Reconciling uncertainty of costs and outcomes with the need for access to orphan medicinal products

15 Pages·2014·1.18 MB·English

Moreletal.OrphanetJournalofRareDiseases2013,8:198
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RESEARCH Open Access
Reconciling uncertainty of costs and outcomes
with the need for access to orphan medicinal
products: a comparative study of managed entry
agreements across seven European countries
Thomas Morel1*, Francis Arickx2, Gustaf Befrits3, Paolo Siviero4, Caroline van der Meijden5, Entela Xoxi4
and Steven Simoens1
Abstract
Background: National payers across Europe have been increasingly looking intoinnovative reimbursement
approaches –called managed entry agreements(MEAs) –to balance theneed to provide rapid access to
potentially beneficial orphan medicinalproducts (OMPs) with the requirements to circumscribe uncertainty,obtain
best value for money or to ensure affordability. This study aimed to identify, describe and classify MEAs applied to
OMPs by national payers and to analyse their practice in Europe.
Methods: To identify and describe MEAs, national health technologyassessmentsand reimbursement decisions on
OMPs across seven European countries were reviewed and their main characteristics extracted. Tofill data gaps and
validate the accuracy of theextraction, collaboration was sought from national payers. Toclassify MEAs, a bespoke
taxonomy was implemented. Identified MEAs were analysed and comparedby focusing on five key themes, namely
bydescribing the MEAs in relation to: drug targetsand therapeutic classes, geographical spread, type of MEA
applied, declaredrationale for setting-up of MEAs, and evolution over time.
Results: 42 MEAs for 26 OMPs,implemented between 2006 and 2012 and representing a variety of MEA designs,
were identified. Italy was thecountry with the highest number ofschemes (n=15), followed by theNetherlands
(n=10), England and Wales (n=8), Sweden(n=5) and Belgium (n=4). No MEA was identifiedfor France and Germany
due to data unavailability. Antineoplastic agents were theprimary targets of MEAs. 55% ofthe identified MEAs were
performance-based risk-sharing arrangements; the other 45% were financial-based. Nine of these26 OMPs were
subject to MEAs intwo or threedifferent countries, resulting in24 MEAs. 60% of identified MEAs focused on
conditions whose prevalenceis less than 1 per10,000.
Conclusions: This study confirmed that a variety of MEAs were increasingly used by Europeanpayers to manage
aspects of uncertainty associated withtheintroduction ofOMPs inthe healthcare system, and which may be of a
clinical, utilisation, or budgetary nature. It remains unclear whether differences inthe use ofMEAs reflect differences
inhow ‘uncertainty’and ‘value’ are perceived across healthcare systems.
Keywords: Managed entry agreements,Orphan drugs, Orphan medicinal products, Access, Reimbursement,
Risk sharing, Uncertainty, Health technology assessment, Payers, Pricing, Performance
*Correspondence:[email protected]
1KULeuvenDepartmentofPharmaceuticalandPharmacologicalSciences,
O&N2bus521,Herestraat49,Leuven,Belgium
Fulllistofauthorinformationisavailableattheendofthearticle
©2013Moreletal.;licenseeBioMedCentralLtd.ThisisanopenaccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.
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Background reimbursement agreements and have been studied ex-
As a new orphan medicinal product (OMP) receives tensively, with the subsequent development of a number
European marketing authorisation across the European of taxonomies [18-24]. The HTAi Policy Forum grouped
Union (EU), national health technology assessment these many terms under the terminology of ‘managed
(HTA) bodies and national healthcare payers subse- entry agreements’ (MEAs), defined as “an arrangement
quently determine its value to inform or decide reim- between a [pharmaceutical] manufacturer and payer/
bursement. This is usually not a straightforward exercise provider that enables access to (coverage or reimburse-
as there is often considerable uncertainty about the ment of) a health technology subject to specific condi-
ultimate real-world clinical and economic performance tions. These arrangements can use a variety of
ofthatnewOMP. mechanisms to address uncertainty about the perfor-
Oftenasaresultoftheinherentnatureofrarediseases mance of technologies or to manage the adoption of tech-
(i.e. life-threatening or chronically debilitating diseases nologies in order to maximise their effective use, or limit
with aprevalenceof5out of10,000 orless) [1], the clin- their budget impact” [21]. In other words, MEAs may
ical evidence package on OMPs that is submitted to na- take a variety of forms depending on the nature of the
tional healthcare payers in the context ofreimbursement concerns they are addressing, namely: managing budget
applications tends to be limited relative to drugs for impact; managing uncertainty relating to clinical and/or
common diseases [2-7]. Their clinical evidence package cost-effectiveness; or managing utilisation to optimise
is often associated with uncertainty at product launch performance.
due to the difficulty of recruiting a sufficient number of The present study, focusing on seven European coun-
patients (as a result, reaching statistically significant re- tries, had three main objectives, namely to: (i) examine
sults may be challenging), patient population is often the processes through which MEAs are implemented by
heterogeneous, many trials of approved OMPs are only national healthcare payers, (ii) identify, describe and
based on surrogate endpoints (e.g. time to progression, classify MEAs applied to OMPs by national healthcare
response rate or progression free survival), traditional payers, and (iii) analyse and compare identified MEAs
study designs are sometimes not feasible (e.g. rando- relatedtoOMPswithin andbetween countries.
