Assessing options for treating haemophilia with inhibitors

Substitution of the missing factor through infusion of concentrates remains the mainstay of the treatment of haemophilia. For the past 20 years, the transmission of infectious disease through contaminated plasma products has been virtually eliminated through the incorporation of dedicated pathogen reduction steps in their manufacture, although their continued use in low resource countries still poses a significant threat in these areas 1. The historically established risk of inhibitor formation following replacement therapy has assumed increased visibility as the infectious disease risk has receded and now constitutes the major hazard of haemophilia treatment in those countries able to provide it for their patient communities. As pressures on health care costs increase payers in such countries are scrutinizing, increasingly, the cost of haemophilia care, which, with the improved survival and quality of life afforded by modern treatment, continues to rise 2. This scrutiny has included the use of Health Technology Assessment (HTA) to assist an understanding of which treatment modalities are most effective clinically and best value for money for payers. We have commented previously on the use and limitations of HTA in assessing therapies for rare chronic disorders 3. Quantitative Decision Modelling (QDM) as a tool to contribute to HTA in haemophilia has been used extensively in important clinical questions such as the choice between prophylaxis and on-demand therapy 4, 5 and also in analysing the relative cost-effectiveness of alternative approaches to the treatment of inhibitors to Factor VIII in haemophilia A 6.

Two papers in this issue of Haemophilia now augment the recent evaluation of Bahaipour and Carlssen 6. Earnshaw et al. 7 use a cost utility analysis to assess the relative cost-effectiveness of Immune Tolerance Induction (ITI) and prophylactic or on-demand treatment for bleeds, for haemophilia A patients with inhibitors in the USA. Villarrubia et al. 8use similar methodology to compare on-demand and prophylactic treatment with different products, for inhibitor patients in Spain. While these studies make useful contributions to the literature on the subject, there are aspects within their analyses which accentuate the customary difficulties in performing this kind of work in the haemophilia context. Earnshaw et al.'s choice of non-inhibitor patients for sourcing the utility measurements for Quality Adjusted Life Year (QALY) estimation may be challenged given the availability of these metrics for patients with inhibitors 9, while their extraction of data from the Joint Outcome Study 9 as the sole source of bleeding events may have been enhanced through the additional use, possibly through a meta-analysis, of the other trials published subsequently 10, 11. We will comment further on such an approach below. Earnshaw et al. also adopt a very conservative policy in discounting the benefits accruable over life for the different treatments, given that HTA agencies such as the United Kingdom's national Institute for Clinical Excellence (NICE) permit a more liberal approach for treatments such as ITI which lead to a lifelong benefit 12. In Villarrubia et al.'s paper, a very short time horizon is chosen, presumably because the authors did not attempt to examine the effect of a lifelong “cure” for inhibitors in the form of ITI; nevertheless given the long-term benefits of prophylaxis, including rare morbidities such as intra-cranial haemorrhage (ICH) whose probability increases with age 13, a longer horizon would have been preferable. Villarrubia et al.'s decision to limit their analysis to treatment options on the basis of the high cost of ITI is also questionable, not just on the basis of Earnshaw et al.'s study but also through other work derived from clinical experience 14.

The literature on QDM for haemophilia, exemplified by these two papers, seeks primarily to justify the costs of haemophilia treatment to policy makers used to employing these methods to assist their decisions. As such, some of these studies, including our own previous work 5, are, perhaps unconsciously, challenging some of the basic principles of health care, such as the tenet that prevention is better than cure, by seeking to justify interventions such as prophylaxis and ITI. Unquestionably, these analyses would not be performed if factor costs were not as high as they have been historically. In addition, in an era when personalized treatment for haemophilia is being increasingly advocated 15, the inherent assumptions in these analyses include uniformity in the therapeutic products, a presumption denied by the therapeutics industry as well as by the marketing approval authorities, as well as in the treated patients themselves. In a question such as that posed by Villarrubia et al.'s analysis, where two specific products are being compared with, in this instance, individually assigned indications (FEIBA for prophylactic treatment and Factor VIIa for on-demand treatment), the former problem does not arise, but we note that Earnshaw and Villarrubia come to different conclusions with Earnshaw finding on-demand therapy more cost-effective than prophylaxis, as opposed to Villarrubia's conclusions. This mirrors the brisk controversy around this issue in other studies 16, and may be the result of the different time horizon used in these two papers. Further refinement of such models, incorporating the kind of clinical algorithms for inhibitor patients proposed by Young et al. 17 may resolve these differences, as well as resonating to the differences in patient characteristics and responses which are basically ignored in most QDMs.

The assertion by Earnshaw et al. that all products are equivalent for the purposes of ITI may bear some scrutiny. Several reviews 18, 19 have supported this assertion, but we note that Earnshaw et al.'s protocol for secondary (“rescue”) ITI includes the option of using concentrates containing Factor VIII complexed to von-Willebrand factor (VWF). A recent systematic review and meta-analysis 20 assessed the effect of VWF on inhibitor eradication in patients with severe haemophilia A but failed to demonstrate an association between product type and ITI outcome, although the heterogeneity observed by the authors among different studies might reflect differences in the response to different products. Thus, considering this background and also that the final results of the randomized controlled RESIST study 21, which could contribute to clarify this controversial issue, are still awaited, we concur with the most recent Cochrane Review on ITI 20 that “The choice of immune tolerance induction regimen should be considered individually for each case, until further research provides additional evidence”. We would suggest that this principle should be embedded in all aspects of haemophilia treatment.

To summarize, these studies and other QDMs applied to haemophilia have contributed to a heightened awareness of the funding issues around this rare, chronic disease and its complications. As the field has evolved, so have the financial pressures and the interest of HTA authorities in, e.g. Sweden 22 and Germany 23 attest to this. Clearly, the major driver of costs in haemophilia continues to be the price of factor concentrates, as demonstrated by the different pharmaco-economic outcomes in for scenarios such as prophylaxis different countries 5. We point out the substantial variation in prices elicited in countries with similar health care and economic infrastructure, noting that, e.g. funders in the United Kingdom 24 and Australia 25 acquiring factor products at prices substantially lower than the countries specified above. It may be that it is in the study of this discrepancy, rather than in the generation of more QDMs, that the future funding of haemophilia therapies lies.

Disclosures

Albert Farrugia has provided contractual services to a trade association representing manufacturers of haemophilia treatment products described in this article. Cedric Hermans has received honoraria as a paid lecturer and board member from Baxter and Novo Nordisk in the previous 36 months. No other conflicts have been found.