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ONCOLOGY HORIZON SCANNING PROJECT

VLERICK HMC REPORT 2015-1

WALTER VAN DYCK AND TINE GELDOF JUNE 9, 2015

Our solution to your specific needs

ONCOLOGY HORIZON SCANNING PROJECT

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Executive summary

A very strong pipeline of oncology precision medicines will become accessible to patients

now and in the immediate future. Over the next five years a range of innovative

precision medicines or targeted therapies will reach the market, followed by new

immunotherapies. Also, taking as a basis this raising targeted therapeutics pipeline we

showed an equivalently raising diagnostics pipeline, not only used for properly targeting

precision medicines, but also more and more for screening, monitoring and treatment

optimization.

In this study we investigate whether Belgium is ready to make this disruptive medical

technology available to its citizens. With innovative precision medicines in oncology at

5% of the total present Belgian pharmaceutical specialties budget but forecasted in this

study to raise to 8.9 to 9.5% of the total budget in 2020, the budget capacity and

budgeting process to allow for this innovation to reach the Belgian market is considered

to be not adapted and in need of review. Especially in these times of austerity

characterised by historically stagnating or even declining budgets. Second, next to the

sheer height of the pharmaceutical specialties budget, access timing is considered to be

a key problem to be resolved in the Belgian health system.

To cope with the imminent innovation bubble of precision medicine therapies in the field

of oncology we propose, first, a case-based method to review personalized medicine-

based drug- and diagnostic submissions in an EU-National harmonized and synchronized

market authorization and reimbursement process, in which the Drug Reimbursement

Committee and the Technical Medical Council act in concerted practice. Doing so will

reduce access delays and increase reimbursement decision alignment. Second, to

improve foresight and channel budget means to the most promising innovative therapies

becoming available a horizon scanning-based transversal 5-year rolling budget

forecasting concept and rationale is proposed, starting for pharmaceutical specialties,

later for diagnostics.

As a result for Belgium, from a simulation using the 5-year horizon scanning-based

transversal budgeting methodology we propose, this would mean that, in order to cope

with the imminent innovative oncology precision medicine pipeline the pharmaceuticals

specialties budget should raise with a compound annual growth rate (CAGR) above

inflation ranging between 0,89% and 2,05% over the next 5 years, contingent upon the

budget for conventional medicine remaining constant or growing at its historical rate.

This required pharmaceutical specialties budget growth rate can only be reduced if one

decides to take into account possible effects from de-reimbursement or from transversal

budget impacts, i.e. by funding pharmaceutical innovation using the savings projected to

be made by precision medicine in other healthcare areas. To cope with the upcoming

innovation pipeline, then, the essence of the proposed transversal way of budget

thinking, cutting across budget silos comes down to the choice for the pharmaceutical

specialties budget to grow with the abovementioned CAGR of 1,47% ± 0,58% or to

benefit from €208M – €461M of budget spill-overs and de-reimbursements. However, it

should be made clear that for this transversal budget thinking to work in practice a real

world data infrastructure integrating scientific and health economic data should be made

operational.

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Vlerick Healthcare Management Centre

The Vlerick Healthcare Management Centre (HMC) is a European, Brussels-based non-

profit independent think tank and education provider advancing innovative and actionable

management and policy solutions in the field of healthcare and life sciences.

The Vlerick HMC research agenda is set by its Director after consultation with the Vlerick

HMC International Advisory Board, chaired by Prof Dr Leo Neels and composed of the

following members; Prof Dr Richard Barker (CASMI, UK), Mr Jo De Cock (NIHDI, BE),

Prof Dr Denis Lacombe (EORTC), Prof Dr Kjeld Möller Pedersen (COHERE, DK), Prof. Dr.

Maarten Postma (RUG, NL).

Vlerick HMC is led by Prof Dr Walter Van Dyck, Vlerick Business School partner, Roche-

Chaired professor and acting as the Centre’s Director.

Financial and competing interests disclosure

Vlerick HMC is fully owned by Vlerick Business School, a Public Utility Foundation, and

funded by grants from public institutions and private organisations. To conduct its

applied business and policy research, Vlerick HMC benefits from a Research Chair from

Roche focussing on patient access to medical innovation, and from MSD as a Knowledge

Partner with ASZ Aalst, AZ Alma, AZ Jan Palfijn, AZ Maria Middelares, AZ Nikolaas, AZ

Sint-Lucas, AZ Sint-Maarten, AZ Sint-Maria, Jan Yperman Ziekenhuis, Jessa Ziekenhuis,

Maria ziekenhuis Noord-Limburg, united as MINOZ Research Members.

About this report

This report was made possible by an unconditional grant provided by AstraZeneca.

Prof Dr Walter Van Dyck is the lead author of this report.

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Report

Title Oncology horizon scanning project

Authors Walter Van Dyck, Tine Geldof

External experts Consulted for their input to this report: Francis Arickx

(RIZIV/INAMI, Brussels), Jean-Jacques Cassiman (VKL,

Brussels), Bart De Greef (pharma.be Brussels), Jacques De

Grève (UZB, Brussels), Hans Hellinckx (UNAMEC, Brussels),

Marc Herlant (BCG), Frank Hulstaert (KCE, Brussels), Denis

Lacombe (EORTC, Brussels), Ingrid Maes (Inovigate), Gert

Matthijs (KU Leuven UZ), Raf Pasmans (Biocartis, Mechelen),

Patrick Pauwels (UZA, Antwerp), Sander Perret-Gentil (Roche

Diagnostics NL), Marieke Siemons (AstraZeneca), Eva Smets

(Roche Diagnostics NL), Françoise Stryckman (pharma.be),

Peter Vandenberghe (KU Leuven, UZ), Richard Van Den

Broeck (UNAMEC, Brussels), Katleen Vandeweyer (Roche

Diagnostics, Vilvoorde), Marc Van Den Bulcke (WIV), Jules

Verrooten (UNAMEC, Brussels), Anouk Waeytens

(RIZIV/INAMI, Brussels), Lieve Wollaert (AstraZeneca).

External validators Asked for methodological and internal validation of the

report: Leo Neels (Chairman Vlerick HMC International

Advisory Board), Lieven Annemans (UGent), Ri De Ridder

(NIHDI).

Disclaimer Only the authors are responsible for possible errors or

omissions. Expressed viewpoints and policy

recommendations are also under the full responsibility of the

authors.

Please cite as:

Van Dyck, W., & Geldof, T. 2015. The Oncology horizon scanning project, Vlerick HMC

Report 2015-1. Brussels: Vlerick Healthcare Management Centre.

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Table of contents

Executive summary .................................................................................... 2

Vlerick Healthcare Management Centre ......................................................... 3

Report ...................................................................................................... 4

Glossary .................................................................................................... 7

List of abbreviations ................................................................................... 8

1. Introduction ....................................................................................... 10 1.1 Background .................................................................................. 10

1.2 Study objectives ............................................................................ 11

1.3 Study methodology ........................................................................ 11

2. The microeconomics of Precision Medicine .............................................. 13 2.1 The Targeted Therapeutics market ................................................... 13

2.2 The Diagnostics market for Precision Medicine ................................... 18

2.3 The effect of diagnostic accuracy on Precision Medicine budgeting and

cost-effectiveness .......................................................................... 21

2.4 Conclusions .................................................................................. 23

3. History and projection of Belgian unmet need for Oncology PMx ............... 24 3.1 PMx/Dx history in Belgium .............................................................. 24

3.2 PMx 2020 projection ...................................................................... 30

3.3 Dx budget projection ..................................................................... 34

3.4 Conclusions .................................................................................. 35

4. Challenges of the market authorization and reimbursement procedures in the Belgian Health Care system .................................................................. 36 4.1 Current Belgian market authorization and reimbursement system ....... 36

4.2 Accessibility of the Belgian HC system to PMx: An analysis of

recommendations from previous studies (2005 – 2015) ..................... 40

4.3 Conclusions .................................................................................. 44

5. Towards a synchronized PMx/Dx market authorization and reimbursement process .............................................................................................. 45

5.1 The need for a harmonized and synchronized evaluation process ......... 45

5.2 Need for concertation between CRM and TMC in a joint CRM-TMC

evaluation group ........................................................................... 47

5.3 Discussion of the four cases ............................................................ 47

5.4 Conclusions .................................................................................. 52

6. Towards a 5-year horizon scanning-based transversal pharmaceutical

specialties budgeting system ................................................................ 53 6.1 Societal unmet need articulation ...................................................... 53

6.2 The present pharmaceutical specialties budget and “buffer” system ..... 53

6.3 Towards an advanced pharmaceutical specialties and diagnostics

budgeting system .......................................................................... 54

6.4 Conclusions .................................................................................. 59

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7. Study conclusions and recommendations ............................................... 60

APPENDIX I: Previous study recommendations summaries ............................ 63

The Flemish Cancer League .................................................................. 63

NIHDI ................................................................................................ 66

Ghent University: Prof Lieven Annemans ............................................... 68

Belgian Healthcare Knowledge Centre (KCE 147A, 20A, 240, 100C) ......... 69

Boston Consulting Group (BCG) ............................................................ 73

Awada et al. 2013 ............................................................................... 74

APPENDIX II: List of current molecular diagnostic tests and the use of Art. 33bis

........................................................................................................ 75

APPENDIX III: Assumptions made for 2020 PMx projection ............................ 78

APPENDIX IV: Assumptions for and calculation of the effect of diagnostic accuracy on PMx budgeting and cost-effectivenes ................................... 89

References .............................................................................................. 91

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Glossary

Biomarker A biomarker provides information about pathophysiological

processes that can be objectively measured and evaluated in

order to detect or define disease progression, or to predict

treatment response. Traditional biomarker analysis consists

of surrogate physiological measurements, individual protein

molecules such as PSA and CEA, and imaging techniques.

Companion diagnostic Diagnostic test specifically carried out for a particular

treatment decision, in particular to identify sub-populations

of patients for whom treatment is likely to be more effective

or safer.

ICER threshold value Benchmark for ICERs (incremental cost-effectiveness ratios)

to assess an intervention’s cost-effectiveness. Interventions

with an ICER below the ICER threshold value are considered

cost-effective, interventions with an ICER above the ICER

threshold value are considered not cost-effective.

Quality-adjusted life year Measure for health outcomes that includes both quality and

quantity of life a patient is expected to have. Quality-

adjusted life years are calculated by estimating the total life

years gained from a treatment and weighting each time

period within these life years gained with a quality-of-life

score between 0 (dead) to 1 (perfect health) that reflects the

health-related preference of the population for the QoL

(Quality of Life) status in that period.

Societal willingness to pay Societal willingness to pay refers to the maximum amount

society is willing to pay for a unit of health gain (e.g. QALY or

life-year gained). It reflects what society is willing to sacrifice

in terms of other goods or services for a unit of health gain

and hence it reflects the same unit of measurement as the

ICER threshold.

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List of abbreviations

ALL Acute lymphoblastic leukemia

AML Acute myeloid leukemia

BELAC Belgian accreditation body

BIA Budget Impact Analysis

BSC Best Supportive Care

CAGR Compound Annual Growth Rate

CDx Companion Diagnostic

CEA Carcinoembryonic Antigen

CLL Chronic lymphocytic leukemia

CME Centrum Menselijke Erfelijkheid (Centre for Human Genetics)

CML Chronic myelogenous leukemia

CRM Commision of Reimbursement of Medicines (Commissie Tegemoetkoming

Geneesmiddelen CTG/Commission de Remboursement des Médicaments CRM)

DALY Disability-Adjusted Life Years

DDD Daily Defined Dose

Dx Diagnostic test

EFPIA European Federation of Pharmaceutical Industries and Associations

EGF Epidermal growth factor

EGFR Epidermal growth factor receptor

EMA European Medicines Agency

EPEMED European personalised medicine association

EQA External quality assurance

ER Estrogen receptor

ETA Early Temporary Access

ETR Early Temprary Reimbursement

EU European Union

FAGG Federaal agentschap voor gezondheidsproducten (Federal Agency for

Medicines and Health Products)

FISH Fluorescence In Situ Hybridisation

FDA Food and Drug Administration

GB GVU Globale Begrotingsdoelstelling Geneeskundige Verzorging en Uitkering

(Global Budgetary target Medical Care and Payment)

GIST Gastrointestinal stromal tumours

HER2 Human Epidermal growth factor Receptor 2

HNSCC Head and Neck Squasmous Cell Cancer

HTA Health Technology Assessment

ICER Incremental cost-effectiveness ratio

IHC Immunohistochemistry

IMA – AIM InterMutualistisch Agentschap Agence Intermutuélle (Belgian association

amongst sick funds

INAMI Institut national d'assurance maladie invalidité

INCa Institut National de Cancer

ISH In situ hybridisation

ISPOR International Society for Pharmacoeconomics and Outcomes Research

IVD In Vitro Diagnostic

KCE Belgian Health Care Knowledge Centre

LDT Lab Developed Test (home-brew test)

MCDA Multi Criterion Decision Analysis

NGS Next generation sequencing

NICE National institute for health and care excellence

NIHDI Belgian National Institute for Health and Disability Insurance

(NIHDI/RIZIV/INAMI)

NSCLC Non-small cell lung cancer

PFS Pricing for Pharmaceutical Specialties

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PMA Pre-Market Approval

PMx Personalized or Stratified Medicine or Precision Medicine

PSA Prostate-Specific Antigen

QALY Quality-adjusted Life Year

QoL Quality of Life

RIZIV Rijksinstituut voor ziekte- en invaliditeitsverzekering

Rx Therapeutic drug

SNP Single Nucleotide Polymorphism

TGR/TMC Belgian Technical Medical Council (Technisch Geneeskundige Raad TGR)

Tx Targeted therapeutic drug

UNAMEC Belgian Federation of the industry of medical technologies (Belgische

federatie van de industrie van de medische technologieën)

VAT Value Added taks

WE West European

WIV-ISP Wetenschappelijk instituut voor volksgezondheid – Institut Scientifique de

Santé Publique

WTP Societal Willingness-to-Pay

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1. Introduction

1.1 Background

Discoveries from the mapping of the human genome were the driving force for the

development of Precision Medicine, used interchangeably with ‘genomic medicine’,

‘stratified medicine’ or ‘targeted therapies’. The deeper understanding of the biological

origins of disease created the possibility for medicines to be tailored to specific

subpopulations of individuals that are susceptible to a particular disease or who have a

particular response to a certain treatment. Precision medicine (PMx) has shown to carry

the potential to disrupt the conventional way of practising medicine.

The disruptive difference between these targeted treatments (Tx) and conventional

medicine’s undifferentiated one-size-fits-all approach to medicine is that they make

medication-based treatment objectively measurable. Using biomarkers1 for screening,

monitoring, diagnosis and treatment optimization, they have the potential to improve

patient outcomes and to reduce the costs associated with inappropriate or suboptimal

treatment regimens (Schneider et al., 2012). To measure the presence of biomarkers,

diagnostic tests (Dx) make use of SNP analysis, genomic and proteomic profiling,

epigenetic and gene expression profiling, thus leading to a patient profile consisting of

objectively measurable characteristics. Companion diagnostics (CDx) are diagnostic tests

addressing one specific clinical question, like whether a patient would be a good

candidate for a particular treatment. As an example, Roche Diagnostics’ Herceptest is

used to measure the presence of HER2, a protein biomarker that has proven to play an

important role in the development and progression of certain aggressive types of breast

cancer. As a predictive tool it is used to make the decision whether or not to administer

Herceptin (Trastuzumab), a monoclonal antibody-based targeted treatment launched by

Roche.

According to the Personalized Medicine Special Interest Group of ISPOR Precision

Medicine has the following benefits: (1) Increased certainty about diagnosis and

mechanism of disease; (2) Improved estimation of patients’ risk of later outcomes (e.g.

prognosis), which could influence treatment management decisions; (3) Better prediction

of response to therapy or drug metabolism rates or a reduced potential for adverse

events; (4) Reduced wastage of health resources associated with treating non

responders; (5) Improvement in quality and cost-effectiveness of patient-tailored

treatment versus empirical approaches to prescribing” (Faulkner et al., 2012). However,

as we will further study in this report and also acknowledged by these authors,

Personalized Medicine may also lead to additional costs due to false positive patients,

decreased Quality of Life (QoL) due to false negative patients, increased diagnostic

budgets and expanded patient populations subjected to screening and prevention.

In the last few years, the largest evolution in the development of Precision Medicine is

found in the area of oncology, with the knowledge about the biology of tumours and

cancers growing exponentially. It will continue to be the leading area in this field in the

immediate future (Davis et al., 2009), with immune system-related medical technology

now becoming available on the market.

Scientific challenges like poor understanding of molecular disease mechanisms or the

lack of biomarkers associated with a disease continue to be an obstacle to the

advancement of science and eventual patient access to precision medicine. However,

more and more, microeconomic challenges such as poorly aligned incentive structures

1 See glossary.

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amongst health care players or operational challenges such as the non-available

qualitative and standardized electronic tracking of the newly acquired diagnostic

information are becoming the most preponderant roadblocks to advance the precision

medicine paradigm into practice (Davis et al., 2009).

From a payer perspective, Precision Medicine allows medical innovation to be targeted to

the most adequate patients, which should have the potential to dramatically reduce

healthcare costs while avoiding expensive therapies to be falsely administered, by

minimizing costly adverse events or by keeping the right patients out of the later-stage

expensive phases of the oncological treatment pathways using population stratification

(Van Dyck et al., 2012). However, predominantly while being targeted at smaller

populations, targeted therapies are considered to be expensive by payers for the benefit

they potentially deliver, leading to scrutinized market access evaluations. PMx

technology enabled biopharmaceutical innovation strategy to move from a blockbuster to

a niche buster business model (Eichler et al., 2015) which also leads to higher prices.

Given the promising Precision Medicine pipeline in the Oncology field now becoming

accessible to global markets in the present and immediate future, in this study, we want

to investigate the challenges we experience in the Belgian health care system accessing

this disruptive medical technology; do we potentially have access to all targeted

treatments granted authorization at EMA level? Do we get timely access in comparison to

our neighbouring countries? Do we get affordable and equitable access while not stifling

medical technology industry-based innovation? Are access granting and reimbursement

decision making processes of the complementary therapeutic and diagnostic components

of PMx synchronized and harmonized amongst European and National levels? Previous

studies proposed a set of recommendations for doing so at the Belgian health care

system level. In this study we will take stock of these recommendations and take them

one level deeper towards tangible decision making process changes and organisational

arrangements suggested to be necessary to make PMx a continuing reality in Belgium.

1.2 Study objectives

The oncology horizon scanning project will provide the Belgian health regulatory and

payment authorities, actors and influencers with recommendations on how to ensure and

possibly improve patient access to Precision Medicine i.e. targeted therapeutics (Tx) and

their accompanying diagnostic tests (Dx) in the near future (< 5years) in the field of

oncology.

The study has as its objectives to;

Provide a mapping of expected oncology medication and companion diagnostics in

the coming 5 years

Evaluate the diverse factors (regulatory & payment pathways, budgets, legal,

organizational) that enhance or inhibit market access to these healthcare

solutions in Belgium

Provide recommendations for improving appropriate patient access to precision

medicine in Belgium

1.3 Study methodology

We performed our analysis in three phases. In a first phase, a literature study was

conducted on health policy and health economics-related opportunities and challenges of

precision medicine in general and on its implementation in the Belgian healthcare system

context in particular.

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In a second phase, we conducted a series of exploratory interviews with stakeholders

from NIHDI (RIZIV/INAMI), health care providers and research institutions in the

oncology and pathology domains, oncology patient organisations, and biopharmaceutical

and diagnostics manufacturer sides of the healthcare system. Interviews were recorded

and transcribed. The list of interviewees is available in Appendix.

During this second phase, in a second parallel work stream, the history of the Belgian

PMx portfolio was mapped since 2003, which led the research team to develop an

assumptions-based methodology to make a projection of the oncology pipeline for the

period 2015 – 2020.

Concluding the two phases, interview results and literature study were clustered to lead

to the formulation of four main areas of attention for subsequent recommendation

formulation. A workshop meeting with pharma.be UNAMEC and UGent Health Policy

representatives preliminary validated our forecast data and main areas of attention.

Based on a review of previously conducted studies pertaining to the Belgian healthcare

system context, the two most quoted areas of attention (of the initially four) were

chosen for further elaboration and final recommendations formulation.

In a third and final phase decision-making systems were designed for the two most

prominent areas of attention to promote access to precision medicine in Belgium; a well-

tailored (1) synchronized reimbursement system for both targeted therapeutics and

diagnostic tests at the Belgian national level, and (2) a rolling forecast-based holistic

(i.e. considering the budget impact and cost-effectiveness for the full health care

system) budgeting system. Results and recommendations were validated in a concluding

expert workshop with representatives from industry (biopharmaceuticals and

diagnostics), payers (NIHDI), KCE, and UGent Health Policy.

In the following Chapters we will first discuss the microeconomics of Precision Medicine

to understand the co-evolutionary nature of the therapeutic and diagnostic markets, the

two main components of a PMx therapy. In Chapter 3 we will plot the projected pipeline

for oncology precision medicines and diagnostics, which is bound to create a bubble in

the 2015 – 2020 timeframe. In Chapter 4, based on interviews and a study of previously

conducted studies on the Belgian health care system we will describe and cluster the

challenges and opportunities for improvement of the current market authorization and

reimbursement process into four areas in need of change. Following, we will propose our

solution for two of these need areas in the next two chapters. In Chapter 5 we will

describe a harmonized and synchronized market authorization and reimbursement

process for granting access and reimbursement of both therapy and diagnostic

components of PMx innovative therapies. In Chapter 6 we will propose a horizon-scan

based transversal budgeting system, providing longer term foresight, necessary to cope

with emerging pipelines of innovative therapies. Finally, in Chapter 7 we give a summary

of our recommendations promoting access to oncology-based Precision Medicines to the

Belgian health care system.

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2. The microeconomics of Precision Medicine

Precision Medicine is carried out making use of two components; a therapeutic (Tx) and

a diagnostic (Dx) component, not necessarily developed and brought to market by the

same medical technology company. While historically regulated markets for therapeutics

and diagnostics have separately developed, with Precision Medicine they now become

co-evolving with targeted therapeutics co-creating value. The therapeutic component

captures the bulk of the value created. With a typical molecular diagnostic test at a price

of $100 - $3000 and accounting for 5% of hospital costs they only capture a small

portion of the value created. However, they are acknowledged to influence 60-70% of all

treatment decisions (Davis et al., 2009; Wolcott & Goodman, 2009).

Therapeutics and diagnostics markets develop separately but are linked to each other,

i.e. they co-evolve; therapeutics offer a differentiating solution to (a set of) unmet

need(s). Diagnostics are offered as a health service, using IVD technology or lab-

developed tests (LDT), the latter sometimes referred to as “home-brew” offered by an

accredited lab (in Belgium). In connection to targeted therapeutics they are used as

Companion Diagnostic tests to one or more Tx specifically carried out for a particular

treatment decision, in particular to identify sub-populations of patients for whom

treatment is likely to be more effective or safer.

2.1 The Targeted Therapeutics market

Targeted therapeutics Tx are treatments designed to benefit a particular targeted

subpopulation with specific characteristics. The use of Tx in another subpopulation, with

different indications or a lack of the specific characteristics, might be especially

disadvantageous or require different dosing.

For drug developers embracing the Precision Medicine paradigm shift this would lead to

lower development costs while having to include fewer patients in clinical trials, having

higher success rates while targeting better-defined homogeneous patient populations,

and by expediting market access. This would lower the financial threshold for engaging

in expensive drug research at the scientific frontier and hence lead to a richer pipeline of

new drugs becoming accessible (Kocher & Roberts, 2014). This paradigm shift, together

with the need of cost-constrained payers in need of more differentiating value

propositions for new drug proposals has accelerated the transition from the blockbuster

to the niche buster business model (Eichler et al., 2015; Trusheim, Berndt, & Douglas,

2007).

Figure 1: The evolving oncology market towards targeted therapies in the top seven

countries, including 5 countries from Europe, from 2003 to 2013 (IMS, 2014).

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According to IMS Health the total oncology drug market is forecasted to significantly

increase to reach roughly $100 billion by 2018, up from $68 billion in 2013. This is being

caused by a very strong oncology pipeline becoming accessible now and in the

immediate future. Over the next five years a range of innovative new drugs will reach

the market, including several new immunotherapies and targeted therapies2, the latter

currently representing 48%, up from 11% in 2003, of the total market size (Figure 1).