mization and inclusion of control arms may be uneth-
ical), and the assessment of the observed clinical Methods & taxonomy
improvement may be difficult as little is usually known The following European countries were included in this
about thenatural historyofthedisease. analysis: Belgium, England and Wales, France, Germany,
Moreover, many OMPs are associated with relatively Italy, the Netherlands and Sweden. These countries,
high treatment costs [8-14], which adds to the budgetary spread across the northern and southern parts of the EU
uncertainty dimension and/or to the financial risk to the and characterised by different healthcare financing
payer in the event the treatment does not work in real methods, are usually considered as priority market tar-
life as well as anticipated. In contrast to industry- gets for new drug launches. They were selected to en-
sponsored predictions stating that the rate of budget sure representation of key healthcare markets in Europe.
impact of OMPs is expected to grow slowly from 2010 The inclusion of these countries in the study aimed to
to 2016, at which time it is expected to plateau at maximise the opportunity to capture a broad and repre-
approximately 4.6% of total pharmaceutical market sentative range of MEAs for OMPs. Together, these
expenditure [15], a recent study across the main five EU countries represent approximately 60% of the rare dis-
countries suggests that OMP expenditure and utilisation easepopulationintheEU.
are rapidly growing, particularly for some ATC groups,
such asantineoplasticdrugs.Findings show thatinthose Methods
countries both expenditure and utilisation increased in The first study objective was addressed by exploring
the year 2010 compared to 2009, ranging from 13 to relevant national healthcare payers’ websites and reposi-
28%and7to17%respectively [16]. tories of national legal documents. Statutes establishing
Against that background of ambient uncertainty, na- nationalpayer bodiesanddocumentsdescribingnational
tional healthcare payers have been increasingly looking MEA processes of health technologies were searched,
into innovative reimbursement approaches to balance with particular emphasis to identify specific references
the need to provide rapid access to potentially beneficial to orphan technologies. Where possible, searches were
health technologies to patients with the requirements to conducted in local language (Dutch, English, French,
obtain best value for money and to ensure affordability German and Italian) to increase accuracy and compre-
[17]. These innovative reimbursement mechanisms have hensiveness of the extraction. This approach, which
been referred to by a variety of names, such as risk sha- focusedonretrievinginformationfromsourcedocuments,
ring, patient access schemes, or performance-based was preferred to exclusive reliance on summarised
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statements about MEA practices in the literature. In MEAs possible within a national pricing and reimburse-
addition,validationoftheidentifiedprocessflowsandpo- ment framework [20]. However, the chosen taxonomy
licy or legal references wassoughtfrom representativesof was further adapted to fit the research objective and an
nationalhealthcarepayers. arm related to financial-based arrangements was speci-
To identify, describe and classify MEAs applied to fiedasthelatter were outofscope ofthe ISPOR work.
OMPs, three steps were implemented. Firstly, to identify Identified MEAs related to OMPs captured in the
relevant MEAs, HTA appraisals and reimbursement de- dataset were then analysed and compared by focusing
cisions from national bodies across seven European on five key themes, namely by describing the MEAs in
countries were reviewed as well as congresses (e.g. Inter- relation to: drug targets and therapeutic classes, geo-
national Society for Pharmacoeconomics and Outcomes graphical spread, type of MEA applied, declared ration-
Research (ISPOR), Drug Information Association (DIA)) ale for setting-up of MEAs, and evolution over time.
andpayerbodies’annualreports.Allsourcesmentioning Data were structured in Excel format to allow for de-
MEAs related to OMPs between 2006 and 2012 were scription of trends, similarities and differences according
kept. Search was conducted in multiple languages, as to the themes mentioned above in the total sample or
above. Secondly, to describe MEAs, a data extraction stratifiedbycountry.
sheet was developed to capture the evidence needed for
analysis. A data extraction protocol was followed to in- Results
crease homogeneity of the extraction. MEAs were char- Taxonomy
acterised in terms of the country involved, compound (i. The taxonomy used in our study distinguishes between
e. name, marketing authorisation date, indication, preva- MEAsthatmeasurehealthoutcomesincharacterisingper-
lence, therapeutic subgroup (ATC levels 1 and 2)), date formance (i.e. performance-based risk-sharing schemes)
and outcome of the HTA appraisal or reimbursement and those that do not consider outcomes but focus on
decision, rationale for setting up a MEA, scheme details keeping expenditure within agreed limits (i.e. financial-
(i.e. main objectives and mechanisms, start date, end- basedarrangements)(Figure1).
