nEUroped Project Grant Agreement number 2007 122

Deliverable D13

Capacity Building Workshop for Patient Networks AHC and Narcolepsy

21st of November 2010, Brussels, BE

Delivery date: M33

Lead Partner: 06-EURORDIS-FR

European Commission Executive Agency for Health and Consumers (EAHC)

To the attention of Mr. Luc Briol, Director Scientific Unit

DROSBACH A3/029 L-2920 Luxembourg

nEUroped

EUROPEAN NETWORK OF EXPERTISE FOR RARE PEDIATRIC NEUROLOGICAL DISEASES

nEUroped

EU co- funded project under the Public Health Program 2007

1. HEALTH INFORMATION (HI 2007)

1.4. DEVELOPING STRATEGIES FOR INFORMATION EXCHANGE AND RESPONDING TO NON

COMMUNICABLE HEALTH THREATS

24th April 2008- 23rd April 2011

Coordinator: Professor Alexis ARZIMANOGLOU

REPORT

Capacity Building Workshop for Patient Networks AHC and Narcolepsy

21st of November 2010, 9:30 – 17:00 pm

Fondation Universitaire, Brussels, Belgium

Author(s): Anna Kole (06-EURORDIS); Monique Sallaz (01-HCL-FR)

Reviewer(s): Alexis Arzimanoglou (01-HCL-FR)

Identifier: Capacity Building Workshop for Patient Networks AHC and Narcolepsy M31_21.11.10_ Brussels, BE

Dissemination level: RES

Contractual Date: 12.2010

Actual Date: 11.01.2011

Number of pages: 46

Approved by the Partners X Coordinator X

Date: 11.01.2011

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LIST OF PARTICIPANTS

1. Patient representatives:

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2. Health care professionals and academics:

Name Structure

1 Arzamanoglou Alexis 01-HCL-FR

2 Sallaz Monique 01-HCL-FR

3 Sona Nevsimalova 03-CUNI-CZ

4 David Kemlink 03-CUNI-CZ

5 Poli, Francesca 05-UNIBO-IT

6 Francis Crawley 07-GCPA-BE

7 Urania Kotzaeridou 09- UKH-DE

8 Claudio Zucca 10-MEDEA-IT

9 Jaime Campistol 12-HSJD-ES

10 Elisa De Grandis

11 Ine Cockerell

12 Nadia Peppa

13 Marit Bjornvold

14 Michael Rotstein

15 Mirjana Pavlick

16 Barbaro Gnidovec

17 Damian Oscedich

18 Francesca Ingravallo

19 Cristina Villar

20 Rose Peraita

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nEUroped ENM Agenda

Preliminary Workshop: Sunday, 21st of November 2010 Patients and Clinicians

Reviewing and Challenging the nEUroped Achievements

Session A: Capacity-building Workshop: Patients, nEUroped, and Disease Registries

9:30-9:55 Welcome and Introduction to the Workshop and the Participants

Anna Kole, European Organisation for Rare Diseases (EURORDIS), nEUroped, France

9:55-10:05 The nEUroped Project: Objectives and Workpackages Francis P. Crawley, Good Clinical Practice Alliance – Europe (GCPA), nEUroped, Belgium

10:05-10:15 The Role of Patients in the nEUroped Project Tsveta Schyns, European Network for Research on Alternating Hemiplegia (ENRAH), nEUroped, Belgium

10:15-11:00 Presentation on Patient Registries: Definitions, Benefits and Pitfalls Jeanne-Hélène di Donato, 3 C-R (Consulting and expertise for databases and biobanks)

11:00-11:30 Coffee Break

11:30-12:30 The Role of Patients, Researchers, and Sponsors in a Patient Registry: Case Study: I.B.AHC Biobank and Clinical Registry for Alternating Hemiplegia Rosaria Vavassori, I.B.AHC Project Coordinator and President AISEA, Italy

12:30-13:00 Discussion

13:00-14:00 Lunch

Session B: Using Disease Registries to Address Rare Paediatric Neurological Diseases

14:00-14:30 Developing Guidelines for Patient Care in the nEUroped Project: Surveying Patient Needs, Medical Assessments, and Registry Fit Brian Neville, nEUroped Clinician and Research Expert; Institute for Child Health, University College London, United Kingdom

14:30-15:30 Plenary Discussion: Integrating Patient Needs into the nEUroped Project A discussion oriented toward gathering information and an understanding of the experiences of patients and their families regarding the childhood neurological diseases and the patients’ expectations for future research.

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Potential questions to be addressed by the three working group participants: 1. What are the principle needs of children with specific nEUrological diseases regarding research? 2. Which kinds of research would patients and their families wish to see prioritised within nEUroped? 3. What are the challenges, hindrances, to full patient participation in the nEUroped project?

15:30-17:00 Working Groups: The Future of Patients in the nEUroped Project: Progress, Expectations, and Challenges in AHC, Narcolepsy, and RSTES Introduction to the discussion by a clinical and research expert from nEUroped regarding the current medical and scientific understanding of the specific disease as well as expectations for future progress in the disease from medical science.

A. Working Group on Alternating Hemiplegia in Childhood (AHC) Patients, Families, and Patient Organisations

B. Working Group on Narcolepsy Patients, Families, and Patient Organisations

C. Working Group on RSTES Patients, Families, and Patient Organisations

Potential questions to be addressed by the three working group participants: 1. Given the current progress and expectations for the future development of preventive, diagnostic, and therapeutic interventions in your disease area, what would patients, their families and organisations expect from nEUroped? 2. What kind of organisation and communication structures should be developed within nEUroped in order to meet the needs of patients, their families, and their organisations? 3. What specific roles should patients, their families, and their organisations take up in nEUroped? What should be the tasks and responsibilities of patients, their families, and their organisations in nEUroped?

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Capacity Building and Patient Network Integration into nEUroped nEUroped Extended Network Meeting Pre-Conference Workshop Report

21st of November 2010, 9:30 – 17:00 Fondation Universitaire, Brussels, Belgium

On Sunday 21, November members of the nEUroped Extended Network including the Patient Network (patients and parents identified across Europe concerned with Alternating Hemiplegia, Narcolepsy and Rare Surgically Treatable Epileptic Syndromes (RSTES), project partners and other interested Extended Network members were invited to attend the pre-conference workshop focused on the roles of patients and clinicians in nEUroped and how nEUroped can be further developed to meet patient needs and interests in addressing rare paediatric neurological disease. This meeting marked the 2nd face-to-face meeting of patient groups and parents identified by the European Organisation for Rare Diseases (EURORDIS).

