Postauthorization safety surveillance of ADVATE [antihaemophilic factor (recombinant), plasma/albumin‐free method] demonstrates efficacy, safety and low‐risk for immunogenicity in routine clinical practice

Oldenburg, Johannes; Goudemand, Jenny; Valentino, Leonard A.; Richards, Michael; Luu, Huong; Kriukov, Alexander Y.; Gajek, Hartwig; Spotts, Gerald; Ewenstein, Bruce M.

doi:10.1111/j.1365-2516.2010.02332.x

Cited by 32 publications

(36 citation statements)

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“…Seven were formal pivotal prospective studies in support of product licensure: six of them multinational trials and one a multicenter study in China [3][4][5][6][7][8][9][10][11][12][13]. Six were prospective multinational pharmacosurveillance studies [14][15][16][17][18][19]. Five were prospective multicenter pharmacosurveillance studies in Germany [20,21] and Japan [22][23][24].…”

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confidence: 99%

Best evidence on B‐domain deletion and the immunogenicity of recombinant factor VIII

Aledort

Navickis²,

Wilkes³

2011

Journal of Thrombosis and Haemostasis

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To cite this article: Aledort LM, Navickis RJ, Wilkes MM. Best evidence on B-domain deletion and the immunogenicity of recombinant factor VIII. J Thromb Haemost 2011; 9: 2325-7.See also Aledort LM, Navickis RJ, Wilkes MM. Can B-domain deletion alter the immunogenicity of recombinant factor VIII? A meta-analysis of prospective clinical studies. This issue, pp 2180-92; Mannucci PM. Factor VIII inhibitors in previously treated hemophilic patients. This issue, pp 2328-9.Development of inhibitors to factor VIII (FVIII) is recognized as the most serious complication of hemophilia A therapy. Attendant morbidity risk, quality of life impairment and treatment costs are high. Accordingly, the assessment of potentially avoidable risk factors such as use of more highly immunogenic FVIII products remains a high priority. Timely evaluation of accumulating evidence on such risk factors is essential, and meta-analysis can serve as a valuable tool in this endeavor.In our meta-analysis of 29 prospective clinical studies with over 3000 previously treated patients [1], de novo inhibitors of any titer were seven times as frequent after exposure to Bdomain-deleted recombinant FVIII (BDD-rFVIII) as fulllength recombinant FVIII (FL-rFVIII). High-titer de novo inhibitors (> 5 Bethesda units) were 11 times as frequent. These differences were highly statistically significant. The robustness of these observations is supported by several methodological features of the meta-analysis, as outlined in our paper. First, only prospective clinical studies were included. Second, Cox regression was employed to account fully for length of follow-up. Third, intent-to-treat analyses were performed. Lastly, sensitivity analyses were used to rule out confounding by other variables.We nevertheless urged caution in interpreting our results, chiefly because the included studies predominantly involved single cohorts with no control group. However, while limitations of our meta-analysis should be recognized, they should not be exaggerated, as have Iorio and colleagues in their commentary [2]. They wrongly contend that most of the included studies were Ôretrospective assessments of prospectively collected case recordsÕ. In fact, nearly all the included studies were clearly well-designed and rigorously conducted prospective investigations. As indicated in our paper, the suppliers of the evaluated recombinant FVIII (rFVIII) products were direct participants and/or sponsors for at least 79% of the studies. Seven were formal pivotal prospective studies in support of product licensure: six of them multinational trials and one a multicenter study in China [3][4][5][6][7][8][9][10][11][12][13]. Six were prospective multinational pharmacosurveillance studies [14][15][16][17][18][19]. Five were prospective multicenter pharmacosurveillance studies in Germany [20,21] and Japan [22][23][24]. rFVIII efficacy and safety were the subject of three multicenter studies in Italy [25], Japan [26] and Taiwan [27] and a single-center study in the Netherlands [28]. Five studies were...

