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L'appropriatezza di impiego dei nuovi farmaci target Horizon scanning per i nuovi
farmaci target e modalità di valutazione (es.: Grading) per efficacia/sicurezza
eseguite dalle agenzie regionali-nazionali per l'uso di questi nuovi farmaci (con
specifici esempi) e gli algoritmi del registro onco-AIFA
Joppi R, Pase D.
UOSD Ricerca Clinica & Valutazione Farmaci – Dipartimento Farmaceutico - Verona
SIFACT
Evoluzione dei trattamenti nella leucemia mieloide cronica:
Sostenibilità, Appropriatezza e Governance delle nuove terapie target
Padova, 18 Novembre 2015
ONCO Studies currently recruiting
Total World: 6,422
Total EU: 1,986
ClinicalTrials.gov 27/10/2015
Studies on CML currently recruiting
Phase IV
1%
Phase III
14%
Phase I
31%
Total World: 164
Phase II
54%
Phase IV
3%
Phase III
25%
Phase I
20%
Total EU: 40
Phase II
52%
ClinicalTrials.gov 27/10/2015
Sales Forecast by Therapeutic Areas
Host organization: Azienda ULSS 20 in Verona
EuroScan
The international information network on new and emerging health technologies
“A collaborative network of member agencies for the exchange of information on
important emerging technologies and the principal global forum for the sharing
and development of methods for the early identification and assessment “
19 Agencies in 15 different Countries in 4 continents:
Asia, Australia, Europe and North America
euroscan.org.uk
2007
2008
EUROSCAN
August 2006
IHSP kickoff
IHSP Chronology
2009 2010 2011
2012 2013 2014 2015
2016
Database
set up
- 36 reports
-
60
65
60
60
60
60
60
20
- 18 reports
-
39
34
29
26
30
25
31
11
-
9
9
9
9
9
7
9
8*
NPIR
Total IHSP documents (n): 739;
(*)reports ongoing
Update October 2015
Aims
TO ORGANIZE and EVALUATE available information on emerging drugs
BEFORE SUBMISSION of a MAA to Regulatory Agency and before any
decision on COSTS and POSSIBLE CLASS OF REIMBURSEMENT
Specific aims:
 to produce periodical lists of emerging drugs for which a MA will be
expected within 12-36 months
 to evaluate potential clinical impact and cost effectiveness in terms of
healthcare and cost for National Health Service
 to give well-timed
emerging drugs
information to improve regulatory
decisions about
 to identify further research fields needed to be investigated
IHSP Workflow
Database IHSP
Emerging drugs
- 36 months report
PRELIMINARY SELECTION (SC-IHSP)
Selected Drugs
-18 months report
New Product Information
Report - NPIR
(-12 months M.A.)
Evaluation
Team
PRIORITIZATION
SC-IHSP
MinSal
REGIONS
The IHSP Database, Oct. 2015
Priority-setting criteria used by SC-IHSP
AREA to INVESTIGATE
PARAMETERS
EVALUATION
Burden of disease
Epidemiology
Rare
Not rare
Severity
Severe
Not severe
Duration
Acute
Chronic
Treatment
Available
Absent
Efficacy vs. current treatments (mortality, morbility, quality of life, etc.)
Higher
Equal or Lower
Safety vs. current treatments
Higher
Equal or Lower
Compliance vs. current treatments
Higher
Equal or Lower
Social impact (Media, patients associations, lobbies ...)
YES
NO
Service reorganization and/or staff training required
YES
NO
Possible off-label use
YES
NO
Economic impact on the NHS
High
Low
Possible launch date
< 18 months
> 18 months
Drug in development for other indications of interest
YES
NO
Other drugs in development for the same indication
YES
NO
Patient impact
NHS Pressures
Others
IHSP
Outputs
-36
MONTHS
REPORT
Produced
annually
NPIR
general information

licensee

stage of development

possible submission date of the MAA

main proposed indication(s)

ongoing studies
“Drug Indication”
Drug/brand name /active substance
Company
ATC Group
Route of administration

general information

possible submission date of the MAA

proposed indication(s)

summary of the available data on clinical efficacy and safety

overview of all ongoing trials and completed studies not published

possible price and economic impact (if available)

alternative(s) already on the market

possible competitors in development

Active substance
Brand name
Company
ATC Group
general information
Dosage
Route of administration
Development state
……
clinical need and burden of disease

summary of efficacy/safety data from available clinical trials

clinical critical assessment

social / economic impact

ongoing trial(s) for the same or other indication(s)