Specific Workshop Objectives

The specific objectives of this workshop were to continue the integration and empowerment of patients affected by rare paediatric neurological diseases by having their input and involvement in nEUroped by:

• presenting the status of nEUroped outcomes • building the capacity of patients to understand the basic principles of patient

registries and discuss the specific role of patient groups in the nEUroped registry • breaking out into disease specific groups to foster communication between patient

groups and professionals on current and future expectations of the nEUroped consortium.

Workshop Programme

Workshop objectives were addressed by a diverse programme including:

A. Introductions by the EURORDIS and their role in integrating patients into the project, the European Network for Research on Alternating Hemiplegia (ENRAH) and their role as initiators of nEUroped and the Good Clinical Practice Alliance (GCPA).

B. A Capacity Building on Patient Registries: Definitions, Benefits, Pitfalls and Patient

Involvement by Jeanne-Helene di Donato, 3C-R consulting

C. A presentation of an example of a patient-led registry and biobank: IBAHC Biobank and Clinical Registry for Alternating Hemiplegia Biobank and Clinical Registry for Alternating hemiplegia coordinated by the Italian Patient Association for Alternagting Hemiplegia (AISEA)

D. A general presentation of the project’s progress and plenary discussion on how to best

integrate patient needs and expectations, Alexis Arzimanoglou, Hospices Civil Lyon

E. Presentations on the progress by disease specific Working Group leaders in the project (Alternating Hemiplegia - Brian Neville; Narcolepsy - Sona Nevsilmalova; RSTES - Alexis Arzimanoglou)

o Discussion on proposed Care Management Guidelines o Sharing of experiences to receive patient input into nEUroped and their future

expectations for involvement in the consortium

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Achievements

A. Patients were introduced to EURORDIS’ role in the nEUroped project. As an umbrella rare disease organisation, EURORDIS is experienced in identifying and creating relationships with patient support groups their members and families, identifying their needs and expectations as related to their disease and ensuring that these needs and expectations are understood by all other project stakeholders and integrated into the projects activities. EURORDIS is also in charge of setting up platforms for communication within disease specific patient communities either through mailing lists or larger online patient communities.

ENRAH, through previous European Commission funding, is an established network of patients, parents and researchers concerned with Alternating Hemiplegia for which specific objectives included:

• Pragmatic identification of patients with Alternating Hemiplegia across Europe

• Identification of researchers and small to medium sized enterprises interested in progressing research in the field

• Raising awareness of the disease in Europe • Providing accurate information for patients and caregivers when it exists

This preliminary work serves as the basis for continued networking at the European level among all stakeholders concerned with Alternating Hemiplegia via the nEUroped project.

B. Patients were presented with the basic definitions of the nEUroped patient registry as an on-going, exhaustive system of data collection of patients with epileptic, narcoleptic or hemiplegic paroxysmal attacks via Centers of Expertise across Europe that treat a steady number of patients with Alternating Hemiplegia, narcolepsy and rare RSTES. Beyond collecting data, the nEUroped registry will increase knowledge on the diseases included, support further research by pooling data in order to achieve a sufficient sample size for epidemiologic and clinical research and perhaps one day constitute a key instrument in allowing drug surveillance and supporting health service planning for patients affected with these rare paediatric neurological diseases.

The Patient Network and other workshop participants were also presented with the reality that although very thorough and effective research infrastructures, patient registries are tools that require significant time and financial investment and thorough planning to meet the needs of all stakeholders involved. As such, collaborative efforts to establish, manage and derive outcomes from patient registries are paramount in a network such as nEUroped which above all integrates the expectations of patients and their families.

C. Participants of the Workshop were presented with an example of a registry (and biobank)

established, managed and maintained by a patient organisation.

A. S. I. EA Onlus, the Italian Association for the AHC, was created in 1999 with the mission to support families affected by Alternating Hemiplegia, spread knowledge about the disease, and promote and support research. Since its inception, the association decided that the best way to achieve this objective was to make clinical data and biological samples available and easily accessible to research groups. In 2004, the I.B.AHC (Italian Biobank and Clinical Registry for Alternating Hemiplegia) was by the association A.I.S.EA Onlus, on behalf of its patients, to physicians and researchers interested in

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carrying out studies and research projects on Alternating Hemiplegia in Childhood (AHC). I.B.AHC is composed of two main repositories, the Clinical Registry and the Biological Bank, designed to gather, organise, store, and share the biologic material (DNA, RNA, Cellular Lines) and the clinical data of the patients affected by AHC.

The diagnosis of all the cases entered in the I.B.AHC Biobank and Clinical Registry are validated by the Scientific Committee of A.I.S.EA Onlus and by the treating physicians of the participating patients.

More specifically, the objectives of I.B.AHC are:

1. To support the scientific research of the causes of AHC and of an effective treatment, by making available the medical and scientific data and the biological material of a large number of validated cases to any research group presenting a written request

2. To facilitate the definition of new research lines and the start of new large-scale collaborating projects, through the sharing of the clinical information and the biological material and of the results of the studies using them,

3. To develop the knowledge of AHC and a better diagnosis and care for the patients, by making available the clinical history (evolution of the symptoms, effectiveness of the drugs ...) of the entered cases and by networking all the involved expertises (researchers, clinicians, patients, rehabilitation therapists, public institutions ...)

Currently, 35 cases are available, complete with clinical data and biological samples.

D. Participants were briefly presented with the original objectives of the nEUroped registry:

• Creation of one common registry for Alternating Hemiplegia, Narcolepsy and RSTES – diseases with the common symptom of paroxysmal events

• Identification of centres of expertise across Europe able and willing to enter data into the registry

An open discussion centred on three questions regarding the needs, expectations and involvement of patient groups, patients and their families. The discussion began in a plenary format with the following general conclusions.

