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E-Rare

Report of the Workshop on Clinical Trials and Natural History of Rare Diseases

14-15th April 2008, Madrid

CLINICAL TRIALS: CHALLENGES AND PERSPECTIVES

Background The strategy meeting held in Rome reflected the importance of better identifying and discussing research needs in different areas (deliverable D4.2 of the E-Rare work programme). Accordingly, and considering also the experience of the first joint transnational call launched in 2007 (JTC-2007), the Network Steering Committee (NSC) of the E-Rare project decided to organise 2 thematic workshops to discuss the current status and identify priority needs in the following thematic areas:

- clinical trials for rare diseases - natural history of rare diseases

Renowned international experts have been invited to provide an overview of the situation in both research fields, to highlight major challenges and identify possible solutions. The following discussion, based on the input of the workshop, focused also on whether the E-Rare consortium should be extended and whether the next transnational call (JTC-2009) could contribute to find solutions to the priority needs in the two areas treated during the workshop. Members of E-Rare´s External Advisory Board (EAB) were also invited to the workshop in order to contribute to the discussions, including the role of the E-Rare project. The list of the participants is attached in Annex 1, the agenda of the workshop in Annex 2. A summary of the presentations and of the discussions is reported in the following paragraphs.

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April 14th 2008: Clinical trials in rare diseases The situation of clinical trials in Europe Conducting clinical trials (CT) in rare diseases (RD) has many challenges. However, when discussing CT in RD it is important to highlight important achievements that will contribute to support CT in RD. Basic research in RD has often been mentioned as an example of high-quality research, especially with regards to the development of disease models, genomic research and/or animal models. Thus, it will be important to build on successes achieved in RD basic research. Today, good examples of professional networks and patient organisation networks do exist and it will also be important to build on such collaborative efforts. In addition, innovative regulatory approaches including the recognition of the importance of innovative designs for RD research should be considered. One of the major problem is that information on which CT in RD are ongoing is poorly available. Information on CT is available in the USA since 2003. In Europe, the EUDRACT database is not publicly accessible. Public dedicated websites are available (see box 1), however, it is impossible to define whether such database are comprehensive and/or how many CTs are not registered in such databases. It is therefore difficult to have a clear picture of which or how many CTs are actually ongoing in- and outside the EU. Box 1: Public websites dedicated to clinical trials (in general)

The following summarizes a few data available from Orphanet´s database on RD:

- Out of 979 national CT registered, the majority (N=720) are investigating new drug/indication, 228 new protocol and only a minority (N=31) gene/cell therapies

- Cancers (N=114), haematology (N=109) and neurology (N=61) are the most common medical areas where CTs are actually ongoing

In conclusion, many drugs on RD are in development in Europe, many trials are going on developed by both the academic sector and the industry. However, it is very difficult to have a complete overview of the situation because of the lack of transparency from EMEA and most national agencies.

www.clinicaltrials.gov – NIH of the USA – Global database

www.ifpma.org – International federation of pharmaceutical manufacturers and associations

www.who.int/ictrp/en – Catalogue of public databases (limited info up to now) – National drug agencies in Europe – Netherlands – Italy

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Methods for clinical trials and applicability to rare diseases Specific methodological approaches exist, which can be applied to increase the efficiency of the statistical analysis in small-sample CTs, for example:

- Suitable choice of response variables

o Generally metric response variables are more powerful than qualitative variables

o Avoid dichotomising response variables that are observed on original metric scale

- Adaptive randomisation

o Response-adaptive treatment allocation

o Covariate-adaptive treatment allocation

- Group sequential (adaptive) designs

- Repeated measurement designs (Longitudinal data analysis, incl. N-of-1 designs)

- Adjustment for prognostic variables; analysis of variances

- Non-parametric resampling methods

- Bayesian methods

Each approach in itself yields only a small increase in efficiency, but in combining the different approaches a substantial increase in efficiency can be obtained. Naturally, however, the possibilities are not unlimited. In the case of too small sample sizes, one has to compensate for this by paying a price. This price may be

– required additional (possibly restrictive) model assumptions – defeasibility and reduced acceptance of the results obtained

