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Progetti e attività Internazionali


NEPHIRD (acronym derived from "Network of Public Health Institutions on Rare Diseases) is a project supported by the European Commission following the decision (No 1295/99) for a 4-year period (starting October 2001).

Fifteen EU and associated Countries were involved: Armenia, Belgium, Croatia, Denmark, Finland, France, Germany, Italy, Lithuania, Malta, Netherlands, Portugal, Spain, Sweden and UK.
NEPHIRD closely collaborated with EURORDIS and ORPHANET.

The project was comprised of the Project Managememnt Group (PMG) and the Expert Working Groups (EWGs).
The PMG was appointed to coordinate, monitor progresses and to provide directions to the overall implementation of the project.

The EWGs were responsible for the implementation of the project activities and specifically:
- assessment of the quality of and accessibility to healthcare and social services for Rare Diseases patients
- evaluation of the Quality of Life
- development of reccommendations for the establishment of a network for data collection at the EU level on Rare Diseases
- approach in assessing health indicators on Rare Diseases.


NEPHIRD aimed at discussing and analysing the epidemiological data collection for rare diseases (RDs) in participating countries in order to identify and suggest possible approaches for estimating epidemiological indices (incidence and prevalence). It aimed also at analysing the state of the art with regard to RDs focusing on health care services accessibility and quality for RDs patients and undertaking a specific assessment of the quality of life of RDs patients.

1) Assessment of the Situation of Rare Diseases in the Participating Countries

In 2001, in the framework of the project “NEPHIRD 1 - feasibility phase” a questionnaire was sent to all NEPHIRD partners to collect information about Rare Diseases within their countries.

Following the 2001 experience, in 2005 the NEPHIRD project, in collaboration with the Rare Diseases Task Force, decided to undertake another assessment of the situation on Rare Diseases to update the information considering the increased efforts of EU Member States with regard to Rare Diseases.

In 2001, a questionnaire was sent to all NEPHIRD partners. The questionnaire aimed at collecting the following information:
1. policy and major public health measures taken by the Government of each Country;
2. existing surveillance or data collection systems for Rare Diseases;
3. availability of centres able to diagnose the selected diseases and
4. availability of a systematic data collection process within the centre.

In 2005, in collaboration with the Rare Diseases Task Force, a new questionnaire was sent to NEPHIRD partners. The new questionnaire explored additional topics regarding Rare Diseases at the European level as follows:
1. availability of National Plans and/or National Centres for treatment of rare diseases;
2. availability of National Networks for data collection;
3. availability of National Registries on Rare Diseases.

Accordingly to the assessment, the situation is non homogeneous: many Countries have public funded structures for Rare Diseases however, MS have different policy attitudes for Rare Diseases; epidemiological data at EU level are scarce; there is poor collaboration among MS in the research field and limited attention is given to the role of patients organisations.

It will be important to immediately address the obstacles in order to ensure the establishment of a surveillance system at the European level. The collaboration at the European level, the development of national plans at the country level will be essential to ensure the comprehensive approach for addressing Rare Diseases.

2) Estimation of Epidemiological Indices (I.E. Incidence, Prevalence) at the European Level

In order to estimate prevalence and incidence of Rare Diseases, two possible methods/data source were considered: literature review and registry-based data collection.

The literature review was undertaken to estimate prevalence and incidence of the Myasthenia Gravis (MG); the registry data were used to estimate prevalence and incidence of the Cornelia de Lange syndrome (CdLS).

Epidemiology of the Myasthenia Gravis
A review of the relevant scientific literature was undertaken to serve as an example of how to estimate the prevalence of Rare Diseases that don’t have a routine epidemiological data collection system, such as Myasthenia Gravis.

Searches were conducted in Pubmed, selecting all articles with the objectives of estimating epidemiological indices of prevalence and/or incidence during the last twenty years only in NEPHIRD partner countries. Thirteen studies on the epidemiology of MG during the last twenty years in the European countries were found.

The review of the epidemiology of MG suggests that it’s difficult to have a reliable estimation of prevalence (or incidence) at the European level, however a literature review can provide rapid, cheap and crude values Two useful tools for conducting a systematic review were developed:
a) Steps in conducting a systematic review (view attached document): How to assess the prevalence in Europe of each rare disease and
b) Data extraction form (view attached document): How to collect the data of each scietific article

Epidemiology of the Cornelia de Lange Syndrome
The data provided by registries were used to serve as an example of how to estimate the prevalence from routine data collection systems. This study has been performed through a formal collaboration between NEPHIRD and EUROCAT, a large European network of birth defect registries. This collaboration has made it possible to conduct a population-based study of the epidemiologic and clinical aspects of the classical form of Cornelia de Lange Syndrome. The data were provided by 33 registries from 16 European countries that register congenital malformations in live births, stillbirths and terminations of pregnancy covering approximately 25% of annual births in the countries included in the EUROCAT network.