1. What are the patient expectations for the development, future management, and future use of data collected in the nEUroped registry?

a. To identify patients across Europe and centralise general knowledge about their treatment and care

b. Opening of the network to new specialist canters interested into contributing data

c. To establish better communication and collaboration across the medical community

d. To be consulted on request to use registry data e. To guarantee continuation and sustainability of the registry

through long-term funding plan

Participants feel that currently not enough research to improve care and treatment for rare neurological paediatric diseases is being done. It is expected that the registration of patients and their outcomes in the nEUroped registry will lead to better existing knowledge on the causes and effective care and treatments. Patient groups expect all specialised centres across

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Europe who follow patients with these rare neurological syndromes will be invited to contribute to the registry and that once collected data will be openly available to all interested research teams. Patients groups expect to be notified of all requests to analyse registry data. Finally it is expected that a solution to sustain the registry should be developed and agreed upon.

2. How can patient groups contribute to the success of the nEUroped registry?

a. Agree to participate b. Help recruit other patients c. Communicate its existence to health care professionals

interested in entering and eventually using data d. Enter data themselves and propose self reporting data

components

Patients, parents and their representatives can contribute to the success of the registry by communicating its existence to patients and clinicians and by recruiting patients and clinicians to participate. They can also contribute to the sustainability of the network once European Commission funding has ended.

3. What are the challenges, hindrances, to full patient participation in the nEUroped registry and project?

a. Lack of collaboration between experts scattered across Europe and subsequent fragmentation in research

b. Lack of clarity for future sustainability of the registry c. Need for regular communication back to patients on the progress and

outcomes to maintain their motivation to take part d. Need to develop standardised informed consent forms

It was signalled that the fact that the registry is structured around the common symptom of paroxysmal attacks rather than diseases may make it difficult for patients, parents and patient groups to know that they can contribute.

The uncertainty of the sustainability of the nEUroped registry results in the hesitation of some patients and parents in contributing their data.

E. Participants separated into three disease-specific groups to discuss: • discuss draft management guidelines • to discuss progress in the project as a whole and specifically on any advances in

Narcolepsy • to continue discussion around the questions above

Summaries of break-out sessions are included in Annex 1.

Indicators

A total of 48 participants registered for the Preliminary Workshop of the Extended Network meeting on November 21st. Of these participants, 24 parents, patients or patient representatives representing the 15 patient groups listed below attended:

- European Network for Research in Alternating Hemiplegia (ENRAH) - Associazione Italiana Narcolettici – Narcolepsy, Italy

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- Associazione Italiana per la Sindrome di Emiplegia Alternante (AISEA) – Alternating Hemiplegia, Italy

- Landau Kleffner Syndrome, Norway - Alternating Hemiplegia, Ireland - Association Française de Narcolepsie-cataplexie et Hypersomnie – Narcolepsy,

France - Narkolepsie Deutschland e. V. – Narcolepsy, Germany - Nederlandse Vereniging voor Narcolepsie – Narcolepsy, Netherlands - Association Française de l'Hémiplégie Alternante – Alternating Hemiplegia, France - Alternating Hemiplegia Support Group – Alternating Hemiplegia, UK - AHC Association of Iceland – Alternating Hemiplegia, Iceland - ALTERNERENDE HEMIPLEGI Danmark – Alternating Hemiplegia, Denmark - Asociación Española del síndrome de la Hemiplejía Alternante – Alternating

Hemiplegia, Spain - Epilepsy HERE - Help, Education, and Research for Epilepsy - Epilepsy, UK - Sturge-Weber Foundation - Sturge Weber UK

In addition, 22 participants from nEUroped project partnering institutions and five additional interested individuals from the paediatric neurological scientific community attended the workshop. Additionally, 2 new members of the nEUroped Extended Network registered to participate in the workshop.

Recommendations

Survey on Patient Needs Include the input of patient groups on the structure and content of surveys on patient needs to best encourage feedback and guarantee that feedback is useful. Is the tool appropriate in asking the right questions, can the answers to these questions give feedback onto the daily needs of patients? Surveys should be streamlined to allow for easier translation and back translation or only allow responses in English given the centralisation of results by national patient groups in their native language. Survey on Ethical Issues The survey on ethical issues should be finalised and distributed to the patient network and the larger extended network as soon as possible. Ethical guidelines drafted before the beginning of data collections should incorporate responses from this survey. Guidelines Feedback from the patient perspective should be considered in the final publication of existing care management guidelines for Narcolepsy and Alternating Hemiplegia. Care management guidelines for RSTES should still be drafted and circulated for feedback from the patient perspective before final validation and publication. Registry More regular updates on the specific progress of the development of the registry should be communicated to the Patient Network, including the latest request to prolong the nEUroped project and a precise plan for sustainability. Overall Integration of Patients in the Project Integration of patients in the project through formal collaboration has led and will continue to lead to:

• Identification of patients not necessarily followed by specialists in this network • Evaluation of patient needs and expectations • Education and training for patients

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• Identification and recruitment of patients or health care professionals • Governance of registries and the network overall • Contribution to items to be documented in registry such as patient satisfaction

indicators and quality of life data • Contribute to ethics board for project activities such as development or review of

informed consent forms • … amongst many other beneficial points of collaboration

Successfully involving patient groups should bring win-win situation for all stakeholders: patients, health professionals, health authorities and industry by expanding the network and encouraging centres in other countries in Europe to join; by improving the quality of networking activities by ensuring that the needs of patients are directly reflected; and ultimately by improving progress in the knowledge diagnosis care research and treatment of Alternating Hemiplegia, Narcolepsy and many rare epileptic syndromes.

Conclusions

Patients appreciate physically getting together to meet and discuss and have the opportunity to interact with nEUroped project partners but also with other professionals and patient representatives outside the project interested and motivated in networking. Understanding the technical aspects and medical concerns on what should be included in a registry is still limited. Theoretical guidelines for how this should be best done and how patients can be involved was proposed by an external consultant, but how these principles are being or can be applied to the nEUroped registry remains uncertain as a global presentation of the status of the nEUroped registry was not presented during the Pre-conference workshop as planned. During break-out sessions, the WG leader of the group did present the status of the registry with examples of data fields related to narcolepsy included in the registry template. Patients, parents and representatives present in this group were very assured by this presentation. There is a general disappointment from the parent/patient perspective that there are significant delays in the project and more worrisome the source of the delays that seem to be related to:

1) A lack of efficient coordination of stakeholders 2) A lack of commitment from the core project partners and willingness to open to other

interested clinicians/researchers 3) A lack of a concrete plan on how to accomplish delayed objectives and how to

continue networking beyond the proposal for sustainability 4) A lack of recognition for a harmonised consent form and its implementation in

Centres of Expertise in the nEUroped network Patient groups involved in nEUroped have an intimate knowledge of their diseases as well as of the barriers to research and access to medical and social services, enabling them to bring a different insightful and creative perspective and dedication. The effective participation of patient representatives has the potential to redefine innovative research, the highest standards of management guidelines and the most efficient healthcare pathways for greater quality, efficacy and cost effectiveness of care.

