1. Market Access
Newsletter also applies to regulatory decision making. Regulators have
Editorial instituted in Europe : conditional approval or risk management
plans which could also be seen as a kind of regulatory
conditional approval process; the qualification of a lack of
by Prof. Mondher Toumi efficacy as adverse events, which altogether contribute to shift
EMAUD Chairman the marketing authorization approval from a punctual decision
making process to a lengthy procedure. This shift from
decision point to decision window becomes an increasing a
reality for pharmaceutical companies. An understanding of the
Dear Colleagues & Friends,
needs to close or minimize the uncertainty gap before
approval and market access negotiations has become a critical
At the time of approval for new pharmaceuticals/ issue for the pharmaceutical industry.
technologies, payers usually have to deal with difficult Through these changes, we observe that the tacit share
decisions on whether to cover or not these new technologies. of risk between manufacturers and payers has come to an
De facto, positive and negative decisions are difficult to make end. Indeed, manufacturers used to bear the whole pre-
and a “wait and see” attitude is often taken. The lack of approval risks while payers used to bear post-approval risks.
appropriate information to inform payers’ decision making has Nowadays, the trend is that manufacturers bear all the risks at
often been the main reason for delayed or negative decisions. pre- and post- approval, which leads to an increasing request
Over the years, we could see in many countries the for payers to acknowledge these factors and increase drug
development of conditional coverage schemes usually called prices.
Coverage with Evidence Development (CED). CED allows the Addressing these risks requires manufacturers to
adoption of a careful attitude that grants patients early access develop and optimize the use of appropriate modeling
with all the associated benefits of promising new technology. techniques to support internal decision making. Such expertise
The CED implies that some clear uncertainty has been already exists within the pharmaceutical industry, but is often
identified and a clear study design is able to address the too restricted to target external payers, forgetting internal
aforementioned uncertainty at a reasonable cost and stakeholders.
timeframe. Moreover, the decision under CED is considered as Over the next ten years, companies’ internal decision
potentially reversible without major damages or costs for making capabilities will have to evolve and be able to manage
society. During the CED period, the intervention is covered and product’s uncertainty to feed go/no-go decisions and to
funded by the insurance. However, if it appears to payers that narrow uncertainty at the time of launch.
the resulting evidence does not support the intervention’s It is my pleasure to welcome Prof. Claudio Jommi from
value; the expenses should be reimbursed by the Bocconi University in Milan, who will be discussing about what
manufacturer. Some payers then have developed escrow is going on in Italy after agreements like risk-sharing, payment
agreements to complement the CED. by performance and cost-sharing have taken place, and it may
Sweden has been a leader in implementing CED to be time to draw an outcome and question whether CED will
secure quick access to innovation and appropriate data come on stage soon. Alongside Prof. Jommi, I am also grateful
collection to address the new intervention’s uncertainty. We for having the contribution of Mr. Love Linnér, from TLV in
could see such agreements growing over the next few years, Sweden, who highlights how Sweden has signed up with CED.
and are already being widely adopted in countries like the
Netherlands, and more recently France.
As a matter of consequence, the access of medicines
that used to happen at a distinct point in time, has become a
long term process that now takes place over a window period
of time. This process is not specific to market access but it
©EMAUD. Newsletter #5, June 2012

2. Managed Market Entry for Drugs in
Italy Expert Viewpoint
Prof. Claudio Jommi References
Associate Professor of Management, Fattore G, Jommi C, The last decade of Italian pharmaceutical policy:
Università del Piemonte Orientale and instability or consolidation? Pharmacoeconomics. 2008;26(1):5-15.
Director of Pharmaceutical Observatory, http://www.efpia.eu/content/default.asp?PageID=559&DocID=9239 (last
CERGAS Bocconi – Italy access, June, 22nd, 2012).
Russo P, Mennini FS, Siviero PD, Rasi G. Time to market and patient access
claudio.jommi@unibocconi.it
to new oncology products in Italy: a multistep pathway from European
context to regional health care providers, Ann Oncol. 2010
The most important drivers of pharmaceutical policy Oct;21(10):2081-7.
Garattini L, Casadei G, Risk sharing agreements: what lessons from Italy?
in Italy are the drug budget, a tough price negotiation, Int J Technol Assess Health Care. 2011 Apr;27(2):169-72.
managed market entry contracts, and regionalization. http://antineoplastici.agenziafarmaco.it (last access: June, 22nd, 2012).