(-12 months to
M.A.)
“Drug Name”
Drug/brand name/ active substance
Company
ATC Group

-18 MONTHS
REPORT
Produced every
6 months
DRUGS FOR CML COMING SOON
Premessa
 Aumenta il numero di farmaci di tipo «biologico»;
 La durata degli RCT è insufficiente per conoscere i nuovi farmaci;
 I nuovi farmaci sono studiati per il loro effetto diretto, non come parte di
una strategia terapeutica (resezione/irradiazione o sospensione/ripresa in
relazione alla risposta);
 Aumenta il rischio di non utilizzare al meglio i farmaci disponibili e/o di
utilizzarli «off-label»;
 Sequenze/combinazioni di farmaci sono il presente, in futuro saranno
sostenibili?
 Se il target è assente: Chemioterapia più attiva della Target Therapy;
 La nuova Immunotherapy è una Target Therapy?
 Trattamento personalizzato è sempre più vantaggioso vs. trattamento non
personalizzato;
Qualche semplificazione….
….mab = anticorpo monoclonale che agisce bloccando un
recettore o il ligando di un recettore
….ib = piccola molecola che agisce togliendo energia ad un
«nodo» di trasmissione, in genere occupando la «tasca» dove
si va ad inserire l’ATP
Quali i «…mab/…ib» all’orizzonte?
Farmaci registrati in Italia per il trattamento della CML
con Registro AIFA
Registro
Medicinale
Principio attivo
Codice ATC
MEAs (accordo)
Data inizio
monitoraggio
ICLUSIG
PONATINIB
L01XE24
Accordo basato su outcome
25/12/2014
ICLUSIG
PONATINIB
L01XE24
Accordo basato su outcome
25/12/2014
DACOGEN
DECITABINE
L01BC08
Accordo finanziario
13/11/2014
SPRYCEL
DASATINIB
L01XE06
Accordo finanziario
07/12/2011
TASIGNA
NILOTINIB
L01XE08
Accordo finanziario
07/12/2011
ARZERRA
OFATUMOMAB
L01XC10
Accordo finanziario
14/06/2011
REVLIMID
LENALIDOMIDE
L04AX04
Appropriatezza prescrittiva
24/05/2011
REVLIMID
LENALIDOMIDE
L04AX04
Appropriatezza prescrittiva
24/05/2011
TASIGNA
NILOTINIB
L01XE08
Accordo basato su outcome
08/08/2008
SPRYCEL
DASATINIB
L01XE06
Accordo finanziario
26/05/2007
In phase I or II of development
Molecule
Mechanism
Classification
Route
Originator / Licensee
Note
…IB / ….MAB
Binimetinib
Inhibitor of MAP kinase 1 and 2
(MEK1/2)
Danusertib
Inhibitor of the ATP site of aurora kinases
A, B and C
NCE
IV
Glasdegib
SMO inhibitor
NCE
Oral
Pfizer
Rebastinib
Protein kinase inhibitor
NCE
Oral
Deciphera Pharmaceuticals
NCE
Oral
Array BioPharma
In combination with NILOTINIB;
> II° line
In advanced CML
JTCR 016
T lymphocyte immunotherapy
Inotuzumab
Anti-CD22
monoclonal
calicheamicin conjugate
NCE
antibody-
NCE
IV
IV
Nerviano Medical Sciences
Juno Therapeutics
UCB Pfizer
In combination with NILOTINIB;
I° line
In relapsed pts after Allogenic
Hematopoietic Stem Cell
Transplantation
In combination with BOSUTINIB;
> II° line
ALTRO
Inecalcitol
Calcitriol receptor agonist
NCE
Oral
Ropeginterferon
alfa-2b
Third generation long-acting interferon
alpha 2b stimulants