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Annex 1

nEUroped Extended Network Meeting Pre-Conference Workshop

Disease-specific Breakout Sessions

21st of November 2010, 15:30 – 17:00

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I. Alternating Hemiplegia Working Group Led by Brian Neville

1. What are the principle needs of children with specific neurological diseases regarding research?

Comments that were made on the “Draft guidelines for the management of alternating hemiplegia”: - Should the name of the condition “Alternating Hemiplegia of Childhood” loose the

childhood part of it? The group agreed that it can be misleading and it can cause problems when the children enter adulthood within the social systems of various countries. There could be a problem with discarding the “childhood”part because most of the associations have websites that have the AHC in it and also most of the information already out there refers to Alternating Hemiplegia of Childhood.

- There was a question about the drugs, Flunarizine being the first on the list of drugs

that have worked, could we have a list of other drugs that have worked and also a list of drugs that should not be used? The list could be split in two, the preventive and the rescue drugs.

- Nutrition, not all AHC children have a problem with nutrition ,

Prof. Neville said that the guidelines are referring to height and weight issues. AHC children should eat regularly! Perhaps there should be a research on the nutrition of AHC children? Parents need to be aware that some AHC children need to eat between episodes

- Neuropsychologist has helped a 17 year old girl in Denmark with anger issues –

something that others should be aware of. This has helped teenagers cope with adulthood without using prescribed drugs.

- Is there anything to support that magnesium helps AHC patients?

It is not known. Some of the above questions could be at the end of the guidelines as future research questions There was a discussion about other drugs that could be used like new generation migraine drugs. Add to the guidelines that occupational therapists and physical therapists are normally used to help the AHC children.

- How do we record the episodes and information that we experience throughout the

years? Do parents keep records? History from some parents shows that in the first years there is a lot of data recorded but as time passes the records get less attention perhaps because the records are not being used?

The Italian association introduced a software “Daily report of crisis” that will be available on the bio bank website in January 2011. This software can be used to record the episodes. It is a really good tool that parents and specialists can use. The result would be an information bank that could be used for research. This way there would be a reason for the

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parents to continue to record data because it will be used in the future to help solve the AHC mystery. There was a discussion about that the record should be closely related to the US record that is already being used, that way exchange of records would be made simpler.

- That the information that has been discovered is available - That the medical community is communicating among themselves all around the

globe

2. Which kinds of research would patients and their families wish to see prioritised within nEUroped?

- Research that focus on the basics of AHC, what triggers episodes? What is the core cause of AHC?

- Research that help with daily standard of living for the patients. - Research that will lead to the discovery of a drug that can stop the episodes

entirely.

3. What are the challenges, hindrances, to full patient participation in the nEUroped project?

- If patients are going to participate in the project the patient will have to be sure that the information will be used for research that are driven to solve the AHC mystery or help with the daily standard of living.

- Patients will have to have access to the information and be able to withdraw their information if they feel that it is not used in the right way.

- There will have to be a consent form. - The registry will have to be updated regularly - The registry should be open for other researchers that have the aim to help AHC

patients. - Patients or patient associations should know if a researcher is asking to get

access to the registry. - Patients will have to be sure that the committee that is in charge of nEUroped is

working with the best interest of the patients in mind. - Patients would have to be sure that other countries that are not now a part of the

registry can be a part of the registry and will also be able to use the information that is in the registry for research.

4. What are the challenges, hindrances, to full patient participation in the

nEUroped project?

- If patients are going to participate in the project the patient will have to be sure that the information will be used for research that are driven to solve the AHC mystery or help with the daily standard of living.

- Patients will have to have access to the information and be able to withdraw their information if they feel that it is not used in the right way.

- There will have to be a consent form. - The registry will have to be updated regularly - The registry should be open for other researchers that have the aim to help AHC

patients. - Patients or patient associations should know if a researcher is asking to get

access to the registry. - Patients will have to be sure that the committee that is in charge of nEUroped is

working with the best interest of the patients in mind.

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II. Narcolepsy Working Group Led by Sona Nevsimalova

Comments on the draft care management guidelines were incorporated into the final version in which guidelines on pharmacological therapy were revised to include:

Owing to possible adverse effects (skin and subcutaneous tissue reactions and psychiatric complication), however, European Medicines Agency (EMA) does not recommend it (since June 2010) in children. Based on the experience of using modafinil in children over

the past two decades, the initial dosage varies according to age between 50-100 mg/day in the morning, the therapeutic dosage between 100-300 mg/day divided at morning and noon dosage. Modafinil can be co-administred in children with other stimulants to enhance the alerting effect of either drug alone.

The group reached a consensus that major obstacles in Narcolepsy included:

- delays or incorrect diagnosis, a lack of consensus on diagnostic methods at the European level

- a need to raise awareness of the diseases profile to receive better support from the medical and socio-medical community (including social workers, teachers and other carers for children with Narcolepsy)

- to better educate primary care physicians on the diagnosis, care and treatment of the diseases

- to raise awareness of the need for clinical trials and post-market authorisation surveillance of existing drugs.

More specifically, the benefits of using of Modafil in children (following recent recommendations) is unclear and one aim of the registry maybe to further clarify the most beneficial treatments for narcoleptic disorders in children with the least adverse effects.

Participants expressed their disappointment in the limited nature of elements included in the registry and expected that more qualitative investigation of the real life needs of patients and families. Participants expressed that research focusing on social/scholastic/quality of life issues would be valuable since little information is available about these aspects for children and their families living with narcolepsy.

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III. Rare Surgically Treatable Epileptic Syndromes Working Group

Led by Alexis Arzimonoglou

No Guidelines for the management of RSTES have been drafted.

