Entela Xoxi, PharmD, PhD, MSc. Pharma Pricing & Market Access Congress 2017 22 February 2017 London

1. THE IMPORTANCE OF POST-MARKETING
REGISTRIES FOR PAYERS AND REGULATORS TO
MANAGE DRUG PRICING AND
CONDITIONAL REIMBURSEMENT
Entela Xoxi
PharmD, PhD, M.Sc.
Former Co-ordinator of AIFA’s Registries (until 2016)
Former member European Commission Expert Group STAMP
Former Observer at AdaptSmart, EUnetHTA member

2. The outlines of this talk
① European regulatory process
② Interaction between Regulatory & HTA bodies
③ Registries & Pricing Reimbursement process

3. ① European regulatory process
② Interaction between Regulatory & HTA bodies
③ Registries & Pricing Reimbursement process

4. Positive Opinion: may often have ‘follow up measures’
Post-authorisation Efficacy or Safety Studies (PAES or PASS): ‘Any study relating to an
authorised medicinal product conducted with the aim of identifying, characterising or
quantifying a safety hazard, confirming the safety profile of the medicinal product, or
of measuring the effectiveness of risk management measures’
Full MA (Classic & Accelerate Assessment)
Conditional MA (CMA)
The CMA is granted in order to meet unmet medical needs of patients and in the
interests of public health, before all data are available. When the missing data are
provided, it should be possible to replace it with a Full MA. In contrast, it will
normally never be possible to assemble a full dossier in respect of a MA under EC
Exceptional circumstances MA
This MA may be granted in exceptional circumstances for safety reason. The
medicinal product is authorised only for objective, verifiable reasons and must be
based according to Annex I to Directive 2001/83/EC. Continuation of the
authorisation shall be linked to the annual reassessment of these conditions.
CHMP opinions & Market Authorisation

5. Launched by EMA to enhance support for the development of
medicines that target an unmet medical need.
This voluntary scheme is based on enhanced interaction and early dialogue
with developers of promising medicines, to optimize development plans and
speed up evaluation so these medicines can reach patients earlier.
PRIME scheme
Recommendations on eligibility to PRIME scheme
Cumulative overview of recommendations on PRIME eligibility requests adopted by 26 January 2017
By therapeutic area
* This indicates eligibility requests received but not started by EMA as they were deemed outside the scope of the scheme or with a format and content inadequate to support their
review. These are not included in the breakdown by type of applicant or by therapeutic area.
By type of applicant

6. Adaptive Pathway (2 scenarios) based
on 3 principles
① Iterative development, which either means:
§ approval in stages, beginning with a restricted patient population then
expanding to wider patient populations
§ confirming the B-R balance of a product, following a conditional
approval based on early data (using surrogate endpoints) considered
predictive of important clinical outcomes
② Gathering evidence through real-life use to supplement CTs data
③ Early involvement of patients and HTA bodies in discussions on a medicine’s
development.
- Widening of indication Scenario (1)
- Prospectively planned reduced
Of Uncertainty (CMA) Scenario (2)

7. ① European regulatory process
② Interaction between Regulatory & HTA bodies
③ Registries & Pricing Reimbursement process

