenti1
1 Mariano A et al. Estimating the incidence, prevalence and clinical burden of hepatitis C over time in Italy. Scand J Infect Dis 2009, 41:689---699.
2 Mühlberger N, Schwarzer R, Lettmeier B, Sroczynski G, Zeuzem S, and Siebert U. HCV-related burden of disease in Europe: a systematic assessment of
incidence, prevalence, morbidity, and mortality. BMC Public Health 2009, 9:34 doi:10.1186/1471-2458-9-34
3 Centro Nazionale Trapianti. Attività di donazione e trapianto --- Report 2011 definitivo. http://www.salute.gov.it/imgs/C_17_pubblicazioni_1696_allegato.pdf.
4 Documento di Economia e Finanza 2012. Programma di stabilità dell'Italia. Consiglio dei Ministri, 18 Aprile 2012.
5 Stima costi diretti e indiretti per un totale di circa 872 milioni di euro annui
2.L’EVIDENZA (EFFICACY)
Phase III virological efficacy
Boceprevir ( Victrelis®) or Telaprevir ( Incivo®)
Naive patients
Increased SVR compared to Peg-IFN/RBV
Boceprevir
Telaprevir
SVR increases from 38% to
63/66%
SVR increases from 44% to
72/75%
RBV is needed
Poordad F et al. N Engl J Med 2011: 364: 1195-1206
Sherman KE et al. Hepatology 2010; 52 (Suppl) : 401A.
Jacobson IM et al. Hepatology 2010; 52 (Suppl) : 427A.
Phase III virological efficacy
Boceprevir ( Victrelis®) and Telaprevir
(Incivo ®)
Treatment-experienced patients
Increased SVR compared to Peg-IFN/RBV
Telaprevir
Boceprevir
Relapsers
SVR increases from 29% to
75%
Partial-Responders
SVR increases from 7% to 52%
Relapsers
SVR increases from 24% to
83/88%
Partial-responders
SVR increases from 15% to 5459%
Null-responders
SVR increases from 5% to
29/33%
RBV is needed
Bacon BR., et al. N Engl J Med 2011; 364:1207-1217.
Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3
naive
experienced
EFFECTIVENESS
Totale pazienti tutti i genotipi
2397
1 regione grande =
1/15 del dato nazionale
Italia 1.500.000 HCV+
Lazio, paz. attesi = 100.000
Tx 2.397/100.000 = 2.3%
Italia 1.000.000 HCV+
Lazio, paz. attesi = 67.000
Tx 2.397/67.000= 3.6%
PDTA REGIONE LAZIO
Valutazioni farmaco-economiche sull’uso dei DAA nella Regione Lazio
La tabella sottostante rappresenta la distribuzione, sia in termini percentuali che
numerici, dei pazienti trattati con Genotipo 1 nel Lazio calcolata a partire dai dati
forniti dai clinici.
2010
2011
2012
Totale pazienti trattati regione Lazio G1
1.232
1.244
1.104
Proporzione Pazienti con fibrosi F3
13,6%
12,9%
13,2%
Totale pazienti trattati regione Lazio (F3)
168
160
146
Proporzione Pazienti con fibrosi F4
8,4%
9,3%
8,9%
Totale pazienti trattati regione Lazio (F4)
104
116
98
Proporzione Pazienti con cirrosi compensata
5,8%
6,4%
6,1%
72
80
68
24,7%
27,1%
25,9%
304
338
286
11,7%
12,1%
11,9%
144
151
132
Totale pazienti trattati con cirrosi compensata
Proporzione Pazienti con fibrosi da F0 a F2
Totale pazienti trattati regione Lazio (F0-F2)
Proporzione Pazienti relapser
Totale pazienti trattati relapser
PDTA REGIONE LAZIO
distribuzione media dei due interferoni peghilati
% di utilizzo
Farmaci e confezioni
Costo medio ponderato per
settimana (€)
Costo medio ponderato
annuo (€)
Quota
utilizzo
€ 173,70
€ 6.920,13
77%
€ 151,34
€ 6.029,42
23%
€ 10,50
€ 418,32
costante
Peginterferone alfa-2a
Fiale/penna
180 mcg - 5 ml
93,23%
Fiale/penna
135 mcg - 5 ml
6,77%
Peginterferone alfa-2b
Fiale/penna
50 mcg - 5 ml
2,70%
Fiale/penna
80 mcg - 5 ml
34,54%