Participants began with a general discussion of the status of the nEUroped Patient Registry. To meet ethical standards it was suggested that this was started by an approach to the clinicians in the main paediatric centres in the European Union to report their findings supporting diagnosis of a small number of rare neurological conditions in childhood. These would be maintained in a Register with central custodians who would receive requests to have access thereto. It was also suggested that there should be a supplementary bank of biological resources to supplement the register for research purposes. The parents of patients whose details were to be included in the register would be approached by clinicians to give written formal consent to the details of their children being included in the register and for any biological material to be submitted to the biobank. The extent to which support groups should be able to submit data was a point of discussion within the main meeting but in the smaller breakout session on Rare Surgically Treatable Epilepsy Syndromes (RSTES) the process of submission of information by clinicians to registry was accepted and the role of the support groups would be publicise the existence of the registry to parents and academics and assist the neurologist in obtaining completed permission templates.

5. The session was asked to consider what are the principal needs of children with RSTES regarding research?

It was accepted that the needs for research were driven by the rarity of the individual conditions and that they would need to be directed to either improvements in treatment or improvements in quality of life. Earlier diagnosis was also signalled as a principle need.

6. Which kinds of research would patients and their families wish to see prioritised within nEUroped ?

These were felt to be those likely to lead to early improvements in treatment rather than those of a purely academic nature.

Research leading to improved diagnosis and earlier diagnosis were supported. With regards to Sturge Weber syndrome specifically, patients and families wish to see some investigation into the benefits of taking a small daily dose of aspirin.

7. What are the challenges, hindrances, to full patient participant participation in the nEUroped project?

There may be reluctance on the part of some patients/parents to engage with others or to take part in research projects. Many will have other children and will have to balance the needs of the whole family

Overcoming patients’ apathy was also noted as an obstacle. As such, persuading patients and patient groups to take part in such projects by disseminating information about the project and how to become involved is important.

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Annex 2

nEUroped Extended Network Meeting Pre-Conference Workshop

PATIENT INFORMATION BOOKLET

1

EURORDIS Capacity Building Workshop

on Patient Involvement in Patient Registries

Patient Network Meeting

preceding the

European Network of Rare Paediatric Neurological Diseases (nEUroped)

Extended Network Meeting

Jeanne-Hélène di Donato, 3C-R November 21st, 2010

3C-R

www.3c-r.com jhdd@wanadoo.fr

European Organisation for Rare Diseases www.eurordis.org anna.kole@eurordis.org

2

Contents

1. Introduction ……………………………………………………… 3

2. Design of the registry ……………………………………………………… 4

3. Creation of the registry ……………………………………………………… 7

4. Use of the registry data ……………………………………………………… 9

5. Bibliography ……………………………………………………… 10

6. Glossary ……………………………………………………… 11

7. Examples of registries ……………………………………………………… 12

8. Workshop presentation ……………………………………………………… 13

3

Patient registries: Definitions, Benefits and Pitfalls Research in human health often requires the development of “population-scale” studies. Processing large amounts of data in order to analyse these groups of people (chosen according to pre-defined criteria) allows us to answer new questions raised by scientific research. (Examples: is there a correlation between one's diet and the expression of pathology? Does a mutation found in a family correspond to a disease's gene? Is drug X efficient? Do sleep problems become worse after surgery?) Registries allow for the compilation of large amounts of data on a target population. These are software tools which use multiple and varied data for real-world modelling. (Examples: history of the disease, lifestyle, diet, clinical data, ethnic origin, etc.) Registries are not ready-made solutions but research tools which are custom-made in order to be pertinent and so that the analysed data can lead to new scientific knowledge and results. The software is used to organise data (registry template) in order to construct a usable registry for achieving the goal or goals which have been set. A design phase is therefore necessary before any use or recording of data. In order to prevent numerous errors, needs should be defined carefully in advance of the development phase As with any database, the use of a registry must go through the following steps:

• Design and Development, • Implementation, involving patient recruitment, data recording, and updates, • Use of information and production of results.

4

I: Designing the registry Since asking questions in advance helps avoid problems later on, it is important to approach a registry in the same way as a scientific project. Defining the objectives of the registry As a lot of work and investment are involved in creating a registry, it is pertinent to design the registry not only for one or more precise objectives but also while keeping in mind potential future uses in order to optimise its use. Setting objectives allows us to choose the concerned population(s) and the quality of data to be collected. (Example: The compilation of data in order to write guidelines for families does not require the same information as the study of paroxysmal attacks in different contexts.) Bibliographical study It is always interesting and informative to know what has already been done in the field in order to learn from others’ experiences and avoid making the same mistakes. A bibliographical study on the same pathology, symptoms, and types of research can be a source of inspiration. This inventory of the work already done on the subject should then be analysed in order to identify:

• The studies carried out on the same theme in order to know all existing results on the subject, which will serve as a basis for comparisons and complementary information.

• The existing registries on the subject, in order to avoid duplicates, • The methods used for similar subjects (for example, the same objective in the context

of another pathology, other registries on the same type of pathologies or symptoms) in order to understand the methodology used, the organisation of the database, the results, and any problems encountered

Mobilisation of Stakeholders In the period between data collection and the final scientific result, numerous stakeholders (example: patients, families, patients associations, physicians, etc.) can be called upon to participate in the creation and management of the registry (example: IT specialists, surveyors, epidemiologists) and in the production of results (example: statisticians, epidemiologists, researchers, etc.). The cooperative efforts of stakeholders, whatever their role may be, are important for the successful implementation of the project. Each stakeholder’s roles and responsibilities should be defined in order to avoid deadlock and misunderstandings after the fact. Management of the network of stakeholders is important in order to:

• Involve all parties from the start, to ensure that the study's intended methodology and design are acceptable and feasible for everyone,

• Ensure that the different concerned communities (patients and their families, physicians, IT specialists and researchers) find their role within the project,

• Co-ordinate the study in such a way as to monitor whether it is being carried out correctly,

• Organise the network of partners and define the roles and obligations of everyone, • Define access rights to the database.

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In the case of rare diseases, the contribution of families is important since they not only represent the source individuals (data and samples) but they are also the most apt to provide relevant information on the disease and its symptoms, its management, and its impact on daily life. In particular, the registry’s financing is an issue which must be studied in advance, not only for the development of the registry but also for its long-term maintenance in order to ensure optimal use of the collected data. (Example: calls for tender can lead to financing but often on an intermittent basis, software licences, sponsoring, memberships, public research institutions often can also help finance the maintenance of registries.) The project calendar must be known by all stakeholders in order to:

• Organise the work, • Monitor critical phases, • Monitor the results of activities.

