The Robustness, Validity, and Potential Usefulness of Registry Data for Understanding the Treatment Practices, Safety, and Efficacy of New Therapies for Rare Bleeding Disorders: The Experience of the Hemophilia and Thrombosis Research Society (HTRS) Registry (2004–2007)

In 1999, the Hemophilia Research Society established a registry to collect information on individuals diagnosed with bleeding disorders and on their bleeding episodes. Concurrently, the prospective database was intended to serve as a mechanism to satisfy the post-marketing surveillance requirements of the FDA to assess the safety and efficacy of rFVIIa (NovoSeven®, Novo Nordisk A/S) administered to individuals with congenital hemophilia complicated by alloantibody inhibitors to FVIII or FIX. On January 1, 2004, the database format was re-launched on a 2^nd generation web-based platform and designated as the HTRS Registry. No data were transferred between databases. This study examines the data captured in the HTRS registry from January 2004-December 2007.

The HTRS registry is a web-based single database with 11 component forms and 1564 fields. Any sites or physicians affiliated with the HTRS can participate in the registry after obtaining IRB approval and providing patients with an informed consent to capture de-identified information. Over this interval, 83 sites were IRB approved to participate, and all but 11 entered some data. Assessment of the accuracy and validity of the data contained in the registry was performed by an independent third party as part of an audit in early 2008. Overall there are 2,081 patient registration records in the HTRS database. Of these, 373 patients with ongoing treatment required merger of their data from the initial HRS Registry. A sub-cohort audit of all patients in the HTRS registry indicated that the diagnosis and inhibitor status and elements of the demographic information were accurate in 43/43 patient charts examined. The largest group of patients represent those with congenital hemophilia (Total, 1,432; A, 1,145; B, 287) and congenital hemophilia with inhibitors (Total, 354; A, 321; B, 33). Other common diagnoses were von Willebrand Disease (497), acquired hemophilia (48), congenital FVII deficiency (30), and inherited qualitative platelet disorders (29).

A total of 5,144 bleeding events were captured for 473 patients, including 3,445 bleeds in congenital hemophilia, and 3,007 in 354 patients with alloantibody inhibitors. There were 2,532 bleeds in 293 patients in whom rFVIIa was administered alone or in combination with other agents. These included 2,099 bleeds in patients with congenital hemophilia, of which 1,702 were in 117 patients with inhibitors to FVIII or FIX. Recombinant FVIIa use was also reported in other patient groups, including congenital hemophilia without inhibitors (397 bleeds), congenital FVII deficiency (54), acquired hemophilia (38), Glanzmann’s thrombasthenia (23), and von Willebrand disease (9). A total of 18 serious adverse events were reported in the registry and forwarded to the manufacturer(s) regardless of relationship to therapy.

In the United States (US) clinical research efforts have been focused primarily on evidence based outcomes and development of new therapeutic agents in large disease populations. For rare disorders, such as hemophilia complicated by alloantibody inhibitors, this is not practical or statistically conclusive. An alternative approach to understanding the safety and efficacy of new therapeutic agents in so-called “orphan diseases” involves the analysis of the “collective” experience of patients included in a longitudinal database. This is a labor intensive endeavor, which in the US has been subjugated to the need to deliver care to patients in a rapid fashion with limited infrastructure support. Thus, the documentation of prescribing habits, response to varying treatment modalities, and the reporting of adverse events have lagged. This is in contrast to many national health care systems outside the US, which mandate and finance such activities. The HTRS registry represents an industry- funded effort to satisfy a FDA mandate to monitor the longitudinal safety and efficacy of a clotting factor replacement product for alloantibody inhibitor patients. However, the supervision and oversight of the registry are based in an independent cooperative clinical research group, the HTRS. The significant amount of data accumulated over a 4 year period in the HTRS database will provide insight and important “signals” into current treatment practices and the safety and efficacy of treatment modalities, particularly for more severe bleeds that are treated in an HTC setting.