Brussels, Belgium23-24 May 2014

Crowne Plaza Brussels - Le PalaceRue Gineste 3, B-1210 Brussels, Belgiumwww.crowneplazabrussels.be

The first Pan-European multi-stakeholder colloquium: Exploring opportunities and challenges for improving Multiple Sclerosis management

Calls to Action

EditorProf. Patrick Vermersch

PublisherIsmar Healthcare NVLeopoldplein 39 B1, BE-2500 Lier, Belgium+32 (0)3 491 82 70info@ismar.com

Publication date01.10.2014

Background Multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults (600,000 persons) who are at the peak of their productive life building their career, social status and family. It is associated with a tremendous loss of health-related quality of live, work productivity and unemployment, not only of the sufferers but also of their caregivers (1,000,000 persons).

As such it poses a huge burden on European society which seems to be underestimated in relation to other diseases. There is currently no cure nor are there preventive measures for MS. However, early diagnosis, treatment with disease-modifying drugs (for relapsing-remitting MS) and rehabilitation therapy can reduce relapse rate and/or slow down the progression of disability. Access to quality care varies substantially between member states.

RationaleAlthough the different stakeholders (patients, healthcare professionals, regulators and payers) in MS all have their own platforms, surprisingly there is to date no initiative that aims to increase the cross-talk and mutual understanding of the perspectives of the different stakeholders. Therefore, we organised the first European MS Multi-stakeholder Colloquium from 23-24 May 2014 in Brussels in order to explore and formulate actions considered as priorities to improve the life of people with MS in Europe.

OutcomesBased on the discussions, we have developed ten integrated and interrelated Calls to Action on the European Union (EU), its member states, the research and global community.

Call1, 2 and 4As under allocation of the healthcare budget to MS in member states is detrimental for appropriate access to quality care, Call 1, 2 and 4 address the need for increased funding of research enabling proper estimation of the MS burden. Focus on MS in the call for proposals formulation under the third EU health programme will be very beneficial.

Call 3, 5 and 6Call 3, 5 and 6 relate to the need for increased funding to define patient-centred endpoints and explore and validate biomarkers such as magnetic resonance imaging, neurofilament heavy chain, oligoclonal band immunoglobulin M as well as genetic markers to better predict long-term disability progression and individual

Executive Summary

Focus on MS in the call for proposals formulation under the third EU health programme will be very beneficial.

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long-term treatment response. The promotion of the development of biobanks, as part of large registries such as Multiple Sclerosis dataBase (MSBase) and Observatoire Français de la Sclérose en Plaques (OFSEP) which collect patient, clinical and treatment outcome data is seen as a major need. A focus on MS in the funding programme of Horizon 2020 (personalising health and care) can boost these activities.

Call 7 and 8 We discussed that the current marketing authorisation decision-making process (benefit/risk) assessment lacks transparency, remains too much focused on relapse reduction (instead of patient desired prolongation of disease progression) and is fully segregated from the health technology assessment (HTA) process. These elements may lead to a substantial delay in access to innovative treatments. We were also concerned that the absence of guidelines for evaluating follow-on products of non-biological drugs may lead to exposing MS patients to products for which the long-term safety has not been appropriately assessed. Call 7 and 8 relate to the above-mentioned issues.

Call 9 and 10There was a strong opinion that keeping MS sufferers as long as possible physically active and working is fundamental for their well-being. Call 9 deals with policy unifications across member states needed to enable access to rehabilitation, specialised centres, home adaptations and incentive provisions for employing MS patients.Call 10 deals with a call to the global MS community in Europe for engagement and support of future multi-stakeholder colloquia.

We very much hope that readers will be triggered to contribute to the materialisation of the actions called upon.

Sincerely yours,

Patrick Vermersch,on behalf of the scientific committee of the MS Multi-stakeholder Colloquium

A focus on MS in the funding programme of Horizon 2020 (personalising health and care) can boost these activities.

Inter member state discussion needed for unification and application of best practice policies.

Guidelines needed for evaluating follow-on products of non-biological drugs.

CHMP guideline revision needed with focus on disease progression endpoint definitions.Integration between benefit risk assessment process of CHMP and HTA assessment process needed.