points used, data on possible registry). Websites of orga- Performance-based risk-sharing schemes can be broken
nisations such as the European Medicines Agency down into two categories: (a) ‘performance-linked re-
(EMA) or Orphanet and of clinical trials registers such imbursement’ schemes that aim to manage utilisation
as clinicaltrials.gov were also used extensively to ascer- and guarantee the cost-effectiveness of a new health
tain the clinical evidence package of individual OMPs. technology in the real-world by linking performance
The extraction was performed by a single researcher at the individual patient level to payment or reim-
(TM). To complement this desk research, fill in the data bursement of a new technology; and (b) ‘coverage with
gaps and validate the accuracy of the extraction, formal evidence development’, where coverage decision is condi-
collaboration was sought from a selection of national tioned upon the collection of additional population-level
payers, HTA bodies and insurers to organise structured evidence. Within ‘performance-linked reimbursement’,
interviews and request access to MEA-related databases. while some schemes may relate payment to ‘process of
Collaboration requests were sent out to the following care’ (i.e. payment is directed towards those patients that
entities: the National Institute for Health and Disability satisfy eligibility criteria for a treatment, for example as a
Insurance (INAMI/RIZIV, Belgium), the Healthcare result of a genetic test),some otherschemes focus on ex-
Products Pricing Committee (CEPS, France), the Insti- post reimbursement, measuring intermediate or clinical
tute for Quality and Efficiency in Health Care (IQWiG, endpoints. The latter include: ‘outcomes guarantees’ (i.e.
Germany), the National Association of Statutory Health payment for responders only), ‘money-back guarantees’
Insurance Funds (GKV, Germany), the Italian Medicines (i.e. refund for non-responders or patients having dis-
Agency (AIFA, Italy), the Health Care Insurance Board continued), and ‘conditional treatment continuation’
(CVZ, the Netherlands), the Netherlands Organisation (i.e. payment for continued use of the medicine for
for Health Research and Development (ZonMw, the those patients reaching a pre-defined intermediate treat-
Netherlands), the Dental and Pharmaceutical Benefits ment milestone). ‘Coverage with evidence development’
Agency (TLV, Sweden), and the National Institute for (CED) can be further broken down into schemes that are
Health and Clinical Excellence (NICE, England & ‘onlyinresearch’(i.e.coverageisconditionedonindividual
Wales). Thirdly, to classify MEAs related to OMPs, a lit- participation in research), and CED schemes ‘only with
erature review of existing taxonomies was performed. research’ where all new patients may be treated using the
The taxonomy developed by the ISPOR task force on newtechnology.
performance-based risk-sharing arrangements was se- Financial-based arrangements, the second type of
lected, being the most recently developed and compre- MEAs described in our taxonomy, aim to address con-
hensive in capturing the various types and subtypes of cerns over the budgetary impact associated with the
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Figure1Ataxonomyofmanagedentryagreements(MEAs).
introduction of a new health technology. They may ei- drug but set an annual sales cap for all the drugs used to
ther adopt a patient- or a population-level perspective. treataparticulartherapeuticindication,leadingtorebates
The first category includes: ‘cost capping’ (i.e. the max- foranyexcessaccordingtoeachsponsor’smarketshare.
imum cumulative cost of treatment per patient is speci-
fied [for a period of time] and beyond this threshold, the Managedentryagreements
pharmaceutical manufacturer provides its drug at a dis- References to national MEA processes and policy frame-
count or free of charge), ‘utilisation capping’ (i.e. the works were retrieved for all seven countries in scope of
total number of doses or cycles of treatment is agreed analysis. A total of 42 MEAs specific to 26 OMPs, im-
on. Any excess beyond this limit is penalised financially) plemented between 2006 and 2012 across five European
and ‘free or discounted treatment initiation’ (i.e. therapy countries and representing a variety of MEA designs,
is free or discounted up to a specified number of doses were identified and reviewed. Details of these 42 MEAs
or treatment cycles). Population-level financial-based ar- are fully outlined in Additional file 1: Table S1 and de-
rangements include: ‘discounts’ (i.e. therapy is provided scribedandanalysedbelow.
by the pharmaceutical manufacturer at a reduced cost to Data from national health authorities on MEAs estab-
the National Health Service for all eligible patients) and lished in France and Germany were, unfortunately, un-
‘price-volume agreements’ that may come with caps or available. Neither the German GKV nor the French
not. In price-volume agreements ‘without cap’, the unit Healthcare Products Pricing Committee and Ministry of
price of a drug is linked to the expected volume sold Health responded favourably to our request of research
(negotiated at product launch), so that it declines when collaboration, on grounds of confidentiality. As a result,
volume increases. Price-volume agreements ‘with cap’ only data resulting from desk research of published data
stipulate the volume that may be sold, based on forecast are reported here for France and Germany, which is
sales. If the sales volume or budget is exceeded, the likely to under-estimate the true incidence of MEAs
pharmaceutical manufacturer is penalised, usually by relatedtoOMPsinthese countries.