With an ageing population and a delivering oncology pipeline 94% of expected growth in

the EU market will be attributable to these types of drugs which will no doubt put an

upward pressure on prices. However, with cost-strapped EU payers net growth will be

tempered and industry and government will have to find new ways together to make

access affordable (Burki, 2015).

Market access of Belgium compared to other countries

According to a BCG analysis (BCG, 2014), on a GDP per capita basis depicted in Figure 2,

Belgium spends commensurately with its economic position amongst peer countries on

cancer drugs. The overall cancer ‘case mortality ratio’, i.e. the proportion of patients who

die from their cancer, is lower than the WE average.

Figure 2: Belgium's expenditure is in line with its economic position within Western

European peers (BCG, 2014).

Following the same BCG study, as depicted in Figure 3, Belgium underspends in neuro-

psychiatry and oncology relative to the disease burdens expressed in DALYs for both

therapeutic areas.

In our analysis, this relative under-spending can be caused by drug prices being more

pressurized and/or by innovative drug variety being less accessible than in other WE

countries. While the former was initially confirmed by some of our interviewees –

‘Belgium negotiates and gets lower prices compared to other EU countries’ (source:

interview notes)–, the latter access-to-variety hypothesis deserved further investigation.

2 Also confirmed by our calculations and PMx forecasts.

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Figure 3: ‘Belgium “under-spends” in 2 therapeutic areas accounting for almost half of

the overall disease burden’ [Exhibit 2 of (BCG, 2014)].

To achieve a clear view of the ability of a variety of cancer products to access the

Belgian market and get subscribed to the reimbursement list, we built on Lim et al

(2014) making an international comparison of the factors influencing reimbursement of

targeted anti-cancer drugs. In their analysis, they use a sample of 13 products on 19

indications (see Table 1) considering their reimbursement status for 10 countries as of

February 2013, and to which we added Belgium’s situation at that same time. As

depicted in Figure 4, the US, Japan and France were the most likely to reimburse the

indications (more than 16 out of 19 indications), while Sweden and the UK, with less

than 6 out of 19, were the least likely to reimburse.

Notice that all of these products are currently on the Belgian market, but not necessarily

reimbursed for the same specified indication and conditions as stated in their study

representing the February 2013 situation. Meanwhile, the reimbursement status of

Belgium and the other countries will have changed, due to possible reimbursement

submissions after 2013. As compared to the other countries, Belgium seems to be in the

top 4 of countries with most reimbursed indications (14 out of 19). Mark that currently

(2015) 16 out of 19 indications are reimbursed in Belgium (Pemetrexed as maintenance

therapy and Crizotinib were accepted on the reimbursement list after February 2013),

with one indication (first line treatment of Multiple myeloma with Lenalidomide) being

under assessment as of March. Hence, based upon our meta-analysis of these data, we

see no problems regarding access to a variety of drug innovation in the field of cancer-

related targeted therapeutics.

An additional conclusion was made that there was a strong correlation between the ICER

and the reimbursement approval, i.e. the reimbursements favoured indications with a

low ICER, hence good cost-effectiveness values. Mark that there are many other factors

influencing the adoption decision of a country, such as the patients’ demographics, the

availability of other treatments, the impact on the health care budget, etc.

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For most of the products, the ICER values were extracted from NICE (UK) (when not

available, a literature review was done to obtain the ICER). These are listed in Table 1

for each drug indication in increasing order.

Table 1: Representative incremental cost-effectiveness ratio (ICER) for each product

with its corresponding indication. The ICERs are listed in increasing order.

(Source: Lim et al. 2014)

Drug Indication and reimbursement conditions ICER3

Nilotinib Chronic myeloid leukemia, chronic phase: 1st-line 17.314

Imatinib Gastrointestinal stromal tumor: Adjuvant therapy 29.591

Cetuximab Colorectal cancer (K-RAS wild type): 1st line with oxaliplatin, fluorouracil, and folinic acid

42.026

Pemetrexed NSCLC (for non-squamous histology): 1st line with cisplatin 44.451

Lenalidomide Multiple myeloma: 1st-line 68.941

Pemetrexed NSCLC: Maintenance treatment 73.978

Sorafenib Liver cancer: 1st line 82.792

Sunitinib Renal cell carcinoma: 1st line 85.572

Lapatinib Breast cancer with HER2 overexpression: 2nd line with

capecitabine

93.496

Bevacizumab Colorectal cancer: with irinotecan, fluorouracil, and leucovorin 98.937

Bevacizumab Colorectal cancer: with oxaliplatin, fluorouracil, and folinic acid 110.967

Dasatinib Chronic myeloid leukemia, chronic phase: 1st-line 118.050

Cetuximab Colorectal cancer: with irinotecan 121.528

Temsirolimus Renal cell carcinoma: 1st-line for poor prognosis patients 128.595

Bevacizumab Renal cell carcinoma: 1st line with interferon-α 131.070

Crizotinib NSCLC (ALK fusion positive): 2nd line (vs. docetaxel) 158.133

Bevacizumab NSCLC: 1st line with platinum-based chemotherapy 196.000

Cetuximab Head and neck cancer (squamous cell carcinoma) : 1st line with

platinum-based chemotherapy

261.767

Erlotinib Pancreatic cancer: 1st line with gemcitabine 430.000

The above could mean that the ICER threshold accepted in Belgium is much higher than

the other countries. According to Lim et al (2014), the UK, Australia, Canada and

Sweden apply the cost-effectiveness criteria in a very strict way, which can have as a

result that more negative decisions for reimbursement are advised. Following this

rationale, we could conclude that Belgium did not use the cost-effectiveness criteria as

strict as these countries. Indeed, following a KCE report on the use of threshold values

for cost-effectiveness in healthcare it was clear that the Belgian decision making

process, at least at the time of the report, was a multi-criteria deliberation process

where clinical effectiveness was the most important scientific criterion used in the

decision making process, cost-effectiveness was sometimes considered and the ICER

being considered as less important than the budget impact (Cleemput, Neyt, Thiry, De

Laet, & Leys, 2008). One tried to substantiate the reimbursement decisions with

scientific evidence, i.e. the clinical effectiveness, but not using the ICER criteria

exclusively to make a decision. We do not have further evidence whether such is still the

case today.

Also, it has to be mentioned that a possible reason why we were amongst the top

reimbursing countries is Belgium’s Article 81 regulation in vigour since February 2010,

3 Costs are expressed in US dollars ($).

17


providing a temporary reimbursement market entry arrangement. Therefore, even if the

ICER threshold seems higher in Belgium, this might be an element that is included in

the contract and for which the company needs to pay back up to the level of the ICER

threshold.

Summarizing, although Belgium has evolved from the 2008 situation described above

related to the use of ICERs in decision-making. At least on face value, this meta-analysis

provides illustrative evidence that in 2013 the ICER was not the limiting factor for access

in Belgium as this is only one of the five criteria used to make reimbursement decision.

To structurally integrate clinical, economic and societal views and increase transparency

in the decision-making process it might be recommended to further study the use of

multiple ICER thresholds as applied e.g. in the UK (Cleemput et al., 2008) and multi-

criterion decision analysis (Baltussen & Niessen, 2006).

UK SWE AUS CAN TA KOR GER BE JPN FRA US

Nilotinib (CML)

Imatinib (GIST)

Cetuximab (CRC 1st c FOLFOX)

Pemetrexed (NSCLC 1st)

Lenalidomide (MM)

Pemetrexed (NSCLC Maint.)

Sorafenib (HCC)

Sunitinib (RCC 1st)

Lapatinib (MBC 2nd)

Bevacizumab (CRC c FOLFIRI)

Bevacizumab (CRC c FOLFOX)

Dasatinib (CML)

Cetuximab (CRC c irinotecan)

Temsirolimus (RCC 1st)

Bevacizumab (RCC 1st c IFN)

Crizotinib (NSCLC ALK+)

Bevacizumab (NSCLC 1st)

Cetuximab (HNC 1st)

Erlotinib (Pancrease 1st)

Figure 4: Country reimbursement status v.s. the different indications in Feb 2013: green

represents approved reimbursement, red represents no reimbursement for that

indication. Each indication is sorted according to his ICER from low (top) to high

(bottom).

Finally, to make general conclusions about accessibility, next to variety and price level

also access timing should be considered. Hence, it is not so unusual in the Lim et al

(2014) study that some indications are not reimbursed in the European countries whilst

being approved by the FDA and being reimbursed in the US. This is due to the fact that

these indications where not yet approved for commercialization by EMA while being

already authorized by the FDA. Lenalidomide for first line multiple myeloma has for

example received market authorization by the FDA in 2006 while only being approved by

EMA in February 2015. Other mechanisms in place can provide early access as well, as

was done for Crizotinib which received accelerated approval by the FDA in 2011 while

approval in Europe was granted more than a year later resulting in no reimbursement for

18


this product in these countries. This can mean that in 2013 Europe had a slower

evaluation process and lacked a system for granting early access.

It doesn’t show from this study but access to innovation in Belgium is considered to be

relatively slow compared to the rest of Western Europe. The BCG study mentioned above

(BCG, 2014) refers to an EFPIA study of 66 new medicines approved by the EMA in

2008-2010 ranking Belgium second slowest at granting access, behind Portugal. The

EFPIA analysis for a basket of drugs obtaining EMA approval by February 2012 shows

Belgium’s average time to reimbursement (1 year) to be 50% higher than the average of

ten Western European countries. However, meanwhile a new law on access to

healthcare ( February, 7 2014) was prepared concerning “unmet medical need”, allowing

for faster access to innovative medicines which meet an unmet medical need (a drug

treating a serious or fatal condition for which no therapeutic alternative exists), which

was forced into practice in December 2014.4

2.2 The Diagnostics market for Precision Medicine

Companion diagnostics are accompanying developed tests or professional services

identifying or measuring predictive biomarkers associated with a targeted therapeutic.

Biomarkers are measurable biological parameters (genes, proteins or other substances)

that deliver the most crucial information on a patient’s disease profile, i.e. they are used

to predict the response and/or toxicity of a certain therapy.5 As these markers guide the

therapy and select between patient populations to find the right dose of the right

therapeutic to the right patients, the diagnostic tests guarantee a more efficient use of

innovative medicines and improve therapeutic success.

Commercially available CDx are on the market under the name of in vitro diagnostic

(IVD) kits. The European Medicine Agency (EMA) defines IVD medical devices as (Fabio,

2012): “Any medical device which is a reagent, reagent product, calibrator, control

material, kit, instrument, apparatus, equipment, software or system, whether used alone

or in combination, intended by the manufacturer to be used in vitro for the examination

of specimens, including blood and tissue donations, derived from the human body, solely

or principally for the purpose of providing information: – concerning a physiological or

pathological state; – concerning a congenital abnormality; – concerning the

predisposition to a medical condition or a disease; – to determine the safety and

compatibility with potential recipients; – to predict treatment response or reactions; – to

define or monitor therapeutic measures.” Also, a wide variety of lab-developed tests

(LDT) are being used. This makes it very difficult to define the clinical utility of such

tests, as “the performance characteristics for most of the individual in-house methods

have not been established and may show great variation” (Hulstaert et al., 2005).

The first PMx developments were monotherapies targeting only one biomarker, as the

origins of tumours were understood as the mutation of one molecule. Glivec (Novartis)

was the first registered and reimbursed PMx in Belgium for an indication of chronic

myeloid leukaemia. Today, the knowledge in oncology has grown in such a way,

understanding the more complex compositions of tumours, that we are evolving to the

development of combination, 2nd and 3rd line therapies targeting different biomarkers

present in the cancer. The way these biomarkers are identified by companion diagnostics

is changing as well. Currently, most of the CDx are single-marker diagnostics meaning

that they can detect only one biological characteristic from the body sample, testing one

4 Koninklijk besluit van 12 mei 2014 tot uitvoering van de artikelen 25 en volgende van de wet betreffende de verplichte verzekering voor geneeskundige verzorging en uitkeringen, BS 19 juni 2014. 5 Biomarkers can also be used in other stages of the disease process. In this way, it is possible to distinguish between diagnostic markers, prognostic markers, predictive markers, etc. In the case of PMx, biomarkers are used in a predictive way.

19


clinical research question. They take one to three weeks to be performed with a lot of

handling time leading to a high cost per test. New technologies are allowing for one day

results or are combining different mutations simultaneously in so called panels. For

example, Biocartis will soon launch an NRAS/BRAF/EGFRS492R panel for colorectal

cancer that can provide a result on the same day as their KRAS test when the result of

the latter indicates a KRAS wild-type tumour. Next Generation Sequencing (NGS) is

another example of a technology soon to be launched in Belgium which would be able to

detect all the possible mutations, even those for which no underlying knowledge exists

yet, resulting in a higher information-cost ratio than single-marker tests (Van Den

Bulcke et al., 2015). With increasing therapy options targeting different biomarkers,

panels with multiple biomarkers will support defining the treatment strategy.

In its 2013-2014 Scientific Report (Calvo, 2014), the French National Cancer Research

Centre (INCa) provides a 2014 – 2020 forecast of molecular tests of cancer patients in

France (Figure 5). Following the KCE Report on Next Gen Sequencing (Van Den Bulcke et

al., 2015), to obtain the Belgian demand for NGS tests one needs to divide these

numbers by six, which equates to 7.000 to 10.000 tests. According to the graph below it

looks as if single marker testing will be disappeared from the market by 2019 and will be

gradually taken over by NGS and whole exome sequencing. We do have to remark that

this only counts for the French INCa centres, a group of 28 platforms who focus strongly

on diagnostic innovation and that get central financing. Single marker tests will still be

done in peripheral hospitals, e.g. for disease monitoring. The latter execute 50% of all

tests in France. Since December 2014, KRAS, BRAF and EGFR are seen as routine in

France and are being executed and reimbursed in the periphery. It is probably safe to

say that Belgium should also evolve to such a situation where predictive multi-panel

testing happens in a centralised way while single marker testing for disease monitoring

will be decentralised. It was not within the scope of this study to evaluate possible

optimal testing network compositions.

Figure 5 (INCa Analysis): Projected trends in extensive tumour genome sequencing (Van

Den Bulcke et al., 2015).

20


Regarding accessibility

The question now is whether these evolutions in the field of diagnostic testing would

enable or inhibit future access of PMx in the Belgian market. The release of a CDx on the

European market currently only requires the assessment procedure assigned by the IVD

Directive or are even outside the scope of this Directive in the case of LDTs.

At a central marketing authorization (the EU level), EMA is setting up the required

capacity, i.e. building a new EU public body with sufficiently skilled staff to assess

devices (similar to the U.S. Food and Drug Administration). This scientific evaluation of

diagnostics would be an upgrade of the current CE marking. This would have enormous

impact on the EU budget, on manufacturers in terms of costs and administrative burden

and on innovation in terms of costs for regulatory compliance and time to market. At a

decentralized level, if we would want the FAGG to have this feature as well, we should

work in Belgium at a same capacity to evaluate the diagnostics scientifically in Belgium.

“New risk-based (class A, lowest risk; class D, highest risk) conformity assessment

requirements are proposed on the basis of the Global Harmonization Task Force for

medical devices system of 2008…6 A notified body will be systematically involved in the

conformity assessment procedure of companion diagnostics. This practice represents a

departure from the simpler system of self-certification.” An illustration of the pathway to

CE marking of companion diagnostics under the proposed new legal framework is shown

in Figure 6.

Figure 6: Pathway to CE marking of companion diagnostics under the current legal

framework and possible scenario under proposed new legal framework under discussion.

6 Accordingly, companion diagnostics and devices intended to be used for disease staging or screening or diagnosis of cancer would be classified within class C. Class C devices present a moderate public health risk, or a high individual risk, where an erroneous result would put the patient in an imminent life-threatening situation or would have a major negative impact on outcome.

21


2.3 The effect of diagnostic accuracy on Precision Medicine

budgeting and cost-effectiveness

As mentioned before both Tx and Dx markets co-evolve. More specifically, in the

following we want to show the importance of diagnostic test (Dx) accuracy for targeted

therapy (Tx) budgeting and cost-effectiveness, indicating the need to jointly consider

them when making access or reimbursement decisions.

Diagnostic accuracy refers to the ability of the test to correctly detect or exclude the

presence and/or overexpression of a biomarker compared to a fixed reference test (Van

Den Bulcke et al., 2015). In order to properly obtain the benefits of PMx as indicated by

the Personalized Medicine Special Interest Group of ISPOR (Faulkner et al., 2012) and

hence obtaining an improved safety, effectiveness and health outcome, one has to take

into account the impact of test accuracy i.e. its sensitivity and specificity on the

economic value of “test-intervention combinations”. Hence, higher sensitivity rates mean

that a higher number of patients likely to benefit from the targeted therapy can be

identified to realize the benefits of PMx. On the other hand, higher specificity rates help

to reduce the potential treatment of ‘false positives’, which would result in a high

spending for a proportion of the patient population for which the therapeutic would not

be effective (unnecessary costs and possible health loss from side effects) (Annemans,

Redekop, & Payne, 2013; Van Den Bulcke et al., 2015)

The importance of test accuracy can be explained by a simple example, where the

effects of HER2/neu test accuracies in female breast cancer patients for the usage of

Herceptin (Trastuzumab) on the budget impact are investigated . Different possible test

methods to assess the HER2/neu status of a tumour are for example

immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Both methods

vary in their ability to detect the biomarker and hence vary in sensitivity and specificity

(Annemans et al., 2013). In this example 3 different tests to clarify the effect of

accuracy are used and compared to a golden standard, which is in this case the FISH

test (Table 2)7.

Table 2: Different HER2/neu tests with their sensitivity and specificity.

As shown in Figure 7 the golden standard FISH test has a budget impact of €177 million.

HercepTest 1 has a budget impact of €189 million (notice that in this case a 5,2%

chance exist in getting false positive results and a 1,2% chance of getting false negative

results). For HercepTest 2 (having a smaller chance equal to 0,5% of detecting false

negatives but a higher chance of 10,4% to detect false positives) the budget impact

increases to €208 million. The Oracle test has a budget impact of €176 million. In the

latter case the chance of having false positive and false negative results equals to 1,7 %

and 2,9% respectively. It is clear that the test accuracy, together with the incremental

cost of the targeted therapy, is indeed a crucial factor for having a significant impact on

the overall budget estimations. The influence of the test accuracy is above all superior to

the price of the Dx used (Van Den Bulcke et al., 2015).

7 See appendix IV for details on the assumptions and calculations.

Sensitivity Specificity

FISH 100% 100% HercepTest 1(Moelans et al., 2010) 91% 94% HercepTest 2 (Van Den Bulcke et al., 2015) 96% 88% Oracle (Moelans et al., 2010) 83% 98%

22


Figure 7: The impact of the test accuracy on the trastuzumab treatment for 3 different

ISH tests compared to the standard FISH test.

From Figure 7 we could conclude that we should favour the Oracle test because it has

the smallest budget impact of all. However, to get a complete picture and decide

whether this is really the best option, we should make an additional investigation

considering over- and under-spending. Everything that is spent more than necessary on

false positive tested patients is reflected by overspending (as these patients should not

have been treated with trastuzumab), while everything that is spent too less on false

negative tested patients is reflected by the underspending (because these patients

should be treated with the more expensive trastuzumab treatment instead of the BSC).

Figure 8 shows that the FISH test has zero over- and underspending due to the high

sensitivity and specificity. The other three ISH tests however have a really high

overspending with a maximum of €35 million for the second Herceptest and at least €5

million for the Oracle test. These values are so high due to the fact that these patients

are treated with the expensive trastuzumab treatment together with the BSC performed

after failure of Herceptin. Note that taking into account detrimental effects of false

positive treatments would make these values even higher. The underspending has

values under €5 million. From this figure it seems that the lower the specificity (i.e. the

smaller the probability that a patient without the mutation will have a negative result)

the higher the overspending will be as is the case for Herceptest 2, while the lower the

sensitivity (i.e. the smaller the probability that a patient with the mutation will have a

positive result) the higher the underspending will be as can be seen for Oracle.

Summarizing, joint Tx-Dx considerations on ICER and budget impact play a significant

role in market accessibility considerations for targeted therapeutics. In a previous report,

taking the example of trastuzumab in breast cancer, it was shown that cost effectiveness

of various test alternatives had a varying impact on the targeted therapeutic’s ICER (Van

Den Bulcke et al., 2015). From our analysis above it should be clear that accessibility of

targeted therapeutics should be seen in conjunction with their companion diagnostics

while having a combined impact on the total budget required; on its size, and on the

potential over- or under-spending and a combined impact on the QALYs.

23


Figure 8: The amount of overspending and underspending of each possible ISH test

compared to the FISH test as the golden standard.

2.4 Conclusions

Both therapeutic and diagnostic markets develop separately. However, in the case of

PMx they co-evolve and their accessibility should be synchronized while availability of

only one component results in the total targeted treatment not being accessible to the

patient.

Following our meta-analysis on a recent study on oncology PMx accessibility in a global

context (Lim, Lee, Ko, & Heo, 2014) we conclude that related to accessibility of

oncology PMx, Belgium provides access to a wide variety of drugs at prices probably

below par on a European level8. Compared to other EU countries, access timing is

acknowledged to be an issue. Also, access timing should be seen in conjunction with Dx-

related decision timelines.

From the diagnostic technology evolution we conclude that the 1:1 Tx/Dx case of a novel

therapeutic being co-developed with a CDx is only one of the synchronization scenarios

to be considered. The fast independent scientific evolution in diagnostic testing leads to

1:n and even m:n Tx/Dx cases for access and reimbursement decision making to be

structured, which we will study further in Chapter 5 of this report.

To further rationalize –without becoming purely technocratic– and increase transparency

in decision making we suggest further study integrating multi-criterion decision analysis

(MCDA) and the use of ICER thresholds in both the CMR and TMC decision processes.

8 Not having performed a systematic analysis of the real factors considered in CMR decision-making we can only come to this conclusion based on interviews, hence the qualification ‘probably’.

€17,41

€34,83

€5,80

Reference test:

no over- and underspending

€2,29

€1,02

€4,32

0 10 20 30 40

FISH

Herceptest 1

Herceptest 2

Oracle

Millions

Underspending

Overspending

24


3. History and projection of Belgian unmet need for

Oncology PMx

3.1 PMx/Dx history in Belgium

PMx history

Currently, 18 PMx related to oncology are authorized and reimbursed in Belgium (Table

3). (Van Den Bulcke et al., 2015) Some of these are temporarily reimbursed by a

contract that is in place according to Art. 81. Table 4 shows the RIZIV/INAMI

expenditures over a period of 8 years for each PMx. From 2005 to 2013, the total

expenditures for targeted therapies in oncology increased to a quadruple of its original

value, from €49.5 million to approximately €200 million (Figure 9 and Table 4). The total

budget impact follows a linear upward trend over this short time period. The

corresponding DDDs (Defined Daily Dose) increased from 250 thousand to the fivefold of

1.35 million DDDs. Mark that some PMx, such as Erbitux, are used for other indications

as well, which are however not limited to a biomarker. This means that the data are an

overestimation of the true use of PMx. Although these stratified medicines account for

only 5% of the total oncology treatments’ DDDs in 2013, they represent about 50% of

the total RIZIV/INAMI expenses in cytostatics of oncology products (Figure 10).

Table 3: Targeted therapies in oncology reimbursed in Belgium (situation in December

2014), validated with RIZIV/INAMI.

Name Active

substance

Indication biomarker 1st EMA

registration

Reimbursement

approval

Herceptin Trastuzumab Breast cancer

Gastric cancer

HER2/neu + 28/08/2000

19/01/2010

01/05/2002

01/10/2010

Glivec Imatinib CML

GIST

MDS/MPD

HES/CEL

Ph+ (BCR-ABL)

kit (CD117)

PDGFR

FIP1L1-PDGFRa

07/11/2001

24/05/2002

28/11/2006

28/11/2006

01/11/2002

01/07/2003

no submission

no submission

Mabthera Rituximab Non- Hodgkin disease CD20 21/03/2002 01/12/2002

Zevalin Ibritumomab Follicular Lymphoma CD20 16/01/2004 01/09/2006

Erbitux Cetuximab Colorectal cancer

EGRF

RAS

29/06/2004

10/09/2008

01/07/2006 no longer valid

01/09/2008

Tarceva Erlotinib NSCLC

EGFR (EGFR-TK)

19/09/2005 27/04/2010

01/07/2006 01/05/2011

Sprycel Dasatinib CML Ph+ (BCR-ABL) 20/11/2006 01/09/2007

Tasigna Nilotinib CML Ph+ (BCR-ABL) 19/11/2007 01/09/2008

Vectibix Panitumumab Colorectal cancer RAS 03/12/2007 01/09/2008

Tyverb Lapatinib Breast HER2 + 10/06/2008 01/09/2009

Iressa Gefitinib NSCLC EGFR-TK 24/06/2009 01/07/2010

Zelboraf Vemurafenib Melanoma BRAF V600 17/02/2012 01/04/2013

Xalkori Crizotinib NSCLC ALK 23/10/2012 01/08/2013

Perjeta Pertuzumab Breast cancer HER2/neu 04/03/2013 01/06/2014

Bosulif Bozutinib CML Ph+ (BCR-ABL, not

T315l nor V299L)

27/03/2013 01/04/2014

Tafinlar Dabrafenib Melanoma BRAF V600 26/08/2013 01/05/2014

Giotrif Afatinib Carcinoma, NSCL EGFR-TK 25/09/2013 01/07/2014

Kadcyla Trastuzumab-

emtansine

Breast HER2 + 15/11/2013 01/12/2014

25

Table 4: RIZIV expenditures (€) for the reimbursed targeted therapies in Belgium over a period of 8 years (2005-2013).