NCE
SC
PRI 724
Selective inhibitor of CBP/β-catenin
complex, preventing gene expression of
many proteins necessary for growth
Ghent University
After >2 ys with IMATINIB and with
residual disease (measured by CML
biomarker)
PharmaEssentia Corporation
In combination with DASATINIB in
advanced CML
NCE
IV
PRISM BioLab /Eisai Co Ltd
Phase III Trials
NCT number
Title
Experimental intervention
Comparator
Estimated completion
date
Endpoint
Imatinib Mesylate With or Without Interferon Alfa or
Cytarabine Compared With Interferon Alfa Followed by Donor Imatinib +/- Peg-INF Alpha or
NCT00055874
Stem Cell Transplant in Treating Patients With Newly Cytarabine
Diagnosed Chronic Phase Chronic Myelogenous Leukemia
Interferon Alpha + Donor
Stem Cell Transplantation
OS
December 2016
Clofarabine or Daunorubicin Hydrochloride and Cytarabine
NCT02085408 Followed By Decitabine or Observation in Treating Older Clofarabine + Decitabine
Patients With Newly Diagnosed Acute Myeloid Leukemia
Daunorubicin + Cytarabine
OS
February 2019
Comparison Between Cyclophosphamide and Combination of
NCT01749111 Methotrexate + Calcineurin Inhibitor for GVHD Prophylaxis Cyclophosphamide
(CICLODECH)
Calcineurin inhibitor +
methotrexate
Rate of pts alive one
year
after
bone
December 2016
marrow
transplantation
Comparison of Imatinib Versus Dasatinib in Patients With
NCT01460693 Newly-diagnosed Chronic Phase Chronic Myeloid Leukaemia Dasatinib
(SPIRIT2)
Imatinib
5-year event
survival
Tacrolimus + Methotrexate
Incidence of severe
July 2018
(grade 3-4) mucositis
NCT01951885 Tac, Mini-MTX, MMF Versus Tac, MTX for GVHD Prevention
Tacrolimus + Mycophenolate +
Methotrexate
free
August 2017
Phase III Trial Evaluating the Effectiveness of a Dose
Imatinib Dose Adjustment on the Imatinib 400 mg day
NCT01827930 Adjustment of Imatinib Mesylate on the Molecular Response
molecular response
(standard)
(MIM)
CMR at 12 months
December 2016
Tasigna and Interferon Alpha Evaluation Initiated by the
NCT01657604 German Chronic Myeloid Leukemia Study Group - the TIGER Nilotinib + Peg-IFN Alpha 2b
Study
MMR after 18 ms
December 2018
Nilotinib
ClinicalTrials.gov 17/11/2015
Phase III Trials (2° part)
NCT number
Title
Experimental intervention
Study to Assess Efficacy and Safety of Nilotinib 300mg Twice
Daily in Patients With Philadelphia Positive Chronic Myeloid
NCT02108951
Nilotinib
Leukaemia (CML) in Chronic Phase Who Are Intolerant to Prior
Tyrosine Kinase Inhibitors. (ENESTswift)
Comparator
Endpoint
Estimated completion
date
/
MMR after 24 ms
July 2017
Nilotinib
MR4.5
January 2018
Phase 3b Study to Determine the Conversion Rate From MMR
NCT02174445 to Molecular Response ≥ 4 Log (MR4) After Two Years Imatinib
(DECLINE)
Nilotinib
MR4 at 24 ms
December 2019
Efficacy and Safety of Nilotinib Patients With Newly Diagnosed