having the price of the drug reduced (i.e. discount) or by
having to pay-back (i.e. rebate) the amount of sales Belgium
above the agreed levels. There are a variety of possible MEAprocess
payback clauses. Of note, price-volume agreements may In2010,Belgianlawwasamendedtointroducethepossibil-
take complex forms. For instance, a complex price- ity to negotiateMEAs forClass I drugs(i.e. pharmaceutical
volume agreement ‘with cap’ may not be specific to a products for which there is a claim for added therapeutic
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value)forwhichtherewasanegativemotionforreimburse- related to future budget impact and high treatment cost
ment or no motion from the Drug Reimbursement Com- were the main drivers for setting up these MEAs. All
mittee within the National Institute for Health and four contracts were financial-based arrangements and
Disability Insurance (NIHDI). Contract negotiation is moti- foresaw a re-evaluation of the drug reimbursement sta-
vated by an excessive reimbursement basis claimed by the tus after three years. Albeit financially-based, these
applicant with regard to the considered/recognized thera- schemes also included a secondary outcomes-based per-
peutic or social added-value or by uncertainties related to spective, as they required the submission of Phase IV
thedrugbudgetimpact[25,26].Itisuptothemanufacturer outcomes data at the time of re-evaluation. Two of these
toinformtheMinisterforSocialAffairsandHealthoftheir schemes applied an original type of price-volume agree-
readiness to negotiate an MEA. Procedure involves a 120 ment, which modulates incrementally the amount of
days clock-stop period during which the text of the agree- pay-back as the actual turnover increases and exceeds
mentisnegotiatedbyataskforcecomposedoftheapplicant, the budget cap pre-agreed with NIHDI (Figure 2). For
insurancebodies,representativesfromtheMinistriesforSo- instance, it may be agreed between the pharmaceutical
cial Affairs and Budget, and a member of the Belgian manufacturer and NIHDI that the former pays back 10%
pharmaceuticalassociation.AnMEAisonlysignedbetween of the sales as the real turnover gets to 75% of the fore-
NIHDI and the applicant once the two Ministers involved cast budget, 20% once the 90% level is reached, 40% as
consentand subsequentlyresultsinthetemporaryenlisting turnover equals forecast budget, 60% as 150% of the
of the drug, for a maximum of three years. Drug perform- forecast budget is reached etc. Through this pricing
ance and budgetary impact is assessed over this period of framework, NIHDI accepts to increase its willingness-
time in view of later re-evaluation. Article 83 of the to-pay if it appears that a larger patient population than
amended Royal Decree of 21 December 2001 stresses that expected can be treated and that the level of unmet
MEAs must include some key mechanisms of action medical need is equally larger. That being said, this
such as price-volume agreements with pay-back scheme also allows NIHDI to check that the greater
clauses, cross deals, or reductions of the reimburse- drug salesdonot result fromoff-labeluse.
mentlevel.InDecember2012,aftertwoyearsofimplementa- The third MEA stipulated a patient cost cap arrange-
tionofthenewBelgianpolicy,22MEAshadbeennegotiated ment that ensured that all first-line therapies in the indi-
in the context of reimbursement applications by NIHDI. cation of newly diagnosed Philadelphia-chromosome-
positive chronic myelogenous leukaemia were priced on
IdentifiedMEAsspecifictoorphanmedicinalproducts a par through a refund mechanism. The fourth MEA
Between 2010 and 2012, four MEAs related to OMPs foresees the application of a discount, coupled with a
were negotiatedwiththeBelgianauthorities. Uncertainty price-volumeagreement.
Figure2Exampleofaprice-volumeagreement‘withcap’establishedbyNIHDI.
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England&Wales each indication. Of note, one performance-basedscheme
MEAprocess (and specifically a money-back guarantee) once applied
In 2009, and further to prior developments for drugs in- to an OMP: sorafenib, for the treatment of advanced
dicated for multiple sclerosis and multiple myeloma hepatocellular carcinoma. This scheme was discontinued
[27-29], the Pharmaceutical Price Regulation Scheme inMay2010after rejectionbyNICE[33].
(PPRS) [30] formally introduced patient access schemes
(PAS)asawaytoimproveaccesstoinnovativetreatments Italy
whoseincrementalcost-effectivenessratiowasinitiallytoo MEAprocess
hightomeettherequirementsfromtheNationalInstitute Since 2006 [34], the Italian Medicines Agency (AIFA)
for Health and Clinical Excellence (NICE) to be recom- has entered into a wide range of MEAs whenever any
mended for use. Patient access scheme proposals are newly launched medicine presents some uncertainty
therefore made in the context of a NICE technology ap- over its clinical value/effectiveness, budget impact, or
praisal with the specific purpose of improving the cost- potentialinappropriateuse.
effectiveness of a drug to avoid non-recommendation by Management of uncertainty related to clinical benefit and
NICE. Proposals for a PAS are left to the initiative of the effectivenessisdonethroughtheuseofmonitoringregistries
pharmaceutical company. PAS proposals may be intro- aimedatcollectingdataondrugprescription,administration
duced either at the time of initial submission to NICE or andeffectiveness.TheAIFAmonitoringregistriesareonline
at the endof the appraisal process, once any appeals have toolsthatorganisetheexchangeofdataregardingtheappro-
been heard and NICE’s final guidance has been issued to priate use of medicines according to their approved indica-
theNHS.Onceproposed,PASarereferredbytheDepart- tions between the regulators, dispensing pharmacists,
ment of Health to the Patient Access Schemes Liaison prescribing clinicians, manufacturers and Italian regions.
