Rare Disease Blogs

Public meeting of the advisory committee at the office of the Dutch Healthcare Insurance Board (CVZ) d.d. September 21, 2012

Argument of the Academic Medical Center in response to the preliminary advice from the Dutch Healthcare Insurance Board (CVZ) to stop reimbursement of Fabrazyme and Replagal

I appreciate the opportunity to reflect the view of the AMC.
We disagree with the CVZ to discontinue reimbursement of enzyme replacement therapy (ERT; agalsidase alfa and agalsidase beta) for Fabry disease in the Netherlands.
First of all, as treating physicians, we consider it unacceptable to stop therapy in patients who have been treated for years and have shown benefits of ERT. The preliminary advice suggests that for patients on treatment a transition plan should be developed, which implicates that newly identified patient cannot start therapy. This is unacceptable as well, especially for those patients that we consider as having a high chance of responding favourably. The report by the Committee of Pharmaceutical Help (CFH) has concluded that there is an added value of ERT above standard therapy. To deny further reimbursement means that this decision is primarily based upon the high costs in relation to the relatively moderate effectiveness. The main problem here is that the effectiveness is different for subgroups of patients. A patient with end-stage renal or cardiac disease will profit less, or not at all, from therapy. With the disease model that we developed, we have performed several scenario analyses and we have shown that indeed subgroups exist that apparently profit less or more from ERT. Unfortunately, we had to make a lot of assumptions, simply because the number of patients in the Netherlands is too small. We also established that generation of antibodies impacts negatively on the biochemical response of patients. We are convinced that this translates to decline in clinical effects as well. Again, numbers of data are too small to draw firm conclusions. We disagree with the CVZ that it is unclear how much extra research is needed: we have already written a new study proposal that we can carry out with other EU centers. We strongly advocate, as we have done previously, that international collaboration is stimulated to solve these issues.

With respect to cost-effectiveness: also after more extensive research, the price per QALY will remain unfavourable. But this was already known at the start of the investigations: quality of life in a chronic progressive condition such as Fabry disease will not suddenly improve. You could calculate on the back of a napkin that at drug costs of 200.000 euro’s per year the price per QALY will easily increase to several millions. We did not need 4 years of research to come to that conclusion. Instead what is needed is a better discussion how effectiveness of these treatments can be assessed earlier and better, what society is willing to pay for orphan drugs and whether traditional HTA methodology is suitable to evaluate orphan drugs. If it is decided to preclude ERT from healthcare insurance for all Fabry patients in the Netherlands, then CVZ gives the message that in view of all these uncertainties, we better decide to stop all reimbursements. This would be a tragic mistake.

My advice to the CVZ is to regard these uncertainties as a stimulus to improve the system: create a new temporary regulation, which allows further international research. The Netherlands can fulfil a role here, as we have done in the past years for Fabry disease. Leave the opportunity open to start therapy in new patients. Start discussions with the pharmaceutical industry, but not only about the price. Challenge them also about the lack of initiatives to improve the existing ERT including the problems with antibody formation. Stimulate an international discussion concerning price setting for orphan drugs within the EU and methods for evaluation. There are already several initiatives in this respect as outlined by Yann le Cam, which should be taken into consideration.

Which brings me to the last more general point: the inefficient evaluation of long-term effectiveness of orphan drugs. This has everything to do with the fact that orphan medicinal products enter the market while clinical effectiveness has not yet been proven. The EMA frequently approves such a product on the basis of preliminary data (or surrogate endpoints) and long-term evaluation is left to the pharmaceutical companies. Every EU member state then invents their own reimbursement regulation, usually also with the aim to control costs. This scenario leads exactly to what is happening today in the Netherlands: on the basis of insufficient data patients are being denied to continue their therapy. In conclusion: in reponse to the open questions that remain let’s not decide now to stop reimbursement, but to open the discussions how we can improve evaluations, pricing and regulations in the future.

Carla E.M. Hollak, internist
Professor of Inherited Metabolic Diseases in Adults
Department of Endocrinology and Metabolism, F5-170
Academic Medical Center
PO Box 22660
1100 DD Amsterdam
tel. +31-20-5666071
fax: +31-20-6917682
e-mail: c.e.hollak@amc.uva.nl

Related reading include the blog posts by patient advocate Cees Smit.  Part I, Part II, Part III, Part IV