Scientific Committee:Patrick Vermersch, Professor of Neurology, Lille, France - Chair Ralf Gold, Professor of Neurology, Bochum, Germany - Co-chairChris Holloway, European Regulatory Consultant, Walsrode, Germany - Co-chairMondher Toumi, Professor of Decision Sciences, Lyon, FranceFrauke Zipp, Professor of Neurology, Mainz, Germany

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Table of Contents

Background and rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5

Call 1: Increase awareness and understanding in the European community about the burden of MS,

not only from the patient but also caregiver perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7

Call 2: Obtain better insights in the direct and indirect (patient and caregiver) cost burden of MS . . . . . . .8

Call 3: Perform patient research to (re)define treatment goals and clinical study endpoints from a

humanistic/patient perspective point of view . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Call 4: Develop new tools to better capture the total clinical burden of MS . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Call 5: Develop a protocol for standardisation of magnetic resonance imaging in MS in

order to optimise its use as a marker of disability progression in clinical research

and daily clinical practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Call 6: Support research to find other biomarkers which can predict (and monitor)

individual treatment response with regard to long-term disability progression . . . . . . . . . . . . . . . . . . . . . . . 14

Call 7: Integrate CHMP and HTA decision-making processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Call 8: Develop separate EMA guidelines for evaluating follow-on products of

non-biological complex drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Call 9: Stimulate the implementation of specialised care centres and support

people with MS remaining (physically) active and at work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Call 10: Support the continuation of multi-stakeholder colloquia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

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Background and rationaleMultiple sclerosis (MS) affects over 600,000 people living in Europe and involves around 1,000,000 caregivers and family members of people with MS1. It is nowadays thrice as common in women as in men. There seems to be an underestimation of the clinical, humanistic, and cost burden associated with MS in society in general as well as with policy and decision makers. It is not fully appreciated in society that MS is a disease of young people and the leading cause of non-traumatic disability in young adults (Figure 1). Most people are diagnosed with MS between the ages of 20 and 40 when they are in the peak of their productive life, building their career, family life and social status. Although no two people with MS are affected in the same way, they can suffer from increasing mobility problems, fatigue,

depression, memory loss, bladder and bowel problems, abnormal speech and double vision, and sight impairments (leading to blindness in severe cases). Moreover, MS follows a progressive course in the majority of people, ultimately leading to increasing use of walking aids and a wheelchair to remain mobile when people get older. In addition to gradually increasing walking impairment, fatigue, depression and cognitive problems are considered bothersome albeit less visible symptoms by MS patients2. All together, these symptoms are probably the reason why half of the people with MS become unemployed on average 3 years after diagnosis1 and have to live from a disability pension for the rest of their life.

This does not only dramatically reduce the quality of life (QoL) and financial situation of the people with MS but also that of their caregivers and family members. As such not only people with MS but also their caregivers and family members pose a burden on society.

There is currently no cure nor are there preventive measures for MS. However, early diagnosis, treatment with disease-modifying drugs (DMDs; for relapsing-remitting MS) and rehabilitation therapy can reduce relapse rate and/or slow down the progression of disability. This will improve their ability to lead full lives and keep them longer mobile in order to continue work and remain (financially) independent from their caregiver(s) and society support.

Unfortunately access to quality care varies substantially among different member states in Europe and healthcare systems tend to push MS sufferers into invalidity. The patent expiry of several first-line DMDs in Europe holds the promise of availability of lower priced follow-on products. However, given the complexity of these DMDs, people living with MS, their caregivers and healthcare professionals should be reassured that their follow-on products have demonstrated similarity (based on appropriately established clinical methods) to the originator products with regard to long-term clinical efficacy and safety.

Figure 1: Disability with related immobility is a major problem in relatively young people with MS which requires considerable caregiver support (http://www.underpressureproject.eu/web/living-with-ms-in-europe)

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The different stakeholders in MS all have their own platform:1. Patients: represented by the European

Multiple Sclerosis Platform (EMSP)2. Healthcare professionals: neurologists

represented by e.g. the European Committee for Treatment and Research in MS (ECTRIMS), the European Academy of Neurology (EAN) and the European Charcot Foundation, radiologists represented by e.g. Magnetic Resonance Imaging in MS (MAGNIMS), rehabilitation therapists represented by e.g. Rehabilitation in MS (RIMS) and MS nurses

3. Regulators: the European Medicines Agency (EMA) with the Committee for Medicinal Products for Human Use (CHMP) being responsible for the approval of effective and safe medicines in the European Union (EU)

4. Payers: responsible for access to approved medicines who provide value for money (based on national health technology assessments [HTA]) in the different European countries

Surprisingly there is no initiative that aims to increase the mutual understanding of the perspectives of the different stakeholders. Therefore, we organised the first European MS Multi-stakeholder Colloquium from 23-24 May 2014 in Brussels in order to enhance cross-talk and initiate collaboration between the different stakeholders (http://ms-colloquium.org/programme). Based on the discussions at the Colloquium, we formulated a total of ten integrated Calls to Action considered as priorities to improve the life of people with MS in Europe.