PMx 2005 2006 2007 2008 2009 2010 2011 2012 2013

Herceptin 15.060.196 20.533.533 35.404.658 48.319.576 48.450.330 52.149.598 57.278.985 62.909.498 67.299.911

Glivec 18.653.517 21.989.166 24.424.806 29.235.580 31.050.457 32.281.568 33.862.234 34.798.919 33.968.937

Mabthera 15.817.393 17.368.695 18.755.206 21.751.562 23.916.430 28.330.992 31.133.792 33.704.128 36.835.105

Zevalin 0 122.783 349.262 401.843 369.518 200.914 111.627 55.821 46.034

Erbitux 0 3.932.640 12.629.381 12.890.021 9.880.340 14.289.684 16.936.592 16.549.646 16.525.472

Tarceva 0 2.363.783 9.229.738 10.456.637 11.125.471 11.911.949 11.303.649 11.194.791 10.831.127

Sprycel 0 0 418.540 2.198.299 3.408.983 3.771.648 4.545.323 5.844.421 6.394.908

Tasigna 0 0 0 372.775 1.666.045 2.728.661 4.057.925 7.312.334 10.615.212

Vectibix 0 0 0 909.143 5.245.831 5.115.062 4.316.741 5.103.087 5.369.882

Tyverb 0 0 0 0 1.200.576 3.467.326 3.417.627 3.602.661 3.487.870

Iressa 0 0 0 0 0 489.320 2.770.399 3.824.039 4.540.438

Zelboraf 0 0 0 0 0 0 0 0 3.996.757

Xalkori 0 0 0 0 0 0 0 0 1.059.271

Total (€) 49.531.106 66.310.600 101.211.591 126.535.436 136.313.981 154.736.722 169.734.894 184.899.345 200.970.924

26

Figure 9: Left: Budget impact of reimbursed PMx in Belgium from 2005 to 2013. Right : used DDDs of reimbursed PMx.

(source: NIHDI, Waeytens, 2014)

Figure 10: RIZIV expenditures and used DDD of reimbursed PMx in Belgium compared to reimbursed non-PMx in oncology. (source: NIHDI, Waeytens, 2014)

27


The ratio of PMx expenditures compared to the non-PMx expenditures has increased

from 30% in 2005 to almost 50% in 2013 (Figure 10). This is due to the high cost of

PMx per DDD (Waeytens, 2012).

Figure 11: RIZIV expenditures of PMx (oncology) and non-PMx (total pharmaceutical

specialties) over a period of 8 years.

The contribution of the budget impact of PMx compared to the total NIHDI expenditures

for pharmaceutical specialties, including all disease areas, is represented in Figure 11. It

shows that due to government savings total expenses of reimbursed pharmaceutical

specialties have decreased since 2011, while the relative part of precision medicine,

depicted here in the field of oncology, has continued to raise.

Dx history in Belgium

Detecting mutations in tumour tissue in Belgium was originally performed in the

competent CMEs (Centres for human genetics), billed under Art. 33 of the nomenclature.

Later on, Art. 33bis was created to allow the other laboratories to perform the

reimbursed molecular tests as well. An overall list of current molecular tests billed by

Art. 33bis is given in Appendix II, which demonstrates the complexity of the separate

reimbursement codes for diagnostic and follow-up tests. The most important billing

codes regarding the detection of biomarkers for the usage of targeted therapies are

summarized in Figure 12 and Table 5, together with their evolution of test volume and

NIHDI expenditures from 2008 to 2013. One should take into account that some genetic

centres billed some of these tests under Art. 33 instead of Art. 33bis, this is the reason

why the NIHDI database is in an on-going process of being reworked to be as accurate

as possible. The volume of molecular tests performed under these billing codes has more

than doubled between 2008 and 2013, as has their total expenses. The number of in situ

hybridization tests (ISH) for HER2 in breast cancer (588556-588560) for example,

doubled and is now performed in the majority of breast cancer tissue (over 8307 ISH

tests for about 10000 new breast cancer cases per year) (Van Den Bulcke et al., 2015).

28

Table 5: Budget impact and volume of a selection of Dx, billed according to Art. 33bis, from 2008 to 2013.

(source: RIZIV/INAMI) Code pairs 2008 2009 2010 2011 2012 2013

V Exp (€) V Exp (€) V Exp (€) V Exp (€) V Exp (€) V Exp (€)

588431_588442 Diagnosis acute leukemia

3.249 367.326 3.084 362.106 4.048 480.280 4.245 507.856 4.192 507.801 4.560 557.964

588453_588464 Diagnosis chronic lymphoid

2.500 276.135 2.634 303.585 3.540 413.003 3.180 374.726 3.606 430.731 4.055 489.284

588475_588486 Ig or T-cel rearraged CLL/NHL

7.568 836.910 7.862 910.007 9.190 1.074.485 9.368 1.104.942 10.324 1.233.954 10.125 1.220.323

588490_588501 Ig or T-cel rearraged other

217 24.305 227 26.767 305 36.474 246 29.335 300 36.204 503 61.253

588512_588523 Diagosis CML 2.121 233.448 2.290 263.336 2.455 285.440 2.045 240.169 2.055 244.594 1.926 231.480

588534_588545 Diagosis solid tumor (max2)

1.619 178.173 3.952 453.809 5.024 585.590 5.894 694.680 7.509 896.560 13.181 1.587.932

588556_588560 HER2 ISH breast 3.767 1.141.230 4.570 1.446.925 5.537 1.769.919 6.670 2.152.036 7.852 2.564.496 8.307 2.737.976

588571_588582 non CML monitoring 4.823 532.020 4.819 555.886 5.191 604.975 4.292 505.079 4.453 530.754 5.210 627.857

588593_588604 bcr/abl monitoring 2.802 305.883 3.137 357.453 3.249 374.883 3.445 401.629 3.677 434.145 4.347 518.071

588770_588781 marrow monitoring 54 5.900 58 6.681 36 4.212 6 705 0 0 5 595

589691_589702 JAK2 MPS 0 0 0 0 947 148.630 3.466 548.907 4.304 689.117 4.516 730.813

589713_589724 K-RAS colorectal 0 0 0 0 0 0 1.193 386.888 2.107 688.358 2.580 851.213

TOT 28.720 3.901.330 32.633 4.686.555 39.522 5.777.891 44.050 6.946.952 50.379 8.256.712 59.315 9.614.761

29

Figure 12: Left: Budget impact of a selection of Dx, billed according to Art. 33bis, from 2008 to 2013. Right : Volume per year of these

selected Dx.

(source: RIZIV/INAMI)

30

3.2 PMx 2020 projection

To make a top line PMx pipeline 2020 projection including both existing and new Tx, first,

the expenditures of the existing PMx were projected to 20209 to evaluate the extra

expected costs of the current portfolio without considering any savings by

cannibalisation, i.e. the disappearing of current reimbursed products due to new drugs

targeting the same indications and biomarkers, or by mechanic price cuts, i.e. entry of

reference reimbursement and “old drug” fixed price decreases.

Added to this projection, forecasting the volume of new PMx that have a high probability

of entering the market by 2020 was done by considering drugs registered by EMA which

recently submitted a file for reimbursement to CRM together with the EMA list of drugs

under evaluation. These products can be approved for reimbursement after registration

within a year and when not yet registered within a year and a half (1 year + couple of

months) (Table 6). In doing the analysis, medicines that were not yet approved by EMA

were altered by a correction factor: 91% of medicines under EMA evaluation undergo a

successful transition of one stage to the next, i.e. are successfully approved for market

entrance (Paul et al., 2010). The clinicaltrials.gov database was checked for identifying

PMx which are in their phase III and phase II trials and which have a high probability of

entering the market by 2020 (Table 6). The market entry date was predicted by looking

at the estimated phase completion date and adding the years/months needed to receive

reimbursement in Belgium, i.e. 1,5 years for phase III products and 1,5 + 2,5 years for

phase II products (as these still have to enrol in clinical phase III). Again a correction

factor was used as 70% of phase III drugs go to the next stage and are followed by an

evaluation at EMA level, while only 34% of phase II drugs go to the third clinical phase

(Paul et al., 2010).

From Table 6 and Figure 13 one can verify that the amount of new entries is increasing

each year from 2012 onwards to equal 10 and 12 new products in 2018 and 2020

respectively (not corrected for the probability of reaching market access in Belgium).

Most of the oncology PMx pipeline is found to be in phase 2 clinical trials, hence still at

high risk of not reaching the market, or offering the possibility to be on the market

earlier in case of accelerated approval.

Table 6: The pipeline of targeted therapies, expected to enter the Belgian market and be

reimbursed before the year 2020. Name Active substance Indication biomarker Estimated entry date

Registered by EMA and accepted for reimbursement in Belgium

Perjeta Pertuzumab Breast cancer HER2/neu 01/06/2014

Bosulif Bozutinib CML Ph+ (BCR-ABL, not T315l nor V299L)

01/04/2014

Tafinlar Dabrafenib Melanoma BRAF V600 01/05/2014

Giotrif Afatinib Carcinoma, NSCL EGFR-TK 01/07/2014

Kadcyla Trastuzumab-emtansine

Breast cancer HER2 + 01/12/2014

Registered by EMA and filed for reimbursement

Vargatef Nintedanib Carcinoma, NSCL VEGFR/FGFR/ PDGFR 5/2015

Imbruvica Ibrutinib chronic lymphocytic leukaemia, mantle cell lymphoma

17p deletion/TP53 9/2015

Iclusig Ponatinib leukemia PH+,T315I 02/2016

Lynparza Olaparib ovarian cancer BRCA1, BRCA2 01/2016

Ofev Nintedanib idiopathic pulmonary fibrosis VEGFR/FGFR/ PDGFR 01/2016

9 The projection of the existing portfolio is explained in appendix III.

31


EMA PMx under evaluation

- Necitumumab NSCLC EGFR 2016

Mekinist Trametinib Melanoma BRAF V600 2016

PMx in phase III clinical trials

Zykadia Ceritinib metastatic NSCLC (previously

treated Xalkori)

ALK 2016

- Onartuzumab NSCLC, HER2 negative gastric cancer

HGF/Met 2016

- Talazoparib Breast cancer PARP (BRCA) 2017

MEK 162 Binimetinib Melanoma, NSCLC, ovarian , pancreatic

BRAF, KRAS, NRAS 2017

AEZS-108 Zoptarelin Doxorubicin

Endometrial Cancer LHRH-receptor 2017

E7080 lenvatinib Hepatocellular Carcinoma (HCC) VEGFR, FGFR and RET 2017

AC220 Quizartinib AML FLT3-ITD 2017

BKM120 Buparlisib Breast cancer HER2 negative (PIK3CA)

2017

Palbociclib Palbociclib Breast cancer ER+ 2018

- Rucaparib pancreas cancer, platinum sensitive relapsed ovarian cancer

PARP (BRCA & HRD) 2018

- Niraparib Breast, Ovarian cancer PARP (BRCA1, BRCA2) 2018

LY2835219 NSCLC, Breast KRAS, HER2 2018

LDK378 NSCLC ALK 2018

- selumetinib 2nd line NSCLC BRAF/KRAS 2018

- dovitinib solid tumours FGFR1 2018

PF-00299804

Dacomitinib NSCLC EGFR/ HER2/HER4 2018

MPDL3280A NSCLC BRAF V600 2018

- alectinib NSCLC ALK 2019

PMx in phase II clinical trials

AZD9291 NSCLC EGFR and T790M 2017

- Irosustat Breast cancer ER+ 2018

2B3-101 Breast cancer, Lung cancer, Melanoma, Malignat glioma, brain metastasis

HER2+ 2018

MEHD7945A Duligotuzmab Solid tumours KRAS 2019

- Betalutin lymphoma CD37 2019

AZD 4547 Breast cancer FGFR1, FGFR2 2019

- Veliparib Melanoma, breast cancer BRCA 2019

CO-1686 Rociletinib NSCLC EGFR and T790M 2019

- Neratinib Breast cancer HER2+ 2019

RO5424802 NSCLC ALK 2020

AMG 337 Stomach cancer MET amplification 2020

GDC-0941 Pictilisib Breast cancer, NSCLC HER2, HR+ 2020

- lucitanib Breast/lung cancer FGFR/VEGFR/PDGF 2020

BGJ398 Solid tumors, Melanoma FGFR 2020

DNIB0600A Lifastuzumab vedotin (platinum resistent) ovarian cancer, NSCLC

NaPi2b 2020

AG-221 Solid tumors IDH2 mutation 2020

sym004 Metastatic Colorectal cancer EGFR 2020

TSR-011 NSCLC ALK/TRK 2020

http://clovisoncology.com/products-companion-diagnostics/lucitanib

32


BYL719 Breast cancer, solid tumours, Colorectal, HNSCC

PIK3CA 2020

VS-6063 defactinib NSCLC KRAS 2020

AEB071 Diffuse Large B-Cell Lymphoma CD79A/CD79B 2020

(a)

(b)

Figure 13: (a)Volume of possible PMx entries for each year (solid line) and that volume

corrected by the possibility of successfully reaching the market (dashed line). (b) Volume

of PMx in clinical phase 2 and phase 3 trials, under evaluation by EMA and currently

authorized and reimbursed on the Belgian market.

Estimating the budget impact for each of these new entries10 individually and correcting

these with the probability of reaching the Belgian market gives an estimated total NIHDI

expenditure for oncology PMx of €512 million in 2020, a triple of what was spent in 2013

over a period of 7 years (Figure 14). This estimated projection did not include the effects

of possible price decreases caused by drug cannibalisation11 or entrance of biosimilars

after patent expiries.

Furthermore, according to this analysis and as we will explain in Chapter 6, taking into

consideration PMx price savings, de-reimbursements and budget spill-overs, as shown in

Figure 24(a), in 2020 oncology PMx will represent 8.9 to 9.5%12 of the total

pharmaceutical specialties budget13,14, a raise from 1.6% in 2005.

10 See Appendix III for details on assumptions made. 11 It can be seen from Table 7 that a lot of new PMx products target for example NSCLC or breast cancer, so higher chances of cannibalisation can be expected. 12 Depending on the non-PMx conventional pharmaceutics budget raising or not. 13 Assuming the proportion of non-PMx product expenses accounted for in the pharmaceutical specialties budget to increase with a value of 1.26% each year. This is the growth rate of the non-PMx between 2014 and 2015, which was then assumed to be constant for the rest of the forecasting period. The non-PMx growth rate between 2014 and 2015 was calculated as the mean of 2014 and 2015 estimations of pharma.be and NIHDI for the total pharmaceuticals budget from which our projected PMx pipeline was extracted. 14 Data of the pharmaceutical budget from 2005 through 2014 was received by pharma.be, which included distribution costs (pharmacy, wholesale and TVA) of all reimbursed medicines (branded and generics), and excluded sales tax.

33


Figure 14: Projection of the budget impact before savings of reimbursed PMx in Belgium

from 2005 to 2020.

34


3.3 Dx budget projection

Figure 15: 2020 projection of the Dx.

Likewise, the NIHDI expenditures for Dx according to the billing codes listed above (Table

5) could be projected to 2020 in the same manner as was done for the PMx, meaning

that the current expenditures were linearly extrapolated and the probability adjusted PMx

pipeline was taken as a basis to this forecast (Figure 15). In this case the pipeline

consists of the possible reimbursement of Dx testing new biomarkers or testing existing

biomarkers included in the nomenclature (Art 33bis) but which are not yet reimbursed in

practice (Appendix II). Not all biomarkers could be placed within one of these

nomenclature codes. These were then estimated to have a reimbursement level and

volume equal to the code that corresponds to the indication or cancer type for which the

biomarker will be used. The projection to 2020 gives an estimated expenditure equal to

approximately €40 million, a quadruple of what was spent on molecular tests in 2013.

Notice that on one hand, this is an overestimation as the billing codes cover more than

one indication and/or biomarker, so the volumes extracted from these codes that were

used as volumes for the not yet reimbursed Dx are probably too high. On the other hand,

this does not yet take into consideration the to be expected future extensive use of

molecular testing for screening, monitoring and treatment optimization (Schneider et al.,

2012). In other words much more uncertainty exists regarding this forecast.

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3.4 Conclusions

With the therapeutic areas of CNS and cardiovascular having high potential for PMx, but

still being in early stages of development (Davis et al., 2009), our mapping confirms

oncology to be the first and significant wave of precision medicine innovation becoming

accessible in the 2015 – 2020 timeframe.

With innovative PMx in oncology in 2005 representing 1.6% the total Belgian

pharmaceutical specialties budget but forecasted to raise to 8.9% to 9.5% of the total

budget in 2020, the capacity of the budget and the budgeting process to allow for this

innovation to reach the Belgian market is in need of review, especially in these times of

austerity characterised by historically stagnating or even declining budgets. No doubt this

will put significant pressure on immediate future pharmaceutical specialties and

diagnostics budgets and on reimbursement negotiations in the Belgian health care

system.

Also, taking as a basis the raising Tx pipeline we showed an equivalently raising Dx

pipeline. Even more, given the increased use of these technologies not only for properly

targeting PMx usage, but also more and more for screening, monitoring and treatment

optimization (Schneider et al., 2012) this means that the projected Dx budget will be an

underestimation of the real future need.

36

4. Challenges of the market authorization and

reimbursement procedures in the Belgian Health Care system

To investigate the challenges related to the market authorization and reimbursement of

PMx in the Belgian HC system we conducted a process analysis of the present market

authorization and reimbursement process. We complemented this with a systematic

review of previous recommendations taken from reports pertaining specifically to the

Belgian HC system situation in the 2007 – 2015 period. We summarized our findings into

four main attention areas to be dealt with to accelerate PMx access to the Belgian

market.

4.1 Current Belgian market authorization and reimbursement system

The following section explains the market and reimbursement procedures for

therapeutics on the one hand and diagnostics on the other, as both processes are

currently independent of each other (Figure 16).

Figure 16: Process flowchart of the Belgian procedure for market approval and

reimbursement for Therapeutics Tx and Diagnostics Dx.

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THE PROCEDURE FOR THERAPEUTICS

When a pharmaceutical company wants to release its product on the European market

they are obliged to request for market authorization by submitting a market approval file

at either EMA (European Medicines Agency) via the centralized authorisation procedure

or at FAGG (Federal Agency for Medicines and Health Products) via the decentralised

procedures. Approval of oncology drugs is mostly performed by a request at EMA, who

evaluates the quality, safety and efficacy of the drug. However, obtaining market

authorization is not a sole criterion for actually reaching the market.

When authorization is granted, the company can submit a reimbursement request at

national level to the CRM (“Commissie Terugbetaling Geneesmiddelen”, “Comité de

Remboursement de Medicaments” Commission for Reimbursement of Medicines), existing

out of experts and representatives of different organisations. 15 In this file, the applicant

assigns a class claim to its drugs. “Class 1 is restricted to drugs with added therapeutic

value, Class 2 for drugs with similar or analogous therapeutic value and Class 3 includes

generics and copies.” (Le Polain, Franken, Koopmanschap, & Cleemput, 2010)

The CRM justifies the reimbursement decision in three steps: the assessment process,

the appraisal process and the decision process. Each of these processes will undergo

evaluations based on scientific clinical and economic criteria. (Le Polain et al., 2010)

Assessment process

The scientific criteria of the file are evaluated for registration at European level. For

registration and reimbursement at national level, a group of NIHDI and external experts16

assess the relative added therapeutic value of the drug (i.e. according to the applicants

claim17) and write out a first assessment report in cooperation with the CRM board

(deadline within 60 days), which is appraised by the CRM voting members. The report is

sent to the company who has 20 days to react with any objections or comments.18

Evaluation of the economic criteria of the reimbursement request is afterwards done by a

group of internal (NIHDI) and/or external experts. Following a KCE Report conducted in

2008 (Cleemput et al., 2008), during the assessment process, one considers the budget

impact of the drug to be more important than the ICER, together with the importance of

the clinical effectiveness. Hence, cost-effectiveness calculations were only considered to

be used in some cases. However, we do note that we have no evidence that today this is

still the case (or not).

An appraisal report draft about the assessment is presented by the experts and

appraised by the CRM voting members, who can approve, modify or refuse it. (Le Polain

et al., 2010)

Appraisal process

In the next process the CRM votes19 on the provisional appraisal file, which is written

when the reimbursement modalities approved by the CRM differ from those requested by

the company (deadline before 120 days). Note that approval and rejection of proposals

requires a 2/3 majority. Remarks and/or objections can be sent by the applicant about

15 Information from KCE Report 147A for footnotes 15-17, 19; “The CRM is composed of 1 chairman and 30

members. 23 members are entitled to a voting right while the others have a consultative voice only.” 16 “These experts were appointed by the CRM board, which is on his turn composed of 4 members appointed by the Minister”. 17 “The experts and the CRM first evaluate the Class 1 claim (i.e. added therapeutic value) with regard to efficacy, effectiveness, safety, comfort and applicability as compared with the standard alternative therapy.” 18 Art. 15 van het Koninklijk besluit van 21 december 2001 tot vaststelling van de procedures, termijnen en voorwaarden inzake de tegemoetkoming van de verplichte verzekering voor geneeskundige verzorging en uitkeringen in de kosten van farmaceutische specialiteiten, BS 29 december 2001. 19 “Voting requires at least 12 voter members to be present and is done by a show of hands (except if at least three voter members request a secret voting) in the presence of the all members (consultative members as well).”

38


this provisional proposal (within 10 days)20. The CRM then votes on the final appraisal

report. i.e. the final motivated proposal that is sent to the final decision maker (deadline

within 150 days).21

Decision Process

Finally, the motivated final CRM proposal is sent to the minister of Social Affairs (within

150 days), which is in his turn responsible for the final reimbursement decision (deadline

before 180 days). He/she is advised by the CRM reimbursement proposal, although may

deviate from this advice for certain social and/or budgetary reasons and may take an

independent motivated decision in absence of any CRM proposal.22 Hence, although

efforts are made to ‘rationalise’ the decisions, the decision making process remains

mainly an interactive deliberation process.

The Minister of Economic Affairs is responsible for fixing the maximum ex-factory price

and is advised by the Committee of Pricing for Pharmaceutical Specialties (PFS). It is

possible for the company to further negotiate about the price together with the CRM. (Le

Polain et al., 2010)

Lastly, before adding the product to the ‘positive reimbursement list’, the minister of

Budget is entitled to advice the minister of Social affairs about the budget. The budget

for pharmaceutical specialties is fixed each year and given by the GB of the GVU

(“Globale begrotingsdoelstelling Geneeskundige verzorging en uitkering”).