A national drug budget became law in 2001 and changed
many times. At present, retail and hospital drugs are the industry takes usually the form of credit note for
respectively subject to a 13.3% and a 2.4% budget hospitals, that can be converted into a cash transfer, if
respectively (of the total health fund). If the retail and agreed with the relevant company. 15 PLRAs have signed for
hospital budget are overrun, the industry/distributors and 14 different products so far (Table below). Many other
regions are required to cover the deficit respectively. The cancer drugs are subject to price-discounts (generally 50% of
rules are changing: (i) hospital budget should increase, but prices) for first therapeutic cycles.
the industry will be asked to cover 30% of the deficit, and (ii) PLRAs have had the great advantage to guarantee
retail budget should be cut. market access at a nominal price consistent with price
Reimbursement and prices are simultaneously negotiated by corridor desired by the industry and to link coverage with
the National Drugs Agency (Aifa) and the industry, response to treatment. The literature has also shown that
considering therapeutic added value (and comparator drugs subject to PLRAs have a faster market penetration than
prices), prices in other countries, the impact on the drug other cancer drugs. In addition, reimbursement is applied
budget, and, in principle, cost-efficacy for the most immediately after treatment failure, whereas coverage with
innovative drugs. The negotiation takes a long time and evidence development through observational studies would
companies rarely consider Italy first for market launch. require that studies are concluded.
Hence, Italy shows an average of 306 days in the delay The main critical issue of PLRAs is that they rely on the
between marketing authorisation and reimbursement. collaboration of professionals into hospitals. Actually, despite
Finally, national approval does not mean immediate hospitals are obliged to enrol patients into registry to get
regional and local access. Regions have been putting many public coverage for drugs, some regions are pushing their
efforts to contain costs because of their responsibility for hospitals to implement PLRAs. This indirectly demonstrates
health care budget. Regional policies include regional binding that the system is not deep-rooted in the whole country.
formularies, public procurement based on the lowest offer Finally the evidence on the impact of PLRAs is very limited so
price, budget constraints at the hospital level, prescription far. In 2007, the Aifa had published a National Report on
targets for GPs and specialists. Cancer Drugs subject to the National Registry including
Despite of this tough environment and regardless the information on non responders, but the Report has never
added value, a product for severe diseases is likely to get the been updated afterwards.
reimbursement status, thanks to managed market entry Should Italy rely on PLRAs also in the future, it would
contracts. Aifa has initially mostly relied on financial be desirable to have (i) their application when the response
contracts (price-volume agreements, general price-discounts, rate to drugs is easy, not costly to detect, and not
price-discounts on first therapeutic cycles and yearly controversial (ii) a re-evaluation of the agreement based on
spending cap per patient). More recently, performance- actual response rate, (iii) and more information on impact of
linked reimbursement agreements (PLRAs) have been signed PLRAs. In addition, coverage with evidence development
for expensive cancer medicines. These contracts provide, for could integrate PLRAs when an uncertainty on the risk-
non-responder patients, an obligation for the industry to benefit profile and costs is very high and can be measured
reimburse 50% or 100% of the price to the hospital. PLRAs only in the long-term.
may be suggested by the companies or Aifa (supported by
the Oncology Sub-Committee) during the negotiation
process. The contracts are confidential and include the name
of the drug, the indication, response criteria, and payback
provisions. PLRAs have relied, at least in principle, on the
National Registry for cancer drugs. A national IT Company
(Cineca) is in charge with managing the Registry. Clinicians
and hospital pharmacists populate the Registry (patients
enrolment, drug request, patient assessment and
reimbursement request for non-responders). The payback by

3. Performance linked reimbursement agreement in Italy on cancer drugs
Molecule Brand Indication Date Payback Timing
Non responders after 3
Expert Viewpoint
Everolimus Afinitor mRCC Jun. 2010 100%
treatment months
mRCC (EGRF+, Non responders after 2
Cetuximab Erbitux
KRAS wild-type)
Jun. 2009 50%
treatment months three or four years, describing the real world outcome
Cetuximab Erbitux
Advanced
squamous HNC
Jun. 2010 100%
Non responders after 2
treatment months
related to one or more of the assumptions made in the
Trastuzumab Herceptin EGJ AC Dec. 2010 50%
Non responders after 2 original cost-effectiveness analysis.
cycles
NSCLC EGFR Non responders after 3
At the time of a conditional reimbursement decision
Gefitinib Iressa May 2010 100%
mut treatment months there is no clearly stated accepted level of the variable that is
Non responders after 2
Vinflunine Javlor UCC Dec. 2010 100%
cycles
to be studied by the company, but the findings from the
Mozobil Plenixafor
Stem cell
Dec. 2011 100%
Refund Treatment (if study are to be compared to the assumptions made in the
mobilization CD34+ > 2 x106/Kg)
Non responders after 2
application. If the real world evidence deviates from the
Sorafenib Nexavar HCC Jun. 2008 100%
treatment months original assumptions, TLV may choose to re-evaluate the
Non responders after 1
Dasatinib Sprycel CML / ALL May 2007 100%
treatment month reimbursement status of the product in question.