3) Accessibility to and Quality of Healthcare and Social Services

To assess the accessibility to and the quality of healthcare and social services a pilot survey involving patients' Associations was carried out in the following NEPHIRD countries: Italy, Spain, France, and UK. The survey focused on 4 diseases:
Myasthenia Gravis,
Neurofibromatosis type 1,
Prader Willi Syndrome and
Rett Syndrome.

A self-filled questionnaire was elaborated and validated (view attached document).
The questionnaire asks patients or caregivers how often they had both negative and positive experiences about accessibility to and quality of healthcare and social services

Results suggested that rare conditions have major common problems:
1) lack of social services (educational and work);
2) lack of health information and
3) inadequate provision of legal support.

Our study confirmed the two-fold advantage of carrying out surveys engaging patients and/or their families:
1) it helps healthcare providers to improve the quality of and accessibility to their services and
2) it empowers patients.

4) Assessment of the Quality of Life of Patients (and Families) with Rare Diseases

Three diseases were selected to assess the Quality of Life (QoL), because of their major mental impairment (Prader Willi syndrome), physical involvement (Myasthenia Gravis) or because of the impairment of different systems and/or organs (Neurofibromatosis).
The study protocol was a multiperspective protocol including clinical assessment and patient-oriented measures of QoL. The objective was to link clinical evaluation with Health Related Quality of Life measurements in order to identify the clinical aspects that mainly impair QoL.

To assess the QoL the most validated generic and specific QoL questionnaires for the selected diseases were administered.:
- the Short Form-36 (SF-36) (view attached document) evaluate patients older than 14 years old
- the Child Health Questionnaire-Parent Form 50 (view attached document) evaluate patients from six to fourteen years old

The studies confirmed the heavy impact that Rare Diseases have on both mental and physical aspects of patients’ life. Physical and mental aspects of QoL were impaired in all the diseases studied.
For diseases with more disfigurement such as PWS (presence of characteristics facial features) and NF1 (presence of neurofibromas), mental aspects of quality of life were compromised. For MG, physical aspects of the quality of life was more impaired. Our data demonstrated also that clinical variables are related to the HRQoL.

5) Approach in Assessing Health Indicators on Rare Diseases

The initial discussions and recommendations of NEPHIRD experts on indicators for Rare Diseases focused mainly on 2 categories:
• Health status;
• Health care system.

Health status indicators

The source of information is death certificates; the reliability of mortality data depends on accuracy of the vital registration system in each country. Causes of death are coded according to the International Classification of Diseases and Causes of Death (ICD). Problems of temporal and geographic comparison derive from different versions of the ICD adopted over time.
Mortality data are routinely collected in all countries and are of fairly good quality. In order to use mortality data for studying Rare Diseases, particular attention should be paid to multiple cause-of-death data (including underlying and non-underlying causes) which can allow researchers to maximize the use of the diagnostic information on the death certificate and provide ways of looking at mortality data that go well beyond the typical examination of the underlying cause of death.
In addition, it will be important to consider how to link mortality data with data from other registries to combine the high quality of data from specific pathology registries with the completeness of mortality data.
Moreover, fatal diseases are more likely to be reported on the death certificate. Thus mortality data are more accurate for these diseases and attention should be paid in interpreting data related to non-fatal diseases.
(for more details please view attached document).

Morbidity data
Morbidity rates are the number of cases of a disease within a given time in a defined population. Morbidity can be described using the following frequency measurements: incidence and prevalence.
The importance of these measures differs according to the disease and the age group considered. In younger age groups the most important indicator is the incidence rate; in older people, prevalence is more important since patients with chronic diseases require more continuous therapy and rehabilitation, and have a greater impact on the public health system. For acute events, incidence rates are in general target measures, while for chronic conditions incidence as well as prevalence may be of interest. Incidence is used mostly for etiological research objectives; prevalence is useful for hospital and primary care planning.
Standardised rates are important to make cross-group comparisons and to investigate time trends, although absolute numbers are often necessary to evaluate the burden of the disease.

Generic health status
The most important indicator of generic health status is Quality of Life. This includes measures of perceived health and of health-related quality of life, often expressed in functional terms. Measurement instruments may address each of these health dimension separately. Examples of general ‘health-related quality of life’ instruments are the SF-36 and Euroqol-5D questionnaires.
The importance of QoL measurement in patients with Rare Diseases and issues of the different tools available for QoL assessment have already been discussed in section “Assessment of QoL”.

