The Authors Respond

We thank Preblick et al. for their comments on our article. rVIII-SingleChain has been developed with an improved pharmacokinetic and pharmacodynamic profile compared with standard-acting recombinant FVIII (rFVIII) products¹; this allows for a less frequent dosing regimen compared with standard-acting rFVIII, similar to regimens achievable with other long-acting products. Long-acting products are generally considered to include all the newer rFVIII products with improved pharmacokinetics, compared with standard-acting products, and rVIII-SingleChain has been described as such.^2,3

Given the very limited eligible/available patient pool on each product and the practicality of comparing multiple products across multiple centers, 1:1 and propensity score matching are not possible. We adopted a practical, sequential-like sampling method by completing data collection for the product with the smallest patient pool first and then aiming to obtain charts for patients with similar age and disease severity distributions treated with the other products, in order to achieve comparability across products. As Preblick et al. pointed out, we used the consumption measure normalized by weight (IU/kg/week) and further included weight in the ANCOVA models (in case of any potential effect not known on the normalized consumption); therefore, the effect of weight is already adequately adjusted. In fact, there were studies that suggested a negative association between body mass index and dosing, or using ideal body weight instead of actual body weight in dosing.^4,5 While it is not clear whether this translates to a negative correlation between weight and normalized consumption, we have not found literature indicating the contrary.

While we recognize that additional variables may affect treatment outcomes, there are many challenges to obtain them from patient charts because of frequently missing or incomplete information. Patients may have been using their product for years, and getting accurate previous treatment data may not be feasible. History of inhibitor status is sometimes unknown. Treatment patterns can vary by center, and in practice, it is not possible to account for center effects due to greatly varied product usage across centers. Finally, the existence of arthropathy could be a previous condition or an outcome of current treatment; therefore, it is difficult to standardize. Because of such data quality issues, including these variables can be problematic.

Dosing frequencies vary greatly across products, so the only unbiased estimate for consumption of a product is the overall across all dosing frequencies, as presented in Table 3. We also compared consumption for the 2 times per week and 3 times per week groups because they had the highest patient numbers and were also the only dosing frequencies used across all 3 products. In ANCOVAs for annualized bleeding rates, we included consumption as a covariate, which is statistically more efficient than comparing arbitrarily defined consumption strata.

Because rVIII-SingleChain became available in 2016, we were able to collect previous treatment information for all 40 patients on the product. However, previous treatment data are typically more challenging to collect for products that have a longer history (6 products were included in the study, and a second manuscript describing all 6 is forthcoming). Moreover, because of the heterogeneity in previous treatments, comparing results of switch analyses across products is very difficult.

As with all observational studies, there were limitations in our study, which we acknowledged in the article. It is important and necessary to understand real-world usage of new products outside of the clinical trial setting, and we believe that the data presented in our study successfully accomplished this.