Rare Bleeding Disorder Database (RBDD)
ASH December 9, 2005

Present:
Flora Peyvandi
Marion Koerper
Amy D Shapiro
Michael Soucie
Bruce Evatt
Jean Donadieu
Uri Seligshon

Minutes:
Dr. Peyvandi opened with a presentation on past history of the RBDD including:

1. Necessity to perform cross-sectional studies among different Centers, in order to fill the gap between the knowledge on clinical manifestation/treatment practice/patient outcomes and their integration/availability
2. Established goals of the SSC working group on RBDs: Database development and Product development licensure
3. The International Database considered as a reference informative tool where knowledge and expertise could be collected and shared in order to:
- To evaluate the distribution of patients affected by RBDs in the world
- To identify available treatments and correlated problems such as: drug production, cost and distribution, adverse effects
- To provide evidence-based guidelines for diagnosis and management of patients
4. Identification of the 870 Hemophilia Treatment Centers in the world by the www.wfh.org web site
5. Each Center was invited to fill in a simple and general questionnaire in order to understand: how many Centers would like to participate and what type of intervention needs to be done in each region of the world
6. Report on distribution of patients, available treatment and problems on products distribution for treatment reported by the 50 already joined Centres
7. Sending of a specific tailored questionnaire to all Hemophilia Centers, after their joining to the RBDD, in order to collect more detailed information on each enrolled patient in order to collect individual information on each single patient including: phenotype and genotype analysis, clinical manifestation, type of treatment, on-demand/prophylaxis, treatment-related complications

Dr Peyvandi presented the mission of the RBDD and her vision for use of data housed with the database including:

1. A mechanism by which clinicians throughout the world could locate other treating clinicians and contact them regarding issues related to patient care
2. Identification of treatment modalities employed, and the outcome of these modalities
3. Preparation of a multicenter prospective studies by an expert group is required in order to: design the study, find the funds, analyze the data, prepare guidelines

In order to reach these goals, Dr Peyvandi proposed:

1. It would be useful to appoint an expert group of 2-3 person who has to evaluate all the different aspects of each specific deficiency
2. To gain industry interest in developing missing concentrates

Dr. Donadieu from France presented data regarding France's National bleeding disorder registry and specific data regarding rare disorders within their population.

The Rare bleeding disorders' cohort is nested in France in a general cohort for constitutional bleeding disorders, including hemophilia A & B and Willebrand disease. The hemophilia's cohort started in 1994 in France and the new version, so called FranceCoag started in 2003 (www.francecoag.org). Enrollment is in progress, and exhaustivity is not achieved today. The information currently collected is the demographic status, the biological features including the value (%) of the factor, the major medical events (bleeding, surgery) and the therapy.
At the end of September 2005, the enrollment in FranceCoag was:

Factor I deficiency 21
Factor II deficiency 0
Factor V deficiency 19
Factor VII deficiency 40
Factor X deficiency 7
Factor XI deficiency 34
Factor XIII deficiency 16

Amy Shapiro presented a summary of MASAC's (Medical and Scientific Advisory Council of the National Hemophilia Foundation) position on RBDs and work that has been done to date in the United States. Specifically data and lessons learned from the North American Registry of Rare Bleeding Disorders was provided by Dr. DiMichele and presented. The system in the United Sates of federally recognized hemophilia treatment centers and the data reporting requirements of those centers was presented. The two main mechanisms through which national data are collected in the US include:

1. The Hemophilia Data Set (HDS): this system collects minimal anonymous data on patients throughout the US that are considered active registered patients. Although minimal and anonymous, these data may serve to provide a denominator for RBDs patients in the US
2. The Universal Data Collection System (UDC): participation in this data collection program is mandatory for hemophilia centers; however, patient participation requires consent and is voluntary from the patient's perspective. These data are far more complete and include historic data, interim data for repeat participation, physical therapy measurements, blood draw for viral testing and serum banking.

Advantages to these national registries for data collection are that data submission by centers is mandatory rather than voluntary (such as was the case with the present RBDD and the North American Rare Bleeding Disorder Registry). This increases the opportunities for compilation of more complete and accurate data. Dr. Shapiro reported that MASAC developed a position statement on RBDs in 2004 that reflected their belief that lack of specific product availability for treatment of RBDS represented a safety issue (MASAC Document #143, MASAC Recommendations Regarding Rare Coagulation Factor Disorders at http://www.hemophilia.org/research/masac/masac143.htm ). MASAC subsequently developed a working party to address this problem.
In summary, MASAC supports:

1. The effort to create an international database for RBDs
2. Efforts to work with national agencies to create a system for the US to allow this program to proceed and be successful
3. Efforts to work with the International Society of Thrombosis and Haemostasis (ISTH) RBDD in the hopes that it will serve as the platform for this international effort and as the final repository for data from a variety of independent existing international sources on these disorders.

It is hoped that these efforts will:

1. Serve to improve and increase the access to care for all those affected with RBDs through the world
2. Increase pharmaceutical interest in development for replacement products for these disorders
3. Allow caregivers of those with RBDs an opportunity to find each other and exchange information on these diseases and the treatment modalities employed.