Development of the registry template A database is created from various tables which group data fields according to a particular logic. (Example: the subject table can group together the fields on sex, age, code number, place within the family, etc.; the diagnostic table can contain the fields for pathology name, date of diagnosis, date of first symptoms, associated symptoms.) The links which exist between the different tables help bring together the different data in order to find answers to precise questions. (Example: delay between diagnosis and first symptoms, average age at diagnosis.) Thus, it is important to give careful advance consideration to any registry in order to:

• Define the type and form of the data (Example: age in the form of birth date, IQ test scores according to the WPPSI test) which will characterise the fields to be filled;

• Organise this data by theme (Example: subject, pathology, sleep, diagnosis, cognitive, etc.) which will pre-define the tables;

• Foresee the requests which will need to be made in order to ensure that all data exist and that the tables are linked correctly in order to obtain the expected results;

• Explain the instructions for using the registry (Example: stand-alone, intranet, website) in order to choose the appropriate software tool and implement the necessary security procedures. (Example: managing the privacy of personal data, controlling access to the registry)

This advance planning leads to a more logical and high-performing design of the registry, which will be able to be designed according to user specifications. These user needs are validated by a specifications file which allows IT specialists to understand user objectives and expectations and to develop the best tool possible. Definition of the Population The target population which will be the subject of study must be identified in order to:

• Decide how many subjects are necessary for obtaining pertinent results (in the case of a rare disease registry, exhaustiveness usually is defined for a given geographical area)

6

• Define the inclusion and exclusion criteria by finding a balance so that the population is sufficiently homogeneous but remains representative,

• Define potential needs of the control population. Since registries collect personal data (about the person) and sensitive data (medical, genetic), it is important to ensure the protection of the private life of those who are chosen as "subjects" of the registry. A registry, which has an accrued risk of spreading large quantities of personal data, must respect security norms (example: password, secure server, information encoding, anonymisation) and legislation on the protection of personal data in regards to the recording, use, and transfer of data. In order to respect all national and European laws, patients must give informed consent and retain the right to see or revoke the data concerning them. For paediatric diseases, parents must give consent, with the minor's agreement according to his/her age and ability to understand. Once the minor becomes an adult, the subject must confirm (or invalidate) his/her consent in order to continue using the data and keep it in the registry. Definition of data For each idea to be worked upon, it is necessary to verify that:

• All necessary data has been listed, • The intended data is pertinent (it is often counterproductive to collect data which will

not be used), • The data truly exists and will not be collected at random.

For all data to be collected it is essential to:

• Define whether data is indispensable (collected in 100% of cases), important (collected in the majority of cases) or complementary,

• Give the degree of expected precision (define units and scales), • Define which data is specific to the study and which is general (could be used in

another study); as a lot of time and money is invested in the creation of a database, it is important to be able to anticipate future uses of the registry, even if complementary information must be found,

• Avoid double collection of the same information, • Decide which thesauruses to use in order to harmonise the vocabulary used.

Pilot study After the prototype is developed, a pilot study can be carried out on a small number of cases for:

• Testing the feasibility of the project, • Ensuring that the data and methods are pertinent, • Adjusting the methodology of the main study according to the initial results obtained.

These trials help validate the design studies, improve the project based on real experiences, and avoid committing to a registry which does not perfectly meet initial expectations.

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II: Creation of the registry Data collection Data collection is organised in a structured manner based on:

• Creating a precise questionnaire which must include all the defined items (future fields of the database). If all or part of the questionnaire must be filled out directly by the subject, the questionnaire must be translated in the subject’s native language in order to facilitate comprehension and avoid imprecision;

• The identification and training or informing of the collectors so that they are perfectly aware of the risks and objectives of the registry;

• The organisation of subject recruitment (example: communication and awareness campaigns for the subjects, informing subjects and obtaining consent, defining where and when the information will be collected);

• Monitoring the inclusions to ensure that the project is advancing according to the calendar.

The case report form is a critical step for a registry as it must enable the data to be collected with optimal quality:

• Therefore, the questions must be easy to understand so that the answers are fair; • It is recommended that open-ended questions be avoided as much as possible, as they

can lead to multiple answers or comments which are not easily processed by the database;

• Questionnaires which are too long should also be avoided as they often lead to a drop in attention or interest and thus the gathered information is of a lower quality.

It is important for patients associations to be implicated as they are in contact with all the partners necessary for creating the registries. They can participate in:

• Informing members: thanks to the means of communication at their disposal, they can explain how the data is collected and what objectives are expected from the creation of the file,

• Defining data with the help of their knowledge on the pathology in question and their relationships with various partners (clinicians, researchers, families),

• Collecting data through giving out survey forms and/or centralising the information obtained,

• Using the registry in order to provide information for their members, • Financing the registry.

Recording data The recording of the collected data must be organised according to the organisation which was chosen (immediate or deferred recording, direct recording by the collector, sending the paper questionnaires to be recorded centrally). Whatever the form of organisation chosen, it is important to maintain traceability of the different stakeholders (when monitoring patients and collecting and recording data) in order to be able to contact the person in charge when need be.

8

Verification protocols for the recording or cleaning of data are essential in order to regularly verify the quality of the recorded data, to correct errors, and to add any missing data. Quality indicators (example: number of subjects included, percentage of incomplete obligatory fields) can be monitored in order to ensure proper creation of the registry and allow activity reports to be written (often necessary when communicating with stakeholders). Registry security The registries must be made secure in order to:

• Ensure the confidentiality of the personal data collected, • Avoid the loss of data.

The confidentiality of data is ensured not only through the professional secrecy of the persons involved but also through technical means which prevent non-authorised access to said data:

• Secure IT location and restricted access to authorised personnel, • Password required in order to read, write, or modify data, • Encoding or anonymisation of subjects.

The risk of loss or destruction of the registry is reduced by:

• Using a firewall to avoid unwanted, unauthorised intrusions in the registry via the web,

• Installing uninterruptible power supplies to avoid modifying the power voltage which could damage an in-progress registry,

• Backing up data regularly, • Monitoring backup in different geographical locations.