Fiale/penna
100 mcg - 5 ml
31,14%
Fiale/penna
120 mcg - 5 ml
25,12%
Fiale
150 mcg - 5 ml
6,49%
Ribavirina
168 cps
200 mg
PROGETTO REGIONE LAZIO 2013
TRIPLICE TERAPIA
“The disappearing patient syndrome”
ATTESA TERAPIE 2013:
INIZIO TERAPIA TRIPLICE
Al 15.6.2013
1232
117 (9%)
CACCIA AL VIRUS C
(= CACCIA ALLA
RISPOSTA VIRALE
SOSTENUTA, SVR)
ROAD MAP:
1. LO SCENARIO
2. EFFICACIA VS EFFECTIVENESS
3. BUDGET IMPACT
4.MODELLO FARMACO ECONOMICO TRASPARENTE
CON:
INCLUSIONE DEI COSTI DIRETTI ED INDIRETTI
DROP OUT PER EFFETTI COLL. SEVERI
5. PERCORSO DIAGNOSTICO TERAPEUTICO:
Quale sottogruppo di pazienti naïve ed experience
ammettere alla nuova tripla
(Who Can Wait and Who Can’t)
Who can we treat : data base, file regionale
6. DISINCENTIVI
LE SCELTE
ROAD MAP:
1. LO SCENARIO
2. EFFICACIA VS EFFECTIVENESS
3. BUDGET IMPACT
4.MODELLO FARMACO ECONOMICO TRASPARENTE
CON:
INCLUSIONE DEI COSTI DIRETTI ED INDIRETTI
DROP OUT PER EFFETTI COLL. SEVERI
5. PERCORSO DIAGNOSTICO TERAPEUTICO:
Quale sottogruppo di pazienti naïve ed experience
ammettere alla nuova tripla
(Who Can Wait and Who Can’t)
Who can we treat : data base, file regionale
6. DISINCENTIVI
What is Cost-Effective in HCV?
€
No Tx
(Natural History)
€35K
20 years
€20K
€20K
Antiviral Tx
Time
35 years
Hcc
QALY
Clinical Trials vs Real World
Telaprevir
Boceprevir
PegIFN/RBV
Clinical trials
(including cirrhotics)
Treatment-naive
Real world
(cirrhotics only)
Treatment-experienced
Treatment-experienced
60
50
40
30
20
10
9
12
7
9
12
12
5
5
0
Patients with serious AEs (%)
Patients with serious AEs (%)
60
50
40
49
38
30
20
10
0
ADVANCE
SPRINT-2
REALIZE
RESPOND-2
French realworld
Safety in the real world: increasing frequency of
adverse events with increasing disease severity
EAP3
F3/F4 patients
Major adverse events
• Telaprevir 14%
CUPIC1
F4 patients
Serious adverse events
• Telaprevir 45%
• Boceprevir 33%
German
non-interventional study2
major adverse events: 8%
1. Hézode C, et al. Hepatology 2012;56(Suppl.):217A
2. Berg T, et al. J Int AIDS Soc 2012;15 (Suppl. 4):18424
3. Colombo M, et al. AASLD 2012:LB-15
final safety data
(CUPIC easl barcellona 2012)
Patients ,n (%) patientns with
at last one event)
Telaprevir
N=296
Boceprevir
N=159
Serious Aes (%)
48.6
38.4
Premature Discontinuation
Due to serious AE (%)
26.0
14.5
23.9
7.4
Death (%)
2.0
1.3
Infection (Grade 3/4) (%)
8.8
2.5
Asthenia (Grade 3/4) (%)
4.7
5.7
Rash
Grade 3 (%)
Grade 4 (SCAR) (%)
6.8
0.7
0
0
Pruritus (Grade 3/4) (%)
3.7
0.6
Hepatic decompensation (%)
4.4
4.4
PROGETTO REGIONE LAZIO 2013
TRIPLICE TERAPIA
“The disappearing patient syndrome”
ATTESA TERAPIE 2013:
INIZIO TERAPIA TRIPLICE
Al 15.6.2013
ADR
1232
117 (9%)
TELAP 32%
BOCEP 11%
Cost-effectiveness of treatment for HCV Gt 1
Triple therapy with first-generation PIs in naïve G1 CHC patients:
• improves survival by about 4 years
• is cost-effective, with an ICER per LYG below € 12,000
Cost- effectiveness of triple vs dual therapy in naïve G1 CHC patients:
• is strongly influenced by the IL28B CC prevalence and the ensuing
likelihood of RVR and SVR, but also by the pricing of BOC and TVR
• is optimised by allocating patients according to IL28B and/or RVR
based strategies
- An individualized treatment strategy can avoid triple therapy in 25-33% of naive
HCV G1 patients
Cammà C, et al., Hepatology. 2012 56: 850-60. .