Unit (PASLU) within NICE who then advises whether the Registries track the eligibility of patients (i.e. diagnosis and
scheme is feasible for implementation in the NHS in patientcharacteristics)andthecompletetreatmentflow(i.e.
England and Wales in light of a set of key principles. drug dosage and administration, evaluation of treatment re-
According to the latter, schemes must be operationally sponders,treatmentfailure/endoftreatment,tolerabilityand
manageable, clinically robust and plausible, and without reported adverse events) [35]. Today, the AIFA monitoring
unduly complex monitoring or disproportionate admi- registries cover some 80 therapeutic indications across over
nistrative burden. The Department of Health and the 60medicinesandapproximately450,000patients.
Association of the British Pharmaceutical Industry have In a move to further circumscribe possible uncertainty
agreed on a bespoke typology for PAS. Importantly, onclinicaleffectiveness(andanyriskofsuperfluousexpen-
PAS should be the exception rather than the rule, the ditures for the NHS) AIFA made sure that these monito-
PPRS insists, and particularly outcomes-based schemes. ring registries may also be coupled, if necessary, with
And priority is likely to be given to schemes that deliver performance-based reimbursement schemes, named by
the greatest benefits to patients, for example in enabling AIFA as ‘Payment by results’ and ‘Risk sharing’ schemes.
the NHS to address a previously unmet need. Bothtypesofschemesevaluatetherateoftreatment ‘non-
responders’. For every non-responder, the drug manufac-
IdentifiedMEAsspecifictoorphanmedicinalproducts turer is either expected to grant a discount to the cost of
In December 2012, there were 33 national-level PAS in initial treatment cycles (risk-sharing) or to refund the full
the NHS, of which eight focused on seven OMPs (i.e. costoftherapy(paymentbyresults).Throughtheseagree-
24% of total) [31]. Six of these eight PAS were directed ments, AIFA and the NHS effectivelyshiftpart of the cost
to antineoplastic and immunomodulating agents. All of of evaluating new medicines in clinical practice to their
these PAS were financial-based schemes according to manufacturers.
our taxonomy, and included a mix of patient- and Furthermore, uncertainty around a drug budgetary im-
population-level arrangements, namely: five discount pact may be mitigated by financial-based schemes, in-
schemes, one patient cost cap, and two patient utilisa- cluding ‘price-volume agreements’ and ‘cost-sharing
tion cap schemes. The predominance of discount agreements’ (i.e. a discount applied to the initial cyclesof
schemes reflects the general trend observed across the therapy for all eligible patients). Lastly, to manage util-
33 national-level PAS in place – this type of scheme is isation uncertainty, AIFA may apply ‘Restricting notes for
the easiest to implement and was promoted through the prescription’ whereby it restricts reimbursement to spe-
development of an accelerated process for simple dis- cificpatientpopulations,or ‘Therapeuticplans’thatcon-
count PAS [32]. As laid out in the PPRS, all of these ditions reimbursement to the drug prescription by
PAS were set up to improve the cost-effectiveness of specialisedhealthcare centres.
these new OMPs to enable recommendation by NICE. In early 2013, across all therapeutic indications, 26
Schemes covered the totality of the target population of performance-based schemes existed (i.e. 24 ‘payment by
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results’and 2 ‘risk sharing’), in parallel to over one hun- OMPs1, however, only the continuous monitoring of
dred financial-based schemes (i.e. 20 ‘cost sharing’ and their prescription applies – they are not subject to any
85 ‘price volume agreements’) (Figure 3). No specificlaw type of performance- or financial-based arrangement.
regulates the process of decision-making on MEAs; ra- Most of them are covered by the national monitoring
ther, they are part of the AIFA pricing and reimburse- registry of OMPs (‘Registro nazionale farmaci orfani’),
ment negotiation with the drug manufacturer and are which includes a broader range of pharmacotherapeutic
decidedonacase-by-casebasis. groups, such as anti-haemorrhagic or alimentary tract
andmetabolismproducts.
IdentifiedMEAsspecifictoorphanmedicinalproducts
In December 2012, we listed 15 MEAs applied to 10 TheNetherlands
OMPs–allantineoplasticorimmunomodulatingagents. MEAprocess
Of these 15 MEAs, according to our taxonomy, eight In 2006, the Dutch government introduced a ‘coverage
were ‘performance-based schemes’ whereby non-response with evidence development’system, whereby drugs were
totreatment is sanctioned by a money-back guarantee; initially only temporarily admitted on the expensive or
and seven other MEAs were financial-based (either orphan medicine list of the Dutch Healthcare Authority
‘discounted treatment initiation’ or ‘discount’). Sorafe- (NZa). The policy regulations on expensive and or-
nib, nilotinib and temsirolimus were each subject to phan medicines (‘Beleidsregel dure geneesmiddelen’ and
both categories of MEAs, according to the indication ‘Beleidsregel Weesgeneesmiddelen’) foresaw the possibility
involved. Within the context of ‘performance-based of national subsidies to hospitals to help them finance
schemes’, non-responders are usually identified within their care services and ensure patient access to therapies.