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Increase awareness and understanding in the European community about the burden of MS, not only from the patient but also caregiver perspective

Although most European citizens know at least one person living with MS in their direct or more distant environment, it is particularly the image of becoming wheelchair-bound at older age that is on top of mind when they think of MS. However, MS starts in young people, who are afraid of, or even depressed, about their future with increasing losses of mobility, energy, memory, independence, a high chance of unemployment and social isolation and reduced QoL. This is less visible to and less well recognised by society. Even people with only moderate disability (Expanded Disability Status Scale [EDSS] of 3) have a lower

health-related QoL (HRQoL) utility of 0.56 (as measured by the EQ5D-5L questionnaire on a scale from 0 [normal] to 1 [death])3,4 than patients with chronic ischaemic heart disease (0.64)3 or non-insulin dependent diabetes mellitus (0.67)3. Moreover, this drops to 0.3 if the person with MS becomes dependent of a wheelchair (i.e. at an EDSS of 7; Figure 2)3,4. It is also not well understood that MS poses a huge cost on society in terms of loss of

productivity and unemployment, not only from the person with MS but also from the caregiver. Sick leave and reduced working time account for 10% of the economic burden of MS in the USA, while early retirement accounts for an additional 34% of these costs5. It is therefore important for the general public to become better aware of the huge impact MS has on society. Employers should realise more that keeping people with MS at work (at least partly) by flexible working conditions and adapting workplaces can help the person with MS to maintain a productive life style and can considerably increase the QoL of their employers

as well as their families and therefore reduce costs for society. Politicians and payers should evaluate underfunding of MS relative to other diseases such as cardiovascular disease, diabetes and/or Alzheimer. Funding of MS includes access to MS treatment, incentives for employers to retain people with disabilities and support of rehabilitation therapy and adaptations at home/work (which can help to keep people longer active and at work).

Call 1

Rapid fall in utility on EDSS 0-2.5

Expanded Disability status Scale

Util

ity

Mea

sure

d w

ith E

Q5D

Rapid fall in utility after EDSS 6

Slow fall in utility on EDDS 3-6

Figure 2: The ED5D-5L utility value/HRQoL drops with increasing disability (EDSS)4

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Obtain better insights in the direct and indirect (patient and caregiver) cost burden of MS

When evaluating healthcare costs of a (chronic) disease, it is often distinguished between direct, indirect and intangible costs. Direct healthcare costs usually represent the costs associated with medical resource utilisation such as inpatient (hospital) and outpatient care and, in particular, drug treatment costs. Indirect costs relate to the

expenses incurred from unemployment (and the need for an early retirement pension) or reduction of work productivity as the result of the morbidity associated with the disease. Indirect costs are more difficult to quantify than direct costs. However, in many chronic diseases, indirect costs represent around 50% of total healthcare costs. As in most healthcare systems direct and indirect costs are financed by different stakeholders/ministries, it is very difficult to quantify the total cost burden for society and how changes in one budget impact on the other. Intangible costs relate to losses in HRQoL.

In MS, indirect (and intangible) costs should not only reflect loss of work productivity and HRQoL

of the patient but also of the caregiver(s). Whereas the majority of people with MS are employed at diagnosis, approximately half leave their jobs within a decade6 or even within a mean of 3 years after diagnosis1. In Europe, total direct and indirect costs per patient are estimated at around are 31,000 Euro per year (Figure 3).

Both direct and indirect costs increase significantly with increasing disability, as measured with the EDSS6,7. In the lower disability levels, direct medical costs dominate the total costs. However, as patients progress to higher disability levels, direct non-medical costs (e.g. disability-related home adaptations or time spent caring for patients) and indirect costs increase significantly, outweighing direct medical costs6,7 (Figure 47). Interestingly, the relative contribution of sick leave and early retirement is the greatest in patients with moderate disability (EDSS 4-6.5), who have difficulties in walking and performing activities of daily living (ADL) but do not yet have to use walking aids or a wheelchair to remain mobile. This is because more patients are still at working

Call 2

€ 3201 Informal

caregiving

Total € 31,000 per patient per year

€ 3093 Early

retirement

€ 2057 DMTs

€ 2480 Other drugs Sick leave

Hospitalization Outpatient care

Medical devices and tests

Services Home/car adaptations and special equipment

Figure 3: In Europe, total direct and indirect costs are estimated at 31,000 Euro per MS patient per year

- 8 -

age in this group than in the severely disabled patient group5,8. Therefore, when evaluating drug treatment costs one should also take into account whether the treatment can delay disability progression and keep patients and caregivers longer at work. This may decrease indirect costs

due to reduced work productivity and disability pension, which may potentially reduce the total cost burden for society. In addition, with the recent approval of many new DMDs, there is an urgent need for a new, well-designed economic burden study across Europe.

