ADAPTIVE LICENSING/ADAPTIVE PATHWAYS
Donatella Gramaglia
Congresso SIFACT
Roma, 8-10 ottobre 2015
Dichiarazione di trasparenza/interessi*
Le opinioni espresse in questa presentazione sono personali e non impegnano in alcun modo l’AIFA
Interessi nell’industria farmaceutica
NO
Attualmente
Precedenti 2
anni
Da oltre 2 a 5
anni precedenti
Oltre 5 anni
precedenti
(facoltativo)
Interessi diretti:
Impiego in una società
x
Consulenza per una società
x
Consulente strategico per una società
x
Interessi finanziari
x
Titolarità di un brevetto
x
Interessi indiretti:
Sperimentatore principale
x
Sperimentatore
x
Sovvenzioni o altri fondi finanziari
x
* Donatella Gramaglia, secondo il regolamento sul Conflitto di Interessi approvato dal CdA AIFA in data 25.03.2015 e pubblicato sulla Gazzetta
Ufficiale del 15.05.2015 in accordo con la policy 0044 EMA/513078/2010 sulla gestione del conflitto di interessi dei membri dei Comitati Scientifici
e degli esperti.
N.B. Per questo intervento non ricevo alcun compenso
Regulatory process
①
Scientific Advice (EMA, AIFA,
other NCAs)
①
Clinical trials authorization (AIFA/Ethics Committes)
②
EU/National Marketing Authorizathion
③
Post-authorizathion: PASS, PAES, observational studies,
Registries (to generate further evidence)
④
Governance at national level: MEAs, Registries
3
EMA versus FDA
• Full MA (normal & accelerate)
• Conditional MA
• Under Exceptional circumstances MA
•
•
•
•
Fast Track
Breakthrough Therapy
Accelerated Approval
Priority Review
At EMA level Exceptional Circumstances (EC) and Conditional Approval (CA)
authorizathion procedures are based on limited clinical data sets and with
clear unmet medical need. However, these procedures provide early access
to a limited number of drugs.
EMA’s Marketing Authorisations
Traditional MA
MA under Exceptional Circumstances
Conditional MA
Adaptive Licensing Scenario: one size does not fit all
The basic principles of adaptive
approaches are facilitating early access
by approving medicines early, with
acknowledged uncertainty about the
favourable and unfavourable effects.
AL would make fuller use of all sources
of information to update regulatory and
treatment decisions.
(a) Current scenario
(b) AL scenario
Eichler et al. Clin Pharmacol Ther. 2012 Mar
Is early access to new medicines possible?
Source: Discussion paper by the Escher Project
2012
EMA Adaptive Pathways
• The adaptive pathways approach (formerly known as ‘adaptive
licensing’) is part of the European Medicines Agency’s (EMA) efforts to
improve timely access for patients to new medicines.
• Initial approval in a well-defined patient subgroup with a high medical
need and subsequent widening of the indication to a larger patient
population, or
• An early regulatory approval (e.g. conditional approval) which is
prospectively planned, and where uncertainty is reduced through the
collection of post-approval data on the medicine's use in patients.
• Relevant for medicines with the potential to treat serious conditions
with an unmet medical need, and may reduce the time to a medicine's
approval or to its reimbursement for targeted patient groups.
• Balancing the importance of timely patient access with the need for
adequate, evolving information on a medicine's B/R
Adaptive pathways approach 1
•
•
•
•
Builds on regulatory processes already in place within the
existing European Union legal framework that include:
scientific advice;
compassionate use;
the conditional approval mechanism (for medicines
addressing life-threatening conditions);
patient registries and pharmacovigilance tools that allow
collection of real-life data and development of the riskmanagement plan for each medicine.
Adaptive pathways approach 2
Early discussion between a wide range of stakeholders
to explore ways of optimising development pathways.
