Annual Bleeding Rates: Pitfalls of Clinical Trial Outcomes in Hemophilia Patients

Abstract

Emerging treatment options for hemophilia, including gene therapy, modified factor products, antibody-based products, and other nonreplacement therapies, are in development or on their way to marketing authorization. For proof of efficacy, annual bleeding rates (ABRs) have become an increasingly important endpoint in hemophilia trials. We hypothesized that ABR analyses differ substantially between and within medicinal product classes and that the ABR observation period constitutes a major bias. For ABR characterization, an internal factor VIII (FVIII) treatment database has been built based on confidential clinical trial data submitted to the Paul-Ehrlich-Institut (PEI). Furthermore, anonymized data from 46 trial protocols submitted for review to the PEI were analyzed (FVIII replacement, n = 27; antibody-based, n = 12; and gene therapy, n = 7) for methodology. Definitions of bleeding episodes and ABR observational periods differed substantially in clinical trials. In the initial observation phase, individual ABRs of patients, treated prophylactically for 1 year, vary by about 40% (P < 0.001), which finally led to a significant reduction of the ABR group mean by 20% (P < 0.05). Furthermore, the high variance in ABRs constitutes a major challenge in statistical analyses. In conclusion, considerable heterogeneity and bias in the ABR estimation in clinical trials was identified, which makes it substantially more difficult to compare the efficacy of different treatment regimens and products. Thus, awareness of the important pitfalls when using ABR as a clinical outcome is needed in the evaluation of hemophilia therapies for patients, physicians, regulators, and health technology assessment agencies. www.cts-journal.com Annual Bleeding Rates in Hemophilia Patients Keipert et al.

Indirect Treatment Comparison of Damoctocog Alfa Pegol versus Turoctocog Alfa Pegol as Prophylactic Treatment in Patients with Hemophilia A

“…According to the previous MAICs, 9 ABR (considered the most clinically meaningful efficacy endpoint 16 ) and percentages of patients with zero bleeds were similar were similar comparing BAY 94-9027 with rFVIIIFc, BAX 855, and rAHF-PFM. (Appendix Table 1).…”

Untreated bleeds in people with hemophilia A in a noninterventional study and intrapatient comparison after initiating emicizumab in HAVEN 1–3

“…Collecting data on these untreated bleeds is therefore clinically important; however, many clinical studies document only treated bleeds. 5 In this study, the BMQ allowed participants to capture bleeds and bleed‐related treatment independently, providing granular information on the relative incidence of treated and untreated bleeds. This allows a more comprehensive and informative evaluation of therapies.…”

“…[2][3][4] Annualized bleeding rate (ABR) is often used as the primary end point in clinical trials because the frequency and cumulative occurrence of bleeds is strongly correlated with long-term joint function. 3 However, data collection on bleeds is often connected with treatment in clinical studies, 5 potentially resulting in underestimated ABRs if only treated bleeds are documented, with untreated bleeds remaining unrecorded. When bleeding rates among adults/ adolescents with hemophilia A (with or without FVIII inhibitors) and children with FVIII inhibitors were investigated in an observational, noninterventional study (NIS), [6][7][8] the Bleed and Medication Questionnaire (BMQ), which requires patients to record bleeds independent of treatment, was implemented to facilitate prospective data collection on both untreated and treated bleeds.…”

Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review

“…We hypothesized that many subjects from this study had long-term inhibitors, and, by definition, had severe arthropathy, which is something to keep in mind for physicians. The ABR of treated joint bleeds was also explored because treated joint bleeds are generally better defined, reducing misclassification [43][44][45][46]. In the E max model of treated joint bleeds, the effectiveness plateau was reached at even lower concentrations of 20 µg/mL.…”

“…Subjective assessments, combined with follow-up periods of < 12 months and small study sizes, may have affected the calculated ABRs. Moreover, clinically unstable disease leads to numerous (spontaneous) bleeds, especially in the first weeks of emicizumab treatment, leading to overestimation of ABRs in shorter studies [43][44][45][46]. Recently, the analysis of pooled bleeding data from HAVEN 1−4 reported ABRs maintaining < 1 in 24-week intervals and an increase in the proportion of PwHA without treated bleeds from 70.8% in the first 6 months to 80.2% after 1 year of emicizumab treatment [52].…”