1 | P a g e

Programme of community action in the field of health (2008-2013)

European registry and network for Intoxication type Metabolic Diseases (E-IMD)

Contract no: 2010 12 01

Deliverable 10: Evaluation Report June 2014

2 | P a g e

ACKNOWLEDGEMENTS Evaluation group S. Parker (Orphan Europe and EUCERD member), S. Hannigan (CLIMB, UK), H. Meutgeert (VKS, Netherlands), M. Baumgartner (EUCERD, Switzerland), M. Summar (UCDC, USA), A. Rovsing (PND organisation, Denmark)

Co-ordinator S. Kölker Heidelberg University Children’s Hospital, Heidelberg, Germany (UKL-HD)

Co-beneficiaries I. Baric Sveuciliste u Zagrebu, Mediciniski fakultet, Zagreb, Croatia (UZMS) A. Burlina Azienda Ospedaliera di Padova, Padova, Italy (AZPD) A. Chakrapani Birmingham Children's Hospital NHS foundation trust, Birmingham, UK (BCHNHSFT) D. Dobbelaere Centre Hospitalier Régional et Universitaire de Lille - CHRU de Lille, Lille, France (CHRU L) A. Garcia Cazorla M. Ugarte, B. Merinero Centro de Investigacion Biomedica en Red, Spain (CIBER) S. Günewald Great Ormond Street Hospital for Children NHS Trust, London, UK (GOSH) E. Leao Teles Hospital de Sao Joao, EPE, Porto, Portugal (HSJ) A. Meldgaard Lund Rigshospitalet, Copenhagen, Region Hovedstaden, Denmark (RH) S. Parker Orphan Europe S.a.r.l., Paris, France (OE) J. Sykut-Cegielska Instytut "Pomnik-Centrum Zdrowia Dziecka", Warsaw, Poland V. Valayannopoulos Assistance Publique Hopitaux de Paris, Paris, France F. Wijburg Academisch Medisch Centrum, Amsterdam, Netherlands

Collaborating partners

Australia A. Boneh Royal Children's Hospital Melbourne, Melbourne, Australia

Austria D. Karall Medizinische Universität Innsbruck, Unversitätsklinik für Pädiatrie I, Innsbruck, J. Zschocke Medizinische Universität Innsbruck, Innsbruck, Austria

Belgium G. Debray Centre Hospitalier Universitaire, Liège F. Eyskens Universitair Ziekenhuis Antwerpen, Antwerp C. de Laet Hôpital Universitaire des Enfants Reine Fabiola L. de Meirleir University Hospital Vrije Universiteit Brussel, Brussels D. Roland Center for Inherited Metabolic Diseases, Institute of Pathology and Genetics, Gosselies E. Sokal Cliniques Universitaires St Luc, Brussels

Canada C. Greenberg University of Manitoba, Winnipeg, Manitoba, Canada

Czech Republic T. Honzik Charles University of Prague, Prague J. Zeman

France H. Ogier de Baulny Hôpital Robert Debré, Université Paris VII, Paris, France

3 | P a g e

Germany R. Ensenauer Dr. von Haunersches Kinderspital, Ludwig-Maximilian-Universität München, München, P. Freisinger Klinik für Kinder- und Jugendmedizin, Klinikum Reutlingen, Reutlingen R. Link Representing SSIEM Dietitians Group C. Mühlhausen Universitäts-Klinikum Eppendorf, Hamburg J. O. Sass Universitätsklinikum Freiburg, Freiburg U. Spiekerkötter Universitätsklinikum Düsseldorf, Düsseldorf

Greece P. Augoustides-Savvopoulou Thessaloniki University, Thessaloniki, Greece, and representing KRIKOS ZOIS (PO group) E. Drogari Aghia Sophia Children's Hospital, Athens, Greece

India A. Jalan NIRMAN, Biochemical Genetics, Mumbai, India

Italy C. Dionisi-Vici Ospedale Pediatrico Bambino Gesù, Rome, Italy D. Martinelli