Call 2

Direct medical costs comprise inpatient and outpatient care, consultations, investigations, MS treatments, prescribed

medications and over-the-counter medications. Direct non-medical costs comprise investments/modifications, professional

care (paid) and informal care (unpaid). Indirect costs are related to sick leave and retirement due to MS

Figure 4: At lower disability levels in MS, total costs are dominated by direct medical costs. However, as patients progress to higher disability levels, direct non-medical costs (e.g. disability-related home adaptations or time spent caring for patients) and indirect costs increase significantly, outweighing direct medical costs7

Mea

n co

sts

per M

S pa

tient

per

yea

r (20

09)

by d

isab

ility

sev

erit

y (€

)

EDSS 0-3 (N=818)

Direct medical costsDirect non-medical costsIndirect costs

Fran

ce

Ger

man

y

Italy

Spai

n

Uni

ted

King

dom

Fran

ce

Ger

man

y

Italy

Spai

n

Uni

ted

King

dom

Fran

ce

Ger

man

y

Italy

Spai

n

Uni

ted

King

dom

100,000

90,000

80,000

70,000

60,000

50,000

40,000

30,000

20,000

10,000

0

EDSS 4-6.5 (N=406) EDSS 7-9 (N=37)

Obtain better insights in the direct and indirect (patient and caregiver) cost burden of MS

- 9 -

Perform patient research to (re)define treatment goals and clinical study endpoints from a humanistic/patient perspective point of view

It is becoming more and more obvious that patient perspectives differ considerably from physician perspectives. This also applies to MS. Whereas clinicians consider physical aspects as most important for QoL in MS, patients also put high value on mental, emotional, and general health aspects (Figure 5A)2,9. In addition, patients are more concerned about disability progression

and the risk of developing serious adverse events than about having another relapse (Figure 5B)2,10. Initial research from the MS International Foundation (MSIF) has shown that young patients (between 20-40 years of age) mainly want to remain independent and continue to go to school or work (www.msif.org/msinfocus; Figure 6).

Call 3

6052

41 3833 33 31

12

28

8084

816

52

1216

0

10

20

30

40

50

60

70

80

90

Mental health

Physical function

Physical role

limitations

Emotional role

limitations

General health

Social function

Vitality Bodily painFreq

uenc

y of

cit

ing

dom

ain

amon

g 3

mos

t im

port

ant d

eter

min

ants

of

over

all Q

oL (%

)

Patients (N=42)Clinicians (N=25)

Websurvey among 651 patients with MS (USA; mean age: 47 years):

0.27

0.230.20

0.18

0.12

0.00

0.05

0.10

0.15

0.20

0.25

0.30

Years to progression

PML Liver failure Leukaemia Relapse

Rela

tive

impo

rtan

ce

Treatment attribute

3 safety concerns were deemed more important for pts than reducing relapse rate

A

B

Figure 5: Patient perspectives differ from physician perspectives in MS with patients putting high value on not only physical but also mental/emotional health9 and potential safety risks10

PML: progressive multifocal leukoencephalopathy

- 10 -

This shows that more research should be devoted to what determines treatment success for the individual patient (Figure 7). In addition, clinical trials evaluating the impact of DMDs should not only address clinical/physician-oriented outcomes such as relapse and disability progression, but also include so called patient-reported outcomes. In people living with MS, this would be the assessment of e.g. energy/fatigue levels, cognition, the performance of ADL including going to school/work and HRQoL11.

It is ultimately the patient who determines treatment success/satisfaction and as a consequence of that will or will not continue with the prescribed treatment. Therefore, the patient’s perspectives/ expectations should be taken more into account when evaluating “value for money” during drug approval and HTA decision making.

Call 3

Figure 6: Remaining independent and continuing to go to school/work are important goals for relatively young people with MS according to recent MFIS research (www.msif.org/msinfocus)

Figure 7: Whereas physicians focus on clinical outcomes when measuring treatment (Tx) success, patients are more concerned about the impact on outcomes such as fatigue, cognition, ADL and QoL including the risk of adverse events and convenience of useDAFS: disease-activity-free status; MRI: magnetic resonance imaging; T25FWT: time 25-foot walk test

0

500

1000

1500

2000

2500

Num

ber o

f pat

ient

s

What are the 3 most important issues for young people with MS in your country?