a timeframe of 4 to 8 weeks. Of note, in 2012, the Hospitals received additional funding of 80% of the costs
performance-based scheme applied to dasatinib was of these drugs (100% for OMPs). In return, applicants
replacedbyafinancial-basedarrangement(i.e.discounted were required to conduct outcomes research studies to
treatment initiation). The reported objectives of all generate evidence on appropriate drug use and effective-
these MEAs are to verify and control the appropriate- ness in daily practice and real-world cost-effectiveness
ness of the prescription, and to circumscribe the level [36,37]. A yearly budget impact greater than €0.6 million
of uncertainty around the drug. AIFA’s ‘payment by per hospital was the main criterion to justify the in-
result schemes’ (i.e. ‘money-back guarantee’ schemes clusion of a new OMP into the scheme. After four years,
according to our taxonomy) typically suggest a higher a(re)assessmentbytheDutchHealthcareInsuranceBoard
level of uncertainty. (CVZ) had to take place to advise on the possibility to
Evidently, all of these 10 OMPs have a monitoring continuethenationalsubsidiestohospitalsornot.
registry linked to them (‘Registro farmaci oncologici sot- In January 2012 the reimbursement of inpatient drugs
toposti a monitoraggio AIFA’). For some other nine changed, thereby putting an end to the two policy
Figure3NumberofMEAssetupbyAIFA,describedbyMEAdesign(accordingtoAIFA’sterminology).Note:Asinglemedicinemaybe
subjecttoseveralofthesemechanismsatthesametime.Thisgraphdoesnotshowdetailsforprice-volumeagreementsandrestrictingnotesas
thesearrangementsarenotapplicabletoorphanmedicinalproducts.Source:AIFA,2013.
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regulations on expensive and orphan medicines. Medi- million per QALY for treatment with agalsidase alfa or
cines in hospital settings with annualcosts per patient of beta and €15 million per QALYfor treatment with alglu-
€10,000 or more are now reimbursed via ‘add-on’ fund- cosidase alfa for non-classical Pompe disease. Both
ing, whereby physicians of university hospitals are enti- ICERs were determined in comparison to standard-of-
tled to claim ‘add-on’ drug expenses totreat specificrare care treatments. Once the assessment reports were
diseases. Conditional and temporary entry with the re- established, the appraisal process was initiated. In June
quirement to conduct outcomes research, however, has 2012, CVZ confidentially sent out draft appraisal reports
been maintained and even strengthened [38]. It now ap- to key stakeholders. In this concept advice CVZ pro-
plies across allinpatient drugs that haveabudgetimpact posed that the proof for effectiveness was too limited to
of €2.5 million or more and for which the estimates for justify the high drug costs. These draft reports leaked to
(cost) effectiveness are assessed by CVZ as being sur- the press, which led to a public outcry across the
roundedbyanunacceptablelevelofuncertainty. Netherlands and the rare disease community [42-44]. In
the appraisal committee meeting interested parties were
IdentifiedMEAsspecifictoorphanmedicinalproducts invited to express their viewpoints on the reports, and
In 2012, some 23 medicines (across 32 therapeutic indi- these weretaken into account inthe adviceto the Dutch
cations)and11OMPswereincludedintheDutchpolicy Ministry of Health. Subsequent debate has led to ques-
regulation on expensive medicines and policy regulation tioning both the ethical dimension of decisions to with-
on orphan medicines respectively [39]. Details of ten out draw reimbursement in areas of high unmet needs and
of these eleven coverage with evidence development the relevance of outcomes research studies in patients
(CED) schemes are available in Additional file 1: Table affected by rare conditions that are limited to the
S1 (NB: the CED scheme applied to canakinumab was boundaries of a single country such as the Netherlands.
not analysed as it is no longer an OMP). All ten MEAs Paucity of data resulting from the low number of pa-
can be categorised as CED schemes ‘only with research’ tients may make it difficult to reach indisputable scien-
accordingtoourtaxonomy, meaningthatpositive cover- tific conclusions [45]. However, the reassessment was
age decision is conditional upon the collection of add- not limited to outcome research as the results from out-
itional evidence across all identified patients – usually come research were assessed alongside relevant pub-
over a four-year period – to support continuation or lished (randomized) clinical trials. The assessment
withdrawal of coverage. Half of them were targeted to- conclusions, therefore, were based on all relevant evi-
wards enzyme replacement therapies; the other half in- dence regarding effectiveness, cost-effectiveness, and ap-
volved antineoplastic and immunomodulating drugs. In propriate use available. At time of writing, continued
addition to the criterion related to the €0.6 million coverage of these OMPs was being negotiated between
budgetarythreshold,theneedofadditionallong-termef- the Dutch government and the respective pharmaceu-
fectiveness data usually drives the decision for setting up tical manufacturers, whereby price reductions were
the outcomes research schemes. As illustrated in Add- sought after [46].