Japan F. Endo Representing Japanese Urea Cycle Disorders Consortium (J-UCDC), Kumamoto University Hospital, Kumamoto, Japan

Portugal A. Gaspar Unidade de Doenças Metabólicas, Serviço de Pediatria Hospital Santa Maria Lisboa, Lisbon I. Tavares de Almeida Faculdade de Farmácia da Universidade de Lisboa, Lisbon, Porto L. Vilarinho Metabolic Genetics Center, National Institute of Health (INSA)

Romania P. Avram Institute for Mother and Child Care "Alfred Rusescu", Bucharest

Spain (participating in the CIBER network as co-beneficiary) E. Balmaseda Serrano Complejo Hospitalario Universitario de Albacete, Albacete J. Blasco-Alonso Hospital Materno-Infantil Malaga, Malaga C. Carrascosa Complejo Hospitalario Universitario de Albacete, Albacete M. L. Couce Hospital Clinico Universitario de Santiago de Compostela, Santiago de Compostela, J. M. de Haro Castellano Secretaria Tecnica de CEI-Granada (HUVN), Edificio Licinio de la Fuente, Granada E. Lopez University Hospital Reina Sofia, Cordoba C. Pedrón-Giner Hospital Infantil Universitario Nino Jesus Madrid, Madrid L. Pena Quintana Hospital Universitario Materno-Infantil de Canarias, Las Palmas de Gran Canaria, G. Pintos-Morell University Hospital "German Trias i Pujol", Badalona A. Ribes Institut Bioquimica Clinica, Corpracio Sanitaria Clinic, Barcelona A. Ruiz Gomez Hospital Universitario Son Espases, Balearic Islands, Palma de Mallorca V. Rubio Instituto de Biomedicina de Valencia, Valencia I. Vives Hospital Virgen de la Arrixaca de Murcia, El Palmar

Switzerland M. Baumgartner Kinderspital Zürich, Universitäts-Kinderkliniken, Eleonoren-Stiftung, Zürich J. Häberle J.M. Nuoffer Bern University Hospital, Bern, Switzerland

The Netherlands F. van Spronsen University Medical Center Groningen, Groningen, Netherlands M. Williams Erasmus Universiteit Rotterdam, Rotterdam, Netherlands

4 | P a g e

Turkey M. Demirkol Istanbul University, Children’s Hospital, Istanbul

Taiwan W-L Wu Department of Medical Genetics, National Taiwan University Hospital, Taipei

UK R. Lachmann Representing SSIEM Adult metabolic group, Charles Dent Metabolic Unit, National Hospital for Neurology and Neurosurgery, London J. Walter Central Manchester and Manchester Children's University Hospital, Manchester R. Vara Evelina Children's Hospital, St Thomas' Hospital, London

USA M. Summar K. Chapman Representating Urea Cycle Disorders Consortium (UCDC), Childrens National Medical Center, Washington DC J. Vockley Children’s Hospital of Pittsburgh of UPMC, Pittsburgh

EAHC project officer G. Margetidis

5 | P a g e

Description of the deliverable Outcome and process indicators will be monitored and evaluated during the whole time period of E-IMD. According to the description of indicators evaluation will be performed once or – for process evaluation - on a monthly basis. Table 1: List of indicators as described in the technical Annex 1a:

Indicator Type of indicator

Agreed items to be included in the registry for data collection

Process

Analysis of quality and completeness of records in the database

Process

Number of cases reported in the registry by country/centre

Output

Analysis report on differences in diagnosis, treatment and outcome at start and end of project

Outcome

Agreed contents of website Process

Meetings held on schedule – SIGN methods applied

Process

Number of hits, unique visitors and enquiries to the website

Output

Number of existing recommendations in Europe for OAD and UCD

Output

Analysis of registry to show number of centres using E-IMD recommendations for OAD and UCD

Outcome

6 | P a g e

Contents Acknowledgements ................................................................................................................................. 2

Executive summary ................................................................................................................................. 7

1. Background and purpose ................................................................................................................ 9

2. Evaluation framework and methodology ....................................................................................... 9

3. Results ........................................................................................................................................... 11

