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. 2020 Dec 30;18(1):225.
doi: 10.3390/ijerph18010225.

Epidemiological Challenges in Rare Bleeding Disorders: FVIII Inhibitor Incidence in Haemophilia A Patients-A Known Issue of Unknown Origin

Christine Keipert  1 , Ursula Drechsel-Bäuerle  2 , Doris Oberle  2 , Mirco Müller-Olling  3 , Anneliese Hilger  3
Affiliations

Epidemiological Challenges in Rare Bleeding Disorders: FVIII Inhibitor Incidence in Haemophilia A Patients-A Known Issue of Unknown Origin

Christine Keipert et al. Int J Environ Res Public Health. .

Abstract

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.

Keywords: epidemiology; haemophilia A; inhibitor development; rare diseases.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Time relationship between coagulation factor VIII (FVIII) product approval and triggered regulatory procedures for investigating the inhibitor incidence. License dates of human plasma-derived FVIII products (pdFVIII) and recombinant FVIII products (rFVIII) with marketing authorisation valid in Germany according to [18] are shown in the lower and upper area above the timeline. Qualitative product description is also given in brackets. VWF: von Willebrand factor, sc: single-chain, BDD/BDtr: B-domain deleted/truncated, PEG: PEGylated, Fc: Fc fusion protein.
Figure 2
Figure 2
Flow of information from screening and inclusion process.
Figure 3
Figure 3
Relevant publications according to the parameters demanded in the ClinGL. A table of these 80 publications and the assessment process can be found in the Supplement to this paper (File S2).
Figure 4
Figure 4
Risk of overlap of individual studies—Studies evaluating a single factor concentrate are summarised under the name of the factor concentrate in blue boxes. Studies originating from registry data are presented in yellow boxes and prospective trials in pink boxes. The three remaining relevant studies following the parameters demanded in the ClinGL are shown in purple.
Figure 5
Figure 5
Previously untreated patients (PUP) studies—Number of patients, study start and study duration. Shown are 37 of the 38 publications (for one, the duration could not be found) with the number of recruited patients, the year of study start, and study duration. The publications and underlying data can be found in the Supplement to this paper (File S4).
Figure 6
Figure 6
Analysis results for high severity disease and any titre inhibitor patients of the 22 relevant studies: Forest plot (a), Basic statistics (b). p = plasma-derived; r1g = recombinant 1, generation full length; r2gfl = recombinant 2, generation full-length; r2gbd = recombinant 2, generation B domain deleted; 3gfl = recombinant 3, generation full-length; r3gbd = recombinant 3, generation B domain deleted; rg99 = recombinant not further specified.
Figure 6
Figure 6
Analysis results for high severity disease and any titre inhibitor patients of the 22 relevant studies: Forest plot (a), Basic statistics (b). p = plasma-derived; r1g = recombinant 1, generation full length; r2gfl = recombinant 2, generation full-length; r2gbd = recombinant 2, generation B domain deleted; 3gfl = recombinant 3, generation full-length; r3gbd = recombinant 3, generation B domain deleted; rg99 = recombinant not further specified.
Figure 7
Figure 7
Analysis results for high severity disease and high titre inhibitor patients of the three relevant studies that fulfil all parameters as demanded in the ClinGL: Forest plot (a), Basic statistics (b). p = plasma-derived; r recombinant; r1g = recombinant 1, generation full length; r2gfl = recombinant 2, generation full-length; r2gbd = recombinant 2, generation B domain deleted; 3gfl = recombinant 3, generation full-length; r3gbd = recombinant 3, generation B domain deleted; rg99 = recombinant not further specified.
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