These include organisations such as:
– EMA and other National Agencies
– the pharmaceutical Industry
– Health Technology Assesment (HTA) bodies
– organisations issuing clinical treatment guidelines
– patient and consumer organisations, healthcare
professionals
– researchers and academics
March 2014 – EMA Pilot project
• Companies invited to participate in a pilot project on adaptive pathways
• From adaptive licensing to adaptive pathways to better reflect the idea
of a life-span approach to bring new medicines to patients with clinical
drug development, licensing, reimbursement, and utilization in clinical
practice, and monitoring viewed as a continuum.
• The aim is to understand of how future adaptive pathways might be
designed for different types of products and indications. It provides a
framework for open dialogue between stakeholders, allowing them to
explore different options (“Safe Harbour”)
• Companies interested in participating are asked to submit ongoing
medicine-development programmes that should be in the early stage of
clinical development (i.e. prior to the initiation of confirmatory studies).
Pilot project – Questions from Submission Form
• Does the drug hold sufficient promise to address
an unmet need (e.g. based on convincing mode of action,
impressive preliminary animal/human data)?
• Initial indication sought:
– What evidence would support a positive benefit-risk in the defined
(sub-) population at the time of initial licensing, including surrogacy of
early, pharmacodynamic endpoints?
– What is the risk of failing to identify an important adverse effect based
on early phase clinical trial data?
• Indication(s) subsequently sought (e.g. expansion to new indication,
different subpopulation, different endpoints or confirmation of efficacy in
initial population). Highlight the possibility of iterative discussions along
the progress of development.
Pilot project – Questions from Submission Form
• What possibility there is to draw inferences from observational (nonRCT) data sufficiently reliable to support decision-making for
regulators, payers and prescribers? How you plan to gather Real World
Data and use them to support expansion of the labelling?
• What assurance of commitment from sponsor will there be to conduct
further studies after the initial marketing authorisation. What is the
feasibility of any required follow-on RCTs after initial Marketing
Authorisation (lack of willingness of patients to enrol in RCT)
• What is the level of confidence that definition and control of the
population through regulatory tools will be achieved (e.g. registries,
PASS, PAES, Conditional Approval…).
Pilot project – Questions from Submission Form
• How do you foresee to make more efficient the various regulatory
processes involved in drug licensing into an integrated prospectively
agreed program? Input of downstream stakeholders (HTAs, ethical
committees, patients, organisations issuing clinical treatment
guidelines…) is fundamental. Please consider which stakeholders you
wish to involve in the discussions.
• If it is too premature, you should at least outline what plans you have
with respect of HTA considerations. A fine-tuned program aiming at
both early licensing and early reimbursement is an important goal of
adaptive licensing.
• What is the level of confidence that prescriber behaviour will be as
anticipated? (Risk of large share of off-label use, can this be mitigated
by collaboration with payers?)
A progressive reduction of uncertainty
AP would make fuller use of all
sources of information to update
regulatory and treatment decisions.
For example, a AP pathway could be
the adaptation around: population,
statistical uncertainty, endpoints with
surrogate markers, combination
treatments
(a) Current scenario
(b) AL scenario
Eichler et al. Clin Pharmacol Ther. 2012 Mar
CRITERIA that identify a good candidate product for AP
1. An iterative development plan (e.g. either by gradual expansion of the
target population, perhaps starting from a population with high(est)
medical need, or progressive reduction of uncertainty after initial
authorisation based on surrogate endpoints)
2. Ability to engage HTAs and other downstream stakeholders, with proposals
for how the demands of these stakeholders can be met.
3. Proposals for the monitoring, collection and use of real-world data, postauthorization, as a complement to RCT data, to inform updates to the
regulatory label and to the positions of other stakeholders.
Adaptive Pathways is a prospectively-planned lifespan approach, therefore
discussions will involve experts from various EMA Committees as
applicable. The Adaptive Licensing Discussion Group(ALDG), includes
representatives from the CHMP, CAT, PRAC, PDCO, SAWP, COMP
ADAPTIVE PATHWAY CONCEPT
AP does not aim at instituting new regulatory tools, but at increasing
awareness and optimising the use of all tools and flexibilities within the
existing regulatory framework.