NCT00718263 CML - CP (Chronic Myelogenous Leukemia - Chronic Phase) Nilotinib
(PHCHBS-WD4070)
Imatinib
MMR at 12 months
October 2018
Efficacy of Nilotinib Versus Imatinib in Ph+ CML in Early CP
NCT01400074 Who Have a Suboptimal Molecular Response to Imatinib (RE- Nilotinib 400 mg twice daily
NICE)
Imatinib 400 mg twice daily MMR at 12 months
June 2014
Imatinib
MMR at 12 ms
June 2016
A Randomized Phase III Study to Assess the Effect of a Longer Nilotinib 24 months
NCT01743989 Duration of Consolidation Treatment With Nilotinib on TFR in Consolidation + 24 months of
CP CML. (ENESTPath)
Treatment Free-Remission
12 months Consolidation +
36 months of Treatment
Free -Remission
MR4.0 at 12 ms
July 2020
NCT02381379 Malaysia Stop Tyrosine Kinase Inhibitor Trial (MSIT)
Observation
RR at 3 ys
March 2016
NCT02201459
NCT02204644
Nilotinib ± Peg-IFN for First Line Chronic Phase CML Patients
Peg IFN-Alpha 2a + Nilotinib
(PETALs)
The Study of the Efficay and Safety of Flumatinib vs Imatinib as
Flumatinib
first- line treatment in Patients with CML
Peg IFN-Alpha 2a
Legenda: RR = Relapse Rate; CRR = Complete Response Rate; MMR = Major Molecular Response
ClinicalTrials.gov 17/11/2015
Farmaci oncologici: prima il beneficio ?
Algoritmi ESMO e ASCO
 Il dibattito sul valore dei farmaci oncologici è partito dagli oncologi;
 Già nel 2009 Sobrero e Buzzi avevano proposto di predeterminare una soglia
minima di OS o PFS proporzionale al bisogno medico esistente;
 Tale iniziativa era stata rilanciata nel 2013 da un gruppo di lavoro dell’ASCO;
 La crisi economica mondiale ha spinto la comunità scientifica e sociale a
chiedere di rivelare come siano definiti i prezzi dei farmaci;
 ESMO e ASCO a distanza di un paio di mesi hanno pubblicato due differenti
algoritmi per misurare l’entità del beneficio atteso dalle nuove terapie per i
tumori solidi
G. Casadei Farmaci oncologici: prima il beneficio. R&P 2015; 31: 195-7
ESMO e ASCO
How to assess the clinical value of anti-cancer treatments?
OS: parametro preferenziale;
DSF o PFS: utili solo quando il dato di OS non è maturo o disponibile;
Pathological Complete Remission: non valido nei trial sui trattamenti
neo-adiuvanti
RR: molto popolare negli studi di fase I e II, considerato valido
solamente nei trial non controllati (peso dimezzato rispetto a OS);
Incidenza di eventi avversi di grado +3 e stato di salute del paziente:
criteri secondari utili a definire il beneficio clinico
Che possibilità abbiamo di soddisfare queste condizioni?
Una recente analisi ha evidenziato che in oncologia gli studi sono
preferibilmente:
 NON CONTROLLATI (62% vs. 24%)
 IN APERTO (88% vs. 47%)
 NON RANDOMIZZATI (64% vs. 22%)
G. Casadei Farmaci oncologici: prima il beneficio. R&P 2015; 31: 195-7
FDA EXPEDITED PROGRAMS FOR SERIOUS
CONDITIONS
•FAST TRACK (DESIGNATION)
•BREAKTHROUGH THERAPY (DESIGNATION)