Bayesian methods represent a promising alternative to classical frequentist analyses and their application is accepted in exploratory problems. In confirmatory problems, Bayesian methods may be applicable only in the case of small-sample trials. Otherwise, a paradigm shift towards Bayesian methods is not accepted by regulatory authorities. For further information some bibliographic references are reported in box 2. Box 2: literature on clinical trial methods in rare diseases

EMEA Publications – Innovative Drug Development Approaches (March 2007) – Guideline on Clinical Trials in Small Populations (July 2006)

Generalised Estimating Equations (GEE)

– Dahmen, Rochon, König, Ziegler (2004): Sample Size Calculations for Controlled Clinical Trials Using Generalized Estimating Equations (GEE). Methods Inf Med 43: 451-6.

– Dahmen, Ziegler (2006): Independence Estimating Equations for Controlled Clinical Trials with Small Sample Sizes. Methods Inf Med 45: 430-4.

– Liang, Zeger (1986): Longitudinal Data Analysis Using Generalized Linear Models. Biometrika 73, 13 - 22.

Bayesian data analysis

– Spiegelhalter, Abrams, Myles (2004): Bayesian Approaches to Clinical Trials and Health-Care Evaluation, Wiley.

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Clinical trials: ethical and legal aspects The main ethical credos are non maleficience (do not harm), justice, beneficience (do good) and autonomy (respect persons) and, of course, must also be applied to CTs in RD. In Spain, there were about 650 CTs in 2007, 54 of which dealt with RD. About 80% of these were multi-national CTs, and only 6% multi-centric national CTs. 85% of these 54 CTs in RD were sponsored by the pharmaceutical industry, 15% by academic partners. The Spanish E-Rare partner, ISCIII, funded 19 CTs in 2007. Clinical trials: the industry point of view Particular challenges for conducting CT in rare diseases are as follows:

- disease experts are rare - the recruitment of patients is difficult - time consuming and costly - the natural history is poorly understood and therefore there is a lack of validated biomarkers - the cost of development and manufacturing is the same as for other more common

diseases, BUT the market is limited by the low prevalence - clinical complexity of the diseases lead to an interdisciplinary treatment team - solid data are not acceptable due to the urgency of patient’s expectations (e.g. mortality) - pharmacovigilance and long-term follow-up is required

In designing clinical trials, the site selection is a major challenge because of the low prevalence. Some important questions to bear in mind follow: 1. Where are the disease experts?

§ And are they truly available?

§ What is their past experience in GCP trials?

§ Will they be able to defend the results of the trials with authorities?

2. Do they have the patient population needed?

§ Recruitment numbers are inevitably overestimated

§ Is transportation to the site an issue?

3. Do they have an experienced study co-ordinator?

§ Someone to help with patient logistics (housing, travel, meals..)

4. Are ancillary services available? (e.g. certified biochemistry, specialized pharmacy, pulmonary lab)

In summary:

- the low prevalence of rare diseases requires the development of multi-sites CT - the site selection is difficult as the sites should ensure the availability of experts, of patients

and of adequate services - clinical endpoints are difficult to set up because of the limited information on the natural

history of the disease

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In order to address such challenges Reference Centres ensuring also the availability of disease experts should be identified; patient associations should play a stronger role in CT; and collaborative efforts should be promoted among academic, patients associations, health authorities and industry. Patient’s perspectives in rare diseases Patient’s groups have an important role regarding research on rare diseases:

- They are experts on the “natural history” of their diseases. Their expertise comes from living 24 hours a day and 365 days per year with the disease.

- They play a fundamental role in stimulating research on their own disease. - They contribute to the constitution of patient databases or registries and biological

collection of samples. - They raise funds for specific research projects o 40% of the 342 associations participating in a EURORDIS study funded by the

European Commission declared they were financially supporting fundamental and/or clinical research for their disease

- They disseminate research results to patients, as well as to health professionals and even the scientific community.