3.1. Results of survey to patients organisations .............................................................................. 11

3.2. Results of short post meeting (mid-project) survey to patients organisations (PO) ................ 12

3.3. Results of short post funding survey to network members ..................................................... 12

3.4. Website ..................................................................................................................................... 13

3.5. Registry: timeline of ethics approval 2011-2014 ...................................................................... 16

3.6. Registry: Analysis of geographical coverage and differences in diagnosis and treatment between centres. .................................................................................................................................. 16

3.6.1. Number of cases reported in the registry ............................................................................. 16

3.6.2. Completeness of records ...................................................................................................... 18

3.6.3. Mode of diagnosis ................................................................................................................. 19

3.6.4. Access to treatment .............................................................................................................. 20

3.6.5. Adherence to guidelines ....................................................................................................... 21

4. Discussion of the results ............................................................................................................... 21

5. Conclusion and recommandations ............................................................................................... 22

7 | P a g e

EXECUTIVE SUMMARY Organic acidurias (OAD) and urea cycle defects (UCD) are two groups of life threatening rare intoxication type metabolic diseases (IMD) with overlapping clinical phenotypes. The characteristics of rare diseases – limited number of patients and scarcity of relevant knowledge and expertise – single them out as an area of especially high European added-value. The E-IMD project was funded from 1 January 2011 to 30 April 2014. It has developed beyond expectations and now includes 87 partners from 25 countries establishing links between healthcare professionals, patient representatives, industry and government authorities within European Union Members States (EU MS), EU candidate countries, other European countries, North America, India, Japan, Taiwan, and Australia. An important aspect of any project focused on improving healthcare for patients is evaluation of the effectiveness of the strategy in achieving the outcomes proposed at the start of the project. This report has evaluated results against expectations of the key stakeholders: the patients and families served by the project, the metabolic centres of expertise and other healthcare professionals.

In summary, E-IMD’s main added value to the community includes:

a) Development of an international network for collaboration, sharing knowledge and experience:

During the project, the number of centres applying for participation steadily increased to

European countries that were not initially part of E-IMD and non-European partners. The

network has demanded close collaboration between clinicians, diagnostic laboratories,

scientists, patients and their families. The network serves as a centre for information, research

and knowledge; updating and contributing to the latest scientific findings, and proposing the

best strategies for managing patients.

b) Development of diagnostic and clinical guidelines: The development, translating and

dissemination of evidence-based best practice guidelines for diagnosis and management have

been a core activity. Four guideline papers have been produced and shortened versions are in

the process of translation. They include the provision of recommendations for effective practice

in clinical situations where variations are known to occur and where effective care may not be

delivered uniformly.

c) Development of an international registry for OAD and UCD: The registry plays an important role

in auditing current care, improving knowledge and providing standards to reduce variation and

improve patient outcome. Data from the registry are published in peer review journals.

d) Expansion of the disease panel to homocystinurias, methylation and folate defects: In 2013

homocystinurias, methylation and folate defects were added to the network by achieving

funding for the E-HOD project (EAHC grant no. 2012 12 02). In 2014 it is expected to add

neurometabolic disorders (iTND, Dietmar Hopp Foundation) to make a total of 50 diseases

followed by the network.

e) Development of a Federation of patient organisations: Surveys of patient groups identified a

need for closer working and exploring areas of mutual interest such as setting up a patient

federation of inborn errors of metabolism organizations. The initial steps have been taken, as

indicated by the establishment of the European Metabolic Disorders Alliance (EMDA)

www.eumda.org.

The overall indication from the project evaluation is that EIMD clearly delivers on its general objective of improving OAD and UCD healthcare across Europe.

8 | P a g e

The major concern in maintaining the dynamic of the EIMD network and registry is sustainability, as the infrastructure and coordination have a cost.