•PRIORITY REVIEW (DESIGNATION)
•ACCELERATED APPROVAL
(APPROVAL PATHWAY)
ITEM
FAST TRACK
BREAKTHROUGH THERAPY
PRIORITY REVIEW
AN APPLICATION FOR:
1. A DRUG ADDRESSED TO A
SERIOUS CONDITION WHICH IS
1. A DRUG FOR A SERIOUS
LIKELY TO PROVIDE A SIGNIFICANT
CONDITION WHERE NONA DRUG ADDRESSED TO A
IMPROVEMENT IN SAFETY OR
CLINICAL OR CLINICAL DATA SERIOUS CONDITION WITH
EFFECTIVENESS;
DEMOSTRATE THE
PRELIMINARY DATA SUGGESTING
QUALIFYING
2. A DRUG DESIGNATED AS A
POTENTIAL TO ADDRESS AN A SUBSTANTIAL IMPROVEMENT
CRITERIA
QUALIFIED INFECTIOUS DISEASE
UNMET MEDICAL NEED;
ON CLINICALLY SIGNIFICANT
PRODUCT ;
2. A DRUG DESIGNATED AS A ENDPOINT(S) OVER AVAILABLE
3. A DRUG SUBMITTED WITH A
QUALIFIED INFECTIOUS
TREATMENTS
PRIORITY REVIEW VAUCHER
DISEASE PRODUCT
4. ANY LABELLING CHANGE BASED
ON A PEDIATRIC STUDY
(ACCORDING TO THE 505 ACT)
60 CALENDAR DAYS FROM
TIMELINE FOR
60 CALENDAR DAYS FROM 60 CALENDAR DAYS FROM THE
THEORIGINAL BLA, NDA OR
AGENCY RESPONSE THE REQUEST
REQUEST
EFFICACY SUPPLEMENT
FEATURESS
ACCELERATED APPROVAL
A DRUG ADDRESSED TO A
SERIOUS CONDITION WITH
PRELIMINARY DATA
SUGGESTING A SUBSTANTIAL
IMPROVEMENT OVER
AVAILABLE TREATMENTS ON
THE BASIS OF SURRAGATE OR
INTERMEDIATE CLINICAL
ENDPOINTS, THAT ARE
REASONABLY LIKELY TO PREDICT
CLINICAL BENEFIT
NOT SPECIFIED
1. FREQUENT INTERACTION WITH
THE REVIEW TEAM TO DISCUSS:
1. FREQUENT INTERACTION THE STUDY DESIGN (ALTERNATIVE
WITH THE REVIEW TEAM TO DESIGNS INCLUDED); THE EXTENT
DISCUSS: THE STUDY DESIGN; OF THE REQUIRED SAFETY DATA;
THE EXTENT OF THE
DOSE-RESPONSE CONCERNS; USE
REQUIRED SAFETY DATA;
OF BIOMERKERS
APPROVAL BASED ON A
DOSE-RESPONSE CONCERNS; 2. ROLLING REVIEW: FDA CAN
SHORTER CLOCK FOR REVIEW OF
SURROGATE OR INTERMEDIATE
USE OF BIOMERKERS
CONSIDER THE SUBMISSION OF
MARKETING APPLICATION: 6
CLINICAL ENDPOINT THAT IS
2. ROLLING REVIEW: FDA
PORTIONS OF A MARKETING
MONTHS VS. 10-MONTH STANDARD REASONABLY LIKELY TO PREDICT
CAN CONSIDER THE
APPLICATION, WHEN
REVIEW
A CLINICAL BENEFIT OF THE
SUBMISSION OF PORTIONS PRELIMINARY DATA SUGGEST
DRUG
OF A MARKETING
THAT THE PRODUCT MAY BE
APPLICATION, WHEN
EFFECTIVE;
PRELIMINARY DATA
3. INTENSIVE INVOLVEMENT OF
SUGGEST THAT THE
SENIOR MANAGERS AND
PRODUCT MAY BE EFFECTIVE EXPERIENCED REVIEW STAFF IN A
PROACTIVE COLLABORATIVE,
CROSS-DISCIPLINARY REVIEW
Gruppo di Lavoro Regionale sui Farmaci
Oncologici Innovativi
(DGRV n.199 del 12/11/2014)
Produce raccomandazioni dopo aver esaminato criticamente le evidenze scientifiche
e la loro qualità.
Valuta il rapporto beneficio-rischio, il rapporto costo-beneficio, i costi incrementali
delle alternative terapeutiche disponibili, l’impatto sulla spesa farmaceutica
regionale, evidenziando la forza delle raccomandazioni e gli indicatori.
Componenti
Oncologi
Farmacologi
Farmacisti
Rappresentanti delle organizzazioni dei pazienti
