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.

There is a broad range of factor products approved in Germany for haemophilia A treatment. Since the introduction of recombinant coagulation factor VIII (FVIII) products in the 1990s, there has been substantial debate whether there is a difference in inhibitor incidence between single FVIII products or product classes. Neither haemophilia registries nor clinical studies, including a randomised controlled clinical trial, provided a consistent and definite answer. The reasons were mainly related to methodological challenges in conducting controlled studies in a rare disease. In this analysis, the most relevant epidemiological challenges and main problems were examined, including study bias, potential overlap of individual studies and advanced development of therapy and methods in the course of time. Meta-analyses on two levels showed that therapies using recombinant products resulted in different event rates when compared to plasma-derived products. These results are accompanied by substantial study heterogeneity evidenced by Cochran’s Q tests. Only three studies have been identified that meet the standards of current clinical guidance. To finally resolve this ongoing and disputable safety issue of replacement therapy, collaboration among registry owners, academia and regulators must be fostered.

Due to the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, clinical trial (CT) research for efficacy and safety evaluation of convalescent plasma (CP) accelerated globally. In trial planning and approval, clinical researcher and regulatory agencies worldwide are challenged by limited evidence from the use of convalescent plasma in previous outbreaks of viral diseases and by different possible study approaches. We analyzed CT designs to identify potential opportunities for data aggregation and to facilitate generation of decision-relevant evidence.CP therapy has a long-standing history in the post-exposure prophylaxis and treatment of infectious diseases, including outbreaks of various respiratory infections, such as the 2002-2004 severe acute respiratory syndrome-coronavirus (SARS-CoV) pandemic, the 2009 H1N1 influenza virus pandemic, and the 2012 Middle East respiratory syndrome coronavirus (MERS-CoV) epidemic. Unfortunately, evidence of its efficacy from rigorously controlled CTs is still limited. 1 The number of CTs evaluating CP therapy in patients suffering from coronavirus disease has rapidly grown in response to the COVID-19 pandemic in the absence of a vaccine and a specific antiviral therapy. Over 140 CP-CTs have been registered by a COVID-19 specific CT database. 2 Different study concepts and designs are required for a comprehensive evaluation of the quality, efficacy, and safety aspects of CP therapy. The