9 | P a g e

1. BACKGROUND AND PURPOSE Organic acidurias (OAD) and urea cycle defects (UCD) are two groups of life threatening rare intoxication type metabolic diseases (IMD) with overlapping clinical phenotypes. Patients present predominantly in childhood but better diagnosis and management has resulted in patients surviving into adulthood. The characteristics of rare diseases – limited number of patients and scarcity of relevant knowledge and expertise – single them out as an area of especially high European added-value. One of the main areas of activity for EIMD was the development of a patient registry for OAD and UCD where patient information, including demographic, medical and family history were collected, stored and available for retrieval via standardised and secure methods. The patient registry is a critical tool to improve the knowledge base, to develop European consensus guidelines, to foster networking on a European level and, ultimately, to promote health for patients with OADs and UCDs in Europe. The purpose of this evaluation report is to describe the internal and external evaluation of the activities and progress made against the indicators and target values that were defined in the work programme.

2. EVALUATION FRAMEWORK AND METHODOLOGY The evaluation report is led by S. Parker (Orphan Europe and EUCERD member), the members have included: S. Hannigan (CLIMB, UK), H. Meutgeert (VKS, Netherlands), M. Baumgartner (EUCERD, Switzerland), M. Summar (UCDC, USA), A. Rovsing (PND organisation, Denmark). The group used the following external and internal sources of data and information:

Sources of information:

2.1. Members of patient organisations were asked to complete an online survey. The aim of the survey, which was available in four languages, was to understand how the quality of care and treatment of patients and their families received at their centre or hospital can better meet their needs and expectations. The role of E-IMD was to address any issues. The survey was anonymous.

2.2. Patient organisations were asked to complete a short survey following the first patient

meeting, held in Birmingham September 2012:

What have been the most valuable learning points of this meeting for you?

Following this meeting, what services would you like EIMD to set up for the benefit of

patients?

What issues/topics would you like followed up at a future meeting?

Do you have any further feedback?

2.3. Members of EIMD were asked to complete a similar survey at the end of the project.

2.4. The website is analysed, on a monthly basis, for number of hits and unique visitors. We also

follow up on the number of enquiries to the network coming from the website.

2.5. The patient registry has been externally reviewed by various expert agencies: data

protection, ethical and scientific. The registry has been used to analyse the number of cases

10 | P a g e

reported by country/centre, differences in diagnosis, treatment and compliance to the E-

IMD recommendations for OADs and UCDs.

Limitations of the evaluation approach: A three year project limits the feasibility of monitoring longitudinal “outcome” data.

11 | P a g e

3. RESULTS 3.1. RESULTS OF SURVEY TO PATIENTS ORGANISATIONS

A requirement of the E-IMD project, as part of the evaluation processes, was to undertake two surveys. The first survey was conducted by Climb to known children and adults with an OAD or UCD in the UK to give a baseline. The survey was also put on the website to a larger public. Fifty two responses were received. The age of patients in the survey underlines the projects strength in covering the paediatric population but probably there is an underestimation in the needs of adults. Figure 1 Country of residence (based on 52 replies)

Figure 2: Actual age of patient

Survey respondents were asked about the format and type of information that they received at the time of diagnosis and then about the format of information they think is the most useful (figures 3 & 4); a need to access helplines and online patient communities is considered important whilst this service was rarely proposed. Furthermore 26% of patients declared that they did not receive adequate information at the time of diagnosis. Figure 3

Figure 4

05

10152025

Po

rtu

gal

Un

ite

d…

Net

her

lan

ds

Alb

ania

Ru

ssia

Sou

th A

fric

a

Ital

ia

USA

Ire

lan

d

Au

stra

lia

Ger

man

y

0,00% 10,00% 20,00% 30,00%

1

3

5

7

9

11

12 | P a g e

Patient’s access to expert centres and health care professionals could be improved: nearly 20% of respondents claimed not to be consulting a metabolic disease expert or specialist centres and not all patients were able to meet their doctor as much as desired (figures 5 & 6). Over half of respondents had never contacted a centre outside of their resident country. Figure 5

Figure 6

Until recently metabolic diseases were considered as a specialty for pediatricians. However, as the recognition, diagnosis and management gets better; patients are surviving longer, so adult physicians looking after IMD patients are being presented with patients who are likely to have metabolic decompensations. This survey did not cover the adult population very well; however 16 people evaluated their satisfaction of the transition care from paediatrics to adult: 60 % replied that they were satisfied whilst 40% were not.