Costo TRIPLICE terapia secondo
RCP
Componente duplice terapia
(PegIntron)
Numero
settimane
28
48
48
Costo exfactory per
settimana
€ 140,25
€ 140,25
€ 140,25
Costo exNumero factory per
Costo terapia settimane settimana
€ 3.927
24
€ 604,83
€ 6.732
32
€ 604,83
€ 6.732
44
€ 604,83
Componente duplice terapia
(PegIntron)
Numero
settimane
24
48
48
Costo exfactory per
settimana§
€ 140,25
€ 140,25
€ 140,25
Componente Victrelis
Costo terapia
€ 14.516
€ 19.355
€ 26.613
Componente Telaprevir
Costo exNumero factory per
Costo terapia settimane settimana*
€ 3.366
12
€ 1.666,66
€ 6.732
12
€ 1.666,66
€ 6.732
12
€ 1.666,66
Costo terapia
€ 20.000
€ 20.000
€ 20.000
Costo terapia
con VICTRELIS
Costo totale della
triplice
€ 18.443
€ 26.087
€ 33.345
Costo terapia
con Telaprevir
Costo totale della
triplice
€ 23.366
€ 26.732
€ 26.732
Partizione della durata di trattamento definita in accordo agli studi SPRINT-2 (early responders), RESPOND-2 (late responders, partial responders,
relapsers), PROVIDE (null responders, cirrotici)
ROAD MAP:
1. LO SCENARIO
2. EFFICACIA VS EFFECTIVENESS
3. BUDGET IMPACT
4.MODELLO FARMACO ECONOMICO TRASPARENTE
CON:
INCLUSIONE DEI COSTI DIRETTI ED INDIRETTI
DROP OUT PER EFFETTI COLL. SEVERI
5. PERCORSO DIAGNOSTICO TERAPEUTICO:
Quale sottogruppo di pazienti naïve ed experience
ammettere alla nuova tripla
(Who Can Wait and Who Can’t)
Who can we treat : data base, file regionale
6. DISINCENTIVI
Treatment options for naïve genotype 1
patients
TRIPLE THERAPY
CONSIDER DUAL THERAPY IN
Primary treatment option
in CT/TT or F3–F4
France: ≤F2 with CC and LI RVR+
if CC + ≤F2 with LI RVR–, add PI
Primary treatment option
No advanced fibrosis with CC,
VL <600-800K IU/mL and LI RVR+
Primary treatment option
in F2 with CT/TT or F3-F4
F0–F1 or F2 with CC regardless of RVR
Primary treatment option
(TVR recommended over BOC)
Peg-IFN 2a/RBV if CC, mild fibrosis,
VL<600K IU/mL, <40 years, absence of
metabolic syndrome, IP10 <150pg/mL
If LI RVR–, add PI or watchful waiting
Primary treatment option
≤F2 with viral load <400K IU/mL and RVR+
Primary treatment option
<F4 with VL<400-800K IU/mL
and LI RVR+
AISF recommendation on the management of triple therapy
(Peg-IFN + Ribavirin + first generation Protease Inhibitors)
for genotype 1 chronic hepatitis C patients
Naive patients: who should be treated?
•Treatment should be scheduled (high priority) for patients with severe fibrosis
(METAVIR score F3) to cirrhosis (F4), with compensated liver disease ChildPugh class A (A1)
•Treatment should be scheduled (intermediate priority) for patients with
significant fibrosis (F2); in patients with absent or mild fibrosis (F0-F1), the
indication for and timing of therapy can be individualised, considering low risk
of disease progression, extra-hepatic HCV induced manifestations, patient
motivation and availability of new antiviral drugs (B1)
•Patient deferred to treatment should undergo to surveillance follow up
programs, in order to evaluate progression of liver disease (A1)
Available at http://www.webaisf.org/
AISF recommendation on the management of triple therapy
(Peg-IFN + Ribavirin + first generation Protease Inhibitors)
for genotype 1 chronic hepatitis C patients
Experienced patients: who should be treated?
•Patients failure to dual therapy with Peg/RBV should be considered for
retreatment with Peg/RBV and a protease inhibitor (A1). Indication to retreatment has to take considering the risk of disease progression, chance of
success, safety and future therapy
•In Relapser patients, treatment should be scheduled (high priority) for severe
fibrosis (F3) and cirrhosis (F4) and in patients significant fibrosis (F2)
(intermediate priority). In patients with absent or mild fibrosis (F0-F1), the
indication for and timing of therapy should be discussed case to case,
considering availability of new antiviral drugs (A1)
Available at http://www.webaisf.org/
Indications for treatment: who should be treated?