8. 23 September 2015
EMA/334645/2015
Senior Medical Officer
What can EMA contribute to HTA-JA3?
The European Medicines Agency (EMA) will become a collaborating partner in the Health Technology
Assessment-Joint Action 3 (HTA-JA3), sponsored by the EC. HTA-JA3 will run from 2016-2019. At the
recent (8th
May 2015) EMA-EUnetHTA meeting, EMA was asked by the Commission (Jerome Boehm) to
outline EMA’s estimated contributions - both scientific synergies and resources/logistics - to the HTA-
JA3.
1. Maximise scientific synergies between HTA and regulation
1.1. Shaping the early drug development plan (early scientific advice)
Since 2010 EMA has put in place a pilot project of Parallel Scientific Advice in partnership with HTA
bodies that allows developers to receive simultaneous feedback from both regulators and national HTA
bodies on their development plans for new medicines.
The following HTA bodies have participated so far: AEMPS (Spanish Medicines Agency), AIFA (Italian
Medicines Agency), CAHIAQ (Catalan Agency for Health Information, Assessment and Quality), GBA
(German Federal Joint Committee), HAS (French National Authority for Health), HVB (Association of
Austrian Social Insurance Institutions), IQWiG (Institute for Quality and Efficiency in Healthcare,
Germany), INAMI (National Institute for Sickness and Invalidity Insurance, Belgium), NICE (British
National Institute for Health and Clinical Excellence), NOMA (Norwegian Medicines Agency), TLV
(Swedish Dental and Pharmaceutical Benefits Agency), ZIN (Dutch National Health Care Institute,
formerly CVZ), and AOTMiT (Polish Agency for Health Technology Assessment and Tariff System).
A wide spectrum of indications has been covered, such as diabetes, heart failure, lung cancer, breast
cancer, pancreas cancer, melanoma, mesothelioma, glioblasoma, asthma, rheumatoid arthritis, multi-
resistant bacterial infections, viral and fungal infections, food allergies, diabetic gastroparesis,
Alzheimer’s disease, depression, osteoporosis, ophthalmology conditions such as retinitis pigmentosa What can EMA contribute to HTA-JA3?
framework of the EUnetHTA Joint Actions (JA) 1 and 2, and EMA was invited to participate as observer
in the multi-HTAs early dialogues of EUnetHTA JA2.
Since September 2013, under the coordination by HAS, 14 HTAs have initiated the SEED (Shaping
European Early Dialogues for health technologies) project, financed by the EU Commission, to perform
10 additional multi-HTAs early dialogues (7 on medicinal products and 3 on medical devices) and
explore possible scenarios for conducting early dialogues in the future. EMA is associated to the SEED
project and took part in 4 of these dialogues as EMA SEED parallel advice procedures. These 4
procedures were hosted by EMA.
It is anticipated that the number of procedures and the number of EU-HTA bodies contributing to the
early scientific advice procedure will grow in the near future, i.e. during the period of the HTA-JA3.
EMA is willing and able to continue to support this activity. See paragraphs 2.1. and 2.2.
1.2. Shaping on-market evidence generation (late scientific advice,
registries)
In 2015 EMA is reinforcing its Scientific Advice Working Party with experts in on-market evidence
generation from the Pharmacovigilance Risk Assessment Committee (PRAC). In addition, a new
Scientific Advice Procedure (which may include Parallel Scientific Advice with HTA bodies) will be
introduced that concludes with advice being adopted by the PRAC. This forms the foundation for
pharmaceutical companies to obtain expert advice on the development of their products beyond the
initial marketing authorisation application including evidence generation using observational methods
and including patient outcomes of interest to HTA bodies. In this way EMA can offer to coordinate
Parallel Scientific Advice which delivers expert advice throughout the product lifecycle.
EMA is actively supporting efforts to build capacity to generate on-market evidence, including of
efficacy and safety of medicines and health outcomes. Capacity building efforts will include HTA bodies
where appropriate and this includes:
• supporting the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance
(ENCePP) and developing guidance on methods for studies that can support medicines
regulation and HTA,
• developing and piloting tools to improve the feasibility and quality of patient registries
(including governance models, core protocols and data fields), including registries that can
support both regulatory and HTA questions,
• a pilot of supporting companies to generate evidence by building on existing registries (and
HTA involvement through Parallel Scientific Advice is envisaged),
EMA & HTA bodies interactions