3.2. RESULTS OF SHORT POST MEETING (MID-PROJECT) SURVEY TO PATIENTS ORGANISATIONS

(PO)

Patient organisations were asked to complete a short survey following the first patient meeting, held

in Birmingham September 2012:

Learning points and expectations from a patient organisation viewpoint:

The most valuable learning point from the E-IMD Network is that language is not a barrier to providing support to patients and families

The PO network needs to move forward to enable the uniting of the different national patient organisations for OAD and UCD to form a common umbrella to address topics of joint interest

In future meetings we would expect to see the uniting of different national patient organisations who are working together to support families and patients

3.3. RESULTS OF SHORT POST FUNDING SURVEY TO NETWORK MEMBERS

Network members of E-IMD were asked to complete a survey to understand the most valuable learning points and future expectations of E-IMD. Thirty one replies were received (8 associate partners and 23 collaborating partners). The most valuable learning points and activities of the network for partners were the platform to meet, team work, exchange of knowledge and being able to compare practice and ultimately improve patient care. The registry and guideline developments are regarded as key instruments for improving care and these form the core activities for international collaboration. Collaborating with patient organisations is regarded as necessary and

13 | P a g e

constructive to the network. Nearly 80% or members agreed that annual meetings would be sufficient, preferably before or after the annual metabolic meeting (SSIEM)

Figure 7 summarises the services that members would like E-IMD to continue

The most important hurdles and difficulties in the E-IMD project have been the lack of resources,

sustainability, time to achieving ethical approval for the registry, time for meetings and other

administrative hurdles.

The additional feedback was extremely positive. Partners of E-IMD have enthusiastically embraced

the principles of sharing knowledge and improving access to information. Many have said that this is

an extraordinarily valuable project that must continue. The project was praised in its initiative to

extend to other rare intoxication type metabolic diseases: homocystinurias, methylation and folate

defects (E-HOD).

3.4. WEBSITE

As part of the project a website was developed which had 3 primary functions: To showcase E-IMD and what it is doing – this can also be looked upon as an ‘on-line’

brochure. Helping people to gain a better understanding of OAD and UCD and to enable contact with

E-IMD. To ensure that the E-IMD website is easily found by promoting it through as many media as

possible.

0 5 10 15 20 25 30

Network meetings

Follow-up of registry cohort

Telemedicine

Tele-expertise

Guideline development

Facilitate training and…

Laboratory quality control

What services would you like EIMD to continue supporting/organising?

Network meetings

Follow-up of registry cohort

Telemedicine

Tele-expertise

Guideline development

Facilitate training and education

Laboratory quality control

14 | P a g e

To date the website has achieved a wide area of coverage and accesses have been made from as far north as Honningsvag (North Cape), Norway to Tierra Del Fuego (Cape Horn), South America to Hawaii in the west to Japan in the East. The statistics from the website during the January 2012 to April 2014 are interesting and we have looked at the

Number of accesses per day Total number of true accesses during the period

(accesses who have stayed on the site for longer than 10 seconds) Number of guides downloaded by disease group Number of downloads for younger people

Figure 8

The average accesses to the website were looked at and comparisons made based on a per day/calendar year and per day/working day year for 2012, 2013 and the first 4 months of 2014. Figure 9

From these evaluations of access made to E-IMD website we were able to deduce the amount of time that users stayed on the various pages available to them.

0

50

100

150

200

250

300

2012

2013

2014

5

5,2

5,4

5,6

5,8

6

6,2

6,4

Per Day/Yr2012 Per Day/Yr2013 Per Day/Yr2014

5.51

7.73 6,22

15 | P a g e

Figure 10

The google search engine is efficient and E-IMD is on the first page when typing “organic aciduria” or “urea cycle disorder”.

In order to improve access to the E-IMD website the project (through Climb) have set up Facebook and Twitter accounts to enable the rapid dissemination of information and to reach families and patients more quickly.