According to Art. 81 (February 2010) and Art. 81bis (July 2014) of the Belgian law, the

Minister may allow the negotiation of a reimbursement contract for drugs, which possibly

can fulfil the criteria of being an ‘unmet medical need’, for which there was no definitive

motivated proposal formulated by the CRM within the fixed deadline of 150 days due to

clinical or budgetary uncertainty. This contract can be proposed on the initiative of the

company itself (Art. 81) or by the CRM (Art. 81bis). The timings of the negotiations for

reimbursement are prolonged with a maximum of 120 days. The agreement is formed

between the pharmaceutical company and NIHDI, with consent of the Minister of Social

Affairs and the Minister of Budget, and results in the possibility of a temporary

(maximum three years) reimbursement of the product. The agreement determines the

price and reimbursement level of the product under contract and might obligate the

pharmaceutical company to make a financial commitment for limiting the NIHDI

expenses (e.g. repaying part of the expenses of the product, lowering the reimbursement

level of other products of the company, etc.). Data could be collected during this

temporary period to re-evaluate the therapeutic efficiency, the cost-efficiency and the

budget impact. Products that are qualified for this treatment are orphan medicines, Class

1 drugs or products for which reimbursement for a new indication (with a therapeutic or

social need) is asked, and for products for which the reference product is reimbursed

under “T”.23

20 Art. 17 van het Koninklijk besluit van 21 december 2001 tot vaststelling van de procedures, termijnen en voorwaarden inzake de tegemoetkoming van de verplichte verzekering voor geneeskundige verzorging en uitkeringen in de kosten van farmaceutische specialiteiten, BS 29 december 2001. 21 Art. 18 van het Koninklijk besluit van 21 december 2001 tot vaststelling van de procedures, termijnen en voorwaarden inzake de tegemoetkoming van de verplichte verzekering voor geneeskundige verzorging en uitkeringen in de kosten van farmaceutische specialiteiten, BS 29 december 2001. 22 Art. 18 en Art. 19 van het Koninklijk besluit van 21 december 2001 tot vaststelling van de procedures, termijnen en voorwaarden inzake de tegemoetkoming van de verplichte verzekering voor geneeskundige verzorging en uitkeringen in de kosten van farmaceutische specialiteiten, BS 29 december 2001. 23 Art. 81 en Art 81bis van het Koninklijk besluit van 21 december 2001 tot vaststelling van de procedures, termijnen en voorwaarden inzake de tegemoetkoming van de verplichte verzekering voor geneeskundige verzorging en uitkeringen in de kosten van farmaceutische specialiteiten, BS 29 december 2001, juni 2014.

39


THE PROCEDURE FOR DIAGNOSTICS

Diagnostic products don’t undergo EMA approval and above all have no existing

procedure for reimbursement with fixed deadlines (Figure 16). On the basis of the

current legal framework for medical devices, companion diagnostics for genomic

biomarkers for cancer patient selection generally fall into the classification of in vitro

diagnostic (IVD) medical devices.

“A manufacturer wishing to place a medical device on the EU market under the IVD

Directive must assign the device to the relevant risk category defined in the directive.

Currently, companion diagnostics to assay genomic biomarkers in cancer would be

classified as general IVDs (low risk) for which clinical efficacy data or establishing clinical

utility are not required.” (Pignatti et al., 2014)

Today, self-certification for low-risk IVDs by the manufacturer is sufficient to acquire a

CE marking, i.e. the CE label can be received when the diagnostic company checks that

the product meets the technical requirements (unless verification by an independent

body is needed), which aim to ensure that the devices do not affect patients’ health and

safety (Pignatti et al., 2014). Checking the conformation with the requirements includes

estimating and documenting the possible risks when using the product.24 Finally the CE

mark can be affixed on the Dx product by the company itself, an EU declaration of

conformity should be signed stating that the product meets all legal requirements.

Laboratories which develop their own biomarker tests for in-house use (so called home

brew tests or LDTs) are exempted from CE marking requirements but can only apply for

LDT or IVD-based reimbursement when being an ISO accredited lab. There is no

reimbursement file per lab or per technology. What would be needed in the future is a

national reimbursement procedure for a certain mutation or group of mutations (e.g. all

mutations in the KRAS-gen), which is not brand- or technology-specific. Whether

executed by a LDT, a CE-marked PCR test or an NGS test should not matter (source:

interview notes).

“For higher-risk IVDs, additional requirements apply depending on the classification of

the devices and the conformity assessment route a manufacturer has chosen and may

involve a notified body. A notified body is a third-party certification organization

designated and monitored by the national authority (the competent authority) of a

Member State to carry out one or more of the conformity assessment procedures.”

(Pignatti et al., 2014).

Then the manufacturer investigates whether their test can be reimbursed25 according to

the Belgian nomenclature. The nomenclature is “a limited list of reimbursed diagnostic

and therapeutic procedures with per provision a description, a key letter according to the

medical specialty, a coefficient and a set of application rules. Diagnostics are typically

classified as anatomo-pathology (Art. 32), genetics (Art. 33) and molecular diagnostics

(Art. 33bis) provisions.”(Le Polain et al., 2010). When the test is not included in the (not

yet so flexible) nomenclature, a reimbursement file should be submitted by the

diagnostics provider in order to make changes or additions to the list to include these

new Dx. This is to be proposed by the TMC (Technical Medical Council, “Technisch

Geneeskundige Raad”), which is advised by working groups. For diagnostics this working

group is composed of experts in clinical biology, clinicians, and members of the

commission of clinical biology of the Belgian Scientific Institute of Public Health. “This

24 How to receive CE mark can be seen on the official website of the European Union: http://europa.eu/youreurope/business/product/ce-mark/index_en.htm. 25This is only possible when the diagnostic laboratories, clinical biology, pathology and genetics, are licensed in Belgium and are accredited according to ISO 15189. Van Den Bulcke, M., San Miguel, L., Salgado, R., De Quecker, E., De Schutter, H., Waeytens, A., Van den Berghe, P., Tejpar, s., Van Houdt, J., Van Laere, S., Maes, B., & Hulstaert, F. 2015. Next generation sequencing gene panels for targeted therapy in oncology and haemato-oncology, KCE Report 240 - Health Technology Assessment. Brussels: Belgian Health Care Knowledge Center.

http://europa.eu/youreurope/business/product/ce-mark/index_en.htm

40


working group can formulate new codes or modifies existing ones, together with the

amount of the fee and an estimation of the resulting budget impact. No legally defined

criteria exist for these assessments, which makes this procedure not very transparent.

The working group bases its proposals on evidence based medicine, importance in

medical practice, and social needs, with a large input coming from the field.” (Van Den

Bulcke et al., 2015) The proposal is then discussed and approved by the TMC, where

after it is transferred for approval to the National Committee of Physicians-Insurers

(Medico-Mut), the commission for budget control, the insurance committee, the minister

of social affairs, finance inspection, the state secretary for budget and the Council of

State. (Van Den Bulcke et al., 2015)

The final decisions are published as Royal Decrees, so the King has to sign. (Van Den

Bulcke et al., 2015). As was the case in the drug evaluation procedure, clinical

effectiveness is the most important scientific criterion used in the decision making

process of the TMC. Cost-effectiveness however is rarely considered, as the budget

impact is thought to have a higher importance than the ICER (Cleemput et al., 2008).

Above all, there are no time limits in this approval procedure. This means that the

procedure can take about 18 months or even longer when no budget is available. Some

Dx seem to stay as a ‘to be approved or disapproved’ file and never receive a final

decision. Next to the fact that the diagnostic nomenclature adapts too slow to cope with

the fast evolution in medical technology, there seems to be no system for systematic

revision that can remove obsolete reimbursed tests from the positive reimbursement list.

Currently, Art 33bis and the generic code for molecular biological tests on solid tumours

allow laboratories to perform maximum two reimbursed, non-specified molecular biology

tests per patient per year. This is however insufficient for actual panel testing, as for

each patient the cancer consists of multiple mutations which have to be tested for. For

example, Non Small Lung Cancer patients should be tested for at least two biomarkers,

e.g. the EFGR and ALK gene mutations.

Summarizing this process analysis, the two most important points to mention are (1) the

disconnect between the Tx and Dx approval and reimbursement procedures, and (2) the

Dx reimbursement approval procedure not featuring any fixed deadlines nor a system for

systematic revisions. Without these time limits, a procedure could take about 18 months

or sometimes longer when no budget is available. In a few cases, it seems that the

reimbursement file ‘disappears in thin air’ and never obtains a positive advice.

To avoid these delays and slow adaptations of the Dx nomenclature, a synchronized

approval procedure for both Tx as well ass Dx should be established at national level.

Creating fixed deadlines for the Dx (whether LDT or IVD) reimbursement procedure could

already parallelise these systems, together with appropriate cases for transparent

decision-making.

4.2 Accessibility of the Belgian HC system to PMx: An analysis

of recommendations from previous studies (2005 – 2015)

In general, in healthcare systems the barriers inhibiting access to PMx are seen to be in

the areas of stakeholder involvement, standardisation, interoperable infrastructure,

healthcare system, data and research, funding and policy making (Horgan et al., 2014).

We conducted a meta-analysis on a set of recent studies formulating recommendations

specifically relevant to address the PMx medical technology accessibility problem in the

Belgian health care system. In Appendix I we summarized the previous studies’ results

into a list of 95 recommendations made and judged by us to be relevant (but not

necessarily endorsed by our recommendation) to the study of PMx accessibility.

41


We clustered them into five main areas of need, quoted as recommendations for

changing the current Belgian health care policy:

1. The need for a harmonized (EU/National) and synchronized therapeutic (Tx) and

diagnostic (Dx) authorization and reimbursement process for PMx.

2. The need for an improved budgeting system for pharmaceutical specialties

3. The need for early payer/regulator involvement in market access and

reimbursement decision-making for new drug development

4. The need for a qualitative diagnostic testing infrastructure.

5. The need for a qualitative real world evidence-capturing infrastructure

Following, we provide a synopsis of the clustering results, which is not claimed to be

collectively exhaustive. However, it does provide the main highlights of the studies’

recommendations that we think are relevant for understanding the basis for our

recommendations in this study. With [x] after each quoted item we refer to the

recommendation that can be looked up in Appendix I.

TX-DX DECISION MAKING SYNCHRONISATION

The need for synchronization of both Tx and Dx market authorization and reimbursement

processes for PMx counts most of the recommendations made in the study set.

One study mentions that ‘Belgium should accelerate its approval and reimbursement

process for new medicines. Recent steps have been taken in the right direction, but more

efforts are required to close the significant gap with other Western European countries’

[87]. Although ‘many EU countries including Belgium lack an integrated reimbursement

review of the drug and the companion diagnostic’ [73], the present disconnect between

Tx and Dx authorization and reimbursement procedures is seen as one of the

predominant causes for these market access delays27.

One study mentioned the disconnect ‘to lead to the following problems with a growing

impact given that more of these (Tx-Dx) combinations are coming up; (1) a

reimbursement is provided for the Tx but not for the Dx; because the TMC procedure

takes much longer than the CRM procedure and/or because the budget for tests is closed

and no extra budget is allocated for the new diagnostic test; (2) an exponential increase

of the budget for clinical biology; for existing tests as well as for added tests; (3) it will

take much longer to adapt reimbursement of diagnostics to clinical practice changes

resulting from evolving knowledge than it will take to adapt reimbursement of medicines’

(Van Den Bulcke et al., 2015).

Currently, the authorization and reimbursement advice for targeted therapies and related

diagnostics are handled in separate committees. For PMx, previous studies recommend to

‘give a joint reimbursement advice in one working group with the necessary expertise

which should function between the two committees of the CRM and the TMC. Cost-

effectiveness calculations of a PMx should take into account the diagnostic accuracy and

cost of a companion diagnostic’ [8, 29, 73, 90, 91].

In one study, pharmaceutical companies ‘are urged to provide transparency on how they

determine their price, especially in the case of PMx where prices can be high’, to better

estimate the budget impact of the Tx-Dx combination [2].

One organisation advises to let competition play in the decision-making; ’There are many

new and expensive cancer medicines in development. If two or more targeted cancer

therapies reach the market that have the same molecular target and a similar efficacy,

the government should organise a public tender process for these treatments, in order to

lower the price’ [5].

27 Interview notes.

42


Reimbursement advice should take into consideration cost-effectiveness and budget

impact analysis for the total Tx/Dx solution [30]. ‘Several cases, as exemplified by NICE’s

Diagnostic Assessment Programme (DAP), should be considered to calculate cost-

effectiveness and healthcare budget impact’ [30]. Also, ‘there should be a balanced

representation of social preferences in the appraisal process’ [46], and ‘therapeutic value

should be a necessary, but not sufficient, condition for a higher price or reimbursement

basis. Not enough or lack of added therapeutic value should lead to an equal or lower

reimbursement basis in comparison with that of the best therapeutic and reimbursable

alternative’ [47].

‘No additional information is asked regarding PMx for the submission of a reimbursement

proposal, although this would increase the clearness and transparency of the proposals.

The guidelines for the submission and evaluation of a dossier at the CRM should be

supplemented with specific elements for PMx’ [25].

IMPROVED BUDGETING SYSTEM

The need for an unmet need-driven multiple year forecast-driven budgeting system for

pharmaceutical specialties is also highly quoted in the set of studies.

‘Belgium should consider alternative funding schemes for relevant innovative treatments.

In parallel to developing its risk-sharing framework, Belgium can seek inspiration from

notable initiatives in neighbouring countries and craft alternative funding options for

certain classes of new drugs’ [89].

‘To better plan ahead, the government should perform a horizon scan of the new

medicines and technologies in development’. ‘It will also allow companies to be motivated

about how to price new products in such a way that they fit within the budget plans of

the government’. Collaboration between government and companies is esteemed to be

necessary for this [6, 7, 40].

One study mentions that ‘Belgium needs to reflect on its overall strategy for innovative

drug treatments. Exploiting some of the current and planned headroom would allow the

country to maintain or even further improve its standards of care at no additional cost to

the system’ [86].

‘A procedure must be set out to re-evaluate reimbursed treatments at regular intervals

based on scientific evidence. If necessary, reimbursement should be stopped or

amended following consultation with the various parties involved’ [10].

EARLIER PAYER/REGULATOR INVOLVEMENT

‘The legislation should seek a new balance between optimum protection of patient and

the rapid availability of the potential benefits of the treatment for patients with a high

medical need’ [1].

Providing early access to Class I drugs for life-threatening conditions is applauded

provided risk-sharing schemes between payer and industry are foreseen.

Early consultation in the development of PMx is suggested by EMA and FDA. Also,

companies are suggested to systematically undertake early economic evaluations to

better understand potential value for money of different diagnosis-treatment

combinations [23].

‘Allow conditional (accompanied by specific requests with regard to further development

and safety) and “reversible” drug approval for high impact agents at the international

regulatory level, mainly based on early data when a companion diagnostic is available

43


and high response rates (e.g. >50% antitumour activity in cancer) have been shown in

the target population in early studies, without being outweighed by inacceptable safety

issues, in a population in which available therapy has limited antitumour activity’ [93].

QUALITY OF DIAGNOSTIC TESTING INFRASTRUCTURE

An important point mentioned deals with the fragmentation within the Belgian

laboratories sector. ‘The ISO 15189 accreditation should not only help steering up the

quality of the tests developed in the laboratories, but should help in centralizing the

whole system. ISO 15189 accreditation is granted by BELAC and is required in addition to

the licensing for reimbursement. This however is still not realized, meaning that these

accreditation criteria are probably not yet strict enough’ (Van Den Bulcke et al., 2015).

‘Today, and even more in the future, a whole range of biomarkers should be evaluated

per cancer type. Testing each of these individually will demand a lot of tumour tissue and

will increase the costs drastically. Multi-biomarker tests will be a solution for this,

combining a couple of markers in one array’ [22].

‘Frequently, different tests for the same biomarker are on the market (IVD or home-

brew) and the choice of the test is free. There is need for standardisation. It is necessary

to demand a high quality performance of CDx a high concordance of these tests in order

to achieve reimbursement of the PM. ‘Further standardisation of the ISO accreditation

process and a common EQA for all Belgian centres is needed in the Dx domain’ [28].

‘The financing system should reward the appropriate collection, storage and shipment of

samples as well as the use of appropriate testing algorithms. Therefore, it is suggested to

opt for a lump sum provided for the pathologist/clinician/biologist/geneticist preparing

and shipping the sample and another fee for the selection of tumour cells for analysis and

interpretation of tests’ [77].

‘Increase/promote the adoption of new cost-effective pharmacodiagnostic

technologies/validated biomarkers quickly into hospitals. Explore the validation of

comprehensive genomic screening methods for replacing individual gene testing’ [92].

REAL WORLD EVIDENCE-CAPTURING INFRASTRUCTURE

Finally, the need for a qualitative real world evidence-capturing infrastructure is cited in

the set of studies. Data sharing networks involving all stakeholders at national and

international level, providing clear guidance for the collection, maintenance, and storage

shared data, should be promoted.

Several studies plead for the introduction of performance-based agreements or risk-

sharing schemes requiring prospective data collection about the treatment before and

after approval [11, 30, 37, 88]. ‘Clear legislation allowing risk sharing agreements

recognizing the typical characteristics and uncertainties of PM must be put in place’ [39].

‘Real life data need to be collected, in the short to mid-term via registries within public

private partnerships and in the long run via electronic patient records. The datasets

should be more harmonized and standardized in order to deliver similar and comparable

data in Europe’ [43]. Or, ‘real life data collection is needed to observe the outcomes, the

consequences (of true and false positive and true and false negative results’ [39].

‘Promote data-sharing networks involving all the stakeholders at the national and

international level and provide clear guidance for the collection, maintenance, and

storage of such shared data’ [94]. We should be ‘refining the legal framework for the

design, management and usage of biobanks’ [95].

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‘In order to allow for a correct evaluation of new techniques and technologies, clinical

variables and variables relating to quality of life must be registered in specially designed

databases’ [12].

‘The use of e-Health should be stimulated in all Belgian hospitals to gather and couple

data from different domains. The registration of data regarding PM should be considered

as an application of e-Health’ [24].

‘Indicators for monitoring the effects of reimbursement decisions of drugs should be

developed or refined in further research’ [56].

4.3 Conclusions

Summarizing our study of the current disjoint Tx/Dx authorization and reimbursement

processes and a review of previous studies studying access to PMx in Belgium we can

conclude that;

1. Tx and CDx market access approval and reimbursement decision-making should

be synchronised and be harmonized within the European and National healthcare

decision systems.

2. The pharmaceutical product and diagnostics budgeting process should be revised

to become horizon scanning-based, technology demand-driven and transversal

(i.e. taking a holistic health care system view) in nature;

3. Early payer involvement in the pharmaceutical PMx innovation process is needed

to expedite decision making on market access and facilitate pricing negotiations;

4. A qualitative cost-efficient diagnostic lab testing environment needs to be set up

and maintained.

5. A qualitative real world evidence-capturing infrastructure needs to be set up and

maintained.

In the following we will propose a solution for harmonized and synchronized Tx/Dx

market authorization and reimbursement decision-making (Item 1), and a holistic 5-year

rolling forecast holistic unmet need-driven budgeting system for pharmaceutical

specialties (Item 2).

Although based on this review of previous studies some recommendations will be

formulated on early payer involvement (Item 3), quality of diagnostic testing

infrastructure (Item 4) and real world evidence-capturing infrastructure (Item 5) they

will not be further elaborated upon in this study. They can be the subject of further

studies focussing on how adaptive licensing (Eichler et al., 2015; Eichler et al., 2012) and

the organisation and health economics of managed entry agreements for PMx (Ferrario &

Kanavos, 2013) should be dealt with in Belgium.

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5. Towards a synchronized PMx/Dx market

authorization and reimbursement process

Although several countries like France, Germany, Spain and Italy evaluate Tx and Dx in

separate processes, a synchronized Tx/Dx market authorization and reimbursement

process as used in the UK, integrating the evaluation of the companion diagnostic into

the technology appraisal of the associated pharmaceutical drug is believed to avoid

access delays or inconsistent reimbursement decisions (Bücheler, Brüggenjürgen, &

Willich, 2014).

The NICE institute (UK) developed its Diagnostic Assessment Programme (DAP) to give

guidance in evaluating medical technologies, in particular for diagnostic tests where such

evaluations are complex. One of the aims of the DAP is to “improve rapid and consistent

adoption of innovative clinically and cost-effective diagnostic technologies”. The Dx

qualified for evaluation in the programme are as defined in EU directives, i.e. 93/42/EEC

(medical devices), 98/79/EC (IVD medical devices) and 90/385/EEC (active implantable

medical devices). Genetic tests are covered by the Programme as well, provided they fall

within the scope of European IVD directive42.

Inspired by DAP’s five cases and in collaboration with UNAMEC and pharma.be we

developed a set of four cases proposed to be used for access and reimbursement

decision making in the Belgian health care system. As will be explained in more detail

further on, three of the four cases are proposed to be decided by a new to-be-created

joint CRM/TMC working group, a fourth case is to be decided by the TMC.

5.1 The need for a harmonized and synchronized evaluation

process

Innovative medicines are being evaluated on EMA level based on criteria such as efficacy,

safety and relative efficacy. However, there is a need for further harmonization as the

local HTA agencies and other competent bodies also assess these criteria but now in

connection with the local medical needs, meaning that it should be avoided that the same

exercises are performed at country level with limited resources and no additional value

creation.

Therefore, to speed up the development of innovative medicines and to ensure that

complementary access and reimbursement evaluations are carried out, the EMA proposes

to assess these local medical needs together with the European medical needs before

market authorization is granted by EMA, i.e. joining the scientific advice (SA) with the

Health Technology Assessment (HTA) (Figure 17). This proposed initiative is the so called

Adaptive Pathways Initiative (API). Notice that here the HTA for diagnostic tests is not

integrated in this joint SA-HTA.

In a recently proposed Joint Initiative for Medicine (JIM) the scientific advice during the

development of the drug will in this case join forces with the HTA. Relative efficacy and

effectiveness, payment and reimbursement is then negotiated on national level and can

begin immediately after market authorization is granted, meaning that patients get

earlier access to the medicines (Table 7).

42 NHS, “The NICE Diagnostics Assessment Programme manual.,” National Institute for Health and Clinical Excellence, Manchester, 2011.

46


Figure 17: Joint Scientific Advice, an initiative aiming to speed up the development of

innovative medicines to achieve earlier patient access.

(source: Hans-Georg Eichler – Senior medical Officer EMA)

Table 7: Establishing harmonization of the market authorization assessments in Europe

by integrating JIM (Joint Initiative for Medicines).

(source: Prof. Dr. L. Annemans, Ghent University, IPPC Rome, 2015) CURRENT FUTURE

Assessment criteria for innovative medicines

Centralized Local Integrated Local with exchange

EMA HTA and competent bodies

‘Joint Initiative for Medicines’ (JIM)

HTA bodies and competent bodies

Efficacy

Safety

Relative efficacy ()

Relative effectiveness

EU medical need

Local medical need

Ethical and social

aspects

Cost-effectiveness

Budget impact

Organizational aspects

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5.2 Need for concertation between CRM and TMC in a joint CRM-TMC evaluation group

Currently, the advice about the reimbursement of diagnostic tests and the

reimbursement of the targeted therapies is provided by two committees. The separate

evaluation of Tx and Dx are performed by the CRM and TMC respectively, without any

connection between both procedures. Diagnostic tests have a great influence on the

health outcome of the therapies as well as is on their budget impact. This makes it

essential to take both into consideration during the scientific and economic evaluations.

This means that there will be a need for a joint CRM-TMC evaluation in the case of PMx

evaluation. Although the cooperation of the CRM and TMC would result in a joint

reimbursement advice file for the drug-Dx ‘package’, the healthcare budgets for both the

Tx and Dx can be kept separate. Moreover, the reimbursement files of the Tx and Dx will

be submitted separately by the pharmaceutical company and diagnostic company

respectively. Both dossiers should be evaluated in a joint CRM and TMC working group,

acting in concerted practice. It should also be stressed that in these joint CRM and TMC

decisions one has to consider the cost-effectiveness and, if feasible, the budget impact

for the full health care system.

5.3 Discussion of the four cases

In collaboration with UNAMEC and pharma.be the following four Tx/Dx joint decision

making cases were identified to be decided upon in concerted practice. The first three

cases are used for joint CRM-TMC decision making while the fourth case remains at the

level of the TMC. In the first two cases the pharmaceutical company is considered to be

in the lead, while in the last two cases the diagnostic company will be leading in the

reimbursement file submission process.

Case 1: The drug and Dx are co-developed (the combination is used in the phase

III clinical trials of the drug) and both are bound by market authorization

In the first scenario the Tx-Dx combination is used during their development, i.e. in the

clinical phase III trial of the drug. It is likely that no alternative test options exist for this

new targeted therapy. In this manner, we could consider the drug and the test as a

package throughout the clinical and economic evaluations. In the cost-effectiveness

analysis, one should take into account the budget impact of the medicine that is given to

the selected group of patients, together with the costs of the test performed on the

entire patient population.

Although both are considered as a package, separate dossiers should be submitted to the

assessing committee, which should be evaluated in parallel. With regards to the drug,

the pharmaceutical company submits the reimbursement proposal. The reimbursement

file of the test is submitted by the diagnostic provider (e.g. diagnostic company, genetic

centre, molecular diagnostic centre, etc) and should focus on the specified quality

requirements; i.e. it should be linked to the clinical data of the drug and its medical

value. A budget impact model and cost-effectiveness model should be included in the file

as well. During this parallel process, the CRM and TMC should cooperate in a joint

working group to evaluate both reimbursement proposals in parallel to each other (Figure

18).

