Innovative Haemophilia Treatment - Paul-Ehrlich-Institut develops a better Standard for Efficacy Assessment

13 / 2020

New Therapeutics for persons with haemophilia are under development. The Paul-Ehrlich-Institut has undertaken a scientific analysis of efficacy assessment. It turned out that the definitions for bleeding as well as bleeding rates in clinical trials of different haemophilia therapeutics deviated strongly from each other. This has led to a systematic distortion of the results. Based on this, the expert team of the Paul-Ehrlich-Institut deduced recommendations enabling a reliable assessment, also in other blood coagulation disorders (see Clinical and Translational Science, Online-edition of 30 May 2020).

Data Mining Visualization (Source: Sompong Rattanakunchon/Moment/GettyImages)

The therapeutic spectrum for haemophilia patients is growing: now biomedicines such as modified coagulation factors, antibody-based therapies and gene therapeutics are under development and on the road towards marketing authorisation. An important prerequisite for the assessment of safety and efficacy of new therapeutics and thus, for a reliable risk/benefit assessment are suitable parameters for measuring valid treatment results in the clinical trials.

The efficacy of established coagulation factor preparations is defined by determining the factor levels in the blood in connection with the course of the disease. However, this method can often not be used to assess the new, innovative therapeutics, since they intervene in other sections of the coagulation cascade. The Annualised Bleeding Rate (ABR) of the patient is being increasingly used as a clinical endpoint to assess the efficacy.

Researchers from the Division "Haematology/Transfusion Medicine" of the Paul-Ehrlich-Institut have now studied whether the methods for determining the Annualised Bleeding Rate differ for various products and product classes. They analysed the extent of these differences and their consequences for the evaluation of the products. The Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines is the competent authority for the safety of blood and blood products and for innovative therapeutics such as cell and gene therapeutics in Germany. Based on the institute‘s regulatory tasks in the development and marketing authorisation of haemophilia products, the institute has access to extensive clinical data. The researchers collected and structured these study data in an internal databank to analyse bleeding rates. In addition, they examined clinical study protocols for methodological difference in the ABR determination and in the definition of bleeding events.

Dr Christine Keipert, Dr Mirco Müller-Olling and other experts from the division of Dr Anneliese Hilger were able to show that the definitions of bleeding events and the ABR observation periods in clinical studies differed significantly. In early observation periods, individual bleeding rates of prophylactically treated patients varied by around 40 percent (p<0.01). This alone leads to a significant reduction in the ABR group mean by 20 percent (p<0.05), depending on the observation period. The analyses show that heterogeneous definitions of bleeding events and rates lead to a systematic distortion, which impairs the comparison of different treatment options.

The expert team of the Paul-Ehrlich-Institut has formulated recommendations to avoid these distortions and to allow a reliable benefit assessment based on efficacy data. This includes the use of standardised bleeding definitions as well as the supervision of bleeding episodes by a doctor. In addition, an observation period should last at least twelve months, and the statistical models should be carefully assessed. "This recommendation and others will permit a more reliable assessment of the efficacy of different therapeutics, not only in haemophilia, but also in other blood coagulation disorders," as Dr Anneliese Hilger, head of the Division "Haematology/Transfusion Medicine" explained. She calls on the developers of haemophilia products to implement this recommendation.

Original Publication

Keipert C, Müller-Olling M, Gauly F, Arras-Reiter C, Hilger A (2020): Annual Bleeding Rates: Pitfalls of Clinical Trial Outcomes in Hemophilia Patients.
Clin Transl Sci May 30 [Epub ahead of print].

Updated: 01.07.2020