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confidence: 99%

Best evidence on B‐domain deletion and the immunogenicity of recombinant factor VIII

Aledort

Navickis²,

Wilkes³

2011

Journal of Thrombosis and Haemostasis

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“…For this case, we reanalyzed the same cohort already published by Oldenburg et al32 We used this case to explore and discuss the basics of the Bayesian approach and the pros and cons of choosing different priors.…”

Section: Methodsmentioning

confidence: 99%

“…The individual data sets used to build our cases for illustration purposes32–34 were from the ADVATE post-authorization safety studies (PASS) program. The study population in PASS studies were hemophilia A patients undergoing treatment (prophylaxis or on-demand) with ADVATE in routine clinical use.…”

Section: Methodsmentioning

confidence: 99%

“…The primary safety outcome in these studies is defined as inhibitor levels during the study period including de novo, recurrent, and persistent inhibitors. We adopted the cutoffs of inhibitor classification specified in the original PASS protocols: 1.0 Bethesda unit (BU) for US, EU, and Australian PASS; and 0.6 BU for Japan, Italian, Korean, and Taiwan PASS (studies adopting the Nijmegen modification) 32,33. More detailed description of the data such as hemophilia severity and FVIII exposure history and the case-specific definitions of inhibitors are presented in Table 3.…”

Section: Methodsmentioning

confidence: 99%

“…By using real clinically observed data from the recently published articles,32–34 we aimed to demonstrate the benefits or advantages of Bayesian approach in estimating the risk of developing inhibitors among patients with hemophilia A from the following aspects: increasing the credibility of the results and the understanding of the underlying mechanisms by incorporating external evidence; generating probabilities to be used in a physician-to-patient interaction.…”

Section: Introductionmentioning

confidence: 99%

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Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study

Cheng

Iorio

Marcucci

et al. 2016

JBM

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BackgroundDeveloping inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information.MethodsWe built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs) or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population – patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A) post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1) or random-effects (Case 2 and Case 3) logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical significant inhibitor (10/100, 5/100 [high rates], and 1/86 [the Food and Drug Administration mandated cutoff rate in PTPs]) were calculated. The effect of discounting prior information or scaling up the study data was evaluated.ResultsResults based on noninformative priors were similar to the classical approach. Using priors from PTPs lowered the point estimate and narrowed the 95% credible intervals (Case 1: from 1.3 [0.5, 2.7] to 0.8 [0.5, 1.1]; Case 2: from 1.9 [0.6, 6.0] to 0.8 [0.5, 1.1]; Case 3: 2.3 [0.5, 6.8] to 0.7 [0.5, 1.1]). All probabilities of satisfying a threshold of 1/86 were above 0.65. Increasing the number of patients by two and ten times substantially narrowed the credible intervals for the single cohort study (1.4 [0.7, 2.3] and 1.4 [1.1, 1.8], respectively). Increasing the number of studies by two and ten times for the multiple study scenarios (Case 2: 1.9 [0.6, 4.0] and 1.9 [1.5, 2.6]; Case 3: 2.4 [0.9, 5.0] and 2.6 [1.9, 3.5], respectively) had a similar effect.ConclusionBayesian approach as a robust, transparent, and reproducible analytic method can be efficiently used to estimate the inhibitor rate of hemophilia A in complex clinical settings.

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Products Used to Treat Hemophilia: Recombinant Products

Yoshioka

2014

Textbook of Hemophilia

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Postauthorization safety surveillance of ADVATE [antihaemophilic factor (recombinant), plasma/albumin‐free method] demonstrates efficacy, safety and low‐risk for immunogenicity in routine clinical practice

Cited by 32 publications

References 52 publications

Best evidence on B‐domain deletion and the immunogenicity of recombinant factor VIII

Best evidence on B‐domain deletion and the immunogenicity of recombinant factor VIII

Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study

Products Used to Treat Hemophilia: Recombinant Products

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