9

III: Use of the registry Objectives of using the registry When well-constructed, maintained, and updated, a registry can help carry out prospective or retrospective scientific research (example: correlation study, confirmation of a hypothesis, proof of efficiency, epidemiological study) and the publication of guidelines based on valid and representative compilations of data. The patient registries dedicated to one disease or one family of diseases can be used for (among others):

• Describing the natural history of the disease in order to better understand the pathology;

• Determining the pertinence of the treatments given according to any observed improvements,

• Analysing the care of the patient and obtaining important information from it. In the case of rare diseases, these registries are all the more pertinent because:

• The small number of cases makes it difficult to study them; the exhaustive recording of all known cases helps attain a sufficient critical mass for carrying out studies and obtaining information;

• The pathology is very often complex and poorly recognised; the act of creating a registry helps with modelling the pathology and its symptoms;

• The proposed care is often empirical and only intended to treat the symptoms and not the cause of the disease; the act of compiling information on treatments given and the results obtained can lead to new ideas for research and improved recommendations for treatment.

Epidemiologists are very often mobilised to ensure the relevance of the study and the tests used, and to avoid interpretation bias which can be very harmful to the results. Registry updates It is important to carry out and monitor all registry updates if it is to remain pertinent. This is often a critical step in the life of a registry, requiring continued financing and long-term motivation from the team. This update can have different objectives, such as:

• Recording new data for the longitudinal monitoring of a cohort, • Recording data generated by the research, • Modifying the registry with new modules which allow for recording information

which is necessary for future studies.

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Bibliography Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data http://eur-lex.europa.eu/smartapi/cgi/sga_doc?smartapi!celexplus!prod!DocNumber&type_doc=Directive&an_doc=1995&nu_doc=46&lg=en ) Registries for evaluating patient outcomes : a user's guide Agency of HealthCare Research and Quality, September 2010- 367 pages http://www.effectivehealthcare.ahrq.gov/ehc/products/74/531/Registries%202nd%20ed%20final%20to%20Eisenberg%209-15-10.pdf National Institute of neurological Disorders and Stroke http://www.ninds.nih.gov/disorders/alternatinghemiplegia/alternatinghemiplegia.htm

11

Glossary Bias Methodological default in organisation (inclusion bias),

collecting of information (measurement bias), or analysis of data leading to distorted interpretation of results

Biobank Infrastructure which manages biological resources and collections for research

Cohort Group of persons included in a study, chosen according to a theme of research and who may be monitored over time

Database A structured collection of files containing large quantities of information that is organised so that its contents can be easily stored and retrieved.

Exclusion criteria Negative criteria describing the characteristics which a person must not have to be included in the study

Personal data Any information concerning an identified or identifiable physical person.

Prospective study Study requiring the collecting of new data

Retrospective study Study carried out on existing data

Data integrity Assurance that the content of information has not been altered or modified during the course of an exchange

Registry Continual, exhaustive gathering of standardised cases of a disease in a defined geographical area

Thesaurus Hierarchical set of key terms in a particular field. They are organised in themes and possess semantic links between themselves: synonymy, equivalence, specific term (link to a more concise concept of meaning), general term (link to a larger concept of meaning).

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Examples of registries United Kingdom Primary Sjogren's Syndrome Registry (http://www.sjogrensregistry.org/ ) Objectives of registry :

- to facilitate clinical trials and academic research studies in order to improve our understanding of what causes Primary Sjögren's Syndrome and to find better, more effective treatment for people with this condition

- to promote good clinical care and facilitate research and communication among clinicians and researchers in Sjögren's syndrome.

Membership of registry - Hospital (32) - the British Sjögren's Syndrome Association (BSSA) - Health care professionals

Specifical problem of the Patholy : - Many symptoms - Underdiagnosed

A national registry for juvenile dermatomyositis and other paediatric idiopathic inflammatory myopathies (http://www.juveniledermatomyositis.org.uk/Research.html) Objectives of registry : - To obtain adequate standardized clinical data linked to biological samples in sufficient

numbers for research Membership of registry - 10 rheumatology units in England Specifical problem of the Patholy :

- Rare disorder - Pediatric - lack of evidence base for current treatment protocols

North West Thames registry of neurological disease http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1437986/pdf/jrsocmed00248-0073.pdf Objectives of registry : To obtain data on incidence of a specific neurological disease (Guillain-Barré-Strohl syndrome) Membership of registry Hospital of England and Wales

1

Extended Network MeetingCapacity building Workshop

Patients, nEuroped and disease registries

Patient registries :definition, benefits and pitfalls

J Hélè di D tJeanne-Hélène di Donatojhdd@wanadoo.fr

21 novembre 2010 – Bruxel

Thinking before doing

2

ObjectivesObjectives

To answer to the main questions

What is a registry ?How to create a registry ?What are the steps ?What are the pitfalls ?Who can participate ?How patients, their family and association can participate ?

CohortGroup of people Followed over timeEvaluated the health of a population with similar characteristics

VocabularyVocabulary

DataClinical dataBiological dataLife data

TissuesCellsDNA

Biological sample

RegistryData collection representative of populationFollowed over timeStructured and organized files allowing the

storage and the access of big quantities of information

Biobank Biological sample collectionsAssociated with data

3

Software

To set up database

Access

Registry template

IT toolsIT tools

Tool

OrganisationRegistry template

Developement of particular database

nEUropedDatabase

Registries Narcolepsy AHC RSTES

nEUroped Database

Organisation

Data

Contents of DatabaseDatabase Database Database

Scientific Tool Information on a specific populationRealistic representation

Registry : customized toolRegistry : customized tool

+ +

Registry

Idea Software

=

Data

Use of the dataStatistic

Compilation

New ResultsKnowledge

4

Create database

Registry Registry

Data Use

Records data

ResearchCompilation Up date

Results

Comparison

Guidelines for familiesInformation for diagnosisInformation for treatment

Up date

SpecificationsSpecifications

Expression of precise needs

Written Specifications

Conception Computer

Trap of nightmares

5

ThinkThink ofof the the registryregistry as a as a scientificscientific projectproject

Objectives

K l d / l d d

Choice of population

Choice and characterisation of data

Designing

WhoResponsibilities

Knowledge/ already done

Stakeholders

Time schedule

Financing

Development

Pilot study

ThinkThink ofof the the registryregistry as a as a scientificscientific projectprojectCreation