1183

142 135 197 205 124 24

1392

164 132 209 215 140 19

0

500

1000

1500

2000

2500

3000

3500

2014

2013

2012

16 | P a g e

3.5. REGISTRY: TIMELINE OF ETHICS APPROVAL 2011-2014

Approval by the Heidelberg research ethics committee was obtained in January 2011. Heidelberg gave support to other partners providing a template for the ethics application, patient and parent information, and informed consent forms in English. Translation of the ethics template in other languages, adaptation to the requirements of individual centres and countries and the external evaluation process have been time-consuming. Furthermore, a significant difference in the duration of this process in European countries has been identified. At the end of the project 44 partners in 22 countries had received ethics approval.

3.6. REGISTRY: ANALYSIS OF GEOGRAPHICAL COVERAGE AND DIFFERENCES IN DIAGNOSIS AND

TREATMENT BETWEEN CENTRES.

3.6.1. NUMBER OF CASES REPORTED IN THE REGISTRY

Figure 11: Number of cases in the registry from 1 Jan 2011 – 30 April 2014

From the start of the project until 30 April 2014, 1009 patients have been registered with a confirmed diagnosis of OAD or UCD. For the evaluation report, we looked at the number of cases reported in the registry by country/centre. For the interim data analysis for the publications, cut-off date was set at 22 October, 2013. Table 2: Cumulative frequencies of patients with OAD and UCD in European countries from Jan 2011 – April 2014

17 | P a g e

Country Patients Population* Frequency

(N) (N) (N per 1 M citizens)

Denmark 47 5602628 8.39

Croatia 22 4262140 5.16

Portugal 34 10487289 3.24

Spain 145 46704308 3.10

Switzerland 24 8039060 2.99

France 189 65633194 2.88

Czech Republic 29 10516125 2.76

Netherlands 44 16779575 2.62

Austria 22 8451860 2.60

United Kingdom 129 63887988 2.02

Belgium 22 11161642 1.97

Germany 160 82020578 1.95

Italy 65 59685227 1.09

Poland 36 38533299 0.93

Greece 8 11062508 0.72

Romania 3 20057458 0.15

TOTAL (EU MS) 952 454845819 2.09

*Population size in 2013 according to EUROSTAT This data shows significant variation between countries (range 8.39 – 0.93 for associate partners; 2.99 – 0.15 for collaborating partners). There could be a number of reasons for this difference: patients are living longer (better outcome), centralization between paediatric and adult patients, difference in diseases, higher prevalence or undiagnosed patients in other countries. The most likely explanation is that some centres are recording all or most cases in their country, whilst other centres may only have a regional coverage (particularly collaborating partners). Partners were therefore asked to estimate the population covered by their centre or network. This partly explained the variation in some less centralized countries. We note that Switzerland, Czech Republic and Austria have performed remarkably well despite their collaborating partner status and lack of funding from the Commission.

We also looked at variation in the number of patients with specific diseases in each country. Figure 12 shows a high percentage of glutaric aciduria type 1 (GA1) patients in Denmark, Germany, Poland and Spain; and a high percentage of female (ornithine transcarbamylase) OTC carriers in Portugal. Figure 12 Percentage of patients with a particular disease by country

18 | P a g e

3.6.2. COMPLETENESS OF RECORDS

After looking at total numbers of patients we then analysed the completeness of records through the types of visit and follow up. The greater the number of follow-up visits compared to the total number of patients for that centre, the more complete the record. High performers are Croatia, Denmark and Germany. On average there are 1.5 follow-up visits per patient. In the coming months and years, centres must be encouraged to complete records and focus on follow-up visits. Table 3: Number of visits by type and country