9. JA3 EUnetHTA Work Package 5 - Life cycle
approach to improve Evidence Generation
Strand A:
Early dialogues (initial evidence generation)
Strand B:
Post-Launch Evidence Generation & Registries
• Standards for registers in HTA tool - Candidate registers and participating
HTA agencies identified.
• Report on current processes for using register data in HTA assessments in
European HTA agencies.
• Start of pilots
• Identify options for a mechanism for independently accrediting or
assuring registers using the Quality Standards for Registers in HTA,
including updating the standards in line with methodological
developments.
• Tool for Registers in HTA prepared.
• Post Launch Evidence Generation, start of last pilots
Options for a business model for ongoing delivery of a mechanism for
independently accrediting or assuring registers using the Quality
• Standards for Registers in HTA, including updating the standards in line
with methodological developments.
• Post-launch evidence generation tool produced

10. § Patients
§ Patient organisations
§ Regulatory authority
§ P & R body, Insurance bodies
§ HTA body
§ Physicians
§ Pharmacists
§ Pharma companies
§ Regions
§ Health managers
§ CRO
§ Ethical Committees
Stakeholders: rules & responsabilities
Region
Local Health Unit
Pharmacy
Pharma Industry
Region
Local Health Unit/
Hospital Public
Corporation
Hospital
Pharmacy
Pharma Industry
Region
Local Health Unit/
Hospital Public
Corporation
Hospital
Department
Section
Hospital-PhysicianHospitalPharmacyTerritoryPharmacy

11. Patients are not equally
responsive to beneficial
effects, and not equally
susceptible to AEs.
Bridging the efficacy-effectiveness gap: a regulator's
perspective on addressing variability of drug response.
Nat Rev Drug Discov. 2011 Jul 1;10(7):495-506. Eichler
HG, et al.
Bridging the efficacy – effectiveness gap
Regulatory decisions are
based on population-level
information, with an
understanding that the B-R
will not necessarily be
positive for all treated
patients.

12. 4
DatasourcesDatasources
Patient derived data
(via smart phone or web
based technologies)
Electronic
health records
Primary care data, hospital records
Registries
Existing disease
Registries / new
product registries
Prescription databases
Drug utilisation
Patient and
caregiver surveys
Which Data?
The Future
Social media
data
Claims data
RWE is already in routine use in the EU
Particularly true for marketed products - safety monitoring
and drug utilisation.

13. Registries as part of Real World Data
REGISTRIES are one of the
many sources of RWD:
• electronic medical
records, observational
studies,
• administrative data,
• claims databases,
• health surveys,
• patient reported
outcomes (PROs)
RWD is defined as an umbrella
term regarding the effects of
health interventions that are not
collected in the context of
conventional RCTs.
RWE is defined as the evidence
derived from the analysis and/or
synthesis of RWD
(GetReal Consortium. IMI-GetReal Glossary. IMI-GetReal;
2015)
Adaptive pathways workshop, 2016/12/13
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/
events/2016/09/event_detail_001324.jsp&mid=WC0b01ac058004d5c3

14. 1. RWD collection and use for reimbursement activities, such as
relative effectiveness assessment, risk-sharing agreements and
pharmaco-economics analysis is the most noted actual context.
2. RWD collection and use for regulatory activities. RWS can be designed to
collect information on long-term safety and effectiveness as part of phase
IV, PASS and pharmacovigilance commitments. RWS can also demonstrate
compliance of prescribing patterns in populations approved in marketing
authorizations or adherence to national guidance. In some cases, they
can also inform a need for treatment pathways, or license extension to a
new indication or treatment population.
3. Collection and use of RWD during drug development. RWD is used,
amongst other things, to help drug developers study the natural history of
disease, define patient populations for CTs, standardize outcome
measurements, define sub-populations for treatment, understand
treatment patterns both pre- and at product launch, and, as previously-
stated, long-term safety and effectiveness outcomes.
4. Use of RWD in drug utilisation studies to investigate, for example, drug
dosing in clinical practice, patient compliance, SoC & treatment flows in
different clinical contexts.