• All treatment-naïve patients with
compensated disease due to HCV should
be considered for therapy (A1).
• Treatment should be scheduled, not
deferred, for patients with significant
fibrosis (METAVIR score F3 to F4) (A1).
• In patients with less severe disease, the
indication for and timing of therapy can be
individualised (B1).
Univariate analysis of predictors
of SVR
Multivariate analysis
A: baseline predictors only
B :baseline predictors + RVR
RVR n = 287 (24%)
O.R
82%
IL28 CC
4.95 (3.56-6.89)
Low HCV-RNA
2.76 (2.02-3.77)
F0-F2
1.48 (1.05-2.10)
Age < 50 yrs
1.39 (1.02-1.89)
25%
O.R
232/923
NO
235/287
Yes
RVR
6.77 (4.64-9.89)
IL28B
3.36 (2.35-4.81)
Low HCV-RNA
2.07 (1.48-2.09)
Andriulli et al, J Hepatol in press
Prediction of SVR following PegPeg-IFN/RBV therapy in HCV genotype 1 pts,
pts,
by baseline features and RVR
16% of pts (191/1210) could be predicted to have a >80% chance of SVR
following dual therapy by estimating RVR and some baseline features
Andriulli et al, J Hepatol in press
.
Prediction of SVR following PegPeg-IFN/RBV therapy in HCV genotype 1 pts,
pts,
by baseline features and RVR
16% of pts (191/1210) could be predicted to have a >80% chance of SVR
following dual therapy by estimating RVR and some baseline features
Andriulli et al, J Hepatol in press
.
ROAD MAP:
1. LO SCENARIO
2. EFFICACIA VS EFFECTIVENESS
3. BUDGET IMPACT
4.MODELLO FARMACO ECONOMICO TRASPARENTE
CON:
INCLUSIONE DEI COSTI DIRETTI ED INDIRETTI
DROP OUT PER EFFETTI COLL. SEVERI
5. PERCORSO DIAGNOSTICO TERAPEUTICO:
Quale sottogruppo di pazienti naïve ed experience
ammettere alla nuova tripla
(Who Can Wait and Who Can’t)
Who can we treat : data base, file regionale
6. DISINCENTIVI
Totale richieste per regione
Number of tumor marker requests
Marker
Veneto
Puglia
Toscana
CEA
178.810
37.248
170.847
AFP
96.840
29.428
78.209
CA15.3
74.247
18.917
73.484
CA125
64.039
22.394
79.252
CA19.9
103.653
30.225
124.449
TPSA
336.919
45.833
259.888
FPSA
69.306
13.649
89.798
(Prevalence data from AIRTUM 2010, Gion et al)
Pancreatic cancer
Region
Veneto
Expected Surveyed
∆%
Prevalent
CA19.9
CA19.9
cases
Sur./Exp.
(*)
(&)
656
103,653 15,800%
328
(*) assuming 2 tests per year to all prevalent cases
(&) projection to 100% of the sample (from surveyed data)
(Prevalence data from AIRTUM 2010)
LO STRANO CASO DEI FARMACI ONCOLOGICI
MEDICARE : IL 25% DELLE SPESE VA AL 5% DEI PAZIENTI
(ONCOLOGICI) PER I LORO ULTIMI 6 (?) MESI DI VITA
"Mi sono dovuta sottoporre a 21 cicli di chemioterapia dopo un intervento per
eliminare un carcinoma. Ad ogni seduta la ASL (parlo di Torino) mi forniva un nutrito
corredo di farmaci costosissimi che dovevano aiutarmi a combattere gli effetti
collaterali della chemio. Parlo di 3-400.000 delle vecchie lire a confezione.
Sacrosanto, certamente. Però, per mia grande fortuna, non ho avuto praticamente
nessun effetto collaterale e di conseguenza credo di aver usato un paio di pastiglie
su centinaia e centinaia che me ne sono state date. Ad ogni chemio io arrivavo con
le mie scatole intonse e pregavo di non averne altre, ma la prassi era quella e
bisognava seguirla. Mi sono ritrovata a fine trattamento con un bauletto pieno di
medicinali mai utilizzati, che l'oncologa che mi aveva in cura non ha voluto indietro,
non potevano riprenderli, per un valore complessivo credo di almeno una decina di
milioni che a tempo debito sono finiti nei cassonetti dei farmaci scaduti.