Accessi

ble public tr

ansp

ort

and build

ings

Public perce

ption of M

S

Accessi

ng financia

l or

socia

l servi

ces s

upport

Access

to aff

ordab

le

treatm

ents

Being able to

be independent

Being able to

contin

ue

at work

or in educa

tion

Access

to healt

hcare

professi

onals

Classical clinical e�cacy outcomes• Relapse

• EDSS• MRI lesions

Risk of adverse eventsConvenience of use

• Mode of administration• Need for regular monitoring

CognitionFatigue

Mobility/ADL (continue to go to school or work)

HRQoL

Newer clinical e�cacy outcomes• DAFS

• Gait: T25FWT• Upper extremity motor skills: 9-hole peg test

• MRI whole brain atrophy

Measuringindividual Tx success

Perform patient research to (re)define treatment goals and clinical study endpoints from a humanistic/patient perspective point of view

- 11 -

Develop new tools to better capture the total clinical burden of MS

An important treatment goal in MS, in particular from the patients’ point of view, is not only to continue to lead their full lives but also to prevent or at least delay disability progression in the long run. The EDSS is the most frequently used tool to monitor disability progression in MS12. It mainly evaluates physical impairment on a scale from 0 (normal neurological examination) to 10 (death due to MS)(Figure 8). In patients with an EDSS ≤ 5, a 1 point change from baseline sustained for 3 months is usually considered as progression. At onset of the secondary progressive phase in a Canadian natural history study, the median EDSS was 3. In a French natural history study, it took on average 8 years for people with relapsing-remitting MS to reach an EDSS of 4, 20 years to reach an EDSS of 6 and 30 years to reach an EDSS of 7.

Although it has been recognised for many years that the EDSS has several limitations, it is still recommended by regulators such as the EMA to document disability progression in clinical trials. The limitations include poor inter- and intra-rater reliability and too much focus on capturing physical disability/mobility. Moreover, because it is a non-linear ordinal scale, it is less sensitive to change in people with MS who have severe disability at baseline (EDSS ≥ 4). Therefore, it is felt that more efforts/research should be undertaken to develop a disability tool, which (in addition to mobility) also captures less visible but bothersome symptoms such as fatigue and/or cognition. Alternatively, one could develop separate well-validated tools, endorsed by the EAN and regulators, for optimally measuring fatigue and cognition (e.g. the Brief International Cognitive Assessment for MS [BICAMS]13) in people with MS.

Call 4

A 1-point change from baseline sustainedfor 3 months is usually considered as progression (for EDSS ≤ 5)

Disability

0 1 2 3 4 5 6 7 8 9 10

Normalneurologicalexamination

No disability

Minimaldisability

Moderatedisability

Relatively severe

disability

Disabilityprecludesfull dailyactivities

Assistancerequired to

walkRestricted

to a wheelchair

Restricted to bed or

chair

Confinedto bed

Death

Figure 8: The EDSS is mainly focused at measuring disability

- 12 -

Develop a protocol for standardisation of magnetic resonance imaging in MS in order to optimise its use as a marker of disability progression in clinical research and daily clinical practice

The rate of disability progression in MS is variable and it is currently not possible to predict the disease course in an individual person with MS at onset. Moreover, it is difficult to capture clinically relevant disability progression (e.g. the percentage of patients requiring a walking aid or becoming wheelchair-bound) in clinical trials with DMDs of 2 years duration. Therefore, research should focus on finding markers (or preferably surrogate endpoints) for long-term disability progression. Later age at onset, male gender, high number of relapses in the first 2 years from onset, incomplete recovery from the first relapse and high lesion load at the magnetic resonance imaging (MRI) scan are clinical indicators of a higher risk of disability progression. Several studies have shown that whole brain atrophy at MRI scans (Figure 9A), which reflects the net effect of brain tissue damage, also seems to predict long-term disability progression14,15 (Figure 9B15). This holds in particular for brain atrophy measured in the grey matter/cortex.

Unfortunately, although whole brain atrophy is a sensitive MRI measure to predict disability progression, there are currently several limitations with its use:

1) the change of volume over time is relatively small (0.1-0.3%/year with normal ageing vs. 0.5-1%/year in MS) and is not linear, which makes progression in an individual hard to predict

2) the quality of the image may not always be sufficient

3) the visual and planimetric rating is radiologist-dependent and needs training

4) there is no common agreement on the measurement technique (2D vs. 3D images)

5) reduction in inflammation due to the use of DMDs may induce (temporary) pseudo-atrophy

6) other risk factors (e.g. cardiovascular, smoking, genetic) may also induce atrophy

7) change in water content due to e.g. hydration or steroid use may also impact on atrophy

Therefore, in order to overcome these limitations and make measurement of brain atrophy applicable in the daily clinical workflow, it is essential to develop a protocol for standardisation of this MRI measure. This also applies for other more advanced imaging techniques such as magnetisation transfer ratio and double inversion recovery imaging to assess lesion volume and cortical lesions.

