SSC Working group on Factor VIII and Factor IX, Rare Bleeding Disorders (RBDs)
1st July, 2006, Oslo, Norway
Chair: K. Mertens (The Netherlands) Co-chairs: J.C. Gill (USA), C. Lee (UK), J. Oldenburg (Germany), F. Peyvandi (Italy), J.M. Saint-Remy (Belgium), A. Srivastava (India), H.M. van den Berg (The Netherlands)
The Chairman opened the Subcommittee meeting at 14.15 for an audience of approximately 170 attendants. He announced a few amendments to the final program and provided the timing details of the various sections in the agenda.
ISTH-SSC Working Party on RARE BLEEDING DISORDERS (RBDs) Co-chairs: F. Peyvandi (Italy), C. Lee (UK)
RBDD project: state of the art
F. Peyvandi (Italy)
In 2004, a SSC working group on "Rare Bleeding Disorders" was established with these summarised first aims of the project:
	· Database development: Identify current databases and potential collaborators world-wide, Perfect database tools and data collection protocols and disseminate them worldwide, Develop a steering committee for data evaluation
	· Product development licensure: Perfect common regulatory requirements within FDA/EMEA, Identify products already available, Design clinical trials in order to get global licensing, To explore new product development (FV), To implement post-licensing surveillance
- A report on the Steering committee held in Vancouver (WFH, May 2006) was made:
	· presentation of different National databases: WFH, Swiss, North American, UK, French, Egyptian, Iranian and Indian
	· RBDs distribution according to these registries and RBDD. Since 2004, 58 centres from all over the world joined the International Database of Rare Bleeding Disorder (RBDD) by including data on 2665 patients. Preliminary information on distribution of affected patients in the world and the available treatment for them are reported at www.rbdd.org.
- The future RBDD plan after Vancouver meeting were discussed:
	· to design a specific and homogeneous questionnaire reviewed by experts in the field of RBDs to be used as a specific data collection tool by a majority of the countries around the world. This will contain the most important clinical and therapeutic data useful to answer the missing information that remains unanswered in the field of RBDs
	· to form subcommittees for each deficiency in order to review literature, to plan multicenter studies, to prepare evidence-based guidelines using data collected in either RBDD or other available National Registries, to develop a specific part of the website/RBDD that addressed these disorders, to develop a clinical research agenda for these disorders
RBDs in the USA (US working group on RBDs)
A. Shapiro (USA)
The rare bleeding disorder group in the United States will be developing a resource center hosted on-line by the National Hemophilia Foundation that will contain information on many rare plasma protein deficiencies. Links to existing websites, registries, and organizations related to these disorders will be included. The material developed for this resource center will be submitted for publication. In addition, the development of a national database in the United States is presently underway and a uniform platform has been adopted. Development of a database for rare bleeding disorders will be included in this national database effort. The rare bleeding disorder group in the US wishes to collaborate on an international level to further both development of international data collection and research efforts, including expansion of treatment options.
Glanzmann thrombasthenia: World distribution, mutations and founder effects
U. Seligsohn (Israel)
A preliminary survey was performed in order to estimate the minimal prevalence of the disease in different populations, the mutations so far detected and founder effects. Data were extracted from reports involving ³9 unrelated patients, national and reference center registries, a database of mutations (by Debra French and Alan Nurden) or personal communications.
	Table: minimal prevalence of Glanzmann thrombasthenia Country n Minimal prevalence Jordan 73 1:81.000 Israel 70 1:143.000 Iran (Shiraz) (Tehran) 23 1:170.000 382 Tunisia 22 1:256.000 17 Oman 9 1:340.000 S.A. 30 1:880.000 UK 85 1:706.000 Japan 192 1:664.000 India (Vellore) 254 ? 20 30 75 France 64 1:192.000
The minimal prevalence ranged from 1:80,000 in Jordanian, 1:143,000 in Israelis and Palestinians to 1:2,800,000 in Indians, with an average global prevalence of 1:1.1x106.
- As of May 2006, 159 mutations have been reported in peer-reviewed journals:
	· 159 published (69 b3, 90 aIIb) · 133 described in individuals · 26 in more than one individuals
For 7 of the 26 mutations, a founder effect was discerned by haplotype analysis: 2 in Iraqi Jews, 1 in Palestinians, 1 in Jordanians, 2 in Indians and 1 in Manouce Gypsies in France. This preliminary survey is a rough estimate of the global problem related to this severe hemostatic abnormality, but is somewhat limited because of lack of data from China, Africa, Latin America, Eastern Europe and densely populated countries like Pakistan, Bangladesh, etc.