An example of this scenario is Zelboraf®, a PMx targeting the biomarker BRAF co-

developed with the BRAF test (which is reimbursed through a generic code). The test was

used in the clinical phase III trial of Zelboraf®. Notice that the laboratories should be

accredited to perform these developed tests. Future therapies targeting PD-L1 (for the

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indications lung cancer and bladder cancer), targeting ROS and RET-mutations (lung

cancer), PIK3CA (breast cancer and mCRC) will follow the same scenario.

Figure 18: Flowchart for case 1: The drug and Dx are co-developed and both are bound

by market authorization.

Case 2: The drug and Dx are independently developed. The drug is a new drug

or has a new clinical indication used with the existing Dx.

In scenario 2, an independently developed drug uses an existing and already reimbursed

test. The drug is either a new therapy which uses the test in its phase III clinical trial or

is undergoing clinical trials for a new indication. Firstly, the evaluation should be

performed as explained in the previous scenario, considering the budget impacts of both

the drug and the test. Secondly, one should take into account that in this case the

possibility exists that alternative test options are available, meaning that these should be

considered during the evaluation as well. Hence, sensitivity analysis typically will be

performed by the providers of these alternative tests to determine the diagnostic

accuracy of each alternative in order to see whether these other tests show equivalent

results to the Dx used in the clinical trial. When this is the case, cost-effectiveness

analysis should be performed for each Tx-Dx combination.

Again, the pharmaceutical company will be responsible to submit the reimbursement file

for the drug it developed or the new indication it wants to apply for. The Belgian

reimbursement nomenclature for tests should be adapted to include this new indication.

All relevant stakeholders can submit such a request to add the indication to the

nomenclature, e.g. the pharmaceutical manufacturer, the diagnostic manufacturer,

physicians, etc. (Figure 19). Notice that the diagnostic companies are responsible

themselves to perform the sensitivity analysis to show equivalent results obtained by

their alternative existing tests.

Today, the price and the fee of a test is only being indexed. Extending the test’s volume,

i.e. including more patients that qualify for being tested with e.g. the HER2 test, means

that actually the price of the test should be questioned which will have an impact on the

49


reimbursement level (assuming that the test is in all indications reimbursed at the same

level).

The case of Olaparib, acting against cancers in people with hereditary BRCA1 or BRCA2

mutations would be an example. Another example is Herceptin®, that extended its

indication to HER2 amplified gastric cancer patients. Although the test is reimbursed for

this additional indication, the fee is not of the same level as for the breast cancer

indication. Hence, the Belgian nomenclature should be adapted in this case to include the

reimbursement of the HER2 tests at the same level for gastric cancers as it is for breast

cancers. As indicated before, several drugs in clinical phase III are targeting existing

mutations in new indications, such as KRAS or BRAF in lung cancer. Possible corrections

for the increased volume would be recommended. In the future, it is possible that drugs

broaden their indications to an indication with a mutation that is already covered by, for

example, an existing Next Generation Sequencing (NGS) panel.

Figure 19: Flowchart for case 2: The drug is a new drug or has a new clinical indication

and uses the existing Dx in its phase III clinical trial.

Case 3: The drug and Dx are independently developed, a new or alternative Dx

can improve the drug outcomes and is added in the drug label.

Thirdly, a Dx is developed independently from the drug, but has the possibility of

improving the drug outcomes. This means that during the development of the drug, no

test was used in its clinical phases and hence no phase III clinical utility evidence will be

available for the test. In this manner, sensitivity analysis should not only be performed

on the diagnostic accuracy of the Dx, but on the budget impact of the Dx as well in order

to investigate whether the Dx has a clear added value. As the test will be added to the

drug label, the patient population qualified for the specific drug can increase when the

drug was already targeted or can be reduced when the drug was a treat-all therapy.

The challenge in the latter is to create clear incentives for the pharmaceutical industry in

order to perform further investigations to include the mandatory testing of an additional

biomarker to the drug label. A possible incentive could be to increase the response rate

level of a drug to reach (currently about 30%), meaning that in some cases the

pharmaceutical companies would be forced to investigate whether a biomarker can

improve the outcomes. Another incentive for the industry to invest in further

investigations is when the indications can be added to the list of unmet medical needs. Of

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course, it is not necessarily (only) the pharmaceutical company that can do such

investigations. During the evaluations cost-effectiveness analysis should be performed on

the drug-Dx combination.

As before, a separate reimbursement dossiers for the Dx should be submitted to the CRM

and TMC cooperating working group. The specific dossier for the test can be submitted by

the diagnostic company with a possible cooperation with the pharmaceutical industry or

the other parties that performed the additional investigation. The drug label will be

adapted to add the mandatory use of the test to the reimbursement conditions (Figure

20). Notice that the qualified patient population for the drug can be either increased or

decreased by this procedure, depending on whether the drug was originally a targeted or

treat-all therapy respectively. This could mean that the price of the drug can be

questioned due to volume changes. For this an additional file should be submitted to the

CRM, which can be done by different stakeholders.

For example, in the case of Erbitux® and Vectibix® testing for NRAS mutations improved

the drug outcomes. Initially, Erbitux® and Vectibix® were only reimbursed for KRAS wild-

type patients. Independent publications showed that within the group of KRAS wild-type

patients, patients with NRAS mutation showed similar, low clinical outcomes as patients

with KRAS mutations. The EMA-label and international guidelines for Erbitux® and

Vectibix® now include “RAS-testing” instead of only KRAS testing. This should result in a

new reimbursement dossier for NRAS for an existing drug. Further expansion of relevant

genes or exons for diagnostic tests for existing drugs are expected in the future, meaning

that this scenario is really up to date.

Figure 20: Flowchart for case 3: The drug and Dx are independently developed, a new or

alternative Dx can improve the drug outcomes and is added in the drug label.

Case 4: The Dx is developed independently and offers potential to improve

targeting of existing drug(s)

Case 4 is much like scenario 3, with that difference that the independently developed test

improves the targeting of the already reimbursed indication and biomarker of the existing

drug, instead of adding a new condition to the drugs indication. In this scenario,

“improving the targeting of the drug” can be defined as (1) the improvement of the drug

outcomes, e.g. due to better quality, sensitivity and specificity; (2) the improvement of

the affordability due to lower costs although having a similar outcome; (3) the

improvement of the speed of detecting the mutations and/or decreasing the hands-on

51


time; (4) a combination of the three improvements. There is a high possibility that

multiple drugs exist that target that specific biomarker. Notice that there will possibly be

no evidence of clinical utility for this Dx (linking diagnostic test results to final patient

outcomes). The development of this Dx can thus improve the targeting of all these drugs.

As before, sensitivity analysis should be performed on the diagnostic accuracy and the

budget impact of the Dx and cost-effectiveness analyses should be done on each drug-Dx

combination.

The diagnostic company should submit a specific reimbursement file to the TMC, which

should evaluate the diagnostic accuracy of the test together with the cost-effectiveness

of each drug-Dx combination (Figure 21).

OncotypeDx and Mamaprint are two examples that assess the need for chemotherapy

compared to hormone therapy alone in breast cancer. In contrary to the first two cases,

where a specific test has to be performed in order to validate the use of a therapy, these

techniques decide which treatment is most suitable. NGS is another example for this

scenario. Complete DNA sequencing allows for direct inclusion of new target mutations

based on guidelines or literature. In the future, drug resistance monitoring will be

possible through the testing of mutations in plasma, i.e. “cell-free DNA” or liquid

biopsies. An example of a liquid biopsy is the testing of the human blood. This will make

testing more easily to perform and will guide changes in therapy.

Figure 21: Flowchart for case 4: The Dx is developed independently and offers potential

to improve targeting of existing drug(s).

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5.4 Conclusions

In the proposed decision system the CRM and TMC, in a joint working group decide in

concerted practice on PMx access and reimbursement based upon the four cases and

following the present CRM timelines.

The reimbursement files of the Tx and Dx will be submitted separately by the

pharmaceutical company and the diagnostic provider respectively. Both budgets can be

kept separate but in alignment by evaluating the dossiers in parallel and in connection

with each other.

Making the distinction between co-developed and independently developed Tx and Dx the

four cases specify the responsibilities of submitting parties and decision bodies. In the

first two cases the pharmaceutical company is considered to be in the lead, while in the

last two cases the diagnostic company will be leading in the reimbursement file

submission process.

The new joint decision making system will improve the quality of reimbursement

decisions with value-based pricing as a basis and access timelines made by the TMC,

whilst executing them in concerted practice with the CRM.

A set of guiding principles for concerted CRM-TMC decision making for initial and

subsequent indications should be worked out taking as a basis the four cases mentioned.

Market authorization and reimbursement decision for Dx should be conducted beyond the

present CE label and ISO certification. They should pass a national HTA.

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6. Towards a 5-year horizon scanning-based

transversal pharmaceutical specialties budgeting system

As a general principle, drug-based therapy forecasting and budgeting systems should

direct means to those therapeutic areas where a high share of disease burden in society

is matched by promising innovative therapies. While societal disease burden is the more

stable component, therapeutic innovation is the most difficult to act upon while being

unpredictable in time to access. To fund promising innovative PMx therapies we believe

the present Belgian budget forecasting system for pharmaceutical specialties is too short-

sighted and linear in nature to cope with the exponential raises in budget demand as

presently expected in the oncology PMx domain. Therefore, in this chapter we will

suggest a more advanced 5-year horizon scanning-based transversal pharmaceutical

specialties pipeline forecasting and budgeting concept that will be able to capture and

budget for these expected exponential raises. At a later time, the concept can be

extended to be applicable to diagnostics forecasting and planning.

6.1 Societal unmet need articulation

The starting point of a holistic or transversal budgeting system should be societal need as

evidenced in a politically agreed budget growth factor G and a set of priority unmet

needs to focus on. Methods to determine and prioritize societal unmet need and how this

feeds the budgeting process are not part of this study. Instead, we will focus on budget

availability while being a potentially limiting or inhibiting factor in PMx market access.

6.2 The present pharmaceutical specialties budget and

“buffer” system

Given societal unmet needs, the Belgian NIHDI is responsible for the determination of the

financial needs in the pharmaceutical sector. On a yearly basis and in alignment with

pharma.be they make a technical estimation of the needed budget for the

pharmaceutical specialties on the one hand by evaluating the evolution of the previous

years and on the other hand by taking into account some additional needs. The technical

estimation is then examined by the insurance committee and proposed to the AR

(Algemene Raad) and the Budgetary Committee. The AR approves the yearly global

budgetary objectives for the insurance of health care after consultation with the

representative members of the drug industry, i.e. the Belgian Pharmaceutical Industry

Association (Algemene Vereniging van de Geneesmiddelenindustrie AVGI – pharma.be).

This system is applicable since 2001 on the budget of pharmaceutical specialties. In

other words, the fixed budget for pharmaceutical specialties is based on the estimations

of NIHDI and takes into account new austerities. No similar system exists for the

diagnostic component in PMx, nor for IVD, nor for LDT.

In case the pharmaceutical specialties budget is exceeded a “claw-back” system is in

place financed by the industry as a matter of compensation. Before 2005 this claw-back

system ensured the government that part of the overrun (first 65%, later on 72%) of the

pharmaceutical specialties budget was repaid (Art 191 15° quater §1). This system

evolved into a “buffer-system” where 100% of the overrun with a cap of €100 million is

54


to be repaid by the industry in case of overshoot. It is allocated to the companies

according to their turnovers.

6.3 Towards an advanced pharmaceutical specialties and

diagnostics budgeting system

The present budgeting system provides a one-year forecast of pharmaceutical specialties

expenditure. Although budget projection accuracy is rather high (source: report Deloitte)

we do consider taking only a one year planning horizon to be too short sighted to detect

longer term new product innovation bubbles as seen now in the present day case of

oncology PMx. Also, budgeting for innovation in diagnostics is presently not covered.

Instead, we propose a three-step forecasting & budgeting concept entailing;

1. On an international level, a five-year rolling (i.e. updated every year with the

most recent insights) horizon forecast is built, providing a window on innovation

on the EMA pipeline, taking into consideration probability-adjusted Phase II, Phase

III, and approval stage-compounds.

2. The five-year forecast provides the input for a national transversal budgeting

exercise superimposing this input to the budget needs of the extrapolated present

pipeline, taking a product lifecycle perspective. The proposed transversal nature of

the budgeting system implies that to cater for this total need, savings, de-

reimbursements and potential spill-overs from impacted other healthcare budgets

such as surgery, hospitalisation and radiotherapy are taken into account to

calculate a net yearly need for budget for each of the following years of the

forecasting horizon.

3. The net yearly budget need projection can then be used to calculate the needed

compound annual growth rate (CAGR) G over the forecasting horizon to fund

innovation. If necessary, to fund exponential raises the yearly surplus during the

under-spending years could be used to fund the over-spending years of the

planning horizon.

Step 1: Conduct an international 5-year horizon scan of the upcoming drug

specialties and diagnostics pipeline

To increase horizon scan reliability and robustness, a pharmaceutical specialties and

diagnostics pipeline forecast should be done at an international, possibly European level.

Also, the horizon scan time laps should be fixed at 5 year instead of shorter periods. This

is caused by the fact that in the pharmaceutical industry the time to get certainty about

projected probability of access is too long. Especially now in the oncology PMx case we

described here before where the majority of the pipeline is now in Phase II (Figure 13)

and hence still featuring low access probability and being separated 3 to 5 years from

market access. Appendix III contains the assumptions we made for the horizon scan.

Step 2: Conduct a national transversal budgeting exercise to calculate the net

yearly budget needed to fund the horizon scan-based projected therapy pipeline

To do this, a product lifecycle perspective should be taken to all products in the portfolio.

Following this perspective, a product undergoes 4 phases in its life cycle when it is

approved for reimbursement in Belgium (Figure 22). The first year is the so called

introduction year, where the budget impact of a product follows an uptake profile which

is assumed to be equal to the mean uptake profile of the known products (see Appendix

III). The product then goes into the first 11 years during which its expenses follow a

linear increase. After 12 years of being reimbursed in Belgium, unless still being under

patent, the product is labelled as an “old drug” and undergoes a fixed price decrease of

17%.

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After three years the price cut increases to 19% in stage 343., i.e. after a total of 18

years of reimbursement. On top of these 4 stages the product can lose patent and

expire. This causes an automatic price reduction (entry of reference reimbursement)

equal to approximately 31%-41% (depending on level of reimbursement) on top of the

fixed price decreases, leading to a total of 45,33% up to 52,21% reductions.

As PMx will mostly be classified as class 1 drugs, the patent induced price decrease will

most likely lean to about 41%. Notice that both the fixed and automatic price reductions

give room for competition between the PMx and newer and/or cheaper products,

including generics and biosimilars after patent loss. Further price decreases after 2, 4

and 6 years of patent expiry can result to a total decrease of 54,35% up to 60,73%,

depending on level of reimbursement.

Figure 22: Product Life Cycle in Belgium after reimbursement approval.

As summarized in formula (1), the budget need estimation for the present and upcoming

portfolio consists of determining over the horizon scan timeline the yearly budget Bi

based upon the previous year budget plus the probability-adjusted pipeline and the

potential savings Si from price decreases on “old drugs” and agents facing patent expiry

within the next five years. Provided a holistic or transversal budget impact analysis has

been made for the innovative PMx, projected spill-overs from other budgets could be

taken into account to fund innovation. Finally, an error term takes into consideration the

difference between projected and real budget impact. This latter term can obviously only

be taken into consideration if the necessary real world evidence infrastructure is in place

to effectuate this analysis.

(1)

With fi, Gi < 1 the uptake factor and growth factor respectively and pj (j = phase 2,

phase 3 or PMA) the probability that the new entries reach the market successfully.

The market uptake factor fi reflects the growth in expenses of the existing portfolio, as

was shown in Figure 14 for the PMx, not including the new pipeline. As we will

43 In case of biological products a fourth stage can be added after 18 years of reimbursement leading to a 25% price decrease for the product in that year compared to the first year of reimbursement, although the reference reimbursement does not apply for these biologicals.

56


hypothesize the growth factor to be constant throughout the 5 years, we will leave the

yearly index for this parameter behind.

Assuming that f < G, the following should be true to have a sustainable budgeting

system using a rolling five-year horizon forecast:

(2)

In other words, in formula (2) we can verify that the budget impact of the innovative

therapies (new entries) corrected by their access probability, plus the existing

reimbursed product portfolio over the forecast horizon of five years, should be smaller

than or equal to the cumulative savings over the same time period from the existing

product portfolio together with the transversal budgets potentially coming from other

areas, and a potential raise of the budget. In concept, the budgeting exercise should first

try to finance innovation by savings and spill-overs before one considers raising the

budget. The use of this formula can be extended to all medicinal products or even

extended to other sectors.

Budget simulation 2015 – 2020 using the proposed budgeting system

Figure 23 summarizes the results of a simulation of formula (1) using data covering the

2005 – 2013 period on NIHDI expenditures for each of these PMx (see Appendix III for

details). Notice that in this calculation, according to formula (1), no cannibalisation of

existing PMx by new entries resulting in de-reimbursement was taken into account.

Taking a 5-year planning horizon we see that the extra cumulative sales from the current

PMx portfolio and new innovative PMx therapies amounts to €616M. This increase is

funded by a cumulative release of €408M composed of current PMx portfolio savings

only, which accounts for 66% of the increase. Taking a 3-year planning horizon, expected

release can fund 84% of the increase hence showing a more balanced forecast. So note

that for this calculation we kept the transversal effect of spill-overs at zero.

If no growth of the conventional medicine (non-PMx) budget is assumed this would mean

that €208M of de-reimbursements and spill-overs accumulated over the 5-year planning

horizon would balance the budget. If the conventional medicine budget would be allowed

to grow on top of the PMx innovation pipeline44 then €461M of de-reimbursements and

spill-overs would be needed over the 5-year planning horizon for the total pharmaceutical

specialties budget not to raise from its starting level of the planning horizon.

Mark that taking a 5-year planning horizon covers best the uncertainty profile of the

innovative therapy pipeline. Instead, taking a 3-year planning horizon the extra

estimated sales is almost fully (84%) covered indicating no upcoming problems although

the pipeline does predict a bubble coming up. Therefore, we conclude that taking a

planning horizon of 3 years will still lead to myopic planning behaviour and potentially not

being prepared to cater for upcoming budget overruns. Hence the choice for a 5-year

planning horizon.

44 See the scenarios for non-PMx growth explained under Step 3 below

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Figure 23: 2020 projection of funding released through expected mechanistic price cuts

in Belgium and the expected sales from new PMx. The total price reductions over these 5

years can fund up to 66% of the 5 year budget impact of new PMx and present pipeline

indexation.

Step 3: Calculate the net needed pharmaceutical specialties budget growth rate

needed to finance innovative therapies

In this final step we will calculate, based on formula (2) the growth of the total

pharmaceutical specialties budget needed to fund the innovative therapy (in this case the

oncology PMx) pipeline only, after having deducted present portfolio-based savings and

budget spillovers (when a transversal budget is in place). We consider G as the constant

growth rate G over the planning horizon, hence the CAGR (Compact Annual Growth

Rate):

(3)

The budget impact of PMx on the total RIZIV expenditures for pharmaceutical specialties,

including all possible disease areas, is shown in Figure 24 by the green area. As shown,

targeted therapies (green area) contributed only for 1,6% to the total expenses in 2005,

increasing to 5% in 2013 and estimated to be 8,9% to 9.5% of the total pharmaceutical

specialties budget in 2020.

The total non-PMx budget is shown in light blue. The dark blue area indicates the

uncertainty range for this non-PMx budget. While its detailed analysis was not part of this

study but needed to calculate the CAGR required over the planning horizon to fund the

oncology PMx innovation pipeline, we considered two scenarios;

Scenario 1: The non-PMx budget does not grow (G non-PMx = 0%) from its 2015

position, then the total forecasted pharmaceutical specialties sales in 2020

amounts to € 4,284 Million representing the lower bottom line of the dark blue

area.

Scenario 2: The non-PMx budget keeps on growing at the yearly rate at which it

grew between 2014 and 2015 –based on the average of the pharma.be and NIHDI

projections– (G non-PMx = 1.26%), then the total forecasted pharmaceutical

specialties sales in 2020 amounts to € 4,535 Million.

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Taking into account these two scenarios for the non-PMx budget part, and the

uncertainty-adjusted PMx innovative pipeline, the composed pharmaceutical specialties

budget is forecasted to be in the € 4,410 M ±126 M range45.

Figure 24: Projection of the RIZIV expenditures of oncology PMx and non-PMx (total

pharmaceutical specialties) over a period of 7 years with a G equal to zero, equal to the

current value and equal to the needed value.

Using formula (3) we can now calculate that to make this 2020 budget happen, the

needed CAGR = 1,47% ± 0,58% over the 5-year forecasting period. If the non-PMx

budget growth stagnates over the planning horizon the CAGR equals 0.89%, if instead

the needed non-PMx grows at the above-indicated rate the CAGR equals 2.05%.

Now, to put this result into perspective in Table 8 we take the present one-year planning

view depicting the annual growth rates needed to reach the required budget range

indicated above. It can be verified that only in the Best-case scenario the CAGR would be

an upper limit to the required growth, with the last three falling within range.

However, if the Worst case scenario materializes then the projected growth ranges all fall

within the CAGR range except for 2018-2019 where more than the calculated range is

required.

Table 8: Annual growth rates for realizing a pharmaceutical specialties budget in a

€ 4,410 M ±126 M range.

Gi 2015-2016 2016-2017 2017-2018 2018-2019 2019-2020

Best case 0,65% 0,59% 0,99% 1,32% 0,89% Worst case 1,85% 1,78% 2,15% 2,45% 2,01%

45 It should be clearly noted that this is the result of a simulation exercise based on publicly available data and extrapolation assumptions made and explicated by the research team. It is clear that in reality this budgeting exercise should be conducted in close alignment with industry, preferably at an international level, increasing the accuracy of the assumptions made.

59


Hence, instead of acting without foresight in the present system our 5-year horizon

scanning-based transversal budgeting method allows to plan ahead and incorporate the

budget need-lowering effect of de-reimbursements and transversally affected budgets

like surgery, radiotherapy, or hospitalisation. As to the latter, provided of course the real

world evidence infrastructure is in place to measure and confirm the real budget impact

of PMx-based innovation.

To cope with the upcoming PMx innovation pipeline, then, the essence of this transversal

way of budget thinking, cutting across budget silos comes down to the choice for the

pharmaceutical specialties budget to grow with a CAGR of 0.89 – 2.05% or to benefit

from €208M – €461M of budget spill-overs and de-reimbursements.

6.4 Conclusions

We proposed a more advanced 5-year horizon scanning-based transversal pharmaceutical specialties pipeline forecasting and budgeting concept that will be less myopic than the present budgeting system and able to capture and budget for the exponential raises to be imminent in the oncology PMx domain.

The core concept of the proposed forecasting and budgeting system for pharmaceutical

specialties is 5-year horizon scanning based, funding innovation in a first step with

present portfolio savings and de-reimbursements, and is transversal in nature i.e. taking

budget impact of innovative medicines in other affected health budgets into consideration

to fill the spending gap. In a second step the remaining gap between innovation and

savings should be funded by budget growth for which a calculation method is specified.

Using the horizon scanning-based budgeting methodology we propose, at present not

taking into account effects from de-reimbursement nor from transversal budget impact,

for Belgium this would mean that, in order to cope with the exponential emergence of the

oncology PMx pipeline the pharmaceuticals specialties budget should raise with a

constant growth ranging between 0,89% and 2,05% per annum over the next 5 years.

Considering the rolling basis of the forecast this will then be revised next year.

Given the size of the budget and the imminent need in the field of oncology PMx, we

suggest to start with the pharmaceutical specialties budget. It can easily be extended to

diagnostics or other health sectors afterwards.

Finally, from an ethical perspective, note that the pharmaceutical budgeting system

should is based on resolving unmet needs and responding to societal preferences,

specifying societal urgency. However, transparency on the proposed budget allocation

system releasing means to the most scientifically-ready areas should be well managed

towards public opinion and societal expectations without giving a guarantee for results.

60

7. Study conclusions and recommendations

Given the promising Precision Medicine pipeline in the Oncology field now becoming

accessible to global markets in the present and immediate future, in this study, we

investigated the challenges confronting the Belgian health care system to provide access

to this disruptive medical technology.