15. 24
Patient Registries
Strengths
• Systematic assessment of investigator
designed measurements of relevant
clinical parameters
• Natural history of disease
• Disease burden
• Standard of care
• Patient stratification
• RCTs
• Open label studies possible
• Capture off label use
• Captures information on high risk
groups and rare diseases
• Patient reported outcomes
Limitations
• Substantial set up and running costs
(sustainability)
• Time consuming to initiate
• Medications commonly missing
• ADRS not routinely recorded
• Co-morbidities missing
• Data ownership/governance
challenges
• Data Quality - absence of clear
benefit for clinical practice limits HCP
commitment
• If no comparator will limit utility
Adaptive pathways workshop, 2016/12/13
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/events/
2016/09/event_detail_001324.jsp&mid=WC0b01ac058004d5c3

16. q Fragmentation
q Lack of interoperability
q Increased cross border collaborations are required to leverage
existing data and knowledge.
26
….fragmentation,
……lack of interoperability,
……..increased cross border collaborations are required to leverage existing data and knowledge
RWE is already in routine use in Europe, particularly true in the post
authorisation stage Europe is rich in datasets but there are multiple
challenges in their exploitation. Integration of multiple databases may
be needed to increase power in order to study rare exposures or
outcomes or diverse populations.

17. Redefined eHealth European Interoperability Framework (2015)
Legal and
regulatory
Policy
Research process
Information
Applications
IT Infrastructure
Legal and
regulatory
Policy
Care process
Information
Applications
IT Infrastructure
Compatible legislation and
regulations
Collaboration agreements
Alignment of care processes and
workflows
Data model, terminologies,
formatting
Integration in healthcare
applications
Communication and network
protocols
Organization A Organization BChange
Change
Change
Change
Change
Change
The Belgian “start up” project on patient registries
EMA Patient Registries Workshop, 2016.10.28 - London
[Healthcare data – Interoperability] = Pain

18. BIG DATA (4V’s)
means different things to different
people and there isn’t, and probably
never will be, a commonly agreed
upon definition out there.
But the phenomenon is real and it is
producing benefits in so many different
areas, so it makes sense for all of us to
have a working understanding of the
concept.
BIG DATA is that everything we
do is increasingly leaving a
digital trace (or data), which we
(and others) can use and
analyze.
Big Data therefore refers to that
data being collected and our
ability to make use of it.

19. ① European regulatory process
② Interaction between Regulatory & HTA bodies
③ Registries & Pricing Reimbursement process

20. Early dialogue/
scientific
advice
European &
National
approval
Conditional
Reimbursement
(MEAs)
Re-
assessment
The Italian approach
Clinical drug-
development
Market Entry
Monitoring
Registries
Further policy
actions