Country nb patients

Baseline Regular Emergency Fatal

disease Subtotal

% with baseline

Av. nb follow-up by

patient

Austria 22 22 6 1 0 29 100% 0.32

Belgium 22 21 0 0 0 21 95% 0

Croatia 22 21 96 22 2 141 95% 5.45

Czech Republic 29 29 15 0 0 44 100% 0.52

Denmark 47 47 169 151 1 368 100% 6.83

France 189 185 103 4 0 292 98% 0.57

Germany 160 156 425 187 7 775 98% 3.87

Greece 8 6 5 0 0 11 75% 0.63

Italy 65 65 40 0 0 105 100% 0.62

Netherlands 44 43 44 18 0 105 98% 1.41

Poland 36 36 34 13 1 84 100% 1.33

Portugal 34 34 33 13 1 81 100% 1.38

Spain 145 144 97 1 2 244 99% 0.69

Switzerland 24 24 1 0 0 25 100% 0.04

United 129 88 4 3 0 95 68% 0.05

0%

10%

20%

30%

40%

50%

60%

70%

Au

stri

a

Be

lgiu

m

Cro

atia

Cze

ch R

epu

blic

De

nm

ark

Fran

ce

Ger

man

y

Gre

ece

Ital

y

Net

her

lan

ds

Po

lan

d

Po

rtu

gal

Ro

man

ia

Serb

ia

Spai

n

Swit

zerl

and

Un

ite

d K

ingd

om

MMA

PA

IVA

GA1

NAGS

CPS1

OTC (m)

OTC (f)

ASS

ASL

ARG1

19 | P a g e

Kingdom

Subtotal 976 929 1072 413 14 2428 95% 1.54

3.6.3. MODE OF DIAGNOSIS

We were particularly interested to look at the number of patients picked up though newborn screening (NBS); since not all countries perform NBS. Figures 13 & 14 show the mode of diagnosis for OAD and UCD for the total patient population in the registry Figure 13 mode of diagnosis OAD

Figure 14 mode of diagnosis UCD

We then looked specifically at differences in the total number of patients in countries with NBS compared to those without. Table 4 – 8 show the frequency of patients (per million population) entered into the registry compared to the country population. Green highlights indicate that newborn screening is performed in this country. From this crude analysis, there seems to be a higher frequency of these diseases in countries performing newborn screening, although this is less obvious for MMA. Table 4

Country MMA

Denmark 1.785

Croatia 1.642

Czech Republic 0.666

Belgium 0.627

Switzerland 0.622

France 0.594

Spain 0.514

Netherlands 0.477

Germany 0.280

Austria 0.237

United Kingdom 0.219

Portugal 0.191

Poland 0.182

Italy 0.168

Greece 0.090

Table 6

Country PA

Austria 1.065

Croatia 0.938

Denmark 0.892

Switzerland 0.622

France 0.549

Belgium 0.448

Netherlands 0.298

Spain 0.214

Germany 0.207

Portugal 0.191

Czech Republic 0.190

United Kingdom 0.188

Greece 0.181

Italy 0.134

Poland 0.130

Table 8

Country IVA

20 | P a g e

Denmark 0.714

Netherlands 0.417

Czech Republic 0.285

Switzerland 0.249

Germany 0.244

Croatia 0.235

France 0.168

United Kingdom 0.157

Poland 0.104

Belgium 0.090

Italy 0.050

Spain 0.021

Austria 0

Portugal 0

Greece 0

Table 5

Country GA1

Denmark 2.856

Croatia 1.173

Spain 1.006

Germany 0.500

Czech Republic 0.475

Austria 0.473

Netherlands 0.358

France 0.259

Switzerland 0.249

Poland 0.234

United Kingdom 0.141

Portugal 0.095

Italy 0.034

Belgium 0

Greece 0

Table 7

Country ASS

Switzerland 0.373

Denmark 0.357

Portugal 0.286

Spain 0.278

France 0.213

United Kingdom 0.203

Belgium 0.179

Netherlands 0.179

Italy 0.168

Germany 0.122

Croatia 0

Czech Republic 0

Austria 0

Poland 0

Greece 0

Further data would be needed to look at the presence of symptoms, number of crisis, and outcome in patients that have been diagnosed prenatally or through NBS compared to those diagnosed after the onset of symptoms.