Call 5

14.3

29.4 28.6

55.9

0

10

1.3 to-0.26

-0.27 to-0.89

-0.9 to-1.7

-1.7 to-6.5

20

30

40

50

60

Patie

nts

with

ED

SS ≥

6.0

at

8 ye

ars

of fo

llow

-up

(%)

PBVC from baseline to year 2 (N=138)

Healthy person Person with MS

A B

Figure 9: (A) Whole brain atrophy is higher in patients with MS than in healthy subjects and (B) the higher the whole brain atrophy/percentage of brain volume change (PBVC), the greater the percentage of patients progression to an EDSS ≥ 6 after 8 years of follow-up15

- 13 -

Support research to find other biomarkers which can predict (and monitor) individual treatment response with regard to long-term disability progression

MRI is currently the most interesting potential biomarker for predicting long-term disability progression. However, funding of research to discover other body fluid or genetic biomarkers, which may predict long-term disability progression and individual response to treatment, should also receive high priority. This will reduce the trial and error to find as quickly as possible the most appropriate/right treatment for each individual patient, i.e. the right treatment for the right patient at the right time. This will also reduce treatment costs. It should be realised that it can take between 5-15 years before a potential biomarker has been validated for use in clinical practice.

In this context, the presence of neurofilament protein subunits, in particular neurofilament heavy chain (NfH), in the cerebrospinal fluid (CSF) may today be the best candidate to validate as a biomarker for predicting disability progression in clinical practice16. Its levels in the CSF can also be altered upon treatment with DMDs16. CSF oligoclonal band (OCB) IgM may be another interesting biomarker to further investigate16.

HLA-DRB1*1501 polymorphisms may be further evaluated for predicting treatment response to e.g. the DMDs interferon (due to the higher risk of developing neutralising antibodies which reduce response to interferon) and glatiramer acetate.

Call 6

- 14 -

Integrate CHMP and HTA decision-making processes

Marketing authorisation of new treatments for MS is centrally arranged in Europe by the CHMP/EMA and involves regulators as well as expert opinion from healthcare professionals. This decision-making process is very much a benefit (efficacy)-risk (safety) assessment, focused at approval of effective but above all safe treatments. This benefit-risk assessment currently lacks transparency towards the involved stakeholders (especially the patients). HTA and subsequent reimbursement decisions are currently taken at the national level. This process mainly involves institutes serving the government/Ministry of Health (such as NICE [National Institute for Health and Care Excellence] for the National Health Service [NHS] in the UK, the HAS [Haute Autorité de Santé] in France and IQWiG [Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen] in Germany) and ultimately payers/large health insurance

companies. HTA decision making is largely driven by demonstrating the (long-term) cost-effectiveness of a new treatment. The result of this central marketing authorisation but decentralised HTA process can be delayed access17 and widespread inequalities in access to MS therapy across Europe (Figure 10)18. In order to improve this situation, the integration of the CHMP/EMA and HTA decision processes should be considered. Moreover, these decisions should not only be taken by regulators, healthcare professionals and payers but should also reflect the patient perspective. In particular, because patients may think differently about the desired outcomes of treatment than the other involved stakeholders, who take decisions which have huge impact on the patient’s daily life.

Call 7

Section 1: Access to treatments and therapies

58

8

67

48 53 5158

69

45

67

25

6854

22

4434

4837

63

45

63 57 58

Austria

Belarus

BelgiumCro

atia

Czech

Republic

Denmark

Finlan

d

Max. score for section 1: 70 points

German

y

Greece

Icelan

d

Irelan

dIta

ly

Norway

Poland

Portugal

Roman

iaRussi

a

Serbia

Slova

kiaSp

ain

Sweden

Switz

erland UK

Figure 10: There are widespread inequalities in access to MS therapy across Europe18

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Develop separate EMA guidelines for evaluating follow-on products of non-biological complex drugs

The availability of lower-priced follow-on products to first-line DMDs has the potential to reduce the direct costs associated with MS.

Small molecule, low molecular weight chemical follow-on products (e.g. corticosteroids) can usually be analytically characterised at a fine/full level of detail for demonstrating pharmaceutical “sameness” as outlined in the development guidelines for generic drugs (Figure 11). In addition to pharmaceutical “sameness”, bio-equivalence (in pharmacokinetic/ pharmacodynamics studies) needs to be demonstrated for follow-on generics.