21. The Italian post-marketing registries
Entela Xoxi, Carlo Tomino, Luca de Nigro, Luca Pani
Italian Medicines Agency, Roma, Italy
The post-marketing registries, established by the Italian Medicines Agency in 2005, represent the example
of a national application of an automated workflow handling the personalized drug distribution in hospital
pharmacies and local public pharmaceutical services, with the intent of both improving the efficacy/
efficiency of analysis and regulatory activities themselves, as well as closely monitoring the clinical activity.
In fact, within the correct clinical practice the prescriber shall take into account the parameters, such as
therapeutic drug indication, actual benefit the patient should gain in comparison to the trials, potential and
actual risk of adverse reactions, drugs interactions, and cost of the therapy. On the track of the cancer
registry’s experience, the Italian Medicines Agency has extended the scope to the following areas:
ophthalmology, rheumatology, dermatology, orphan drugs, cardiology, diabetology, respiratory, and
neurological diseases. It involves more than 60 drugs (most of them with risk sharing schemes on a
population of over 400 000 patients) and is available from http://monitoraggio-farmaci.agenziafarmaco.it.
Keywords: AIFA, MEAs, NHS, DB, CIRR
The Registries of Italian Medicines Agency
The aim of drugs monitoring is the computerized
national management1
of the whole process concern-
ing the request of dispensation and analysis of
consumption data of an innovative drug. The
computerized drugs prescription requires a change
of mentality and a restructuring of the whole process;
for these reasons, it’s still struggling to be used
extensively. The Italian Medicines Agency (AIFA)
has developed a treatment registration form and can
monitor and control in real time the correct use of the
drug. The first regulatory experience was the cancer
drugs register.2
Based on this experience, AIFA has
extended the scope to the following areas: ophthal-
mology, rheumatology, dermatology, orphan drugs,
cardiology, diabetology, respiratory, and neurologi-
cal diseases. It involves more than 60 drugs (most
of them with managed entry agreements (MEAs)
on a population of over 400 000 patients (Table 1)
and is available from http://monitoraggio-farmaci.
agenziafarmaco.it.
Through this network, AIFA will implement the
monitoring process and the exchange of data between
dose of the drug regarding a patient whose diagnosis
corresponds to parameters of the authorized ther-
apeutic indication (Fig. 1). The electronic form
application, valid for a single administration, is
automatically sent by email to the hospital pharmacy,
which proceeds to close the form by formally and
practically dispensing the requested drug. The system
is accessible from any computer connected to the
internet through the use of a username and password.
It is also targeted to non-computer experts and does
not require specific training. The procedures for
entering and managing the data are standardized;
however, the flows depend on the specificity of the
drug and its therapeutic indication.
For each prompt, the system offers additional
compile a number of forms relating to the follow-up.
In addition, and not least, is very important also to
analyse the use of the innovative therapies directly
with the pharmaceutical companies, according to
the principle of risk sharing or pay by result: the
awareness and evaluation of results of clinical
practice and the purpose of defining the right cost
to be incurred by the national health system.
et al., 2012
The boat will leave from the Marine Etablissement Amsterdam.
After the dinner there will be transfer to the hotels and the
Central Station by bus.
Wednesday 2 March (9:00 – 12:45)
Conference venue:
Marine Etablissement Amsterdam (MEA)
Kattenburgerstraat 7, 1018 JA Amsterdam
08:30-09:00h Welcome and coffee
09:00-09:15h Opening and review of Tuesday
Kees de Joncheere, moderator of the conference,
Director, Department of Essential Medicines and Health
Products World Health Organization (WHO) Geneva,
Switzerland
09:15-09:45h Introduction objective 3:
What are necessary conditions to come to an acceptable
outcome of the pathway for the payer (“managed entry
schemes and exit”)
Entela Xoxi, Co-ordinator AIFA Registries, Italian Medicines
Agency (AIFA)
PROGRAMME
‘Innovation for the benefit of the
patient: early interaction between market
authorization, health technology assessment
and payer in order to optimize patient access
to innovative medicines’
Amsterdam, 29 February - 2 March 2016
Monday 29 February (19:00 – 21:00)
Welcome drink and buffet.
Venue: Kitchen & Bar Van Rijn,
Address: Rembrandtplein 17, 1017 CT Amsterdam.
1
PROGRAMME
‘Innovation for the benefit of the
patient: early interaction between market
authorization, health technology assessment
and payer in order to optimize patient access
to innovative medicines’
Amsterdam, 29 February - 2 March 2016
Monday 29 February (19:00 – 21:00)
Welcome drink and buffet.
Venue: Kitchen & Bar Van Rijn,
Address: Rembrandtplein 17, 1017 CT Amsterdam.
Tuesday 1 March (9:00 – 22:00)
Conference venue: Marine Etablissement Amsterdam (MEA)
Address: Kattenburgerstraat 7, 1018 JA Amsterdam
08:30-09:00h Registration and coffee
Make sure you arrive timely as entrance procedures may take
some time
09:00-09:10h Opening
Opening words by Edith Schippers, Dutch Minister of Health,
Welfare and Sport
09:10-09:30h Introduction
Introduction by Kees de Joncheere, moderator of the
conference, Director Department of Essential Medicines and
Health Products World Health Organization (WHO) Geneva,
Switzerland
09:30-10:30h Presentation on Adaptive Pathways –
Regulatory and HTA perspectives
Tomas Salmonson, Chair of Committee for Medicinal
Products for Human Use (CHMP) at the European Medicines
Agency, EMA and Senior Scientific Advisor at the Medical
Products Agency (MPA), Sweden.
Nick Crabb, Programme Director - Scientific Affairs, Centre
for Health Technology Evaluation, National Institute for