3.6.4. ACCESS TO TREATMENT

The data was analysed for differences in access to treatment and compliance to guidelines. There was a low use of unapproved drugs, in general. Only unapproved sodium benzoate (since a licensed drug for oral application is not available) and sodium phenylbutyrate was used for some indications. Carglumic acid was given to 100% of patients with NAGS deficiency and 11% in CPS1 this reflects the guidelines produced by the working group. Figure 15: treatment with carbamylglutamate

Figure 16: treatment with carnitine

21 | P a g e

Figure 17: treatment with sodium benzoate

Figure 18: treatment with sodium phenylbutyrate

3.6.5. ADHERENCE TO GUIDELINES

UCD and revised GA1 guidelines have been published in 2011 and 2012, respectively, MMA/PA guidelines are in the publication process and IVA guidelines will be submitted in the second half of 2014. Therefore, adherence to guidelines and its effect on the health outcome of affected individuals with OAD and UCD cannot be accurately assessed by the end of the funding period for E-IMD. A pilot study in Germany on GA1 patients identified by newborn screening has confirmed that adherence to recommended treatment (maintenance and emergency) and follow-up by a interdisciplinary team of experts significantly reduces the health burden of children with this disease. In analogy, we will carefully evaluate the effect of adherence to diagnostic and therapeutic recommendations for other OAD and UCD. We expect that the combination of newborn screening plus adherence to guideline recommendations will also improve the health of affected individuals with other OAD and UCD.

4. DISCUSSION OF THE RESULTS The survey to patients has provided evidence that there is a need to develop care pathways for OAD and UCD patients and to resolve the difficult issue of transition of adolescents into adult care. From the patient perspective there is also a need to develop the patient organisation community for IMD through the establishment of a helpline and online community. E-IMD has been the catalyser in the funding and launching of the Federation of patient organisations. This is in its early stages but has the potential for presenting a European wide position of patients with an IMD. Furthermore the expertise offered by E-IMD to PO’s is important in giving expert advice, reaching out to patients and providing lay translations of recent research. It also provides an ideal opportunity to share best practice across Europe, and where appropriate worldwide with collaborating partners and their patient communities. The website is the principle means of public communication. E-IMD comes up on the first page of google search engine using the key words “OAD or UCD”; however it was still difficult to get traffic to the website. Facebook and twitter were moderately successful. Centres of expertise unanimously evaluate the project to reach its objective in improving patient care; however internal and external administrative hurdles, time and lack of resources delay project

22 | P a g e

progress and prevent certain partners from their participation. The registry, guideline development and meetings are an essential part of the network. The registry contains data on 1009 individuals with an OAD or UCD; it is evident that funded partners are able to perform better than non-funded partners; this is particularly so when looking at the completeness of data. There must be a concerted effort amongst partners to complete patient records and follow-up this unique cohort. Further data is needed in the registry to better understand the outcome of patients diagnosed through new-born screening compared to those diagnosed after the onset of symptoms. The funding secured to date has allowed the development and expansion of a European Reference Network for this group of rare inherited metabolic disorders (IMD).

5. CONCLUSION AND RECOMMANDATIONS E-IMD is highly successful in its objective of improving healthcare for patients with OAD and UCD and their families wherever they live in Europe. The network of participating centres of expertise is large and partners enthusiastically embrace the principles of widening access to and improving quality of diagnostic and clinical services. Information for patients, families and non-expert clinicians is available in a large variety of European languages. The establishment of the European registry is a major step forward in understanding some of the very complex clinical and biochemical issues related to OAD and UCD. The guidelines provide standards for improving the care of patients and decreasing variability. The network has engendered a momentum and enthusiasm among professionals working in this field to continue and build on what has been achieved so far – this is a good indicator that the network can be sustained through the understanding that collaboration is required in these rare diseases. However without European funding the network will work with reduced activity. This will inevitably imply that less developed countries or structures will be most disadvantaged when having to find national or local funding. A recommendation from the network would be for centres of expertise to reduce the administrative burdens for members to participate in a network and registry by providing staff for the ethical approval, data entry and covering costs and time for experts to attend meetings. All members of E-IMD feel very strongly that the network and registry must continue and that we should apply for European Reference Network status through the future call of interest.