Summarizing, we found that access to variety is not an issue. However, access timing in

comparison to other countries is an issue. Another issue is budget availability to fund an

imminent innovative therapy pipeline in the field of oncology PMx, predicted in our

horizon scan to hit the pharmaceutical specialties budget immediately if it only grows at a

CAGR of 1.5% on top of inflation.

Therefore, we define the following 5 groups of recommendations that are further detailed

below. There is a need for;

1. A synchronized Tx and Dx process for both market authorization and

reimbursement processes

2. A 5-year horizon scanning-based transversal budgeting system

3. Early payer/regulator involvement

4. A qualitative real world evidence capturing infrastructure

5. A qualitative diagnostic testing infrastructure

A synchronized Tx and Dx process for both market authorization and

reimbursement processes

A joint CRM-TMC working group evaluation acting in concerted practice should be

set up to evaluate PMx cases resulting in a joint reimbursement advice file for the

drug-Dx ‘package’. The reimbursement files of the Tx and Dx will be submitted

separately by the pharmaceutical company and the diagnostic provider (concerning

either IVDs or LDTs) respectively. Both dossiers should be evaluated in parallel but

in connection with each other.

Joint CRM-TMC decision making should be based on the four cases specified above.

Guiding principles for concerted CRM-TMC decision making for initial and

subsequent indications should be worked out for the Belgian health system

situation. The use of competitive evaluations should be promoted and be part of the

guiding principles.

Value-based pricing must be the basis for reimbursement file submission and CRM-

TMC decision making.

Relative effectiveness, pricing and reimbursement are negotiated by national

authorities. Ideally, they can start immediately after EMA market authorization. The

EMA decision regards safety and efficacy while the national decision regards relative

efficacy and national (transversal) budget impact.

The joint or parallel Dx and Tx payment and reimbursement proposal following the

four cases should be formulated within 180 days of file submission.

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A 5-year horizon scanning-based transversal pharmaceutical budgeting system

The pharmaceutical budgeting system should be based on resolving unmet needs

and responding to societal preferences, specifying societal urgency. These are

expert-formulated decisions.

To capture the scientific evolution a 5-year rolling forecast should be conducted in

collaboration with the pharmaceutical industry. Ideally this is conducted on an

international or European level.

Transparency on budget allocation should be well managed toward public opinion

and societal expectations. However, it should not be the basis for setting

expectations towards patient populations. The budgeting system should release

means for innovation directed to the most scientifically-ready areas without being

able to give a guarantee for results.

Conducted at national level only, a horizon scanning transversal budgeting system

is used as input to a 5-year rolling (i.e. yearly-adjusted) budget forecast exercise.

Savings take into account product life cycle-based adaptations to prices and de-

reimbursement of actual medications.

Budget spill-overs, calculated from BIAs, are taken into account releasing cross-

budget lines means for innovation, leading to better use of scarce resources. The

transversal system takes into consideration spill-overs from surgery, radiotherapy,

and hospitalisation.

Early payer/regulator involvement

Initiatives increasing early payer and HTA advice involvement in clinical

development decision making should be stimulated. Early advice is scientific in

nature and hence dealing with concerns on comparators and end points, pragmatic

(i.e. better attuned to real-life evidence) trials not being too selective in study

populations.

Current Art 81, 81bis and ETA/ETR unmet need initiatives should be further

pursued and expanded providing early access and early visibility on the most value-

adding medical technology innovation.

Early dialogue should also be clear on the unmet clinical need and its implications

for further development and on the link to post-marketing evidence generation.

To accelerate medical progress, incentives should be created to allow research

institutions to access data and samples to identify better biomarkers for better

patient selection

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A qualitative real world evidence capturing infrastructure

Guidelines should be formulated for test formulation by physicians; request in

which cases, what are the outcomes, what has to happen, which treatments have

to be looked at, which biomarkers to be included in the multiplex test panels.

Provide medical technology companies (biopharmaceuticals and medical

technology) with permanent access to sick funds’ IMA-AIM data. This will facilitate

HTA execution, early payer/regulator involvement, and be instrumental for

transversal budget impact analysis.

A qualitative diagnostic testing infrastructure

Market authorization and reimbursement decisions for both IVD and LDT should be

conducted beyond the present CE label for the first and ISO certification for the

latter. To test the clinical value of the test both should pass a national HTA. To

qualify, LDTs should be subject to an external comparison qualification procedure.

To follow the evolution towards more complex testing a set of ISO 15189 accredited

test centres focussing on multiplex test panels should comply with additional

criteria (minimal volume and minimal quality level beyond accreditation) and official

and frequent EQA.

63

APPENDIX I: Previous study recommendations summaries

We defined five clusters for the recommendations made: (1) the Tx/Dx synchronisation;

(2) pharmaceutical budget determination, (3) early payer/regulator involvement, (4)

diagnostic testing and (5) real world evidence capturing infrastructure.

The Flemish Cancer League

The Flemish Cancer League (VKL) wrote a report (2013) regarding the affordability of

cancer treatments in Belgium. They wrote recommendations for an accessible and

sustainable high quality cancer care, which are formulated below.

1 2 3 4 5

1. The procedures and requirements that apply during medicine

development are very stringent and should be more flexible. The

legislation should seek a new balance between optimum protection of

patient and the rapid availability of the potential benefits of the

treatment for patients with a high medical need.

x

2. When determining their price of new medicines or technologies,

companies sometimes test society’s “willingness to pay”: they set a

very high price and see whether the buyers will follow. The method in

which companies determine the price is not transparent: Therefore,

companies must be obliged to motivate in more detail how they

determine the price of a treatment. The government must be able to

check whether the price is fair and does not result in exorbitant profits

for the company.

x x x

3. The negotiations about the price of a new medicine must take place

more at EU level. This makes the insurers and governments involved

stronger in their negotiations to force a fair price from the company. A

supra-national solidarity mechanism should be included to ensure that

the negotiated price does not result in inequality between rich and poor

countries.

x x x

4. It is important to investigate whether the policy makers in healthcare

can set an upper limit for what they will reimburse for an additional

healthy year of life. This amount can vary as a function of the medical

need and the severity of the disease and the domestic product.

x x

5. There are many new and expensive cancer medicines in development.

If two or more targeted cancer therapies reach the market that have

the same molecular target and a similar efficacy, the government

should organise a public tender process for these treatments, in order

to lower the price.

x x

6. Companies decide for which medicines and which indications they wish

to apply for reimbursement. The government does not know exactly

what to expect. Therefore, a horizon scan should be performed of the

new medicines or technologies in development, e.g. by surveying the

on-going phase III studies and questioning companies about the

products that are being developed and for which they will soon apply for

reimbursement. The government can then plan ahead as to the budget

that will be available for the new products, given the limited resources

and the medical needs. Companies are motivated to think about how to

price new products in such a way that they fit within the budget plans

of the government.

x

7. National agencies that are responsible for the reimbursement decision

still perform many double tasks in determining the relative efficacy and

x x

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cost-effectiveness of medicines and other new technologies. They

should cooperate more in the evaluation of new medicines and other

new technologies and for initiatives such as the horizon scan. European

collaboration can result in savings in time and money and a more equal

access to new treatments. The collaboration should also result in

transparent information about the price of new treatments, about the

reimbursement indications and about the periods taken for the

reimbursement decisions in the various EU member states.

8. In PMx, a diagnostic test determines whether it is useful to administer a

targeted medicine to a certain patient or not. Currently, the advice

about the reimbursement of the diagnostic tests and the reimbursement

of the targeted medicines is provided by two separate committees. This

advice should be given by one committee.

x x

9. The procedure in the Commission for the Reimbursement of

Pharmaceuticals (CTG) to advise on the reimbursement of a new

medicine can be improved, for example with regards to the use of

external expertise. The CTG of oncological experts must be able to

provide independent advice about the efficacy of and the medical need

for a new cancer medicine, based on a combination of aspects from

medical practice and scientific data.

x

10. Medical science - and oncology in particular - is evolving rapidly.

Expensive treatments that were useful several years ago may now have

lost their therapeutic value. Therefore, a procedure must be set out to

re-evaluate reimbursed treatments at regular intervals based on

scientific evidence. If necessary, the reimbursement should be stopped

or amended following consultation with the various parties involved.

x

11. If there are no robust data about the efficacy, the cost-effectiveness or

the safety of a new treatment, or if a new treatment has a significant

impact on the healthcare insurance budget, this can result in a delay in

the reimbursement of new treatments. This is problematic if these

treatments provide for a large therapeutic value. In order to make

these treatments available rapidly with limited and controlled risks to

those paying for the treatment, the government should further analyse

and evaluate various innovative contract options and implement these if

indicated. An example is the “performance based agreements”. This

requires systematic, prospective data collection about the treatment.

The reimbursement is adjusted according to the data that was collected.

x x x x

12. In order to allow for a correct evaluation of new techniques and

technologies, clinical variables and variables relating to quality of life

must be registered in specially designed databases.

x

13. In medical practice, techniques are sometimes introduced whilst the

benefits are still begin discussed at the time of introduction. As long as

the benefit of a technique is still being studied, the use of the technique

should be subjected to the principles that generally apply to clinical

studies. (e.g. free for the patient, clear information via the informed

consent from about the experimental nature of the technique).

x

14. Compassionate use and medical need programmes mean that patients

with a severe disease for which is currently no satisfactory treatment

have free access to (as yet) unregistered or (as yet) non-reimbursed

treatments. An accessible central database of “compassionate use” and

“medical need” use of medicines should be made available to ensure

that more patients gain access to these systems and to gain a better

insight into the clinical efficacy for the medicines.

x

15. There are still many options to save money on products that have

already been reimbursed. The use of the cheapest varieties of

medicines with the same therapeutic value should be stimulated. Day

hospitals should implement the system of cheap prescription that is

x

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already in existence in public pharmacies.

16. The administration of various cancer treatments – such as the new

targeted medicines – demands a lot of experience. Some hospitals

perform very few of the more complex and rare treatments, even if it

has been proven that this low volume has a negative effect on the

quality. Therefore, reference centres for the treatment of cancer

should be recognised. A hierarchical structure can be set up with

reference centres where the treatment is planned and local centres

where certain aspects of the treatment are performed. Centralization is

required for other aspects of the treatment, such as complex surgery,

where the expertise of the surgical team is important. The funding of

doctors and hospitals must support close collaboration between

reference centres and local centres.

x

17. Belgium currently does not have a uniform quality system for oncology.

One condition is the integration of 5 elements in a sustainable and

functioning system: 1) clinical practice guidelines and indicators, 2)

effective and feasible data collection, 3) correct data analysis and

interpretation, 4) the option to provide feedback to care providers, 5)

the option to start targeted and corrective measures. We must get to

work on the compulsory implementation of a quality system in

oncology.

x

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NIHDI

In the internship report at RIZIV of Anouck Waeytens (2012), expert

CTG/pharmaceuticals, the challenges for stratified medicine in the Belgian Health care

were described, based upon which recommendations could be formulated.

1 2 3 4 5

18. PMx offers new opportunities regarding the development of new

applications for existing medicines (e.g. review older and cheaper

medicines based on new scientific and genetic knowledge,…), although

the companies are not sensitised to invest in such studies, as these

medicines are cheap and can no longer be patented. Negotiations

between the government, physicians and scientists should take place to

tackle important, non-commercial, clinical problems related to the use

of PM.

x

19. Investments in traditional and clinical research should keep on existing

or even be extended. Mostly phase III and IV studies and the

investigation of the impact on the public health should be stimulated.

x x

20. To evaluate and determine the pharmaceutical policy, information

regarding historical characteristics, the stadium and the localisation of

the tumour during the diagnose should be registered as well as data

regarding the status of the biomarkers (not tested/positively

tested/negatively tested/…), the administered treatment and the

disease progression (recovery/ stabilisation/ progression).

x

21. To maximise the efficiency of PMx the predictive value of biomarkers

should be validated. The research into biomarkers should be integrated

into the evaluation of the target in the beginning of the study. Once

implemented, the clinical study should continue the biomarker research,

parallel to the clinical development programme.

x

22. Today, and even more in the future, a whole range of biomarkers

should be evaluated per cancer type. Testing each of these individually

will demand a lot of tumour tissue and will increase the costs drastically.

Multi-biomarker tests will be a solution for this, combining a couple of

markers in one array.

x x

23. The problem to develop medicines and companion diagnostics in

tandem is that clinical useful biomarkers are only determined late in the

development process of the Tx. Tx with a CDx are frequently asked by

EMA and the government to undergo prospective clinical studies. The

companies, EMA and the FDA advocate for early consultation in the

development of PM, in order for companies to have a clear view of what

the EMA/FDA deem necessary for a possible registration.

x

24. The use of e-Health should be stimulated in all Belgian hospitals to

gather and couple data from different domains. The registration of data

regarding PMx (see recommendation 20) should be considered as an

application of eHealth.

x

25. No additional information is asked regarding PMx for the submission of a

reimbursement proposal, although this would increase the clearness and

transparency of the proposals. The guidelines for the submission and

evaluation of a dossier at the CTG should be supplemented with specific

elements for PMx.

x

26. When initially a higher price was set based on a small patient

population, it is difficult to decrease the price proportionally when

additional indications are requested. For the first allocation of a

reimbursement basis of the stratified medicine one should take into

account the future additional indications.

x x

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27. Due to higher end prices of PMx it is very important to have an as

realistic as possible view on the epidemiology of Belgium, including the

subpopulations which will be positive for the biomarker. For this, the

data mentioned in recommendation 20 above is necessary. Budget

impact calculations should also take into account PMx which will not

replace existing medicines.

x

28. Frequently, different tests for the same biomarker are on the market

(IVD or home-brew) and the choice of the test is free. There is need for

standardisation. It is necessary to demand a high quality performance

of CDx a high concordance of these tests in order to achieve

reimbursement of the PM.

x x

29. The regulation for reimbursement of Tx and Dx is fragmented and the

evaluation is performed by different committees in different ways. There

is a need for official communication between the CTG (or the CTG

board) and the TGR when an application for reimbursement of a PM is

submitted.48

x

30. The cost-efficiency analysis of a PMx should take into account the

diagnostic accuracy and cost of the companion diagnostic. We could

base our analysis on the Diagnostic Assessment Programme (DAP) of

NICE.

x

31. It is not necessary to show cost-effectiveness for each biomarker. Many

proposals are being submitted and it takes a long time to introduce a

new line in the nomenclature. A general rule in the nomenclature for

companion diagnostics will increase the transparency and result in a

time gain.

x x

32. The government should be concerned about the budgetary problems

regarding a monopoly of a company and multi-marker testing. There

are two issues that should be considered during the introduction of a

new general nomenclature rule: the determination of the value of the

CDx and the complexity of the diagnostic.

x x

x

33. Because of the increased complexity it is possible that one prescribes

the wrong tests. One should think about the prospective detection of

emerging biomarkers (a French strategy). A guideline should be

constructed for rational prescriptions of diagnostic tests in the course of

therapy choice.

x

48 The experts who evaluate the reimbursement dossier should already notify the TGR within 8 days when an application for a PM is submitted.

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Ghent University: Prof Lieven Annemans

Professor Lieven Annemans is a health economist at the Ghent University (UGent) and

the University of Brussels (VUB). In a draft position paper (Annemans, 2015),

unpublished at the time of publication of this study report he proposed ten actions to

stimulate access to PM in Europe. His recommendations are listed here.

1 2 3 4 5

34. Companies have to undertake systematically early economic evaluations

(early assessment of economic potentially candidate biomarkers) to

better understand the potential value for money of different diagnosis-

treatment combinations in different indications.

x

35. A general agreement on acceptable flexible/adaptive trial designs need

to be achieved (to allow the identification of optimal biomarkers on a

clinical and economic perspective).

x

36. Early dialogues and joint advice (about the possible methodological and

strategic choices in the clinical development and adaptive pathways)

need to be expanded to meet the specific characteristics of PMx and

should involve repeated meetings.

x

37. Principles of risk management should be systematically applied in the

market authorisation process of PM.

x x

38. The current coverage decision-making processes are not transparent,

fragmented and highly different. Member States should apply integrated

assessment processes and criteria for diagnostic tools and

medicines/devices. This should also translate in the need to assess the

full impact of the PM approach and the absolute avoidance of silo

thinking.

x

39. Clear legislation allowing risk sharing agreements recognizing the

typical characteristics and uncertainties of PM must be put in place. Real

life data collection is needed to observe the outcomes, the

consequences (of true and false positive and true and false negative

results).

x x

40. Horizon scanning is required to better understand the possible future

health care budget impact of PM (forecasting about which PM

innovations to expect In the short to mid-term and which budgets

should be made available for these innovations).

x

41. Organisational measures and financial incentives should be put in place

to encourage the market penetration of truly innovative PM for instance

at regional levels with centres of excellence and quality assurance

systems.

x

42. Training and education about PM is required. x x x

43. Real life data need to be collected, in the short to mid-term via

registries within public private partnerships and in the long run via

electronic patient records. The datasets should be more harmonized and

standardized in order to deliver similar and comparable data in Europe.

x

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Belgian Healthcare Knowledge Centre (KCE 147A, 20A, 240, 100C)

Four KCE studies where investigated. Recommendations from the KCE report Volume

147A (Le Polain et al., 2010) regarding the reimbursement system for medicinal products

are listed below.

1 2 3 4 5

44. Transparency: The evaluation of a product and the appraisal of its

value should be distinguished clearly from each other and should be

carried out in different phases of the reimbursement process. The roles

and responsibilities of the different actors in this should be clearly

defined.

x

45. Transparency: The appraisal and decision processes should be more

transparent and the social criteria’s and appreciation of each of these

criteria during the process should be published to increase the

coherence and responsibility of the decisions.

x

46. Relevance of the decision criteria: There should be a balanced

representation of social preferences in the appraisal process.

x

47. Relevance of the decision criteria: Therapeutic value should be a

necessary, but not sufficient, condition for a higher price or

reimbursement basis. Not enough or lack of added therapeutic value

should lead to an equal or lower reimbursement basis in comparison

with that of the best therapeutic and reimbursable alternative.

x

48. Relevance of the decision criteria: The severity of the disease should

always be considered in the light of the existing alternative treatments.

x

49. Relevance of the decision criteria: To ensure the sustainability of the

system, the value for money, which assesses the reasonableness of

extra costs for extra effects (i.e. cost-effectiveness), should be

discussed during the meetings of the committee of experts and should

be part of the arguments that founds the reimbursement advice.

x

50. Relevance of the decision criteria: In case of uncertainty, the

committee of experts could consider to reduce the estimated level of

added therapeutic value, to reimburse the drug at a lower price, to

enter into agreements for sharing financial or outcome related risks or

to recommend a temporary reimbursement. This should be

accompanied by clear guidelines regarding the kind of evidence that

must be presented for revision and by clear consequences of the

implementation of revision.

x

51. Revisability: Decisions should be revisable, especially in the case of

large uncertainty about the evidence.

x x

52. Revisability: Reasons for revision are: the availability of new possible

treatments (including non-pharmacological), lower efficiency and/or

higher costs than estimated and changes in the economic and/or social

context.

x x

53. Revisability: The removal of products from the reimbursement list

should be a real possibility during revision, if necessary limited to

deletion of specific indications in the case of multiple indications for the

same product.

x

54. Revisability: Major reviews covering groups should be performed in

order to ensure fixed priority for the highest medical, therapeutically

and social needs.

x

55. Enforcement: The performance of the system in terms of transparency,

relevance of decision criteria and revisability of decisions should be

followed systematically.

x x

56. Enforcement: Indicators for monitoring the effects of the

reimbursement decisions of drugs should be developed or refined in

further research.

x x x

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In the following, the recommendations from the KCE report Volume 20A (Hulstaert et al.,

2005) regarding Molecular Diagnostic in Belgium are summarized.

1 2 3 4 5

57. The licensing decree for laboratories performing molecular diagnostic

testing must include a formal accreditation ISO 15189.” This in the

expectation that it will lead to centralisation and high quality.

x

58. National EQA schemes in molecular biology: where possible

(availability of adequate sample material) the national EQA

organization (IPH) shall organize a scheme for the molecular

diagnostic tests included in the nomenclature: (a) if the number of

participants is > 50 an own scheme will be organized; (b) if the

number of participants is < 50 the scheme will be organized in

collaboration with other scheme organizers.

x

59. The clinical evidence of the test methods is relatively underdeveloped

by the CMDs… To asses a test and implement it in a rational way the

KCE recommends to handle a standardized evaluation framework,

which estimates the diagnostic efficacy and aims the efficiency of the

test in the routine.

x

60. During the evaluation of a new medicine by the authorities (e.g.

RIZIV), one should take into account the necessary diagnostic tests in

the evaluation.49

x

61. Tests for which clinical utility is not yet proven should only be carried

out and financed within the context of research protocols... The

government should invest in the necessary expertise for scientific and

economic evaluation.

X

62. Whether an IVD is clinically useful (having a CE label) is preferably no

longer assigned to the producer, as now is the case for the self-

certification in EU. The concept of ‘gene dossier’ which already exists in

the UK for genetic tests is a possible extension.

x

63. Microbiological tests with a low volume have to be carried out in

reference laboratories for microbiology. The amount should be limited

for reasons of expertise, cost and quality. The selection should be

performed transparently with implemented guarantees to service and

speed of test utilisation.

x

64. The amount of molecular labs can be set beforehand via selection

criteria or not. Offering a complete panel of molecular test for

oncology, mandatory accreditation for these tests and the setting up

service level agreements with the involved hospitals should be a

sufficient threshold.

x

65. The reimbursement of molecular tests should be reviewed regularly, as

well as the indication.

x

66. Duplication of tests and double counting cannot be accepted. x

67. It can be useful to have yearly reliable data of the amount of tested

patients and the amount of performed tests for each of the diagnostic

tests.

x

49 A change in the review process to include information on predictive markers of targeted drugs was implemented recently.

71


Recommendations from the KCE report Volume 240 (Van Den Bulcke et al., 2015)

regarding Next Generation Sequencing (NGS) are listed below.

1 2 3 4 5

68. The different steps involved in NGS panel tests need further

standardization, both for use in routine care and in clinical trials, such

that one avoids rendering different results on the same case when

analysed in different laboratories.

x

69. Labs can decide themselves which (ISO accredited) External Quality

Assessment (EQA) scheme(s) fits their needs (the one more difficult to

pass than the others). EQA for molecular tests in Belgium needs to be

streamlined in a transparent way by WIV-ISP and BELAC.

x

70. The existing EQA results show there is room for quality improvement. x

71. Guidelines are available to improve quality of NGS panel tests but no

generally accepted minimum criteria exists for many aspects.”

“National uniform guidelines should be developed, based on

international guidelines so that the use and requests of molecular

assays is uniform across centres.

x

72. Other factors such as prevalence of the biomarker also play an

important role and should be taken into consideration in the evaluation

of the economic value of a test during cost-effectiveness

investigations.

x

73. Many EU countries including Belgium lack an integrated

reimbursement review of the drug and the companion diagnostic.”-

x

74. There is a need for the health insurance to cope in an efficient way

with new markers, technologies and testing algorithms,… the current

codes and tariffs for reimbursement are quickly outdated.” “Art. 33bis

billing codes cannot cope with the speed of change on-going in the

field of oncology.

x x

75. Genomics-related patient care necessitates a multidisciplinary

approach, with the instalment of so called ‘molecular advisory boards’

or ‘molecular sequencing boards.

x

76. There is a need for a multidisciplinary National Committee that

regularly updates the clinically relevant markers in oncology and

interacts with the National Federal Authorities and reimbursement

institutions.

x

77. The financing system should reward the appropriate collection, storage

and shipment of the sample as well as the use of an appropriate

testing algorithm. Therefore it is suggested a lump sum is provided for

the pathologist/clinical biologist/geneticist preparing/shipping the

sample and another fee for the selection of tumour cells for analysis

and interpretation of tests.

x

78. NGS is a valid technique and fits into the budget. x

79. There is a need for a National Committee that updates a list of

evidence-based markers.

x

80. Further standardisation of the ISO accreditation process and a

common EQA for all Belgian centres is in this NGS domain is needed.

x

81. Attention should be given during reimbursement to test accuracy given

the high importance of test specificity. 50

x

50 Recommendations (78) – (81) are obtained by personal communication (Frank Hulstaert).

72


Recommendations from KCE report 100C (Cleemput et al., 2008) regarding the use of

ICER threshold values in the decision making process.