22. Telematic tools @National AND @patient level designed to:
① Verify label use (Appropriateness) collecting post-marketing data on
clinical practice use (broad collection of baseline characteristics
and follow ups)
② Capture DATA available to the HTA bodies and stakeholders for B/R
Assessment
③ Apply a risk-sharing approach or Managed Entry Agreements (*)
④ Govern the public drug expenditure (**)
AIFA Registries within National Pricing &
Reimbursement system
(*) LD 2015
(**) ITS, 135/2012 Italian Law
Patient
Demographic
information
Eligibility &
Clinical
Data
Drug
Prescription
Drug
Dispensing
Follow Up
End of
Treatment

23. DAAs registries
http://www.agenziafarmaco.gov.it/it/content/registri-farmaci-sottoposti-monitoraggio
2017/02/13 update
Criterion 1 - Patients with cirrhosis in Child class A or B and/or HCC with complete response to
therapy resettive surgical or loco regional not candidates for liver transplantation in which the
liver disease significantly affects prognosis
Criterion 2 - Recurrent hepatitis HCV RNA-positive liver transplant patients in clinically stable and
with optimal levels of immunosuppression
Criterion 3 - Chronic hepatitis with severe HCV-related extrahepatic manifestations
(cryoglobulinemic syndrome with organ damage, B-cell lymphoproliferative syndromes)
Criterion 4 - Chronic hepatitis with fibrosis METAVIR F3 (or corresponding Ishak)
Criterion 5 - In the list for liver transplantation with cirrhosis MELD <25 and/or HCC within the
Milan criteria with the possibility of waiting in a list of at least 2 months
Criterion 6 - Chronic hepatitis after solid organ transplantation (not liver) or marrow fibrosis
METAVIR ≥2 (or corresponding Ishack)
Criterion 7 - Chronic hepatitis with fibrosis METAVIR F0-F2 (or corresponding Ishak)
Trend cumulativo dei trattamenti avviati
67,638 patients treated
Trattamenti avviati per criterio
Criterio N. Trattamenti
1 43.145
4 18.229
3 3.145
2 1.903
7 618
6 306
5 292
Criterion Treated patients

