Towards Successful Implementation of Pharmacokinetic-Guided Prophylactic Dosing of Clotting Factor Concentrate in Hemophilia; The Do’s and Don’ts after Discrete Choice Experiment Analysis
Authors: Lock Janske , de Bekker-Grob Esther W. , Urhan Gamze , Middeldorp Saskia , Peters Marjolein , Meijer Karina , Tamminga Rienk Y.J. , Laros-van Gorkum Britta , Brons Paul , Van der Meer Felix J.M. , Driessens Mariette H.E. , Collins Peter W. , Fijnvandraat Karin , Leebeek Frank W.G. , Cnossen Marjon H. 
Published: October 2019

Abstract
Background:
Patients’, parents’ and providers’ preferences with regard to medical interventions may have a major impact on the implementation of innovations, often delaying initiation significantly. Illustratively, as early as 1997, Carlsson et al. suggested that a 30% reduction of consumption of clotting factor concentrate in prophylactic treatment could be attained by dosing based on an individual pharmacokinetic (PK) profile, with a concomitant cost reduction. Therefore, we aim to evaluate do’s and don’ts in hemophilia patients, parents and professionals with regard to individualized dosing according to PK-profile of prophylaxis with clotting factor concentrate. This in order to successfully implement this intervention when imperative.
Methods:
In this study we included patientswith hemophilia currently or previously on prophylactic treatment with clotting factor concentrate (n=114) and parents of patients aged 12-18 years (n=19) from five Dutch Academic Hemophilia Treatment Centers, and hemophilia professionals attending the World Federation of Haemophia congress 2012 from throughout the world (n=91). Data were analysed using a Discrete Choice Experiment. Patients’, parents’ and professionals’ preferences with regard to the intervention, are measured by specific attributes with varying levels: ‘number of blood samples necessary to construct individual PK-profile’, ‘advised frequency of prophylactic infusions’, ‘frequency of repetitive PK-profiling’, ‘risk of bleeding’, ‘estimated cost reduction of treatment with benefit for society’.
Results:
For patients and parents (response rate 64%), a higher dosing frequency e.g. daily dosing was an important barrier. They were however willing to infuse more frequently, if bleeding was consequently reduced. ‘Reduction of costs for society’ by implementation of individualized dosing according to PK profile was found relevant and motivating to implement PK-guided dosing. For professionals the most important attributes driving implementation were an acceptable ‘advised frequency of prophylactic infusions’ and reduction of ‘risk of bleeding’.
Conclusions:
When anticipating implementation of a medical intervention, defining of preferences of those involved is of importance. In case of PK-guided prophylactic dosing in hemophilia conclusions are: realise the impact of daily dosing of clotting factor concentrate, use frequent bleeding as a motivator to initiate PK-guided dosing and actively discuss costs of treatment with those undergoing treatment and the cost reduction that may result from PK-guided dosing. Identification of these preferences will secure successful implementation in the near future.

Disclosures
Lock: ZonMW: Research Funding; Baxter: Research Funding. Laros-van Gorkum:Sanquin: speakers fee Other; Baxter: Unrestricted educational grant was provided to the Hemophilia Treatment Center of the Radboud university medical center, Unrestricted educational grant was provided to the Hemophilia Treatment Center of the Radboud university medical center Other; CSL Behring: Unrestricted educational grant was provided to the Hemophilia Treatment Center of the Radboud university medical center, Unrestricted educational grant was provided to the Hemophilia Treatment Center of the Radboud university medical center Other. Driessens:Baxter: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Bayer Schering Pharma: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work, unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; CSL Behring: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work, unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Eurocept: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work, unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Novo Nordisk: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Pfizer: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other; Sanquin: unrestricted grant for meetings and educational courses with hemophilia patients and members of the Netherlands Hemophilia Patient Society, outside the submitted work Other. Fijnvandraat:Baxter: Member of the European Hemophilia Treatment and Standardisation Board sponsored by Baxter Other; CSL Behring: Research Funding; Pfizer: Has given lectures at educational symposiums organised by Pfizer, Has given lectures at educational symposiums organised by Pfizer Other, Research Funding; Bayer Schering Pharma: Has given lectures at educational symposiums organised by Bayer Schering Pharma, Has given lectures at educational symposiums organised by Bayer Schering Pharma Other, Research Funding. Leebeek:CSL Behring: has served on advisory boards of CSL Behring, outside the submitted work Other, Research Funding; Baxter: has served on advisory boards of Baxter, outside the submitted work, has served on advisory boards of Baxter, outside the submitted work Other. Cnossen:Pfizer: Educational funding Other, Research Funding; Bayer Schering Pharma: Educational funding and travel support, Educational funding and travel support Other, Research Funding; Baxter: Educational funding and travel support, Educational funding and travel support Other, Research Funding; Novo Nordisk: Educational funding, Educational funding Other, Research Funding; Novartis: Educational funding and travel support Other, Research Funding.