EURORDIS supports rare disease research and research awareness through:

1. Research projects, as a leader or a partner 2. Undergoing advocacy, directly at European level and indirectly at National level through

member associations and national alliances 3. Empowering patient organisations

The CAPOIRA project is an important example of EURORDIS´ support to rare diseases research through projects. CAPOIRA aims at facilitating the creation of structural links to bring civil society and the scientific community closer together. Ultimately the goal is to create a common language and mutual understanding. The project involves five partners, out of which four patient organisations from different countries: EURORDIS, the leader of the project; INSERM (Institut National de la Santé et de la Recherche Médicale - France), which co-organises the project with Eurordis; FEDER (Federación Española de Enfermedades Raras - Spain); UNIAMO (Federazione Italiana Malattie Rare - Italy); and RDD (Rare Disorders Denmark). The European Clinical Research Infrastructure Network (ECRIN) is closely associated to the project.

The main idea is to foster the participation of patient organisations in research activities by increasing their knowledge, skills and capabilities in the two areas of clinical trials (private or public; at national or European level) and EU-funded health research projects (clinical or non-clinical). The project is built along two axes:

- ‘Understanding Clinical Trial Protocols’: six training sessions in three countries (Denmark, Italy, and Spain)

- ‘Gaining Access to Rare Disease Research Resources’: a two day European workshop in Paris (4/5 May 2007)

The main recommendations coming out from the workshops follow: Rare disease biobanks: use the EuroBioBank network (www.eurobiobank.org) as a starting point for the creation of new high-quality biobanks; make researchers using biobanks understand that they need to share results with patients

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Patient databases and registries: organise training sessions for patient representatives; write and disseminate EU guidelines on the creation of databases; develop databases linking genotypes and phenotypes that can be operated or supervised by patient groups with the support of specialists Clinical trials: Make the centralised EU registry of clinical trials accessible to the public, at least for the basic information; ensure that results of clinical trials (including negative ones) are fully used by the research community The discussion confirmed that it is difficult to find a balance between researchers´ interests, competition and the need for transparent sharing of information. Clinical trials in rare diseases: the perspective of EMEA Particular problems for rare diseases, seen from the perspective of the EMEA, are:

- Lack of validated biomarkers and surrogate endpoints - Lack of predictive/validated preclinical models - Ethical concerns on the use of placebo (e.g. Emerging therapies) and vulnerable population - Poor participative role of patients - Poorly motivated health professionals/investigators - Lack of information to “care-givers” - Excessive bureaucratic/administrative barriers

Many areas with insufficient research were suggested:

- Epidemiology and disease indicators - Preclinical research

o Pathophysiology and molecular basis knowledge o Disease models (hindering preclinical research)

- Clinical research o Relevance of studying emerging therapies in context of low prevalent diseases o Clinical phases of drug development o Endpoints and surrogaci

- Disease models

o Could support further research (transversal approach) o Increase knowledge on rare disease o Speed up development by selecting the right compounds

- Clinical drug development

o Methodology / analysis § Deviation from conventional designs § Feasibility of research (surrogacy) § Lack of knowledge on molecular basis and pathophysiology – high

pressure/demand (sometimes no therapeutic alternatives)

Considering the drug development process, the limited experience of the sponsor would profit from networking and sharing of expertise. The networking would contribute to reduce the administrative and scientific burden related to the design and implementation of clinical trials. In addition alternative methods/analysis could be made available through networking and finally, the networking of centres would ensure expertise, availability of clinical (diagnostic, recruitment) and laboratory resources (diagnostic, follow up).

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Despite the challenges for RD research, the Reg (EC)141/2000) clearly states: “Patients suffering from rare conditions should be entitled to the same quality of treatment as other patients”. Thus, EMEA expectations are high and include:

- for orphan designation o epidemiological data o data to justify medical plausibility of product for orphan designation

- for marketing authorisation

o quality, safety and efficacy data for marketing authorisation In conclusion,

- Orphan incentives are not enough to “mobilise” research / development to cover all needs - There is need for support for research / development on rare diseases

o Rarity makes research and development even more difficult (few and scattered) o High burden for preclinical and clinical research

However, when randomised trials are necessary, low prevalence and severity of diseases should not be used as excuses not to perform them, profiting from networking and sharing of expertise.

