Paul-Ehrlich-Institut

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Haemophilia A: Epidemiologic Challenges and Recommendations for the Future

02 / 2021

Researchers of the Paul-Ehrlich-Institut have analysed published studies on the efficacy of coagulation factor products for the treatment of haemophilia A from 1990 to 2018. The aim was to establish whether the study design and the performance of the study allow a joint evaluation of the data, and thus a comparison of the efficacy and safety between the different coagulation factor products. The team identified limitations of the study concepts and developed recommendations not only relevant for haemophilia A but also for other rare diseases. Int J. Environ. Res. Public Health reports on the research results in its online edition of 30 December 2020.

Data visualization (Source: Thodonal88 / Shutterstock.com)

Thanks to modern research, innovative medicines are constantly being developed over time to improve therapies, even if therapeutics are already available. At the same time, concepts of clinical trials are also changing. This presents a not to be underestimated challenge for translational research because, due to the evolution of efficacy studies over the past decades and the sometimes different parameters observed in this context, it is difficult to compare products authorised in the past with recently developed medicines from the efficacy point of view.

Haemophilia A (HA) is a rare X-chromosomal bleeding disorder caused by a mutation in the gene which codes for coagulation factor VIII (FVIII). In Europe, the severe form of HA is diagnosed in around 250 newborns annually. It is characterised by a very low residual activity of FVIII of less than one percent. These patients require treatment with exogeneous so-called plasma-derived FVIII (pdFVIII) purified from blood plasma or treatment with biotechnologically manufactured recombinant FVIII (rFVIII).

There is now a wide range of coagulation factor products authorised for treatment in Germany. Since the introduction of recombinant coagulation factors VIII products, there has been intense debate as to whether there is a difference in drug safety between recombinant and blood plasma derived factor products. In particular, this is studied with regard to the development of the inhibitors against coagulation factors. Around 30 percent of the previously untreated patients develop inhibitory antibodies (inhibitors) against FVIII in the course of the treatment.

The analysis performed by the expert team of Dr Christine Keipert and Dr Anneliese Hilger, head of Division Haematology and Transfusion Medicine in cooperation with researchers of Division Safety of Medicines and Medical Devices at the Paul-Ehrlich-Institut, addressed the key issues in comparing such studies over a long period of time. Problems addressed included epidemiological challenges and study distortions, possible overlaps of individual studies, and the further development of therapies and methods in the course of time. The analysis included 38 studies the results of which were published between 1990 and 2018. Only three studies were identified, which met the standards of the current clinical guideline.

"A problem for the evaluation is that for rare diseases, the number of patients that can be recruited in clinical studies is limited. For this reason, randomised clinical studies are a challenge for some products", explains Christine Keipert. Finding a sufficient number of patients required for a robust statistical analysis can take up a great deal of time. In the meantime, both laboratory standards and the knowledge of details of the disease can develop further, which may finally lead to results, which no longer meet the state of the art. Besides, additional parameters, which were not collected as part of the study can become relevant.

But how can this challenge, which is due to the rapid, scientific development, be overcome? One important possibility is the establishment of a network of well-managed patient registries. This would allow the monitoring and examination of those products, which are actually used in the respective patient groups. To achieve this, a well-planned collaboration between managers of registries as well as authorities together with the inclusion of patients as well as scientists, and a previous determination and definition of the regulatory measures would be necessary. Such a register is the German Haemophilia Registry (Deutsches Hämophilieregister, DHR) hosted by the Paul-Ehrlich-Institut. Another important finding is that dedicated collaboration between patients, physicians and regulatory experts is essential for optimal treatment, especially of rare diseases.

Original Publication

Keipert C, Drechsel-Bäuerle U, Oberle D, Müller-Olling M, Hilger A (2021): Epidemiological Challenges in Rare Bleeding Disorders: FVIII Inhibitor Incidence in Haemophilia A Patients - A Known Issue of Unknown Origin.
Int J Environ Res Public Health 18: 225.
Online-Abstract

Updated: 10.02.2021