Large molecule biological follow-on products (e.g. growth hormone and interferon beta) can usually be characterised at a reasonable level of detail by recombinant DNA technology for demonstrating pharmaceutical “similarity” as

outlined in the development guidelines for similar biological medicinal products/biosimilars (Figure 11). In addition to pharmaceutical “similarity”, bio-equivalence (in pharmacokinetic/pharmacodynamics studies) and clinical equivalence in comparative clinical trials need to be demonstrated for biosimilars.

Non-biological complex drugs (NBCDs, e.g. low-molecular weight heparin, iron-carbohydrate drugs and glatiramer acetate) are structurally very complex as they do not consist of a single molecule but are polymeric mixtures of (nanoparticulate) structures. The composition, quality and in vivo effects of NBCDs are highly dependent on the manufacturing processes. Therefore, they cannot be fully characterised by conventional analytical methods for demonstrating pharmaceutical/physicochemical “similarity” (Figure 11).

Call 8

=

Small molecule chemicalfollow-on products(e.g. corticosteroid)

Recombinant DNA technologyfollow-on products(e.g. interferon)

NBCDs follow-on products(e.g. glatiramer acetate)

Characterised at fine level of detail= sameness

Development guidelines for generics

?

Cannot be fully characterised with conventional analytical methods

Separate development guidelines are needed

≈

Characterised at a reasonable level of detail≈ similarity

Development guidelines for biosimilars

Figure 11: Available guidelines to establish similarity of follow-on products

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Advanced analytical methods such as gene expression analysis have shown that with a follow-on product of glatiramer acetate specific pro-inflammatory genes and immune cells were more upregulated than with the original product19,20 (although conventional analytical methods showed similarity). There were also important variations between different batches of the follow-on product. It is also unknown which structural elements are responsible for the therapeutic benefits and risks. For instance, protiramer (or TV-5010), which has a slightly different molecular weight distribution but a similar amino-acid ratio and physical properties as glatiramer acetate, was shown to be more potent than glatiramer acetate in a mouse inflammation model of MS with no toxicity in short-term (13 weeks) rat studies and good safety and tolerability in two short-term (36 weeks) clinical studies in MS patients21. However, it was found to be toxic (increased mortality) in longer term safety studies in monkeys (52 weeks) and rats (26 weeks)22 and subsequent clinical development was stopped. For another NBCD,

i.e. iron sucrose used to replenish iron stores in patients with iron deficiency, a follow-on product approved as generic in e.g. France, showed similar physicochemical properties as the reference product Venofer®. However, the follow-on product was not shown to be therapeutically “equivalent” to the originator product23. A well-controlled haemodialysis population was destabilised with the requirement for higher mean iron doses, an increased mean number of days outside of the target haemoglobin range and increased costs for managing anaemia23.

These examples indicate that for follow-on products to first-line DMDs, that are coming up soon, it is essential for EMA to develop separate more clearly defined guidelines for demonstrating (pharmaceutical, biological and long-term clinical) similarity of follow-on NBCDs in order to guard safety and efficacy for people living with MS.

Call 8Develop separate EMA guidelines for evaluating follow-on products of non-biological complex drugs

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Stimulate the implementation of specialised care centres and support people with MS remaining (physically) active and at work

For the QoL of people living with MS it is important to remain as long as possible mobile and out of a wheelchair. In this way, they can stay as long as possible independent from a caregiver and can continue to work and socialise/participate in society. Family members can continue to live their own life and perform their own job. This all will reduce the cost burden on society. It has been shown by rehabilitation therapists that when people with MS remain physically active/are involved in exercise therapy, this stimulates their muscle function and will keep them involved in mobility-related ADL24,25 (Figure 12). In addition, they continue with socialising, which has a positive impact on their mood/mental QoL. Therefore, people living with MS should be stimulated and supported with exercise-related activities as this

may reduce indirect costs and improve their mental health.

Providing incentives for employers to retain or appoint people living with MS and invest in adaptations in their workplaces will also reduce the indirect costs related to MS and improve the QoL (intangible costs) of patients and their families. In addition to the improved access to (MS specialised) rehabilitation therapists, also improved access to other disciplines within the healthcare sector such as MS specialised nurses and networks of different specialists aware of the specificities of MS care such as psychologists, urologists and social workers will increase the quality of care. This is realised in reference centres which exist in some countries but are absent in most member states.

Call 9

Figure 12: Physical/exercise therapy will stimulate muscle function and mobility-related ADL of MS patients (http://www.underpressureproject.eu/web/living-with-ms-in-europe)

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Support the continuation of multi-stakeholder colloquia

The evaluation of the participants to this first MS Multi-stakeholder Colloquium indicates a high level of commitment to continue our initiative. However far more active involvement in the programme development from EMSP, ECTRIMS, Charcot, MAGNIMS, RIMS, MS nurse

representatives, CHMP, HTA agencies and payer representatives should be achieved and preparatory group workshops should preceed the colloquium discussing the solution propositions for improving the life of MS patients In Europe.