ADDRESSING CLINICAL TRIAL CHALLENGES: EXAMPLES Clinical trials: the European Clinical Research Infrastructure Network (ECRIN) as a possible way to create a EU network for CT

The difficulty of enrolment when patients with a RD are geographically dispersed exist and it is often mentioned as a major challenge that is also related to the cost of the drug. Even if it is a problem, it is not justified to have only 40 or 50 patients in a single country when many thousands of patients are available in Europe. In order to avoid such a situation it is important to keep on promoting EU collaboration, particularly in clinical trials; it is important to have an EU network. To meet this need, ECRIN (http://www.ecrin.org) has been created to connect national networks of research centres and clinical trial units. Although designed to meet the needs of all clinical trials, ECRIN is expected to have a large impact on rare diseases. ECRIN will provide a network to identify patients and will act as a support to sponsors (academic or industry) in the conduct of multinational studies in Europe. Supporting clinical trials: the initiatives of competent authorities Independent research is important as it can contribute to address the limitation of the drug regulation process:

- Insufficient information on long-term efficacy and safety of therapies - Insufficient information on relative efficacy - Frequent use of surrogate end-points - Under-representation of special populations - Conflicts of interest

Independent research is characterised by:

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- Role of researchers in protocol definition - Data ownership - Freedom to analyse and publish - Funding only based on scientific merit - No (limited) conflicts of interest

To support independent research it is important to provide a regulatory framework and provide funding. This was achieved by the competent authorities in Spain and Italy.

In Spain the first call for proposals was launched in 2007. The priority areas follow:

- Orphan drugs (Regl. CE 141/2000) - Drugs with high interest for the National Health System “without commercial interest” (Ley

29/2006) - Clinical research on antibiotic resistance - Clinical research on special populations - Clinical research, pharmacoepidemiology and clinical safety, of drugs under real use

conditions - Clinical research and comparative clinical trials on drugs with “high impact on the NHS”

aimed at improving efficiency

167 projects were funded out of 510 proposal received. 20 out of the 167 projects funded dealth with RD. In Italy, the promotion of independent research is among the missions of the medicinal drug agency (AIFA) and pharmaceutical companies are obliged to devote 5% of their promotional expenditure to a fund for independent research (as par Art. 48, law 326/2003) There are 3 priority areas:

- AREA 1: Orphan drugs for rare diseases and drugs for non-responders - AREA 2: Comparison among drugs and therapeutic strategies - AREA 3: Strategies to improve the appropriateness of drug use and pharmacoepidemiology

studies The AIFA launched the first call for proposal in 2005 and the evaluation of the 3rd call is actually ongoing. 37 study protocols are under evaluation out of the 122 letters of intent submitted. 20 projects on orphan drugs were funded in 2005 and 24 in 2006. Open issues are listed as follows:

- Not only clinical insight: the need for methodological units and a multidisciplinary approach - Time lag between the call for proposals and the presentation of results - Commercial implications of independent research - Which is the focus? Rare vs ultra rare diseases - The relevance of clinical questions in “grey areas”

In conclusion, even if open issues remain, these examples confirm that:

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- It is possible to support independent research within the National Health Systems in areas where commercial support is insufficient

- A rigorous and transparent evaluation process can be implemented - It is required for each study to show what contribution it can make to the totality of evidence

addressing the questions concerned New treatment in rare diseases: organ transplantation Pharmaceutical treatment are not yet available for many RD thus the transplantation of organ represent an important treatment option. Data from Spanish Liver Transplant Registry (from 1984 to 2006) report that:

- 12512 liver transplants have been performed in patients with RD (see table 1) - Kidney transplant are essential for

o Primary glomerulonephitis (IgA nephropathy, Membrano-proliferative GN: type I, Dense deposit disease membranoproliferative GN: type II)

o Familiar/hereditary renal diseases (Polycystic kidneys: infantile (recessive) Medullary cystic disease, Hereditary nephritis with nerve deafness (Alport´s Syndrome), Cystinosis, Primary oxalosis, Fabry´s disease)

o Congenital diseases (Renal hypoplasia (congenital) (type unspecified), Oligomeganephronic hypoplasia, Syndrome of agenesis of abdominal muscles (Prune Belly))

o Secondary glomerular/systemic diseases (Amyloid, Lupus erithematosus, Henoch-Schoenlein purpura, Wegener granulomatosis, Goodpasture Syndrome, Systemic sclerosis (Scleroderma), Haemolytic Uremic Syndrome (including Moschowitz Syndrome)

- Heart transplants performed in o Eisenmenger syndrome patients (N=6) and o Heart tumors patients (N=3)

- Out of 1484 Lung transplants performed, 306 were related to RD as follow o Cystic fibrosis: 239 o Alpha 1 antitrypsin deficiency: 21 o Sarcoidosis: 19 o Histiocytosis: 17 o Silicosis: 8 o Kartagener Syndrome: 2

Table 1. Rare diseases and liver transplants Rare disease n %

Primary biliary cirrhosis 458 3.7 Congenital biliary diseases (Caroli, Alagille…) 413 3.3 Autoinmune Cirrhosis 185 1.5 Primary sclerosing cholangitis 152 1.2 Familial amyloidotic polyneuropathy 102 0.8 Wilson Disease 55 0.4 Budd Chiari 56 0.4 Biliary Tract carcinoma (Klatskin) 41 0.3 Cholangiocarcinoma 22 0.2

TOTAL 1484 11.8

Source: Spanish Liver Transplant Registry

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In addition to organ transplant, hematopoietic progenitors cells transplant are also important for rare diseases treatment. Data from Spain show that this kind of transplant has increased considerably in the last decade, amounting to about 2.000 cases per year since 1997, and dealing with solid tumors, leukaemias, lymphoproliferic diseases, non-malignant diseases and others. Although organ and hematopoietic progenitors cells are important for RDs, limited information is available on these kind of CT. In Spain, there are 2 CT regarding this area:

1. Skin chimera for the Epidermolysis Bullosa treatment 2. Autologous Bone marrow hematopoietic progenitors cells and Amyotrophic Lateral

Sclerosis (Phase I/II) More importance should be imposed on these studies considering the important role that organ and hematopoietic progenitors cells transplant have on RD treatment. RD patients can be utilised also as donors, however major challenges do exist for identifying those who can be a donor. A list of RD that cannot be used as donor was developed and is available on the Orphanet emergencies website.

FROM CLINICAL TRIALS TO HUMAN BENEFITS The need for translational research in rare diseases The question of how to define translational research remains unresolved and controversial. This is partly due to the fact that different stakeholders look at distinct aspects of this issue. For academia, translational research represents a general desire to test novel ideas generated from basic investigation with the hope of turning them into useful clinical applications. For academic purposes, translational research also responds to the need of identifying novel scientific hypotheses relevant to human pathology through direct observation of humans and their diseases. For people more directly involved in clinical practice (physicians, clinical laboratory professionals and patients), translational research responds to the need to accelerate the capture of benefits of research, closing the gap between ‘what we know and what we do’. This means the transfer of diagnostic and therapeutic advances proven effective in large well-conducted trials to daily medical practice. For the commercial sector, translational research refers more to a process aimed at expediting the development of known entities particularly in early phases and/or identifying ways to make early go/no go decisions when the cost of product development is still relatively contained. A simplified definition of translational research that unifies the expectations of all involved including the patients is the following:

Translational research (or translational medicine) represents a discipline that increases the efficiency of determining the relevance of novel discoveries in the biological sciences to human disease and helps clinical researchers identify, through direct human observation, alternative hypotheses relevant to human disease. A further goal is to accelerate the rational transfer of new insights and knowledge into clinical practice for improving patients' outcomes and public health.

The last aspect is important because scientific knowledge often is failing to be translated into tangible human benefits.