1 2 3 4 5

82. Although efforts are made to ‘rationalise’ the decision making process

and substantiate reimbursement requests with scientific evidence,

decision making processes in Belgium remain mainly an interactive

deliberation process.

x

83. Clinical effectiveness is the most important scientific criterion used in

the decision making process of both the CRM and the TCI.

x

84. Cost-effectiveness is sometimes considered in the CRM but rarely in

the TCI.

x

85. Budget impact is by both committees considered more important than

the ICER.

x x

73


Boston Consulting Group (BCG)

The Boston Consulting Group investigated and reflected on the Belgian Health care

system in their recent study of 2014. BCG (BCG, 2014) investigated the opportunities in

Belgium to further improve its standards of care, trying to inspire stakeholders and

contribute to further developments. Their recommendations are listed below.

1 2 3 4 5

86. Belgium has to reflect on its overall strategy for innovative drug

treatments. Exploiting some of the current and planned headroom,

would allow Belgium to maintain or even further improve its standards

of care at no additional cost to the system.

x

87. Belgium should accelerate its approval and reimbursement process for

new medicines. Recent steps have been taken in the right direction,

but more efforts are required to close the significant gap with other

Western European countries.

x

88. Belgium should further elaborate risk-sharing schemes, given the

appetite of the industry and initial legal framework in place. Belgium

should further frame and codify the access to and usage of outcome

data, so that outcomes can be assessed more efficiently and

accurately, and ultimately be an enabler for objective, value-based

health care decisions.

x x

89. Belgium should consider alternative funding schemes for relevant

innovative treatments. In parallel to developing its risk-sharing

framework, Belgium can seek inspiration from notable initiatives in

neighbouring countries and craft alternative funding options for certain

classes of new drugs.

x

74


Awada et al. 2013

Paper specifically addressing the challenges of implementing PMx in the Belgian health

care system. We only selected those recommendations from the paper that are relevant

to our research question (Awada et al., 2013)

1 2 3 4 5

90. Contribute at the national and European level to setting up a

streamlined approval process to facilitate co-development of different

drugs as well as drugs and companion diagnostics.

x x

91. Establish a well-tailored, synchronised reimbursement system for both

drugs and diagnostic tests at the national level. In this respect, the

two commissions with separate healthcare budgets should work

together. It should also be stressed that in these decisions the cost-

effectiveness and the budget impact for the full health care system

must be considered.

x

92. Increase/promote the adoption of new cost-effective

pharmacodiagnostic technologies/validated biomarkers quickly into

hospitals. Explore the validation of comprehensive genomic screening

methods for replacing individual gene testing.

x

93. Allow conditional (accompanied by specific requests with regard to

further development and safety) and “reversible” drug approval for

high impact agents at the international regulatory level, mainly based

on early data when a companion diagnostic is available and high

response rates (e.g. >50% antitumour activity in cancer) have been

shown in the target population in early studies, without being

outweighed by inacceptable safety issues, in a population in which

available therapy has limited antitumour activity.

x x

94. Promote data-sharing networks involving all the stakeholders at the

national and international level and provide clear guidance for the

collection, maintenance, and storage of such shared data.

x

95. Refining the legal framework for the design, management and usage of

biobanks.

x x

75


APPENDIX II: List of current molecular diagnostic tests

and the use of Art. 33bis

Source: (Van Den Bulcke et al., 2015)

Gene Aberration type Pathology Phase Sample

types

DNA or RNA or

nuclei

Techniques Time

impl.

Nomenclature

billing codes

Max Reimb.

in

practice

DNA-NGS

possible?

Why not NGS?

Chimerism post-allo-Tx chimerism AL Follow-up BM DNA or nuclei PCR or FISH 0 588814-588825 1 Yes No Distinct indication

ALK / 2p23 translocation ALCL Diagnosis FFPE, FT nuclei FISH 0 588453-588464 3 Yes No Pathology-specific

aberration

MLL translocation ALL Diagnosis B, BM RNA or nuclei PCR or FISH 0 588431-588442 5 No No RNA analysis

BCR-ABL1 / t(9;22)(q34;q11) translocation ALL Diagnosis B, BM RNA or nuclei RT-PCR or FISH 0 588431-588442 5 Yes No RNA analysis

TCF3-PBX / t(1;19)(q23;p13) translocation ALL Diagnosis B, BM RNA or nuclei RT-PCR or FISH 0 588431-588444 5 Yes No RNA analysis

BCR-ABL1 / t(9;22)(q34;q11) translocation ALL Diagnosis B, BM RNA or nuclei RT-PCR or FISH 0 588431-588444 5 Yes No RNA analysis

ETV6-RUNX1 / translocation ALL Diagnosis B, BM RNA or nuclei RT-PCR or FISH 0 588431-588445 5 Yes No RNA analysis

MLL-AFF1 / t(4;11)(q21;q23) translocation ALL Diagnosis B, BM RNA or nuclei RT-PCR or FISH 0 588431-588445 5 Yes No RNA analysis

BCR-ABL1 / t(9;22)(q34;q11) translocation ALL Follow-up B, BM RNA RT-PCR 0 588571-588582 1 Yes No Individual specific

follow-up marker

TCF3-PBX / t(1;19)(q23;p13) translocation ALL Follow-up B, BM RNA RT-PCR 0 588571-588584 1 Yes No Individual specific

follow-up marker

BCR-ABL1 / t(9;22)(q34;q11) translocation ALL Follow-up B, BM RNA RT-PCR 0 588571-588584 1 Yes No Individual specific

follow-up marker

ETV6-RUNX1 /

t(12;21)(p13;q22)

translocation ALL Follow-up B, BM RNA RT-PCR 0 588571-588585 1 Yes No Individual specific

follow-up marker

MLL-AFF1 / t(4;11)(q21;q23) translocation ALL Follow-up B, BM RNA RT-PCR 0 588571-588585 1 Yes No Individual specific

follow-up marker

MLL translocation AML Diagnosis B, BM RNA or nuclei PCR or FISH 0 588431-588442 5 No No RNA analysis

RUNX1-RUNX1T1 / translocation AML Diagnosis B, BM RNA or nuclei RT-PCR or FISH 0 588431-588442 5 Yes No RNA analysis

CBFB-MYH11 / inv(16)(p13;q22) translocation AML Diagnosis B, BM RNA or nuclei RT-PCR or FISH 0 588431-588443 5 Yes No RNA analysis

PML-RARA / t(15;17)(q22;q12) translocation AML Diagnosis B, BM RNA or nuclei RT-PCR or FISH 0 588431-588443 5 Yes No RNA analysis

BCR-ABL1 / t(9;22)(q34;q11) translocation AML Diagnosis B, BM RNA or nuclei RT-PCR or FISH 0 588431-588444 5 Yes No RNA analysis

DEK-NUP214 / t(6;9)(p23;q34) translocation AML Diagnosis B, BM RNA or nuclei RT-PCR or FISH 0 588431-588444 5 Yes No RNA analysis

NPM1 mutation AML Diagnosis B, BM DNA PCR or Sanger 2 588431-588442 5 No Yes

FLT3-ITD mutation AML Diagnosis B, BM DNA PCR or Sanger 2 588431-588442 5 No Yes

CEBPA mutation AML Diagnosis B, BM DNA PCR or Sanger 2 588431-588442 5 No Yes

DNMT3A multiple

mutations

AML Diagnosis B, BM DNA Sanger or NGS 2 588431-588442 5 No Yes

RUNX1 multiple

mutations



types

DNA or RNA or

nuclei

Techniques Time

impl.

Nomenclature

billing codes

Max Reimb.

in

practice

DNA-NGS

possible?

Why not NGS?

RUNX1 multiple

mutations


IDH1 multiple

mutations


U2AF1 multiple

mutations


ASXL1 multiple

mutations


IDH2 multiple

mutations


RUNX1-RUNX1T1 /

t(8;21)(q22;q22)

translocation AML Follow-up B, BM RNA RT-PCR 0 588571-588582 1 Yes No Individual specific

follow-up marker

CBFB-MYH11 / inv(16)(p13;q22) translocation AML Follow-up B, BM RNA RT-PCR 0 588571-588583 1 Yes No Individual specific

follow-up markerPML-RARA / t(15;17)(q22;q12) translocation AML Follow-up B, BM RNA RT-PCR 0 588571-588583 1 Yes No Individual specific

follow-up marker

BCR-ABL1 / t(9;22)(q34;q11) translocation AML Follow-up B, BM RNA RT-PCR 0 588571-588584 1 Yes No Individual specific

follow-up marker

DEK-NUP214 / t(6;9)(p23;q34) translocation AML Follow-up B, BM RNA RT-PCR 0 588571-588584 1 Yes No Individual specific

follow-up marker

IGH B-cel clonality B-ALL Diagnosis B, BM, FT, DNA PCR 0 588490-588501 2 Yes No Distinct indication

IGH B-cel clonality B-ALL Follow-up B, BM DNA ASO-PCR 0 588571-588582 1 Yes No Distinct indication

MYC / 8q24 translocation BL Diagnosis FFPE, FT nuclei FISH 0 588453-588464 3 Yes No Pathology-specific

aberration

IGH B-cel clonality B-NHL Diagnosis B, BM, FT, DNA PCR 0 588475-588486 2 Yes No Distinct indication

HER2 amplification Breast

carcinoma

Diagnosis FFPE nuclei ISH 0 588556-588560 1 Yes No ISH required for

reimbursement

13q14.3 deletion CLL/SLL Diagnosis B, BM, FT,

FFPE

nuclei FISH (+/- cell

selection)

0 588453-588464 3 No No Other preferred

technique

chr 12 trisomy CLL/SLL Diagnosis B, BM, FT,

FFPE


selection)

0 588453-588464 3 Yes No Other preferred

technique

11q22.3 (ATM) deletion CLL/SLL Diagnosis B, BM, FT,

FFPE


selection)


technique

17p13.1 (TP53) deletion CLL/SLL Diagnosis B, BM, FT,

FFPE


selection)


technique

NOTCH1 mutation CLL/SLL Diagnosis B, BM, FT, DNA Sanger 2 588453-588464 3 No Yes

VH multiple mutation CLL/SLL Diagnosis B, BM, FT, DNA Sanger 0 no reimbursement No No Distinct indication

76



types

DNA or RNA or

nuclei

Techniques Time

impl.

Nomenclature

billing codes

Max Reimb.

in

practice

DNA-NGS

possible?

Why not NGS?

BCR-ABL1 / t(9;22)(q34;q11) translocation CML Diagnosis B, BM RNA or nuclei RT-PCR or FISH 0 588512-588523 1 Yes No Pathology-specific

aberration

BCR-ABL1 / t(9;22)(q34;q11) translocation CML Follow-up B, BM RNA RT-PCR 0 588593-588604 1 Yes No Individual specific

follow-up marker

BRAF V600E mutation Colon

carcinoma

Diagnosis FFPE DNA PCR, Sanger,

Pyrosequencing

or NGS

2 588534-588545 2 No Yes

NRAS multiple

mutations

Colon

carcinoma


Pyrosequencing

or NGS

2 588534-588545 2 Yes Yes

KRAS multiple

mutations

Colon

carcinoma


Pyrosequencing

or NGS

1 589713-589724 1 Yes Yes

MYD88 L265P mutation DLBCL Diagnosis B, BM, FT,

FFPE

DNA PCR or Sanger 2 588453-588464 3 No No Pathology-specific

aberration

MYC / 8q24 translocation DLBCL Diagnosis FFPE, FT nuclei FISH 0 588453-588464 3 Yes No Other preferred

technique

BCL6 / 3q27 translocation DLBCL Diagnosis FFPE, FT nuclei FISH 0 588453-588464 3 Yes No Other preferred

technique

IGH-BCL2 / t(14;18)(q32;q21) translocation DLBCL Diagnosis B, BM, FT,

FFPE

DNA or nuclei PCR or FISH (+/-

cell selection)


technique

IGH-BCL2 / t(14;18)(q32;q21) translocation DLBCL Follow-up B, BM DNA or nuclei PCR or FISH (+/-

cell selection)

0 588571-588582 1 Yes No Pathology-specific

aberration

IGH-BCL2 / t(14;18)(q32;q21) translocation FL Diagnosis B, BM, FT,

FFPE


cell selection)


aberration

IGH-BCL2 / t(14;18)(q32;q21) translocation FL Follow-up B, BM DNA or nuclei PCR or FISH (+/-

cell selection)


aberration

HER2 amplification Gastric

carcinoma

Diagnosis FFPE nuclei ISH 2 588534-588545 2 Yes No Other preferred

technique

KIT multiple

mutations

GIST Diagnosis FFPE DNA Sanger or NGS 2 588534-588545 2 Yes Yes

PDGFRA multiple

mutations

GIST Diagnosis FFPE DNA Sanger or NGS 2 588534-588545 2 Yes Yes


types

DNA or RNA or

nuclei

Techniques Time

impl.

Nomenclature

billing codes

Max Reimb.

in

practice

DNA-NGS

possible?

Why not NGS?

1p36 deletion Glioma Diagnosis FFPE nuclei FISH 2 588534-588545 2 Yes No Other preferred

technique

19q13 deletion Glioma Diagnosis FFPE nuclei FISH 2 588534-588545 2 Yes No Other preferred

technique

IDH1 mutation Glioma Diagnosis FFPE DNA PCR, Sanger or

NGS

2 588534-588545 2 No Yes

IDH2 mutation Glioma Diagnosis FFPE DNA PCR, Sanger or

NGS

2 588534-588545 2 No Yes

BRAF V600E mutation HCL Diagnosis B, BM, FT,

FFPE

DNA PCR or Sanger 2 588453-588464 3 Yes No Pathology-specific

aberration

MYD88 L265P mutation LPL Diagnosis B, BM, FT,

FFPE

DNA PCR or Sanger 2 588453-588464 3 Yes No Pathology-specific

aberration

ALK / 2p23 translocation Lung

carcinoma

Diagnosis FFPE DNA FISH or RT-PCR 2 588534-588545 2 No No Other preferred

technique

ROS1 translocation Lung

carcinoma

Diagnosis FFPE DNA FISH 2 588534-588545 2 No No Other preferred

technique

EGFR multiple

mutations

Lung

carcinoma


Pyrosequencing

or NGS

2 588534-588545 2 Yes Yes

KIT multiple

mutations

Malignant

melanoma

Diagnosis FFPE DNA Sanger or NGS 2 588534-588545 2 No Yes

PDGFRA multiple

mutations

Malignant

melanoma

Diagnosis FFPE DNA Sanger or NGS 2 588534-588545 2 No Yes

BRAF V600E mutation Malignant

melanoma


Pyrosequencing

or NGS

2 588534-588545 2 Yes Yes

NRAS multiple

mutations

Malignant

Melanoma


Pyrosequencing

or NGS

2 588534-588545 2 Yes Yes

MALT1 / 18q21 translocation MALT-L Diagnosis FFPE nuclei FISH 0 588453-588464 3 Yes No Pathology-specific

aberration

KIT D816V mutation Mastocytosis Diagnosis B, BM DNA PCR, Sanger or

NGS

2 no reimbursement No Yes

IGH-CCND1 / t(11;14)(q13;q32) translocation MCL Diagnosis B, BM, FT,

FFPE


cell selection)


aberration

IGH-CCND1 / t(11;14)(q13;q32) translocation MCL Follow-up B, BM DNA or nuclei PCR or FISH (+/-

cell selection)

0 588571-588582 1 Yes No Individual specific

follow-up marker

77



types

DNA or RNA or

nuclei

Techniques Time

impl.

Nomenclature

billing codes

Max Reimb.

in

practice

DNA-NGS

possible?

Why not NGS?

TP53 multiple

mutations

MDS Diagnosis B, BM DNA Sanger or NGS 2 no reimbursement No Yes

IDH1 multiple

mutations

MDS Diagnosis B, BM DNA Sanger or NGS 2 no reimbursement 5 No Yes

IDH2 multiple

mutations

MDS Diagnosis B, BM DNA Sanger or NGS 2 no reimbursement 5 No Yes

SRSF2 multiple

mutations

MDS/CMML Diagnosis B, BM DNA Sanger or NGS 2 no reimbursement No Yes

TET2 multiple

mutations

MDS/CMML Diagnosis B, BM DNA Sanger or NGS 2 no reimbursement No Yes

SF3B1 multiple

mutations

MDS-RARS/

RCMD-RS

Diagnosis B, BM DNA Sanger or NGS 2 no reimbursement No Yes

FIP1L1-PDGFRA translocation MPN Diagnosis B, BM RNA or nuclei RT-PCR or FISH 2 no reimbursement No No RNA analysis

CALR mutation MPN Diagnosis B, BM DNA PCR, Sanger or

NGS


MPL mutation MPN Diagnosis B, BM DNA PCR, Sanger or

NGS


CSFR3 multiple

mutations

MPN Diagnosis B, BM DNA Sanger or NGS 2 no reimbursement No Yes

JAK2 exon 12 mutation MPN Diagnosis B, BM DNA Sanger or NGS 2 no reimbursement No yes

JAK2 V617F mutation MPN Diagnosis B, BM DNA or RNA PCR or RT-PCR 1 589691-589702 1 Yes Yes/No Distinct indication

IGH B-cel clonality NHL Follow-up B, BM DNA PCR 0 588571-588582 1 Yes No Distinct indication

IGH-CCND1 / t(11;14)(q13;q32) translocation PCM Diagnosis BM nuclei FISH (+/- cell

selection)


technique

IGH-MAFB / t(14;20)(q32;q12) translocation PCM Diagnosis BM nuclei FISH (+/- cell

selection)


technique

chr 1q duplication/

amplification

PCM Diagnosis BM nuclei FISH (+/- cell

selection)


technique

13q14 (RB1) deletion PCM Diagnosis BM nuclei FISH (+/- cell

selection)


technique

IGH-FGFR3 / t(4;14)(p16;q32) translocation PCM Diagnosis BM nuclei FISH (+/- cell

selection)


technique

IGH-MAF / t(14;16)(q32;q23) translocation PCM Diagnosis BM nuclei FISH (+/- cell

selection)


technique

17p13.1 (TP53) deletion PCM Diagnosis BM nuclei FISH (+/- cell

selection)


technique


types

DNA or RNA or

nuclei

Techniques Time

impl.

Nomenclature

billing codes

Max Reimb.

in

practice

DNA-NGS

possible?

Why not NGS?

SS18 / 18q11.2 translocation Sarcoma Diagnosis FFPE nuclei FISH 0 588534-588545 2 Yes No Other preferred

technique

DDIT3 / 12q13 translocation Sarcoma Diagnosis FFPE nuclei FISH 0 588534-588545 2 Yes No Other preferred

technique

FUS / 16p11 translocation Sarcoma Diagnosis FFPE nuclei FISH 0 588534-588545 2 Yes No Other preferred

technique

MDM2 amplification Sarcoma Diagnosis FFPE nuclei FISH 0 588534-588545 2 Yes No Other preferred

technique

TCR T-cel clonality T-ALL Diagnosis B, BM, FT, DNA PCR 0 588490-588501 2 Yes No Distinct indication

TCR T-cel clonality T-ALL Follow-up B, BM DNA PCR 0 588571-588582 1 Yes No Distinct indication

TCR T-cel clonality T-NHL Diagnosis B, BM, FT, DNA PCR 0 588475-588486 2 Yes No Distinct indication

TCR T-cel clonality T-NHL Follow-up B, BM DNA PCR 0 588571-588582 1 Yes No Distinct indication

78


APPENDIX III: Assumptions made for 2020 PMx

projection

For making the 2020 projection several assumptions were made, checked with experts

to obtain a correct as possible forecast estimation. First of all the DDD uptake profiles

were calculated for each current reimbursed PMx in Belgium (Table 9). This was done by

dividing the price of the next year by the current year:

. The uptake U is hence

the increase in DDDs from one year to the next. In this way the product life cycle of each

medicinal product was retrieved by looking at the evolution in the uptake profiles

starting from the first year of reimbursement to 2013. The mean uptake profile was

calculated, excluding outliners such as Zevalin which is fading after its second year of

reimbursement, and used as the uptake profile for Zelboraf and Xalkori, i.e. two PMx

reimbursed for the first time in Belgium in 2013 and for which no further data was

available.

Table 9: Uptake profiles of the existing portfolio (reimbursed PMx) in Belgium and the

mean uptake profile. Outliners by dying products or other exceptional events were

excluded from the calculation of the mean. Year of Reimbursement

1 2 3 4 5 6 7 8 9 10 11

Herceptin - - - 1,47 1,67 1,30 1,00 1,08 1,10 1,21 1,05

Glivec - - - 1,19 1,11 1,20 1,06 1,04 1,05 1,03 1,03

Mabthera - - - 1,12 1,07 1,15 1,10 1,19 1,11 1,09 1,09

Zevalin 3,50 0,64 0,76 0,53 0,56 0,60 0,83 - - - -

Erbitux 3,21 1,02 0,82 1,53 1,19 0,98 1,00 - - - -

Tarceva 3,85 1,14 1,06 1,07 0,95 1,00 0,97 - - - -

Sprycel 4,88 1,54 1,14 1,20 7,25 0,99 - - - - -

Tasigna 4,47 1,64 1,56 1,90 1,45 - - - - - -

Vectibix 5,77 0,97 0,85 2,96 1,35 - - - - - -

Tyverb 2,89 0,98 1,07 0,97 - - - - - - -

Iressa 5,66 1,38 1,19 - - - - - - - -

Mean DDD Uptake 4,28 1,28 1,20 1,49 1,26 1,10 1,03 1,10 1,09 1,11 1,06

The same could be done to obtain a declining uptake profile for the medicines Cost per

DDD, i.e. the RIZIV/INAMI expenses of each drug in year i divided by the corresponding

DDD in that year. The uptake U now represents the declining Cost per DDD from one

year to the next (Table 10). In calculating the mean, outliners who increased in cost

were excluded. This mean was then used as the standard for the declining cost profiles

for Zelboraf and Xalkori to obtain their Cost per DDD after the first year of

reimbursement.

79


Table 10: Declining uptake profiles of the Cost/DDD of current reimbursed PMx in

Belgium. Outliners are excluded in the calculation of the mean. Year of Reimbursement

1 2 3 4 5 6 7 8 9 10 11

Herceptin - - - 0,93 1,03 1,05 1,00 1,00 1,00 0,91 1,02

Glivec - - - 0,99 1,00 1,00 1,00 1,00 1,00 1,00 0,95

Mabthera - - - 0,98 1,01 1,00 1,00 0,99 0,99 0,99 1,00

Zevalin 0,81 1,79 1,22 1,03 1,00 0,83 0,99 - - - -

Erbitux 1,00 1,00 0,93 0,94 0,99 1,00 1,00 - - - -

Tarceva 1,01 1,00 1,00 1,00 1,00 0,99 1,00 - - - -

Sprycel 1,08 1,00 0,97 1,00 0,18 1,10 - - - - -

Tasigna 1,00 1,00 0,95 0,95 1,00 - - - - - -

Vectibix 1,00 1,00 1,00 0,40 0,78 - - - - - -

Tyverb 1,00 1,00 0,99 1,00 - - - - - - -

Iressa 1,00 1,00 0,99 - - - - - - - -

Mean C/DDD Uptake

0,99 1,00 0,98 0,91 0,87 1,00 1,00 1,00 0,99 0,97 0,99

The mean uptake profiles were used to determine the costs per DDD and DDDs of the

current PMx portfolio in Belgium from 2013 onwards. Only for the three first products

(Herceptin, Glivec and Mabthera) no information was available to forecast these values

after 11 years of reimbursement. For these products the most constant trend of the last

years was extrapolated, as several earlier events can and have turned the trends of the

expenses and DDD around, i.e. patent expiries, new reimbursed entries targeting the

same indications, etc. For Herceptin for example, the rising expenditures changed to a

somewhat less steep trend after 2008 due to the reimbursement of Tyverb in 2009, a

new breast cancer therapy targeting HER2 amplifications.

Completing the forecast was done by including the pharmaceutical pipeline into the

calculations. There were five PMx which were already approved for market access by

EMA and for reimbursement in Belgium before 2015, which were not yet included into

the data of the expenditures received by RIZIV/INAMI. The list of drugs under evaluation

by EMA was explored for targeted therapies and included into the contributing pipeline. A

correction factor of 0,91 was used for the total budget impact of this part of the pipeline

as only 91% of oncology drugs under evaluation eventually receive successful market

approval in Belgium [Paul at al. nature]. The clinicaltrials.gov database was scanned for

PMx in phase 3 and phase 2 as these have a high potential to apply for market approval

and get reimbursement before 2020. In the case of phase 2 drugs we expect the

pharmaceutical companies to apply for early approval after their second clinical phase

has finished. Again, the total budget impact of all phase 3 drugs were corrected by a

factor of 0,7 x 0,91 and all phase 2 drugs with 0,34 x 0,7 x 0,91 as these have a

probability of transitioning successfully from one stage to the next equal to respectively

70% and 34% (Paul et al., 2010)[Paul at al. nature]. Mark that possible new indications

for the current products are not included.