Raised with this discussion was the issue that not all patients within the US with RBDs are cared for by the federally network of hemophilia centers. If data for hemophilia A and B obtained from a surveillance project that was conducted by the CDC are applicable, then perhaps 70% of these patients are within the system of federally recognized treatment centers and 30% are outside of this system. Therefore, a mechanism should be considered for entry of a patient into the RBDD that was not through the national data collection system. Issues related to this include:

1. Preventing repetitive entries on the same patient from a variety of sources
2. Validation of the data entered including the diagnoses.

Suggestions to address these issues included the possibility of segregating data with in the database into validated data (national sources) and non-validated data (individual submissions, non-national sources). Also discussed were mechanisms though which repetitive entries might be prevented.

Dr. Shapiro requested consideration of the following suggestions:

1. Revisiting initial data collection on RBDs and requesting data from national data sources such as the CDC to provide a more accurate base for the RBDD.
2. Inclusion of other rare disorders such as plasminogen activator inhibitor 1 deficiency and plasminogen deficiency (i.e. expand this system to include rare coagulation factor deficiencies).

Also presented was specific information from both the Hemophilia Data Set and the Universal Data Collection System by Dr. Soucie from the Centers for Disease Control and Prevention. Much of the data collected through the UDC is aimed specifically geared towards hemophilia; yet included within this system are patients with RBDs.

Dr. Soucie suggested that the CDC could consider:

1. Making a priority, enrollment of patients with RBDs into the UDC by hemophilia treatment centers in order to capture more complete data on these disorders
2. Revising the data collection forms to collect data more specific and appropriate to each of these disorders.

Dr. Evatt discussed the perspective of the World Federation of Haemophilia regarding RBDs. A recent objective of the WFH has been to collect data from countries throughout the world on these disorders. Sources through which the data are collected are member organizations rather than national agencies. Dr. Evatt felt that the WFH would be interested in supporting efforts of the RBDD.

The following discussion ensued surrounding objectives as listed:

1. Financial support for RBDD: initially support for this effort was provided through a grant obtained by Dr. Peyvandi from the Bayer Awards Foundation. The time line for this initial project is now drawing to completion and further funding for expansion and efforts will be required. Dr. Shapiro asked whether the ISTH provided financial support to the RBDD; at this time although the RBDD originally was voted by the SSC of the Factor VIII/IX subcommittee, no financial support was available. Dr. Shapiro asked whether the ISTH was a designated "owner" of the database, so that future existence and maintenance could be assured. At this time the RBDD was created by a contracted agency identified by Dr. Peyvandi in Milan and is housed at the institution that Dr. Peyvandi is affiliated (Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre IRCSS Foundation, Maggiore Hospital, Mangiagalli and Regina Elena Luigi Villa Foundation University of Milan, Milan, Italy). Discussion ensued regarding methods to consider housing the database more closely affiliated with the ISTH to allow its continued existence and maintenance over time. This will be investigated. Dr. Shapiro asked about further funding solicitation and support, to whom would these funds be disbursed and would there be associated indirect costs. This issue will also be investigated so that the executive committee is prepared to move ahead to identify and obtain future required funding.
2. Obtaining data from worldwide national sources: Dr. Peyvandi had previously distributed a survey on RBDs to ~850 hemophilia centers throughout the world. Of these ~50 responded and provided data that is housed within the RBDD and serves as the baseline global data on these disorders throughout the world. As previously discussed data submission via this route is voluntary for the centers that were surveyed and limited by the number that respond. A suggestion was made to try to obtain more complete data from national registries such as those represented by Dr. Donadieu from France and Dr. Soucie from the US. These data might be disparate in terms of what is collected but basic data on the number of identified individuals with these disorders would likely be more complete. A discussion regarding the number of countries within the world who have such national databases that could potentially contribute to this effort followed. It was decided that efforts would be made prior to the WFH meeting in Vancouver to identify as many countries as possible with such national registries, determine the agency/individuals within those agencies responsible for these systems and contact them to potentially meet at WFH in 2006 to explore their interest in supporting an international effort through the RBDD.
3. Proceeding with more specific data collection on each disorder: the first issue raised was the development of a specific data collection tool for each disorder. Dr. Peyvandi has developed a general data collection tool (INTERNATIONAL REGISTRY) that could be utilized for all these disorders or could serve as a template for revision for each specific disorder. It was discussed that subcommittees for each disorder could be created and that these subcommittees could be charged with:

a. Development of a specific data collection system for each disorder
b. Development of the specific part of the website/RBDD that addressed these disorders including literature citations, individuals with active research interests in these disorders including those that could provide mutation analysis
c. Development of a clinical research agenda for these disorders.

It was suggested that this could present an opportunity to young members within the filed to serve as members or leaders within these sections.

Action Points:

1. Establish a meeting at the WFH in Vancouver
2. Write hemophilia centers throughout the world in order to

a. Identify if a national data collection system exists for specific countries
b. Identify those agencies that are responsible for these national data collection system
c. Invite these agencies or a responsible individual within these agencies from national data registries throughout the world to the RBDD meeting
d. Develop an agenda for the WFH RBDD meeting
e. Finances
f. Subcommittees for each disease
g. Charter for RBDD
h. Housing of RBDD