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Clinical research is increasingly encumbered by high costs, slow results, lack of funding, regulatory burdens, fragmented infrastructure, incompatible databases, and a shortage of qualified investigators and willing participants. These factors have contributed to impede the translation:

- From basic science discoveries into clinical studies - From clinical studies into medical practice and health decision making in health systems

Discussing fostering rare diseases research and in general research, it will be important to ensure two phases:

1) The “bench-to-bedside” step which aims at harnessing new knowledge from basic sciences to produce new diagnostic tests, drugs, devices or treatment alternatives for patients

2) The translation of research into practice; ie, ensuring that new treatments and research knowledge actually reach the patients or populations for whom they are intended and are implemented correctly

The second phase can be ensured by improving access, reorganizing and coordinating systems of care, helping clinicians and patients to change behaviors and make more informed choices, providing reminders and decision support tools, and strengthening the patient-clinician interaction. To ensure the translation of knowledge into practice and human health benefits it will be necessary that:

• Phase 2 to come out from under the shadow of phase 1 ““bench-to-bedside” “

• Policy makers and researchers come to a clearer understanding of the distinction between developing treatments and getting them used in practice: need of local o context-dependent research

Funding disproportion has consequences, and the current policy of spending less of 2% of research euros/dollars on health services research is probably costing lives.

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April 15th: Natural history of rare diseases Concept and methods for the study of natural history of rare diseases The natural history is a description of the patterns of disease progression over time. It is crucial to the understanding of the health, social and economic impact of the disease on the individual, their family and care-givers, and the society as a whole. Interventions are intended to change the natural history for the better, and the clinical and economic benefits of those interventions must be judged against the (untreated) natural history. The natural history will also have a bearing on the conduct of clinical trials of interventions and the interpretation of their results Natural history studies should address the following issues:

- Related morbidity and mortality o Description of the range of symptoms and associated disabilities both at an

individual and population level - Disability - Classification and prognosis of subgroups:

o To validate for the individual patient over time (i.e. any tendency to move between categories) needs to be assessed.

- Models of progression o Modelling of the progression of disability

§ If possible, to adjust it according to the results of clinical trials § To estimate the benefit covering a period longer than typical trials

In addition to prevent the disease we must understand the natural history of the condition, its distribution in the population, and how to detect early cases. If we don’t know the natural history of the diseases it is difficult to understand the impact of a screening test on patients as we don’t know whether they would have developed the diseases. A summary of the different study designs, showing specific advantages and disadvantages, is provided in figure 1. Case series represent only those involved in the case series thus results cannot be extrapolated to the population and are thus not representative. Population based cohort are appropriate for studying RD. Population based registries are most appropriate for studying the natural history:

• They combine cross-sectional and longitudinal information • Cases from the pre-clinical phases (if a screening is available) can be included • Inference is viable because they have a well known referral population • It is possible to link other studies (clinical trials) • Useful for geographical variability analysis • Many hypothesis can be assessed using nested designs • Providing important knowledge for decisor-makers

However, support by authorities is required for ensuring long-term funds and support.

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Figure 1: Summary of study designs

Funding natural history studies Support for cohort and natural history studies is important because they contribute to:

- Understand the nature of the disease (pathophysiology) o better models o mechanistic insights – new targets; plausible treatments o reliable surrogates of treatment effect (biomarkers)

- Identify the patient diversity of response to treatment o Efficacy of drugs 30% o Personalised medicine o

- Assess the impact of treatment and/or service provision Regardless of their importance, it is difficult to convince funders and peer-reviewers as the outcome of such studies is a long-term outcome and the benefit of such studies is not clear: cohort studies are based on broad hypotheses and don’t necessarily bring direct advantage to people. In addition, natural history studies are expensive and need an open commitment. The support of natural history studies can be provided through the funding of infrastructure or the funding of projects. What is important is to ensure a long-term sustainability of the funding of such studies. Final discussion

The discussion confirmed the need to foster research on RD at different levels, from the pre-clinical to the clinical including the health service research area.

The discussion stressed the need to consider all RDs, i.e. without differentiating rare and ultra rare diseases.