The type of Marketing Authorisation obtained (full, conditional, under
exceptional circumstances), including any potential restrictions or
conditions, will be determined case-by-case depending on the level of
evidence ultimately obtained.
Two scenarios can be envisaged that would allow earlier access:
– In the first, approval is granted in a well-defined, high medical need subgroup, and
subsequently the indication is widened to a larger patient population.
– In the second case, an early (perhaps conditional) approval is prospectively planned, for
example on the basis of surrogate endpoints, and uncertainty is planned to be reduced
through obligations to collect data post-approval with the MA potentially converting to
‘full’ approval once more data are available.
Adaptive pathways to patients: report on the initial
experience of the pilot project
Examples of potential “design features” of AP
Report on the pilot project initial experience
•
•
•
•
•
The Agency has received 34 applications for the pilot project, 6 concerned ATMPs, 12
concerned orphan products, 11 came from SME companies and 14 concerned anticancer
medicinal products.
Ten candidate products fulfilling the criteria for Adaptive Pathways were selected for a
Stage I discussion. A broad range of therapeutic areas were represented by the indications
of the 10 selected products, together with large and small patient populations: 5 were
orphans, 2 ATMPs, 4 were from SMEs. Stage I teleconferences relating to 7 products had
taken place by mid-December 2014.
The ALDG also revisited 9 applications which were not initially selected: these were classic
CMA cases. It is however considered valuable to foster proactive use of the Conditional
Marketing Authorization pathway, where reimbursement decisions have historically been
shown to be difficult, by trying to design a program that addresses HTA needs.
The concerned companies have been invited to develop their proposals in terms of HTA
requirements and plans for real world data acquisition.
Stage II consists of a 2-4 hour meeting for a detailed exploration of proposals (and their
possible alternatives) for the design of a parallel SA/HTA advice.
Adaptive Licensing or Progressive Patient Access
EU activities
Renewal
SA+HTA
SA w. FDA
PIP
Comp. use
Variations
PSURs
ADR
SA
COMP
Biomarker
Qualif.
Approval
I
II
III
IV
Modified after T. Salmonson (CHMP)
Knowledge
CHMP positive opinion with RMP including
missing information, PASS, PAES, risk
minimisation activities etc
Time / Phase of development
Adaptive Licensing or Progressive Patient Access
Registries
"HTA"
Horizon
Scanning
Individual use
SA
CT
I
II
Effectiveness
studies
Approval
III
IV
Modified after T. Salmonson (CHMP)
Knowledge
National activities
Time / Phase of development
Adaptive Licensing or Progressive Patient Access
National activities
EU activities
CHMP positive opinion with RMP including
Biomarker
qualif.
Renewal
Variations
SA+HTA
PSURsis also
”Adaptive
licensing"
SA w. FDA
ADR
about
bringing
all these Registries
PIP
Comp. use
in a introduction
SA incl. activities together
Structured
M&S
prospective
andEffectiveness
structuredstudies
way
"HTA"
Horizon
COMP
Scanning
Individual use
SA
CT
I
II
Approval
III
IV
Modified after T. Salmonson (CHMP)
Knowledge
missing information, PASS, PAES, risk
minimisation activities etc
Time / Phase of development
Conclusions
 The AP is a lifespan approach with the distinctive characteristics of HTA
involvement and consideration to the use of real world data (RWD). For
this reason, input is sought from various EMA committees, and all
stakeholders including patients, as appropriate.
 The AP approach facilitates a more open and timely dialogue and
cooperation between sponsors, regulators and payers.
 AP may reduce the time to full market approval and the overall cost of
development. There are considerable challenges and benefits to fully
implementing AP as the common pathway for drug approval.
