The Acquired Hemophilia Surveillance (AHS) Project: A Novel Mechanism of Capturing Post-Marketing Safety Information on rFVIIa (NovoSeven^®RT) In Acquired Hemophilia.

Acquired hemophilia (AH) is a rare disorder (1 per 1.3 million) characterized by auto-antibodies to coagulation factor VIII. AH can present in the elderly, in association with autoimmune disorders or malignancy, or in the post-partum period and is characterized by often life-threatening bleeding and associated high mortality. The label for recombinant activated factor VII (rFVIIa, NovoSeven^®RT) was amended in October 2006 to reflect an expanded indication for treatment of bleeding in patients with acquired hemophilia. As part of the post-approval commitment, Novo Nordisk agreed to work with the Hemophilia and Thrombosis Research Society (HTRS) Registry to monitor treatment of bleeding episodes in AH patients on an annual basis. Because of the rarity of AH, it proved difficult to capture information from HTRS sites that did not have a sufficient population of AH patients to justify IRB submission, patient informed consent, and detailed data entry required for the HTRS registry. The Acquired Hemophilia Surveillance (AHS) project was therefore designed as a simple web-based interface reporting through www.novosevensurveillance.com to verify identified AH cases, capture the use of rFVIIa, and identify any adverse events associated with treatment. AHS takes advantage of the HIPAA exclusion for collection of safety reporting information (45 CFR §164.512(b)(iii)(D)).

From April 2008 through 31 March 2010, 29 individual reporters submitted 66 case reports to AHS. Of the 66 patients, 27 were male and 39 were female. The mean age was 64 years (range 22–97). The most common associated conditions were autoimmune disorders (22 patients), post-partum state (5 patients) and malignancy (3 patients). Mean FVIII inhibitor titer was 180 Bethesda Units (range 1–3789). FVIII levels were reported for 61 of the 66 patients. Sixty-four percent (39/61) had FVIII levels of <1%. The mean FVIII level in the other 22 patients was 10% (range 2–50%). There were reported to be on average 5.5 discrete bleeding events per patient (range 0–100 episodes). Types of bleeding episodes were reported for 62 case reports and were described as spontaneous (55 patients), surgical (11 patients), and/or related to a procedure (7 patients). No bypassing agent was reported to have been used in 16 patients (24%). The use of rFVIIa was reported in 39 patients (59%), the majority of which were first-line (30 cases, 77%) with 8 second-line (21%), and 1 unspecified. A bypassing agent other than rFVIIa was used in only 11 cases (17%). The acquired hemophilia condition was reported to have been “resolved” in 42 cases (64%) and “not resolved” in 13 cases (20%). Resolution was reported as “unsure” in 10 cases and not reported for 1 case. Resolution after immunosuppressive therapy versus spontaneous remission was not captured. The mean time to AH resolution was 7.4 months (range 1–52 months). There were no reported deaths. The reporters affirmed that none of the 39 rFVIIa-treated cases suffered an adverse event (AE) or thromboembolic event (TE).

The AHS project provides additional information about the treatment of AH in the US, and reaffirms the safety of rFVIIa treatment in AH. The project was designed as a surveillance study to identify exposed patients and AE/TE event rates. Therefore, AHS lacks the detailed information available through traditional research registries at large centers, such as data on individual bleeds, treatment of individual bleeding episodes, and immunosuppressive treatments. AHS does provide an innovative approach for capturing basic safety surveillance data for patients with rare bleeding disorders seen in smaller hemophilia treatment centers and hematology/oncology practices.

Lentz:Novo Nordisk: Consultancy. Cooper:Novo Nordisk Inc.: Employment.