24. Dealing with Uncertainty

25. Managing
budget impact
Non Outcome based
(single or combined)
• Cost sharing
• Capping
• Price volume
Managing uncertainty
relating to clinical
benefit & cost
effectiveness
Outcome based
• Payment by result
• Risk sharing
• Success fee
Managing utilization
to optimize
Appropriateness
• Safety monitoring
• Prescription plans
• AIFA Notes
Combination
MEAs and P&R process
SCHEME AGREEMENTS
chè sono nati i Registri
data di pubblicazione on
ro dei Farmaci Oncologici
OM), con la registrazione
oro di un gruppo multidi-
he ha ideato il progetto e
rmaci oncologici: il grup-
ell’AIFA (Sperimentazione
Informazione sui Farmaci
o di Consultazione sulla
he riuniva rappresentanti
ncologia Medica (AIOM),
ologia (SIE), della Società
gica (SIOG), della Società
era (SIFO), degli Assesso-
lla Commissione Tecnico
frutto di competenze di-
olatorie - scientifiche - as-
rantire la complessità del
assa critica estesa in gra-
dozione delle procedure
a necessità di individuare
novazione e sostenibilità
onsapevolezza che i nuovi
sti di trattamento indotti
per anno) e per le impli-
rocesso assistenziale (de-
terapeutica H-T), doveva-
me terreno di verifica dei
feribilità e di sostenibilità
esentavano due principali
esso FDA (Food and Drug
opean Medicines Agency),
e nei diversi paesi con un
n termini di efficacia e di
ia naturale della malattia;
sposta clinica, per cui si
molti pazienti per avere
uale limitata di casi, ren-
to rischio-beneficio.
si contrapponevano due
eva che non esistevano le
so e mercato e chi affer-
ncrementale doveva esse-
gici.
Per uscire da tale situazione dicotomica l’AIFA ha rite-
nuto necessario, invece, individuare soluzioni e strategie
basate su due principi semplici e condivisi:
- un nuovo farmaco oncologico (o un’estensione delle
indicazioni) va rimborsato solo se efficace nel singo-
lo paziente, in quanto i sistemi sanitari di welfare non
possono farsi carico dei fallimenti (failures) a fronte di
costi così elevati;
- introdurre procedure cliniche ben definite (scheda di
arruolamento - scheda di follow-up - scheda di fine
trattamento) per individuare i pazienti responders e
attribuire alle aziende farmaceutiche i costi di tratta-
mento mediante una procedura di pay-back.
Pertanto l’adozione dei Registri e delle procedure di
share scheme non hanno costituito un atteggiamento
riduttivo o di razionamento ma il vero trade-off tra inno-
vazione e sostenibilità economica.
Veniva pertanto fissato il principio di riconoscere alle
aziende farmaceutiche l’accesso ai nuovi farmaci in on-
cologia ma altrettanto legittimo era il principio dell’AIFA
di rimborsare il nuovo farmaco in quanto efficace, non
essendo possibile sostenere un onere economico ele-
vatissimo, facendosi carico dei fallimenti terapeutici nei
pazienti che, nonostante il nuovo farmaco, manifestava-
no una progressione della malattia.
2.3.2 Metodologia
Nella Figura 15 viene sinteticamente riassunta la metodo-
logia e la procedura di attivazione del Registro di monito-
raggio e dell’adozione della procedura di share scheme.
Risulta evidente che il Registro attraverso la scheda di ar-
ruolamento assicura l’appropriatezza, facendo in modo che
la prescrizione si riferisca esattamente all’indicazione auto-
Figura 15 Metodologia e procedura del Registro di
Monitoraggio
mPFS of KM: tempo di follow-up calcolato sulla mediana della PFS
della curva di Kaplan-Meier nel gruppo di controllo
New
anticancer
drugs
Follow-up
mPFS of KM
control group
Evaluation
of res onse
Entire drug
treat ent
in charge
of
Drug
treat ent
in charge
of Co an
Responders
Non
responders
Pa ent
b results
A ro riateness
Italian LD 2015:Analysis after 2 Ys of monitoring.
If the benefits obtained are lower than those
expected, AIFA must initiate a process of re-
negotiation with MAH, in order to reduce NHS costs

26. 44
Legend: BI: Limit budget impact, CE: Address uncertainties regarding the cost-effectiveness, Use: Monitor use
in clinical practice, Access+CE: Improve patient access and cost-effectiveness. BE: Belgium, CY: Cyprus, CZ:
Czech Republic, EN: England, IT: Italy, LT: Lithuania, MT: Malta, NL: Netherlands, PT: Portugal, SE: Sweden
As shown in
Figure 6.4 the objectives countries are trying to achieve in different disease areas seem to
be distributed across different disease areas proportionally to the number of agreement in
each objective group and the number of agreement per ATC-group. The only objective
which appears to be disproportionately represented among oncological and immune-
modulating treatments is cost-effectiveness. This is not surprising as these types of drugs
0
50
100
150
200
250
IT PT NL LT CZ SE EN BE CY
BI+CE+Use
CE+Use
BI+Use
BI+CE
Use
CE
BI
Managed entry agreements for pharmaceuticals: the
European experience
Alessandra Ferrario and Panos Kanavos