A livello nazionale
Delibera C.d.A. n. 7 del 20 gennaio 2014
Regolamento recante norme sull'organizzazione e il funzionamento della
Commissione consultivaTecnico-Scientifica e Comitato Prezzi e Rimborso
Commissione Consultiva Tecnico - Scientifica (CTS)
Comitato Prezzi e Rimborso (CPR)
29
Principali funzioni della CTS -1
• Valuta le domande nazionali ed europee di Autorizzazione
all’Immissione in Commercio (A.I.C.) per procedure europee
(centralizzate, decentrate e di mutuo riconoscimento) e nazionali
• Valuta problematiche di farmacovigilanza
• Si esprime sulla sperimentazione clinica (in particolare sulle cd.
Terapie Avanzate) e sulle richieste di 648
• Fornisce pareri vincolanti sul place in therapy e sull’innovatività dei
singoli prodotti
• Esprime parere vincolante in merito alle richieste di equivalenza
terapeutica
30
Principali funzioni della CTS-2
• Esprime pareri vincolanti sul regime di fornitura (RR, RNR, RRL, RNRL,
OSP e OSPL, USPL)
• Esprime una proposta sullo schema di rimborsabilità e applicazione
MEAs
• Approva le Note AIFA e fornisce suggerimenti sulla stesura di Piani
Terapeutici
• Consulta e/o effettua audizioni con i rappresentanti delle Aziende
Farmaceutiche, Società scientifiche, Esperti, Associazioni di pazienti o
singoli soggetti portatori di interessi
31
Definizione prezzo e rimborso
tiene conto:
Parte clinica (CTS)
•
•
•
•
•
•
•
AUTORIZZAZIONE IN ALTRI PAESI extra UE ed EVENTUALI
RESTRIZIONI/CONDIZIONI
INQUADRAMENTO TECNICO SCIENTIFICO DEL MEDICINALE
EPIDEMIOLOGIA DELLA PATOLOGIA
PAZIENTI INTERESSATI AL TRATTAMENTO
LINEE GUIDA DI TRATTAMENTO ESISTENTI
TRATTAMENTI DISPONIBILI E DEFINIZIONE DEI COMPARATORI
QUALITÀ, EFFICACIA e SICUREZZA dagli STUDI REGISTRATIVI
PARERE SEGRETARIATO HTA
Definizione prezzo e rimborso
tiene conto
CPR: parte economica
•
•
•
•
•
•
•
•
PREZZO DEL FARMACO IN ALTRI PAESI EUROPEI
PAZIENTI INTERESSATI AL TRATTAMENTO
MERCATO TOTALE DELLO SPECIFICO SETTORE TERAPEUTICO
STIMA QUOTA DI MERCATO/ANNO DEL PRODOTTO NEI PRIMI 3
ANNI DI RIMBORSABILITÀ - STIMA SPESA SSN IN €
ANALOGHI RIMBORSATI E COSTO TERAPIA
STUDI DI FARMACOECONOMIA (qualora presenti)
RAPPORTO INCREMENTALE DI COSTO-EFFICACIA (ICER)
PARERE SEGRETARIATO HTA
Segretariati, CTS & CPR
Ufficio Valutazione
e Autorizzazione (V&A)
Ufficio Ricerca
Sperimentazione
Clinica (RSC)
Segretariato V&A
Segretariato RSC
Ufficio
Farmacovigilanza (FV)
Segretariato FV
Ufficio attività HTA
nel settore farmaceutico
Segretariato HTA
C.T.S.
C.P.R.
C.d.A.
34
Aziende Farmaceutiche per
medicinali approvati con:
Procedura Nazionale
Procedure Comunitarie:
mutuo riconoscimento,
centralizzata EMA
decentrata
AIFA - UFFICIO HTA
CTS stabilisce:
• Place in Therapy
• Innovatività
• Regime di fornitura
• Proposta schema rimborsabilità
CPR:
• Contratta prezzo e condizioni
negoziali di rimborsabilità
• Stesura e firma accordo negoziale
C.d.A.
Delibera finale di AIC
Pubblicazione
determina AIC in
Gazzetta Ufficiale
35
From adaptive licensing to adaptive reimbursement
Managed entry agreements for pharmaceuticals:the European experience. 2013.
Donatella Gramaglia
+390659784527
[email protected]
http://www.agenziafarmaco.gov.it/it
38