In discussing priorities for RD research for an international call (of the E-Rare consortium), it might be important to consider:

- areas for which drugs are not authorised

- common methodological challenges

- level of evidence: randomised trials vs observational studies

- epidemiological studies on the basis of registries and/or data already available

- support for collaborative work

Major issue raised:

- lack of transparency and information on the status of RD research

In promoting transparency and exchange of information it will be important to share information on the results of the different studies including CTs.

- limited use of the information the clinical setting

Supporting the research it will be important to ensure that the results will be available and will be widely diffuse in order to ensure that the new developments and knowledge will be used in the clinical practice.

An important open question that is worth stressing is how the results of independent research should be used. How to ensure that will be used for the benefit of the public?

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Annex 1: List of the participants

Surname Name Institution/organisation Abaitua Ignacio Institute of Health Carlos III (ISCIII), Madrid, Spain Ayme

Ségolène Orphanet

Baanante Ignacio Institute of Health Carlos III (ISCIII), Madrid, Spain Beitia Igor National Institute of Health and Medical Research (INSERM), Paris,

France Ben Gershon Zelina Chief Scientist Office of the Israeli Ministry of Health (CSMOH),

Jerusalem, Israel Carné

Xavier Hospital Clinic de Barcelona

Direskeneli Haner Marmara University Medical School, Turkey de Andrés Rafael Institute of Health Carlos III (ISCIII), Madrid, Spain

de Morcillo

Evanina Spanish Asociation of Epidermolisis Bullosa (AEBE

Faure

Hélène International Standard Randomised Controlled Trial Number Register (ISRCTN)

Ghassibe Michella FNRS, Belgium Giraldo

Pilar Hospital Universitario Miguel Servet

Gómez

Begoña Hospital Clinic de Barcelona

Köpcke

Wolfgang University of Muenster

Koutouzov Sophie National Institute of Health and Medical Research (INSERM), Paris, France

Llinares

Jordi European Medicines Agency (EMEA)

McNamara Joe Medical Research Council (MRC) Mahillo

Beatriz National Transplant Organization (ONT)

Martín Concepción Institute of Health Carlos III (ISCIII), Madrid, Spain Martinez

Carlos Genzyme

Misslisch Hubert Project Management Agency (PT-DLR), Bonn, Germany

Pampols Teresa Instituto de Bioquímica Clínica. Barcelona. Spain Pastor Mercedes Fundación Federación Española de Enfermedades Raras. Madrid,

Spain Posada Manuel Institute of Health Carlos III (ISCIII), Madrid, Spain

Ramirez

Alejandro Institute of Health Carlos III (ISCIII), Madrid, Spain

Sánchez de la Vega

Rosa Federación Española de Enfermedades Raras. Madrid, Spain

Schuster Ralph Project Management Agency (PT-DLR), Bonn, Germany

Serrano

Mariantonia Agencia Española de Medicamentos y Productos Sanitarios (AGEMED)

Serrano Pedro Servicio Canario de Salud. Islas Canarias. Spain Sevimli K. Melike Scientific and Technological Research Council of Turkey

(TÜBITAK), Ankara, Turkey Sitsen Ad Health Care Insurance Board, The Netherlands Terracini

Benedetto Torino University

Tournier- Elisabeth National Institute of Health and Medical Research (INSERM), Paris,

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Lasserve France Trama Annalisa Italian Institute of Health (ISS), Rome, Italy

Traversa

Giussepe Italian Medicines Agency (AIFA)

Vikkula Mikka National Fund for Scientific Research (FNRS), Brussels, Belgium Villaverde Ana Institute of Health Carlos III (ISCIII), Madrid, Spain Wetterauer Birgit Federal Ministry of Education and Research (BMBF), Berlin,

Germany

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Annex 2: Agenda of the workshop

E-RARE “ERA-Net for research programmes on rare diseases”

Workshop on Clinical Trials and Natural History of Rare Diseases

Workshop Agenda 14-15th April 2008, Madrid

Aula Pittaluga, Escuela Nacional de Sanidad Pabellón 7

Instituto de Salud Carlos III Sinesio Delgado 6, Madrid

Chairs

Igor Beitia, Rafael de Andrés and Manuel Posada

Rapporteurs Annalisa Trama and Huber Misslisch

Organizes E-RARE

in collaboration with

ISCIII-FIS Fund for Health Research ISCIII-IIER Research Institute for Rare Diseases