Before estimating the budget impact of the products in the pipeline, the costs per DDD

were calculated per product for each year of reimbursement. This is necessary as we will

take into account the known uptake profiles for each new entry, hence equalize the cost

per DDD of the new product to that of one of the current reimbursed PMx (reference

PMx) while using the DDD at the first year of reimbursement.

(

)

80


With i equal to the year of which we want to estimate the budget impact of the new

product and j equal to the amount of years the new product will be reimbursed in year i.

Hence, the DDD of the reference PMx should be used at j years of reimbursement.

The hard part now is to identify the reference PMx mentioned above and hence the

reference cost per DDD and the DDD as well. When considering a new product in the

pipeline, the reference PMx was equalized to the current used BSC (basic standard care)

for that specific indication and biomarker, which was used before the upcoming of the

new targeted therapy. A new entry targeting HER2 over-expression in breast cancer was

hence set equal to the budget impact of Tyverb. On the other hand, when new entries

target breast cancers with no HER2 gene over-expression, we assumed the DDDs would

be three times the DDDs of Tyverb, as 25% of breast cancers show HER2 gene

amplification while the other 75% do not.(Hamermesh, Selby, & Andrews, 2013)

Indications like orphan diseases for which no current targeted therapy existed yet was

assumed to have the same budget impact as other personalized orphan drugs, i.e. the

mean budget impact of Sprycel and Tasigna were taken. Lastly, other indications for

which no PMx existed yet, such as solid tumours, were assumed to have a budget impact

equal to another product targeting the same biomarker. Mark that not all patient will be

treated with the new therapy and/or not all patient will still receive the previous existing

BSC (when this was already a PMx), meaning that the above analysis is an

overestimation of the reality.

81

Table 11: Assuptions to estimate the expenditures for the pipeline products.

New Drug Indication and biomarker Estimated entry date

Reference drug Reasoning

Products approved for commercialization by EMA after 2013

Perjeta Breast cancer HER2/neu 01/06/2014 Tyverb (Lapatinib) targeting HER2+ breast cancer

- Same uptake profile as Tyverb, DDD of Perjeta in 2014 is equal to the DDD of Tyverb in its first year of reimbursement (2009).

- Price/DDD of Perjeta in 2014 is equal to the price/DDD of Tyverb in 2014.

Bosulif CML Ph+ 01/04/2014 Sprycel (Dasatinib) targeting Ph+ CML

- Same uptake profile as Sprycel, DDD of Bosulif in 2014 is equal to the DDD of Sprycel in its first year of reimbursement (2007).

- Price/DDD of Bosulif in 2014 is equal to the price/DDD of Sprycel in 2014.

Tafinlar Melanoma BRAF V600 01/05/2014 Zelboraf (Vemurafenib) targeting BRAF V600 Melanoma

- Same uptake profile as Zelboraf, DDD of Tafinlar in 2014 is equal to the DDD of Zelboraf in its first year of reimbursement (2013).

- Price/DDD of Bosulif in 2014 is equal to the price/DDD of Sprycel in 2014.

Giotrif NSCL EGFR-TK 01/07/2014 Iressa (Gefitinib) targeting EGFR (-TK) NSCLC

- Same uptake profile as Iressa, DDD of Giotrif in 2014 is equal to the DDD of Iressa in its first year of reimbursement (2010).

- Price/DDD of Giotrif in 2014 is equal to the price/DDD of Iressa in 2014.

Kadcyla Breast HER2 01/12/2014 Tyverb (Lapatinib) targeting HER2+ breast cancer


- Price/DDD of Perjeta in 2014 is equal to the price/DDD of Tyverb in 2014.

Products being evaluated by EMA

Iclusig leukemia PH+,T315I 02/2016 Sprycel (Dasatinib) targeting Ph+ CML

- Same uptake profile as Sprycel, DDD in 2016 is equal to the DDD of Sprycel in its first year of reimbursement (2007).

- Price/DDD in 2016 is equal to the price/DDD of Sprycel in 2016.

Mekinist Melanoma BRAF V600 2016 Zelboraf (Vemurafenib) targeting BRAF V600 Melanoma

- Same uptake profile as Zelboraf, DDD in 2016 is equal to the DDD of Zelboraf in its first year of reimbursement (2013).

- Price/DDD in 2014 is equal to the price/DDD of Zelboraf in 2016.

Imbruvica chronic lymphocytic leukaemia, mantle cell

lymphoma

17p deletion/TP53 9/2015 Sprycel (Dasatinib) targeting Ph+ CML Tasigna (Nilotinib) targeting Ph+ CML

- No reference drug with same indication/biomarker. Imbruvica is an orphan medicine, hence other orphan medicine (Sprycel/Tasigna) are used as reference.

- Same uptake profile as Sprycel/Tasigna, DDD in 2015 is equal to the DDD

of Sprycel/Tasigna in its first year of reimbursement (2007/2008). - Price/DDD in 2015 is equal to the price/DDD of Sprycel/Tasigna in 2015. - The Mean is taken from Sprycel and Tasigna

Lynparza ovarian cancer BRCA1, BRCA2 12/2015– 01/2016

Sprycel (Dasatinib) targeting Ph+ CML Tasigna (Nilotinib)

- No reference drug with same indication/biomarker. Lunparza is an orphan medicine, hence other orphan medicine are used as reference.

- Same uptake profile as Sprycel/Tasigna, DDD in 2016 is equal to the DDD

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targeting Ph+ CML of Sprycel/Tasigna in its first year of reimbursement (2007/2008). - Price/DDD in 2016 is equal to the price/DDD of Sprycel/Tasigna in 2016. - The Mean is taken from Sprycel and Tasigna

Vargatef Carcinoma, NSCL VEGFR/FGFR/ PDGFR

05/2015 Iressa (Gefitinib) targeting EGFR (-TK) NSCLC

- Same uptake profile as Iressa, DDD in 2015 is equal to the DDD of Iressa in its first year of reimbursement (2010).

- Price/DDD in 2016 is equal to the price/DDD of Iressa in 2016.

Ofev idiopathic pulmonary fibrosis

VEGFR/FGFR/ PDGFR

01/2016 Sprycel (Dasatinib) targeting Ph+ CML Tasigna (Nilotinib) targeting Ph+ CML

- No reference drug with same indication/biomarker. Ofev is an orphan medicine, hence other orphan medicine is used as reference.

- Same uptake profile as Sprycel/Tasigna, DDD in 2016 is equal to the DDD of Sprycel/Tasigna in its first year of reimbursement (2007/2008).

- Price/DDD in 2016 is equal to the price/DDD of Sprycel/Tasigna in 2016. - The Mean is taken from Sprycel and Tasigna

Necitumumab NSCLC EGFR 2016 Iressa (Gefitinib) targeting EGFR (-TK) NSCLC



Phase III products

Zykadia metastatic NSCLC ALK 2016 Xalkori (Crizotinib) targeting ALK + NSCLC

- Same uptake profile as Xalkori, DDD in 2016 is equal to the DDD of Xalkori in its first year of reimbursement (2013).

- Price/DDD in 2016 is equal to the price/DDD of Xalkori in 2016.

Onartuzumab NSCLC, HER2 negative gastric cancer

HGF/Met 2016 Iressa (Gefitinib) targeting EGFR (-TK) NSCLC



Talazoparib Breast cancer PARP (BRCA) 2017 Tyverb (Lapatinib) targeting HER2+ breast cancer

- Same indication as Tyverb but other biomarker … - Same uptake profile as Tyverb, DDD in 2017 is equal to the DDD of

Tyverb in its first year of reimbursement (2009). - Price/DDD in 2017 is equal to the price/DDD of Tyverb in 2017.

Binimetinib Melanoma, NSCLC, ovarian, pancreatic

BRAF, KRAS, NRAS

2017 Zelboraf (Vemurafenib) targeting BRAF V600 Melanoma + Sprycel (Dasatinib) targeting Ph+ CML

- Zelbroraf is used as reference for treating melanoma with Binimetinib Same uptake profile as Zelboraf, DDD in 2017 equal to the DDD of

Zelboraf in its first year of reimbursement (2013). Price/DDD in 2017 is equal to the price/DDD of Zelboraf in 2017.

- + Sprycel (orphan drug) is used as reference for targeting ovarian/pancreatic cancer. Same uptake profile as Sprycel, DDD in 2017 equal to the DDD of

Sprycel in its first year of reimbursement (2007). Price/DDD in 2017 is equal to the price/DDD of Sprycel in 2017.

- Both costs are summed.

83

AEZS-108 Endometrial Cancer

LHRH-receptor 2017 Sprycel (Dasatinib) targeting Ph+ CML Tasigna (Nilotinib) targeting Ph+ CML

- No reference drug with same indication/biomarker. AEZS-108 is an orphan medicine, hence other orphan medicine are used as reference.



lenvatinib Hepatocellular Carcinoma (HCC)

VEGFR, FGFR and RET

2017 Tarceva (Erlotinib) targeting EGFR (-TK) NSCLC

- Same uptake profile as Tarceva, DDD in 2017 is equal to the DDD of Tarceva in its first year of reimbursement (2006).


Quizartinib AML FLT3-ITD 2017 Sprycel (Dasatinib) targeting Ph+ CML Tasigna (Nilotinib) targeting Ph+ CML

- No reference drug with same indication/biomarker. Quizartinib is an orphan medicine, hence other orphan medicine are used as reference.



Buparlisib Breast cancer HER2 negative (PIK3CA)

2017 Tyverb (Lapatinib) targeting HER2+ breast cancer


- Price/DDD in 2017 is equal to the price/DDD of Tyverb in 2017. - 25% of breast cancers are HER2+, this drugs targets the other 75% HER2

negative, hence the total Cost is multiplied with 3.

Palbociclib Breast cancer ER+ 2018 Tyverb (Lapatinib) targeting HER2+ breast cancer



Rucaparib pancreas cancer, platinum sensitive relapsed ovarian cancer

PARP (BRCA & HRD)

2018 Sprycel (Dasatinib) targeting Ph+ CML Tasigna (Nilotinib) targeting Ph+ CML

- No reference drug with same indication/biomarker. Rucaparib is an orphan medicine, hence other orphan medicine are used as reference.



Niraparib Breast, Ovarian cancer

PARP (BRCA1, BRCA2)

2018 Tyverb (Lapatinib) targeting HER2+ breast cancer + Sprycel (Dasatinib) targeting Ph+ CML

- Tyverb is used as reference for treating breast cancer Same uptake profile as Tyverb, DDD in 2018 is equal to the DDD of

Tyverb in its first year of reimbursement (2009). Price/DDD in 2018 is equal to the price/DDD of Tyverb in 2018.

- + Sprycel (orphan drug) is used as reference for targeting ovarian cancer. Same uptake profile as Sprycel, DDD in 2018 equal to the DDD of


84

Both costs are summed.

LY2835219 NSCLC, Breast KRAS, HER2 2018 Tyverb (Lapatinib) targeting HER2+ breast cancer + Iressa (Gefitinib) targeting EGFR (-TK) NSCLC



- + Iressa is used as reference for targeting NSCLC. Same uptake profile as Iressa, DDD in 2018 equal to the DDD of Iressa

in its first year of reimbursement (2010). Price/DDD in 2018 is equal to the price/DDD of Iressa in 2018.


LDK378 NSCLC ALK 2018 Xalkori (Crizotinib) targeting ALK+ NSCLC



selumetinib 2nd line NSCLC BRAF/KRAS 2018 Iressa (Gefitinib) targeting EGFR (-TK) NSCLC Xalkori (Crizotinib) targeting ALK+ NSCLC

- Same uptake profile as Iressa/Xalkori, DDD in 2018 is equal to the DDD of Iressa/Xalkori in its first year of reimbursement (2010/2013).

- Price/DDD in 2018 is equal to the price/DDD of Iressa/Xalkori in 2018 - The Mean is taken from Iressa and Xalkori

dovitinib solid tumours FGFR1 2018 Tarceva (Erlotinib) targeting EGFR (-TK) NSCLC

- Approximately the same biomarker for other indication - Same uptake profile as Tarceva, DDD in 2018 is equal to the DDD of

Tarceva in its first year of reimbursement (2006). - Price/DDD in 2018 is equal to the price/DDD of Iressa in 2018.

Dacomitinib NSCLC EGFR/ HER2/HER4 2018 Iressa (Gefitinib) targeting EGFR (-TK) NSCLC



MPDL3280A NSCLC BRAF V600 2018 Iressa (Gefitinib) targeting EGFR (-TK) NSCLC

- Same indication as Iressa but other biomarker … - Same uptake profile as Iressa, DDD in 2018 is equal to the DDD of Iressa

in its first year of reimbursement (2010). - Price/DDD in 2018 is equal to the price/DDD of Iressa in 2018.

alectinib NSCLC ALK 2019 Xalkori (Crizotinib) targeting ALK+ NSCLC



Phase II products

AZD9291 NSCLC EGFR and T790M 2017 Iressa (Gefitinib) targeting EGFR (-TK) NSCLC



85

Irosustat Breast cancer ER+ 2018 Tyverb (Lapatinib) targeting HER2+ breast cancer



2B3-101 Breast cancer, Lung cancer, Melanoma, Malignat glioma, brain metastasis

HER2+ 2018 Tyverb (Lapatinib) targeting HER2+ breast cancer

- Same uptake profile as Tyverb, DDD in 2018 is equal to the DDD of Tyverb in its first year of reimbursement (2009).

- Price/DDD in 2018 is equal to the price/DDD of Tyverb in 2018.

Duligotuzmab Solid tumours KRAS 2019 Erbitux ( Cetuximab) targeting RAS colorectal cancer Vectibix ( Cetuximab) targeting RAS colorectal cancer

- Approximately the same biomarker for other indication - Same uptake profile as Erbitux/Vectibix, DDD in 2019 is equal to the DDD

of Erbitux/Vectibix in its first year of reimbursement (2006/2008). - Price/DDD in 2019 is equal to the price/DDD of Erbitux/Vectibix in 2019. - The Mean is taken from Erbitux and Vectibix

Betalutin lymphoma CD37 2019 Mabthera (Rituximab) targeting CD20 Non-Hodgkin disease

- Will be used when not reacting on standard CD20 therapy (retuximab) - Same uptake profile as Mabthera, DDD in 2019 is equal to the DDD of


AZD 4547 Breast cancer FGFR1, FGFR2 2019 Tyverb (Lapatinib) targeting HER2+ breast cancer



Veliparib Melanoma, breast cancer

BRCA 2019 Tyverb (Lapatinib) targeting HER2+ breast cancer + Zelboraf (Vemurafenib) targeting BRAF V600 Melanoma



- + Zelboraf is used as reference for targeting melanoma. Same uptake profile as Zelboraf, DDD in 2019 equal to the DDD of



Rociletinib NSCLC EGFR and T790M 2019 Iressa (Gefitinib) targeting EGFR (-TK) NSCLC



Neratinib Breast cancer HER2+ 2019 Tyverb (Lapatinib) targeting HER2+ breast cancer



86

RO5424802 NSCLC ALK 2020 Xalkori (Crizotinib) targeting ALK+ NSCLC



AMG 337 Stomach cancer MET amplification 2020 Sprycel (Dasatinib) targeting Ph+ CML Tasigna (Nilotinib) targeting Ph+ CML

- No reference drug with same indication/biomarker. AMG 337 is an orphan medicine, hence other orphan medicine are used as reference.



Pictilisib Breast cancer, NSCLC

HER2, HR+ 2020 Tyverb (Lapatinib) targeting HER2+ breast cancer + Iressa (Gefitinib) targeting EGFR (-TK) NSCLC




in its first year of reimbursement (2010). Price/DDD in 2020 is equal to the price/DDD of Sprycel in 2020.


lucitanib Breast/lung cancer

FGFR/VEGFR/PDGF 2020 Tyverb (Lapatinib) targeting HER2+ breast cancer + Iressa (Gefitinib) targeting EGFR (-TK) NSCLC



- + Iressa is used as reference for targeting lung cancer. Same uptake profile as Iressa, DDD in 2020 equal to the DDD of Iressa



BGJ398 Solid tumors, Melanoma

FGFR 2020 Zelboraf (Vemurafenib) targeting BRAF V600 Melanoma + Tarceva (Erlotinib) targeting EGFR (-TK)

NSCLC

- Zelboraf is used as reference for targeting melanoma. Same uptake profile as Zelboraf, DDD in 2020 equal to the DDD of

Zelboraf in its first year of reimbursement (2013). Price/DDD in 2019 is equal to the price/DDD of Zelboraf in 2020.

- + Tarceva used for targeting FGFR solud tumors. Same uptake profile as Tarceva, DDD in 2020 equal to the DDD of

Tarceva in its first year of reimbursement (2006).

Price/DDD in 2020 is equal to the price/DDD of Tarceva in 2020. - Both costs should be summed…

Lifastuzumab vedotin

(platinum resistent) ovarian cancer, NSCLC

NaPi2b 2020 Sprycel (Dasatinib) targeting Ph+ CML + Iressa (Gefitinib)

- Sprycel is used as reference for treating orphan disease (ovarian cancer) Same uptake profile as Sprycel, DDD in 2020 is equal to the DDD of


http://clovisoncology.com/products-companion-diagnostics/lucitanib

87

targeting EGFR (-TK) NSCLC




AG-221 Solid tumors IDH2 mutation 2020 Tarceva (Erlotinib) targeting EGFR (-TK) NSCLC

- Assumed - Same uptake profile as Tarceva, DDD in 2020 is equal to the DDD of

Tarceva in its first year of reimbursement (2006). - Price/DDD in 2020 is equal to the price/DDD of Iressa in 2020.

sym004 Metastatic Colorectal cancer

EGFR 2020 Erbitux (Cetixumab) targeting RAS colorectal cancer

- Same indication as Erbitux but other biomarker … - Same uptake profile as Erbitux, DDD in 2020 is equal to the DDD of

Erbitux in its first year of reimbursement (2006). - Price/DDD in 2020 is equal to the price/DDD of Erbitux in 2020.

TSR-011 NSCLC ALK/TRK 2020 Xalkori (Crizotinib) targeting ALK+ NSCLC



BYL719 Breast cancer, solid tumours, Colorectal, HNSCC

PIK3CA 2020 Tyverb (Lapatinib) targeting HER2+ breast cancer + Erbitux ( Cetuximab) targeting RAS colorectal cancer



- + Erbitux is used as reference for targeting colorectal cancer. Same uptake profile as Erbitux, DDD in 2020 equal to the DDD of

Erbitux in its first year of reimbursement (2006). Price/DDD in 2020 is equal to the price/DDD of Erbitux in 2020.


defactinib NSCLC KRAS 2020 Iressa (Gefitinib) targeting EGFR (-TK) NSCLC

- Same indication as Iressa but other biomarker … - Same uptake profile as Iressa, DDD in 2020 is equal to the DDD of Iressa

in its first year of reimbursement (2010). - Price/DDD in 2020 is equal to the price/DDD of Iressa in 2020.

AEB071 Diffuse Large B-Cell Lymphoma

CD79A/CD79B 2020 Mabthera (Rituximab) targeting CD20 Non-Hodgkin disease

- … - Same uptake profile as Mabthera, DDD in 2020 is equal to the DDD of


RO5424802 NSCLC ALK 2020 Xalkori (Crizotinib) targeting ALK+ NSCLC



88

Savings due to patent expiries, which enables competition with new market entries (e.g.

generics, biosimilars and other cheaper products) should be taken into account as well.

This automatic reduction of reimbursement level can reach about 31% to 41% as of April

2012, depending on the drug reimbursement class51 (BCG, 2014). Targeted therapies

losing patent protection by 2020 are summed in Table 12. From these, Glivec and

Mabthera already lost patent before 2013, their decrease in budget impact is already

included in the linear extrapolations of their trends above. Next to this leverage

mechanism52, Belgium has a fixed-year price decrease on “old drugs”, i.e. 17% and 19%

price reductions at respectively 12 and 15 years of reimbursement and an extra 7,5%

price reduction after 18 years of reimbursement in the case of biological products (BCG,

2014). This results in a total of 19% ( or 26,5% for biological) decrease in RIZIV/INAMI

expenses for “old drugs”. Looking at Table 3, nine currently reimbursed PMx will be

labelled as “old drugs” between 2014 and 2020 and will hence decrease in cost.

Table 12: Products losing patent protection by 2020.

(Source: IMS Health)

PMx losing patent Expiry date (EU)

Herceptin 2014

Glivec Expired

Mabthera Expired

Erbitux 2016

Using these assumptions, the data of the projection to 2020 including all new entries and

savings was obtained.

51 PMx is assumed to be class I reimbursed products. Entry of reference reimbursement results in a price reduction of 41% in this case. 52 Other mechanisms exist, such as international reference pricing (IRP). This was not taken into account in our analysis.

89

APPENDIX IV: Assumptions for and calculation of the

effect of diagnostic accuracy on PMx budgeting and cost-effectivenes

In the example of HER2/neu tests in breast cancer patients for the usage of Herceptin

(Trastuzumab), we will use 3 different tests to clarify the importance of the test

accuracy; two HercepTests (IHC) with a variation in sensitivity and specificity and the

Oracle test (IHC) (Table 13). In the KCE report of 2006 one estimates the relative

amount of breast cancer patients having HER2/neu expression (HER2/neu FISH positive)

to be 13.55% (Hulstaert et al., 2005). In this example, the FISH test is assumed to be

the golden standard, i.e. the sensitivity and specificity of the FISH test is assumed to be

both 100%. The probability of having the gene (over)expression for breast cancer

patients will be equal to Pgene_expression = 13.55%, while the probability of having no gene

expression will be equal to 86.45%. This information was gathered to draw a decision

tree from which budget impact was calculated (Figure 25).

Table 13: Different HER2/neu tests with their sensitivity and specificity.

The incremental cost of a treatment with trastuzumab depends on different aspects, such

as the dosage, the duration of the treatment, the body weight and the price of the

product. An additional administration cost is also of importance together with an

obligated MUGA scan due to the possible risk of heart failure. The total cost will also

depend on the costs of the diagnostic tests, monitoring procedures after a treatment and

side effects. For this simple example, we will only take into account the costs of the Dx,

the BSC (best supportive care, i.e. treatment without trastuzumab) and the treatment

with trastuzumab (Table 14). Detrimental effects in the case of treatment of false

positive are not considered, although in addition to the trastuzumab treatment the cost

of the BSC is charged. The financing for the FISH test is assumed to be 341 euro while

the IHC tests (Herceptest and Oracle) are estimated at an amount of 78 euro (Van Den

Bulcke et al., 2015). The costs of treatments with and without trastuzumab were taken

from the KCE report (2006).

Table 14: Different parameters to calculate the total incremental cost of the trastuzumab

treatment (treatment costs and test costs) and costs of the best supportive care of

breast cancer treatment.

Parameter Value Source

FISH test 341 € KCE report 240, 2015 IHC tests 78 € KCE report 240, 2015

BSC 14.050 € KCE report 34, 2006 Trastuzumab treatment 31.878 € KCE report 34, 2006

False + treatment (BSC + trastuzumab) 45.928 € Assumed

Sensitivity Specificity

FISH 100% 100% HercepTest 1(Moelans et al., 2010) 91% 94% HercepTest 2 (Van Den Bulcke et al., 2015) 96% 88% Oracle(Moelans et al., 2010) 83% 98%

90


Figure 25: Decision tree for the economic outcomes of trastuzumab-diagnostic

combination.

According to the Belgian cancer registry 10.531 female patients were diagnosed with

breast cancer in 2012, compared to 9405 in 2005 (Wildiers et al., 2013). Using this

yearly amount of 10.531 breast cancer patients, it is possible to make a budget

estimation for the above calculations. This way, the following results were obtained; the

golden standard FISH test has a budget impact of €177 million. The HercepTest with a

sensitivity and specificity of respectively 91% and 94% has a budget impact of €189

million. Notice that in this case a 5,2% chance exist in getting false positive results and a

1,2% chance of getting false negative results. When the HercepTest has a sensitivity and

specificity of respectively 96% (a smaller chance equal to 0,5% of detecting false

negatives) and 88% (but a higher chance of 10,4% to detect false positives), the budget

impact increases to €208 million. The Oracle test with a sensitivity of 83% and a

specificity of 98% has a budget impact of €176 million. In the latter case the chance of

having false positive and false negative results equals to 1,7 % and 2,9% respectively.

91

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