PPTA Comments on the IQWiG Rapid Report on Haemophilia Therapies

On October 11, 2012, the German Federal Ministry of Health (BMG) commissioned the Institute for Quality and Efficiency in Health Care (IQWiG) to assess the treatment of haemophilia patients through the production of a Health Technology Assessment (HTA) Rapid Report.

The report had three goals:

  1. Map the available body of evidence pertaining to the long-term factor treatment of patients with severe hemophilia A or B in terms of different treatment strategies, factor concentrates, dose regimens and prophylactic treatment regimens.

  2. Compare the long-term benefit of prophylactic treatment to on-demand treatment, both in terms of patient-relevant endpoints and based on controlled prospective studies.

  3. Investigate to what extent the current treatment guidelines and algorithms are based on this evidence.


It took almost three years for this report to be completed. IQWiG initiated the gathering of the clinical studies in May 2014 and then manufacturers were contacted to get an overview of their studies. The Report was completed on 28 May 2015. This shows that the time spent for production of analytics and their interpretation has been very limited.

In HTA language, "Rapid" means a truncated methodology, thus not covering all aspects of a full HTA assessment1. A comprehensive review of elements related to economic, ethical, organisational, social and legal domains is simply not part of such an evaluation, although they are very important in the context of haemophilia.

Another important limiting aspect of this review is the methodology that restricted the inclusion of clinical trials to randomized, controlled trials and to clearly prospective, non-randomized intervention trials with parallel control groups and a minimum total population of 50 patients.

With these limitations in mind, it was good news, but no surprise, to read that there is benefit of prophylaxis for children, adolescent and adults with severe haemophilia A. However the wording used by IQWiG is not the most emphatic to support their recommendations: “For adolescents and adults with severe haemophilia A there are hints of an additional benefit of prophylaxis for the endpoints of state of health and pain, and there is an indication of such additional benefit with regard to the endpoint of severe bleeds”.

For severe haemophilia B, considering the limitations of the methodology, no study was taken into account and no comparison of prophylactic versus on-demand treatment with factor IX in these patients was performed.

Thirteen guidelines and four treatment algorithms from German treatment centers specialized in haemophilia care were reviewed. The Report points out that most guidelines do not contradict the results of the benefit assessment. It is however striking to read that the same Report highlights that one guideline is a deviation as it principally recommends prophylactic treatment as the best treatment regimen for children!

The IQWiG report implies and indirectly suggests a need to conduct more RCTs between prophylaxis and on-demand treatments for haemophilia concentrates that have already been approved by regulatory agencies. As it has been clearly expressed in the December 2014 EHC Newsletter2, randomizing patients into a prophylaxis group and a “control” on-demand group will lead to permanent and progressive joint damage in the “control” group. PPTA is of the opinion that exposing persons with haemophilia unnecessarily to joint damage is a violation of ethical principles!

The same article2 reiterates that superiority of prophylaxis continues to be demonstrated and takes as an example a study comparing prophylaxis and on-demand regimens in haemophilia B3! Needless to say that this study did not pass the inclusion criteria for the IQWiG methodology.

One could ask if the IQWiG methodology was the most appropriate for assessing the treatment of haemophilia, considering the level of current knowledge and the specificities related to the low number of patients with haemophilia. The HTA assessments will probably need more customization in the future to assess rare diseases.

We hope that haemophilia patients in Germany will keep the most optimal access to care.

The English summary of the IQWiG rapid report can be found on the following link.

For more information, we refer also to the EHC comments that were published on the following link.


1. HTA Core Model for Rapid Relative Effectiveness Assessment of Pharmaceuticals: http://www.eunethta.eu/sites/5026.fedimbo.belgium.be/files/Model%20for%20Rapid%20REA%20of%20pharmaceuticals_final_20130311_reduced.pdf
2. EHC Newsletter December 2014, pp. 40-41: http://www.ehc.eu/ehc-newsletter-december-2014/
3. http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM415248.pdf