Composite health status
These indicators are constructed as combinations of mortality data, on one hand, and data on morbidity or generic health status measures, on the other. We propose to consider disability as a composite measure of health status according to ECHI definitions. Rare Diseases are the leading cause of disabilities. The indicator of Disability is Disability-Adjusted Life Year-DALY: years lost due to premature mortality and years lived with disability. It is equal to the sum of the number of years lost due to Rare Diseases in a population (YLL) and to the number of years lived with disability of known severity and duration for a Rare Diseases in a population (YLD). Routinely data collection and indicators on these indicators are still not available.

Health care system indicators

Possible indicators for health care systems are those related to the quality of the service provided. Because the quality of care is mainly assessed through the assessment of patient’s and caregivers opinions, an ad hoc questionnaire needs to be developed to get information on health service quality.

Other important indicators with regard to the health care system are those of utilisation.

Moreover, indicators should be identified and defined for the following areas: neonatal screening; access to care, health operator training; reference centres or reference networks; highly specialized technologies, transplantation, access to innovative drugs, therapeutic trial participation, insurance coverage for costly drugs, expenditures for specific diseases, equity of access, genetic laboratories, prenatal diagnosis, public health surveillance programs, public policies for rare diseases, clinical research support and fundamental research.

Final Meeting

The Italian National Institute of Public Health (Istituto Superiore di Sanità) organised a 6-day-conference to discuss the results of the NEPHIRD project and to continue the discussion on strategies and actions required to address Rare Diseases.

The meeting was also an opportunity to increase awareness on Rare Diseases and to advocate for immediate actions to tackle Rare Diseases.

The NEPHIRD conference was organized as follows:
a) Plenary discussion in the morning;
b) Discussion Working Groups in the afternoon focused on the topics addressed in the morning;
Each group was composed of about 10 participants with a discussion leader and a rapporteur; the latter was in charge of reporting the outcomes of the group work in the plenary;

A full day was dedicated to seminars on each of the Rare Diseases studied in NEPHIRD in order to increase the knowledge about these diseases (Neurofibromatosis, Cornelia de Lange syndrome, Rett Syndrome, Prader Willi syndrome, Myasthenia Gravis).
In order to include all stakeholders, the conference was open to Representatives of EU institutions and Authorities, Italian Representatives of Regions, Research Institutes, Hospitals and Patients Associations. The Italian Minister of Health, Hon. Livia Turco, contributed to the discussion confirming the commitment of the Italian Government with regard to Rare Diseases. The Chairperson of the Committee for Orphan Medicinal Product (COMP), the Chairperson of the Rare Disease Task Force, Representatives from the EU and other European and non-European countries attended the conference. Considering the USA experience on rare diseases, it is worth mentioning the participation of the Director of the Office for Rare Disease of the National Institute of Health (USA) and of the Director of the Office of Orphan Products Development, FDA - USA.

Conclusion of the Conference
The conference confirmed Rare Diseases as an important and relevant public health problem that needs to be addressed in a comprehensive and collaborative way.
In the last 10 years the EU and each individual country have increased their efforts to address Rare Diseases, however gaps still remain and information on the epidemiology, the natural history, the diagnosis and the potential prevention and treatment strategies for Rare Diseases is still needed.
In this regard, the collaboration among European and non-European countries needs to be strengthened in order to promote better and coordinated research (to provide scientific evidence addressing the existing information gaps) and to ensure access to treatment and care to patients in need. The collaboration among countries is essential to share information, to develop diagnostic and therapeutic guidelines and to conduct relevant research. The coordination and the establishment of networks at the European level is essential in order to maximise the limited resources and to address the problems related to the “rareness” of the rare diseases: few cases, limited information on the disease versus the great number of rare diseases (approximately 6.000).
The Conference provided an opportunity to give voice to patients and Patients’ Associations. It is not the first time that the Italian National Institute of Public Health has provided a forum for the Patients’ Association recognising their importance and promoting their engagement. Rare diseases are complex diseases and require a multidisciplinary approach for their diagnosis and treatment. In this view the conference highlighted the importance of considering the psychosocial impact of rare disease and the need to address the social needs and the patients’ needs. Assessments of the Quality of Life and the Narrative Medicine were presented as methods to better understand and address such needs.
The Conference concluded that strategies and solutions need to be discussed and developed in collaboration, however each country has a major role to play in the implementation of such recommendations.
“ Think globally … Act locally”.


Pubblicato il 25-10-2014 in Progetti e attività Internazionali , aggiornato al 25-02-2015


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