Menorrhagia in women affected by RBDs. Proposal of an International study
F. Peyvandi (Italy)
- A significant number of women affected by blood coagulation diseases present with Bleeding risk during reproductive life:
	· Menorrhagia: defined as menses > 7 days · Pregnancy · Perinatal · Post-partum
- On 261 severe RBDs women (retrospective study), menorrhagia occurred in >50% of the patients - In an Italian study with 119 patients affected by RBDs (34%), mostly FXI and FVII, VWD (40%) and Hemophilia carriers (26%):
	· Menorrhagia was present in 45% RBDs, 55% carriers of hemophilia and 46% in VWD · Bleeding during pregnancy was present in 30% RBDs and 8% of VWD. This symptom was absent in carriers of haemophilia · Post-partum bleeding present in 45% RBDs, 38% carriers of hemophilia and 42% of VWD
Previous studies on this issue are not very informative due to the heterogeneous group of patients enrolled and the different methodologies used to analyze the data. We therefore propose a multicentre prospective study (10-15 International Centers) which enrol a large number of female patients affected by vWD, rare bleeding disorders and carriers of hemophilia (500-600 patients and controls). Based on a specific questionnaire designed to collect clinical data in a homogeneous format. In future it could be available online (www.rbdd.org) for the participating centers. The results obtained will be examined by a scientific committee and then published on the space assigned to on-line studies within the URL: www.rbdd.org. The results of this project will provide information on the incidence of bleeding complications and to assess whether hormone therapy, anti-fibrinolytic and replacement therapy could have beneficial effects on bleeding symptoms and on quality of life of these patients.
Long term prophylaxis in afibrinogenemic patients: a rationale based on results from single dose PK
T. Waegemans (France)
FIBRINOGENE T-I (LFB) is a new concentrate of human plasma fibrinogen. It is derived from cryoprecipitate and its manufacturing process includes three major biological safety steps. A single dose PK study performed in 5 afibrinogenemic patients showed homogeneous results within a one-compartment pharmacokinetic model with IV infusion and first order elimination. This model was applied to simulate PK profiles at steady-state after repeated infusions. A selection of targeted parameters will allow investigators to determine individualized dosage regimens before initiating a long term prophylaxis in afibrinogenemic patients. A design of PK study was presented, aiming at comparing the values predicted by the simulation with those observed during the prospective follow-up of patients. - Presented study:
	· Multicenter · Multinational, non comparative · PK study · 10-15 patients · primary end-point: document PK and develop prophylactic dose · secondary end-point: safety and efficacy
Getting products to patients: industry options
J. Lloyd (UK)
2 years ago, BPL identified market access, regulatory requirement and clinical trial design as constraints to manufacturing products for RBD.
	· Market access: need to have patients number and treatment regimen
	· Regulatory: existence of multiple dossiers because of 1. different countries mean different regulation 2. multiple trials in different countries 3. provide language to local country (product labelling) 4. many countries and small number of patients (not practical) Can have orphan drug designation? What to do? One common dossier? One trial?
	· Clinical trials, are difficult because of: 1. few patients 2. different sight for children 3. cross over - what product costs
Over the past two years there have been some advances made. Registries and databases of rare bleeding disorders have made it easier to establish patient numbers and treatment regimes to support orphan drug designation. Further development and support of these registries is required to aid industry in deciding whether to develop a product. Orphan drug designation and the parallel scientific advice available from the FDA and EMEA have potentially reduced the need for multiple dossiers and trials. Clinical trial design and support remains an issue, which is overcome by protocol assistance from regulators. There are still some major hurdles for industry to overcome. Further ongoing cooperation between regulatory agencies is required. The maintenance of parallel scientific advice provided by the EMEA and FDA is vital.
General discussion and concluding remarks
In the discussion Dr. Peyvandi raised the issue how to proceed with the Rare Bleeding Disorders now her outside funding for this project expires. The Chairman indicated that SSC activities in general would benefit from some level of funding by ISTH. This particularly includes Working Groups or Working Parties that have formally been endorsed by SSC. This issue was discussed in more detail in the audience. It was believed that ISTH, by virtue of its established authority, could drive related national or regional projects under the same umbrella. The general feeling was that ISTH could show leadership in providing funding for those SSC activities that are considered to have appropriate priority. The Chairman mentioned that this issue has been brought to the attention of the SSC Chairman. He concluded the meeting thanking all speakers for their presentations and the audience for attending and contributing to the discussions.