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April 14th : Clinical Trials and Rare Diseases

Registration 8.45-9.15

Facilitators

Sophie Koutouzov and Igor Beitia

1. Welcome and introduction 09.15-09.30

Welcome by the organizers Joaquín Arenas, Deputy Director FIS

Introduction to the Workshop

Manuel Posada, IIER-ISCIII Rafael de Andrés, FIS-ISCIII Igor Beitia, Inserm

2. Clinical Trials in rare diseases 09.30:10.30

2.1 Clinical trial mapping in Europe Ségolnè Ayme, Orphanet

2.2 Clinical Trials methods and its applicability to Rare Diseases

Wolfgang Köpcke, University of Muenster 2.3 How to test a new or an existing drug on rare diseases? Vision from the industry

Carlos Martinez, Genzyme

∼ Coffee Break ∼ 10.30-11.00

3. Clinical Trials: ethical and legal aspects, implications and problems 11.00-11.25

encountered Mariantonia Serrano, Agencia Española de Medicamentos y Productos Sanitarios (AGEMED) 4. New treatments on Rare diseases: 11.25-11.50

3.1 Organ donation and transplantation in rare diseases: the experience from the National Transplant Organization (ONT)

Beatriz Mahillo, National Transplant Organization (ONT)

5. Multicentre or multinational trials: integrating national clinical 11.50-12.15 research facilities into a EU-wide network: the ECRIN project experience Xavier Carné, Hospital Clinic de Barcelona

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∼ Lunch ∼ 12.15-13.30

Facilitators

K. Melike Sevimli and Birgit Wetterauer 6. Clinical trials in independent research calls 13.30-14.20

Health Research Funding Agencies and their experiences with clinical trials funding Giussepe Traversa, Italian Medicines Agency (AIFA) Begoña Gómez, Hospital Clinic de Barcelona

7. Patient’s perspectives in rare diseases research (CAPOIRA study) 14.20-14.45 Evanina de Morcillo, Spanish Asociation of Epidermolisis Bullosa (AEBE)

8. Clinical Trial Registration and rare diseases 14.45-15.10 Hélène Faure, International Standard Randomised Controlled Trial Number Register (ISRCTN) 9. E-RARE and orphan drug research: how to meet EMEA expectations 15.10-15.35

Jordi Llinares, European Medicines Agency (EMEA)

∼ Coffee Break ∼ 15.35-16.00

10. Summary and recommendations (from day 1) 16.00-17.00

K. Melike Sevimli and Birgit Wetterauer

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April 15th Natural History and Rare Diseases

Facilitators Zelina Bengershon and Erica Hackenitz

1. Introduction 9.15-9.30 Manuel Posada, IIER-ISCIII Rafael de Andrés, FIS-ISCIII

Igor Beitia, Inserm

2. Natural History of rare diseases 9.30-10.20 2.1 Concept and methods for the study of natural history of disease

Manuel Posada, IIER-ISCIII 2.2 Funding of natural history studies: the problem of long-term sustainability

Joe McNamara, Medical Research Council (MRC)

3. Translational research: Placing natural history and its modification 10.20-10.45 in perspective

Pedro Serrano, Servicio Canario de Salud

∼ Coffee Break ∼ 10.45-11.15

4. Ethical considerations of the natural history studies 11.15-11.40 Benedetto Terracini, Torino University

5. Success story: modification of natural history of a rare disease 11.40-12.05

Pilar Giraldo, Hospital Universitario Miguel Servet

6. Recommendations of the External Advisory Board 12.05-12.30

∼ Lunch ∼ 12.30-13.30

Facilitators

Igor Beitia, Rafael de Andrés and Manuel Posada 7. Recommendations of the External Advisory Board (continuation) 13.30-14.30

8. Summary and recommendations (from day 2) 14.30-15.30

∼ Coffee Break ∼

15.30-16.00 9. Closure of the workshop: general conclusions from the workshop 16.00-16.30