CML
Non responders after 1
Nilotinib Tasigna Philadelphia Aug. 2008 100%
chromosome+
treatment month During the past year, TLV has evaluated follow-up
Temsirolimus Torisel mRCC Oct. 2008 100%
Non responders after 2
treatment months
reports for a number of products with conditional
Lapatinib Tyverb mBC May 2009 100%
Non responders after 3 reimbursement and established a process for how the
cycles (6 months)
mRCC (EGRF+, Non responders after 2
outcome of the evaluation guides further decisions for the
Panitumumab Vectibix Jan. 2009 50%
KRAS wild-type) treatment months product:
Non responders after
Votrient Pazopanib RCC May 2011 100%
24 treatment weeks
Non responders after 2 • TLVs’ evaluations of the reports for Risperdal Consta
Trabectedina Yondelis ASTS Jan. 2009 100%
cycles
(risperidone i.m.), Lucentis (ranibizumab) and Champix
Acronyms (varenicline) resulted in no further actions by the agency
ALL Acute Lymphoblastic Leukemia since the assumptions made in the original applications
ASTS Advanced Soft Tissue Sarcoma for reimbursement, and that was studied, appeared to be
CML Chronic Mieloid Leukemia valid.
EGFR mut Epidermal Growth Factor Receptor - activating
mutations
EGJ AC Early esophago-Gastric Junction AdenoCarcinoma • Cymbalta (duloxetine) is a product among many with
HCC HepatoCellular Carcinoma limited reimbursement in Sweden, i.e. only a subset of
HNC Head and Neck Carcinoma the patients included in the full indication for the product
mBC metastatic Breast Cancer should have it prescribed with reimbursement. The
mRCC metastatic Renal Cell Carcinoma
NSCLC Non-Small-Cell Lung Cancer follow-up report for Cymbalta indicated that prescribers
UCC Urothelial Carcinoma (transitional cell carcinoma) in Sweden in some instances prescribe the product with
reimbursement to patients not included in the limitation
set by TLV. The report was based on data from the
Recent development for CED in Swedish Prescribed Drug Register which was analyzed in a
Sweden joint effort by TLV and the company. The price of the
product was later changed by the company to
compensate for the limitations in quality of prescribing.
The report for Replens (water-based gel), also a product
Mr. Love Linnér, PhD
with limited reimbursement, was later analyzed via a
Coordinator observational studies
The Dental and Pharmaceutical
similar methodology and the price was also corrected
Benefits Agency, Sweden based on data from the Prescribed Drug Register.
love.linner@tlv.se
• TLVs’ evaluations of the reports for Firazyr (icatibant)
and Berinert (human C1 esterase inhibitor) resulted in a
The Dental and Pharmaceutical Benefits Agency, TLV, recommendation to re-evaluate the pricing of products
is a central government agency whose remit is to determine used for the treatment of hereditary angioedema.
whether a pharmaceutical product shall be subsidized by the
state. The reimbursement of a product may in some
instances be coupled to product specific restrictions, e.g.
second line usage only, or other special conditions such as
requirements for the company to report outcomes from
follow-up studies.
Conditional reimbursement based on further evidence
development (CED) has been included in a limited share of
the reimbursement decisions made by the TLV since 2003. A
company whose product is subject to a conditional
reimbursement is normally to report a follow up study within

4. Are you looking for an insightful
course in Market Access?
EMAUD News
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The programme that follows each step of the life cycle
of a drug, integrating market access theory and
practice for results to be applied in the real world.
Students will acquire the necessary skills to develop
and implement a market access plan.
Candidates,
registration open until 30 September!
Market Access Day IV
11 December 2012, CIU Paris
Students Corner
Contributions and debates will take place around the theme:
“From point decision to window decision”
In more and more countries, pricing and
reimbursement decisions are no longer taken at a fixed time
point, but over a period of time during which pharmaceutical
companies are expected to provide additional information to
reduce any uncertainty around the value of a new product.
Recently, regulators have been dealing with three main facts:
conditional approvals; the lack of efficacy now considered as
an adverse event, and as such should be reported to by
prescribers; risk management plans that have been instituted
to track the lack of efficacy as one of the potential adverse
Prof. Toumi & the Students of Class 2011-2012 events. The first two being recent in the EU compared to the
May 2012, Module 5 USA.
Therefore, there has been a move from a decision
In 2011-2012, 60 students attended the session: point for regulatory approval, pricing and market access
• 36 students from the industry, decisions, towards a timeframe that has turned into a
• 13 students from public institutions, decision window. This allows regulators and payers to
• 11 students from consulting and other, minimize the risk associated with the introduction of a new
•18 countries were represented, mostly European product. This is also contributing to the increased dialogue
countries, and also Brazil, Canada, China, Russia and the between regulators and payers.
USA. In 2012, the Annual Market Access Day will review
the impact of the change of paradigm on patient access,
payers new practice, and will review the evolution of
Students: Connect on Linkedin! companies to fit a new changing environment.
The EMAUD Alumni group is intended as a debating and
networking platform for the students and contributors of our Join us for living and inspiring discussions!
educational programme. Be aware of latest news, articles,
regulations etc. via our discussions and connections.
EMAUD Contact
Prof. M. Toumi, Chair
mondher.toumi@univ-lyon1.fr
Mrs. O. Barthez, Programme Coordinator & Communications Manager
odile.barthez@emaud.org
Mrs. F. Guetatlia, Administrative support
farida.guetatlia@emaud.org
www.emaud.org