itional file 1: Table S1, the requirements in terms of
study design and outcomes are usually extensive and Sweden
prescriptive, encompassing clinical, quality of life, re- MEAprocess
source use, and cost data. Sometimes, data from inter- In October 2002 the Swedish ‘Act on Pharmaceutical
national registries or studies (e.g. the International Benefits’ [47] came into effect and the Dental and
Hunter Outcome Survey) is used in combination to Pharmaceutical Benefits Agency (TLV) subsequently
Dutch data. Cost-effectiveness analysis is usually derived started its role as Sweden’s independent agency respon-
from theseoutcomesresearch studiestoinformonvalue sible for reimbursement and pricing decisions of new
formoney. medicines2. Until recently3, TLV’s remit was limited to
At the end of 2012, three OMPs had gone through the prescription drugs. The three primary criteria that TLV
(re-)assessment and appraisal process at CVZ, namely appliesinmakingdecisionsare:equity,needandsolidar-
alglucosidase alfa for Pompe disease and agalsidase alfa ity and cost-effectiveness. There is no specific policy for
and agalsidase beta for Fabry disease. Study results for OMPs in reimbursement decisions, which means that
non-classicalPompediseaseindicatedthatonoverallpa- any manufacturer of a new OMP must comply with the
tient group level efficacy was limited and that responder same requirement as any other medicine. However, in
thresholds had not been reached [40,41]. Overall, the as- addition to a more lenient stance on the level of submit-
sessment committee determined that, on average, these ted evidence for OMPs compared to that for non-
OMPs had limited therapeutic added-value for the ma- orphans and the acceptance of higher cost per quality-
jority of patients. Moreover, limited therapeutic value adjusted life years ratios in some instances [48,49], TLV
was contrasted with high costs, leading to ICERs of €3 also agreed on setting up a number of CED schemes
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whereby temporary reimbursement is granted in return IdentifiedMEAsspecifictoorphanmedicinalproducts
for the collection of additional real-life data by the In 2008, as a steady increase in the sales of OMPs was
manufacturer to reduce the level of uncertainty sur- observed, CEPS “questioned the value of continuing to
roundingthenewmedicine. provide support and special benefits for medicines that
make a high turnover when their profitability on the
IdentifiedMEAsspecifictoorphanmedicinalproducts market is at least as firmly guaranteed as that of most
From June 2003 to April 2010, TLV received requests non-orphan medicines” [52]. As a result, CEPS decided
for reimbursement for 30 OMPs. It awarded reimburse- to propose ad hoc agreements to the pharmaceutical
ment to 29, six of which were reimbursed with limita- companies concerned whereby they would undertake to
tions. Only one drug was denied reimbursement [49,50]. supply their medicine to all patients who might benefit
Since 2006, five CED schemes were set up by TLV to from it without restriction, whilst paying back to na-
manage some form of uncertainty surrounding the evi- tional health insurance ‘the whole’ turnover they make
dence package of new OMPs. Only one is on-going (i.e. above an agreed fixed ceiling [53]. This mechanism was
everolimus). The main uncertainties that led to the de- implemented on two occasions in 2008: the first in-
velopment of these schemes were (i) the need of real-life volved galsulfase (treatment for mucopolysaccharide
data (e.g. adherence to treatment, number of patients type VI disease); the second related to eculizumab (for
treated, drug dosage) and (ii) the need to validate the as- paroxysmal nocturnal haemoglobinuria). According to
sumptions used in the ex-ante cost-effectiveness model our taxonomy, these schemes could be defined as ‘price-
submitted to TLV. According to our taxonomy these are volume agreements with cap’. Two years later, a legal
CED schemes ‘only with research’ where all new patients amendment was introduced to the contractual frame-
must be treated using the new technology while new work between CEPS and the pharmaceutical industry,
data are generated. Timeframe for generating new data with a specific focus on access to OMPs. Article 10bis of
ranged between two and three years. TLV was usually the amended framework stated: “to ensure that patients
not prescriptive as to the outcomes data that it wished continue to have access to orphan medicines under con-
to seere-submitted but usually offeredinformalprotocol ditions that are acceptable to the pharmaceutical com-
assistance to manufacturers to develop the data gene- panies and the national health insurance alike, […] the
ration plan. In theory, failure to comply with these data committee [CEPS] may request a company selling an or-
requirements may result in delisting. To our knowledge, phan medicine costing more than €50K per patient per
thishasnot happened. year […] to undertake to supply the medicine to all pa-
tients eligible for the treatment without restriction in re-
France turn for setting a price in keeping with standard
MEAprocess international prices, up to a set turnover threshold” [54].