Data collection

Protocol for Collect

Controls

Use

Recording Data

Quality points

Evaluation

Use of data

Up date

6

Immediate precise Objective(s)QuestionFormalize

Objective(s)Objective(s)

Future perspective (s)and

Global vision

Future objective(s)Optimisation of

the registry

Literature review Literature review

Same ObjectiveEpidemiologic studyGenetic studyGuidelines for patients

Research on existing registries Same type of Pathology

PediatryNeurological disease

IDEAPITFALLS

PROBLEMS

Same symptomsEpilepsyMotor management

7

Researchers

Associations

StakeholdersStakeholders

Data collector

Epidemiologists

PhysiciansPatients

Statisticiens

Associations

Families

Data collector

IT Specialists

Organisation of the network Organisation of the network

Network

OrganisationGovernanceCommunicationFinancing

Right and duty

FinancingSurveyDefinition of quality

StakeholdersRight and dutyPrecise roleObligationControl

8

Privacy protectionPrivacy protection

Personal data Computerisation

Ethnic group Health data Genetic data

Storage Cross-referencing of dataDissemination

Gathering Processing Transfer

Compliance with local data protection legislation

Genetic data Dissemination

Population

RecruitmentRecruitment

Inclusion criteriaExclusion criteriaNumber of casesControl case or comparative elementIncomplete cohort

Poor representativity Length of observationPoor representativity Bad precision

RecruitmentWhere (at hospital, during a medical visit, by

phone, by mail …)CommunicationInformation and consent (children and their

Identifiers N° of centerN° of patient (coded or totally anonymised)Date

Duplication No possible come back

Information and consent (children and their families)

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Item Item

Type of dataWhat type of dataWhat are the critical and essential values?Which data are desirable but not essential ?

Improperly observations Complementary informationImproperly observations

How is measured ? (knowledge scale (score), need to create written instructions, personal training

What precision neededQuality of data

Innacurate measure

pValidation of their originSupervison of collection (rate of recruitment,

missing values)Cleaning protocol (out-of range value, logically

inconsistent values)

Data (Form)Data (Form)

LanguageMother tongueEnglishTranslation between sheet and database

Thesaurus To avoid mutiple terms for the same thingRecognised items

Translation between sheet and databaseMisunderstanding

Bad interpretation

ConsentConfidentialityAnonymisationPrivacy

Security

Loss of the workNon ethical work

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CollectCollect

Information of the people who collect the information

Comprehension of the stakeGood explanationComplete information obtention

Incomplete data

Information of families

Communication by Patient AssociationComprehensive written informationConsent

SimpleSingle –idea questions

Non-ethical activitiesPoor involvement

Incomplete data

Single idea questionsNot open answerNot too longMust be tested before Who will fill out this form ?Where it will be filled out ?

Case report form

Improper observation Protocol deviation

Data sourcesData sources

Primary source First data collectedFor the direct purpose of registry

Complementary data

Collected for another purpose (clinical data, administrative data, related another existing registries)

Generated data from researchThey need to be matched with the primary

« Pollution » Errors y p y

dataTheir quality must be verified and

validatedHow they can be imported into the

database

Errors

11

Needs’ expression

SpecificationsSpecifications

Development Test Use

Users IT Users

For each new development

Incomplete databaseConfusing data Restarting the entire study

D t

Sort

Data

Optimised Database

To build

12

Pilot studyPilot study

FeasibilityBurden ComprehensionAccuracy

To verify

Tests

AccuracyMissing data Implication of partners

SampleSome cases

Records

Data recordData record

Who is recording the data ?When ? (immediatly, centralized data)

Wh t th t l ?

ControlsWhat are the controls ?When do the controls occur Avoid missing dataError reportsIntegrity test (to make sure that data are not altered)

Safegard

Confidentiality (only authorised and autheticated individuals access to data)

Regulary back upComputer protection (firewall, virus

protection, password)

13

t ti pathology genetic

StudiesStudies

Correlation study

Effectiveness of a treatment

Proof of Efficacy

Real Treatment effect

Bias

dose

Result confirmation mutation pathology genetic

Time

Epidemiologic study DescriptiveAnalytic

Compilation of knowledgeEstablish GuidelineAssess trends of disease

Database follow up Database follow up

CheckingEvaluationMissing values

Incorrect valuesDiscrepancy values

Up date

Evolution Longitudinal studyGenerated data New objective

Added complementaries values

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ConclusionConclusion

Quality of a registry refers to the confidence that the design, Q y g y g ,conduct and analysis of registry can avoid:

Unused or incomplete registryerror or erroneous conclusions from a study

Extended Network MeetingCapacity building Workshop

Patients, nEuroped and disease registries

The roles of Patients, Researchers and Sponsors in a patient registry

J Hélè di DJeanne-Hélène di Donatojhdd@wanadoo.fr

21 novembre 2010 – Bruxel

15

Purposes

Patient registries Patient registries

To describe the natural history of diseaseTo determine clinical effectiveness of health careTo determine effectiveness of health servicesTo measure quality of life

Need of patients information

Under-recognized diseasesUnder-researched

Rare diseases No simple diseases

Why a Registry could be important in the rare Why a Registry could be important in the rare disorders area disorders area

Management by familiesDaily surveillance

Expressed in early childhoodChronic diseases

Empirical treatment Care only for symptomNo results evidence after treatment

Individuals observations Often based on little

personal attitudes

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Knowledge of their life Experience of their pathology

Link to physician

Families’ Contribution Families’ Contribution

PatientsSamples

Clinical dataEpidemiologic data

Physicians - Researchers

Data base Collections

Scattered Information

Work togetherWork together

Put together all information Several communities

Display the information Update the knowledge

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Daily expertise

ChallengesChallenges

Different levels of information

Medical expertise

Scientific research

Win-Win

Management of the disease

Diffuse the information through the networkImprove the diagnosis Obtain performed treatment/better careHelp with « life » management (behaviour, nutrition, motor

management and so on)

IdeaPurposeFinancing

Project

Patient association involvement Patient association involvement

gSetup registry

CommunicateRecruitmentFinancing Participate

Use of registry Family help and informationImprove quality of lifeDetermine treatment effectivenessHelp ResearchImprove the diagnosis

                                       

  This publication (or activity) has been funded with support from the European Union's Health Programme. This material only reflects the views of the author, and funders cannot be held responsible for any use which may be made of the information contained herein.