Call 10

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Abbreviation Full description

ADL Activities of Daily Living

BICAMS Brief International Cognitive Assessment for MS

CHMP Committee for Medicinal Products for Human Use

CSF CerebroSpinal Fluid

DAFS Disease-Activity-Free Status

DMD Disease-Modifying Drug

EAN European Academy of Neurology

ECTRIMS European Committee for Treatment and Research in MS

EDSS Expanded Disability Status Scale

EMA European Medicines Agency

EMSP European Multiple Sclerosis Platform

EU European Union

HAS Haute Autorité de Santé

HRQoL Health-Related Quality of Life

HTA Health Technology Assessment

IQWiG Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen

MAGNIMS Magnetic Resonance Imaging in Multiple Sclerosis

MRI Magnetic Resonance Imaging

MS Multiple Sclerosis

MSBase Multiple Sclerosis dataBase

MSIF Multiple Sclerosis International Foundation

NBCDs Non-Biological Complex Drugs

NfH Neurofilament Heavy chain

NHS National Health Service

NICE National Institute for health and Care Excellence

OCB OligoClonal Band

OFSEP Observatoire Français de la Sclérose en Plaques

PBVC Percentage Brain Volume Change

PML Progressive Multifocal Leukoencephalopathy

QoL Quality of Life

RIMS Rehabilitation In Multiple Sclerosis

T25FWT Timed 25-Foot Walk Test

Tx Treatment

Abbreviations

- 20 -

AcknowledgementsBianca Meesen and Louis Smets from Ismar Healthcare, Lier, Belgium, provided assistance with the writing of this document based on the content of the presentations given at the Colloquium and the outcome of the related discussions and voting polls.

The organisation of the Colloquium was supported by an educational grant from Teva Pharmaceuticals Europe.

Photos from the “Under Pressure” project used, courtesy of EMSP

Many thanks for the contributions of:INVITED FACULTY

Karl Broich, Vice-President of the Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany

Declan Chard, Senior Clinical Research Associate, UCL Institute of Neurology, London, UK

Daan Crommelin, Professor at the Department of Pharmaceutics and Chair Executive Board TI Pharma University of Utrecht, Utrecht, Netherlands

George Ebers, Professor of Clinical Neurology, University of Oxford, Oxford, UK

Andreas Faller, Vice director of the Federal Office of Public Health Switzerland (OFSP) until 2012, Federal Office of Public Health (FOPH), Berne, Switzerland

Emer Fogarty, Health-economist National Centre for Pharmacoeconomics, St James Hospital, Dublin, Ireland

Carsten Lukas, Professor of Neurology, St. Josef Hospital, Ruhr University, Bochum, Germany

Jana Preiningerova, Assistant Professor Charles University in Prague 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic

Jean-Louis Prugnaud, Head of the Pharmacy Department at Hopital St Antoine and Chairman of the Genetic and Cellular Therapy Commission until 2012; National Security Agency of Medicines (ANSM), Paris, France

Beatriz Silva-Lima, Professor of Pharmacology and Pharmacotoxicology (Non-Clinical safety and Regulatory Science), University of Lisbon, Lisbon, Portugal

Christoph Thalheim, Deputy CEO & Director External Affairs European Multiple Sclerosis Platform (EMSP), Brussels, Belgium

Maria Trojano, Professor of Neurology, University of Bari, Bari, Italy

Luiza Wieczyńska, Secretary General, deputy CEO Polish MS Patient association, Warsaw, Poland

SCIENTIFIC COMMITTEE

Chair Patrick Vermersch, Professor of Neurology,University Hospital of Lille, Lille, France

Co-ChairRalf Gold, Professor of Neurology,St Josef Hospital, Bochum, Germany

Co-ChairChris Holloway, European Regulatory Consultant, Owner, ERA Consulting GmbHWalsrode, Germany

Mondher Toumi, Professor of Decision Sciences, Founder and CEO of Creativ-Ceutical University of Lyon, Lyon, France

Frauke Zipp, Professor of Neurology,University Medical Centre of the Johannes-Gutenberg, University of Mainz, Mainz, Germany

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Brussels, Belgium23-24 May 2014

www.ms-colloquium.org

Crowne Plaza Brussels - Le PalaceRue Gineste 3, B-1210 Brussels, Belgiumwww.crowneplazabrussels.be

The first Pan-European multi-stakeholder colloquium: Exploring opportunities and challenges for improving Multiple Sclerosis management

Supported by an unrestricted grant from TEVA Pharmaceuticals Europe B.V.