Based onarticle L.162-16-4 ofthe French Social Security With this provision, the ‘capping’ approach per patient
Code, the retail price of a drug is set by means of a ne- per year thus gained a legal dimension. Therefore, in
gotiated agreement between the pharmaceutical com- France, MEAsaretraditionallyprice-volume contracts.
pany selling the drug and the French Healthcare
Products Pricing Committee (Comité économique des Germany
produits de santé, CEPS). The primary considerations MEAprocess
forpricesetting areany additionalmedicalbenefitwhich Since 2003, Germany’s Statutory Health Insurance (SHI)
the drug provides, the prices of other drugs providing providers have had the option to negotiate individual
the same treatment, and the forecast or recorded sales rebate or discount contracts with pharmaceutical com-
volumes of the drug. For innovative medicines given a panies. This option to allow SHI funds, instead of the
strong incremental medical improvement rating (i.e. Federal Joint Committee (G-BA), to negotiate contracts
with ASMR I to III), these agreements guarantee that directly was confirmed with the ‘Act to Reinforce Com-
the price set will be no lower than the lowest price in petition between the German Statutory Health Insur-
force in the four main comparable EU markets [51]. In ance’ (GKV-WSG) of 2007. As a result, MEAs in
return, drug listing may be conditioned to volume Germany have taken place at the regional or individual
clauses, whereby the pharmaceutical company under- sick fund level, not at the national level. Both financial-
takes to compensate by means of clawback payments for based and performance-guarantee types of MEAs were
any additional costs to national health insurance in the reportedly implemented[18].
event that its actual sales volume exceeds the forecast With the Act on the Reform of the Market for Medi-
volume level mentioned in the price submission applica- cinal Products (AMNOG) coming into force in January
tion. Similarly, price reductions and Phase IV studies 2011, the procedure of ‘early benefit assessment’ became
mayberequired. mandatory to obtain reimbursement for new drugs in
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Germany. In case of additional benefit, price negotia- used in this research, we observe that, except for ‘price-
tions follow between the pharmaceutical manufacturer volumeagreementwithoutcap’,everyotherpossible type
and the Federal Association of Statutory Health Insu- of financial mechanism was used across these five coun-
rance Funds. The additional medical benefit has been tries. In contrast, out of the six possible performance-
regarded as proven for OMPs, as a result of the market- based MEAs, ‘CED with research’ and ‘money-back
ingauthorization byEMA. guarantees’ were the only two utilised forms observed.
As described in the previous sections, the rationale for
IdentifiedMEAsspecifictoorphanmedicinalproducts setting up aMEAdiffers across countries.If we revert to
Experience on reimbursement and pricing negotiations our taxonomy, CED schemes aim ‘to provide evidence
under AMNOG is limited. In July 2012, pirfenidon be- regarding decision uncertainty’, with Sweden and the
came the second medicine (and first OMP) to be priced Netherlands requiring real-life data to generate evidence
within Germany’s new reimbursement system. Negoti- on appropriate drug use or validation of a cost-
ation outcome was an 11% rebate (on top of a 16% effectiveness model. Financial-based arrangements focus
mandatory rebate) [55]. The contract has a duration of on ‘managing budget impact’, with the implementation
two years. of patient cost caps, discounts, or discounted treatment
initiation primarily adopted by England and Wales, Italy,
Comparativeanalysis or Belgium. MEAs aimed at the ‘management of utilisa-
If we consider those countries where MEA-related data tion in the real-world’ (by assessing drug performance
were accessible (i.e. Belgium, England and Wales, Italy, through intermediate or clinical endpoints) were found
the Netherlands and Sweden), then a total of 42 MEAs onlyinItaly.
applied to 26 OMPs were available for analysis. Italy was Antineoplastic agents were by far the primary targets
the country with the highest number of schemes (n=15), of MEAs (n=23), followed by immunostimulants (n=6)
followed by the Netherlands (n=10), England and Wales and enzyme-replacement therapies (n=5). The 42 MEAs
(n=8), Sweden (n=5)andBelgium(n=4). reviewed applied to 26 OMPs, which suggests that some
Across this sample of MEAs, performance-based risk- OMPs were subject to several MEAs across countries.
sharing arrangements (n=23, 55% of total) were slightly Nine of these 26 OMPs were subject to MEAs in two or
more prevalent than financial-based schemes (n=19) three different countries, resulting in 24 MEAs (i.e. 57%
(Table 1). Performance-based risk-sharing arrangements of the total number of MEAs mapped) across seven dif-
were relatively more common in Italy, the Netherlands ferent types of MEAs. MEAs limited to a single country
and Sweden; financial-based schemes were mainly en- were applied totheremaining17OMPs.
countered in Belgium, England and Wales, and Italy. 25 MEAs focused on conditions whose prevalence is
Overall, if we consider the adapted taxonomy of MEAs less than 1 per 10,000 (NB: a third of these applied to
Table1OverviewofMEAsidentifiedacrossfiveEuropeancountries,describedbycountryanddesign
TypesofMEAs Countries NumberofMEAs
B E I NL S
Performance-basedarrangements 23
Performance-linkedreimbursementschemes 8
Money-backguarantees x 8
Coveragewithevidencedevelopment(CED) 15
CED‘onlywithresearch’ x x 15
Financial-basedarrangements 19
Patient-levelfinancialschemes 10
Discountedtreatmentinitiation x 6
Patientutilisationcap x 2
Patientcostcap x x 2
Population-levelfinancialschemes 9
Discount x x x 7
Price-volumeagreementwithbudgetcap x 2
Grandtotal 4 8 15 10 5 42
B:Belgium;E:England&Wales;I:Italy;NL:Netherlands;S:Sweden.