Esperti in Economia sanitaria e HTA
Manager della Sanità regionale
Medici di Medicina Generale
Componenti (votanti)
CONTE PierFranco, Direttore UOC Oncologia Medica 2 - IOV Padova (Coordinatore)
BASSAN Franco, Direttore UOC Oncologia Medica - Azienda ULSS 4 Alto Vicentino
DEL GIUDICE Augusta, Associazione Noi e il cancro – Volontà di Vivere ONLUS - Padova
FERRARESE Annalisa, Direttore SOC Farmacia ospedaliera - Azienda ULSS 18 Rovigo
GASPARETTO Teresa, Responsabile Ricerca Innovazione e Health Technology Assessment - Regione Veneto
GORI Stefania, Direttore UOC Oncologia - Ospedale Sacro Cuore Don Calabria, Negrar (VR)
LEONE Roberto, Professore Associato di Farmacologia - Università degli Studi di Verona
MORANDI Paolo, UOC Oncologia Medica - Azienda ULSS 12 Veneziana Ospedale Dell’Angelo, Mestre
PERTILE Paolo, Ricercatore Dipartimento di Scienze Economiche - Università degli Studi di Verona
SAUGO Mario, Servizio Epidemiologico Regionale - Regione Veneto
SCANNAPIECO Gianluigi, Direttore Sanitario - Azienda Ospedaliera Padova
SCROCCARO Giovanna, Dirigente Settore Farmaceutico Protesica Dispositivi Medici Regionale - Regione
Veneto
TORTORA Giampaolo, Direttore Oncologia Medica A dU - Azienda Ospedaliera Universitaria Integrata
Verona
TOTTOLO Paolo, Medico di Medicina Generale - Azienda ULSS 9 Treviso
ZAGONEL Vittorina, Direttore UOC Oncologia Medica 1 - IOV Padova
Segreteria Scientifica
ADAMI Silvia Coordinamento Regionale Unico sul Farmaco (CRUF) Regione Veneto
BORTOLAMI Alberto Coordinamento Tecnico-Scientifico Rete Oncologica Veneta
CONTE PierFranco Coordinatore Tecnico-Scientifico Rete Oncologica Veneta
SCROCCARO Giovanna Dirigente Settore Farmaceutico – Protesica – Dispositivi Medici - Regione Veneto
Coordinatore Organizzatore ROV (Rete Oncologica Veneta) MARCHESE Fortunata
Settore Farmaceutico – Protesica – Dispositivi Medici RONI Chiara Farmacista
IL METODO GRADE
(Grading of Recommandations Assessment, Development and Evaluation)
Nato dall’attività avviata nel 2000 da un gruppo di lavoro internazionale con lo
scopo di definire un metodo rigoroso ed esplicito per la produzione di
raccomandazioni cliniche.
Ha fornito indicazioni per la produzione di raccomandazioni in campo
terapeutico, diagnostico e su come incorporare elementi di valutazione
economica nelle raccomandazioni cliniche.
Il GRADE prevede un approccio strutturato in 3 fasi principali:
1. Formulazione di un quesito clinico con scelta e valutazione formale
degli outcome ad esso correlati; valutazione sistematica della
letteratura scientifica e della qualità delle prove reperite.
2. Valutazione di benefici e rischi associati all’intervento considerando le
preferenze dei pazienti, la fattibilità e l’impiego di risorse necessario.
3. Definizione formale della forza della raccomandazione
GRAZIE PER L’ATTENZIONE