27. 30/03/201612/11/201523/07/2015
http://www.aifa.gov.it/it/content/sovaldiharvoni-attività-di-rimborso-alle-regioni-attuazione-del-meccanismo-prezzovolume
http://www.aifa.gov.it/it/content/sovaldi-harvoni-attività-di-rimborso-alle-regioni-attuazione-del-meccanismo-prezzo-volume
http://www.agenziafarmaco.gov.it/it/content/sovaldiharvoni-attivit%C3%A0-di-rimborso-alle-regioni-attuazione-del-meccanismo-prezzovolume-0
http://www.aifa.gov.it/it/content/farmaci-anti-hcv-raggiunti-scaglioni-stabiliti-da-accordi-prezzovolume-che-consentono-rimbor
Regional allocations of P/V Agreement
by Gilead (≈ 835MM)
27/12/2016

28. NO EU Regulation & Legal framework

29. Indication
MEA should
match the
clinical indication
and should
mitigate
uncertainties
associated with it
Proper Contract
MEA should use
appropriate
parameters and
should be
consensually
accepted by
stakeholders
Organization
Budget holder
should have
dedicated
person or unit in
charge of
contract design
and monitoring
Databases
Budget holder
should have the
necessary
infrastructure for
data collection
and validation
MEAs can only be successful if:
Adopted by David Dankò SEFH Managed Entry Agreements workshop 2016/11/03

30. • Long-term and
comparative effectiveness
• Place in therapy
• Long-term safety profile
Clinical
• Future costs
• Cost-effectiveness
• Measures of QoL
Economic
• Number of eligibles
• Market share
• Treatment duration
Utilisation
• Overall impact on
healthcare budgetFinancial
Even if cost-
effectiveness analysis
did provide a reliable
way forward, there is
still a budgetary
problem to be
considered.
Bach, N Engl J Med 2015
Value-based pricing under Uncertainty
Xoxi E, Agenda item 4 - Real world evidence data collection Italian Experience on Registries, Commission expert
group on "Safe and Timely Access to Medicines for Patients" (STAMP) Brussels, 10 March 2016
https://ec.europa.eu/health/sites/health/files/files/committee/stamp
2016-03_stamp4/4_real_world_evidence_aifa_presentation.pdf

31. Specific MEA for each therapeutic indication (Bach, Jama
2014)‘when costs are essentially the same but benefit differs widely,
Value si not the same’ à crude metric value cost/Y of life gained
Multiple drug-indications:
Discrimination Price
DrugX
(List Price €1,000)
Indication1
PbR
T = 4 months
Indication2
PbR
T = 6 months
Ceiling cap
€ 20mln
Indication3
CS
(20% discount
3 cycles
Same list price,
value-based
cost
Xoxi E, Agenda item 4 - Real world evidence data collection Italian Experience on Registries, Commission expert group on "Safe
and Timely Access to Medicines for Patients" (STAMP) Brussels, 10 March 2016
https://ec.europa.eu/health/sites/health/files/files/committee/stamp
2016-03_stamp4/4_real_world_evidence_aifa_presentation.pdf

32. ① All stakeholders – regulators, HTAbs, payers, healthcare professionals
and patients – live with some uncertainty, and regulatory decisions
routinely take account of the Uncertainty in the evaluation of the
benefits and risks of medicines (*)
② RWE as a complement to RCTs; in particular in the post-authorisation
phase where RCTs might become less feasible and might not be an
appropriate method to address the question of interest (*)
③ From a national payer perspective, registries should accelerate
access of drugs to sub clusters of patients
§ Prevent exclusion of drugs with potential efficacy
§ Early exclusion of drugs with safety issues
④ Generate RWD. Integration of multiple databases may be needed
to increase power in order to study rare exposures or outcomes or
diverse populations (*)
⑤ Contain NHS expenditure optimizing allocation of resources and the
sustainability of the system
Conclusions
(*) Adaptive pathways workshop briefing book Readers’ guidance
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/11/WC500216553.pdf

33. Thank you for the attention
Entela Xoxi
PharmD, PhD, MSci
entelaxoxi@gmail.com
www.linkedin.com/in/entela-xoxi
@exoxi