Assessment of Orphan Drugs: Standards need to remain achievable!

The IQWiG is one of the authorities conducting benefit assessments of approved drugs in Germany. In a recent article published in the British Medical Journal (Kranz et al. 2023), members of the IQWiG argue that the efficacy and benefit of drugs for rare diseases should be assessed by basically applying the same criteria as for drugs for common diseases. We strongly disagree with the arguments and conclusions put forward by the authors and question the validity of the presented analysis. Therefore, together with the German patient organisation for erythropoietic protoporphyria (EPP) we responded to the article with a letter to the editor, in which we outlined our concerns:

Barman-Aksözen, J.; Hauke, E.; Falchetto, R. (2023): Rapid Response: A rare disease patient perspective on the proposed changes of orphan drug regulations, BMJ 23 May 2023. (last accessed 18 June 2023)

One of the aspects we criticize is the proposed requirement to strictly measure efficacy and benefit of orphan drugs in randomized controlled clinical trials and by using generic (non-specific) and validated patient reported outcome measures and quality-of-life questionnaires. While such data can and should be generated in more common conditions, the situation is often more complex for rare diseases, in which the number of potential clinical trial participants (even when using worldwide registries for their recruitment) and the knowledge about the condition are limited and often no validated measures to quantify the treatment effects exist.

A simple search for publications listed in PubMed, a publicly accessible database for medical articles, illustrates why it would be inherently unfair to apply the same criteria when assessing drugs for common and rare diseases: While around 600‘000 articles can be found in PubMed for “diabetes mellitus”, the search for the ultra-rare condition “erythropoietic protoporphyria” currently only generates around 1‘000 hits (June 2023). Therefore, the research on diabetes mellitus already received roughly 600 times more research funding and opportunities to develop and validate patient reported outcome measures and quality-of-life questionnaires compared to EPP.

Patients with EPP have the same right to health care as patients with diabetes. Afamelanotide, the first safe and effective treatment for EPP, has been recommended for approval by the European Medicines Agency (EMA) in 2014 based on the acknowledged life-changing effects for the patients. However, because generic quality-of-life questionnaires are demonstrably not sensitive to the disease characteristics and treatment effects and the validation of the EPP-specific questionnaire was still ongoing during the clinical trials, national authorities all over Europe question the benefit the afamelanotide treatment provides. Surprisingly, data from the mandatory post-authorisation efficacy and safety study commissioned by the EMA and conducted in all EU countries using the now validated EPP quality-of-life questionnaire is usually not accepted for the benefit assessment, either.

The current orphan drug regulations were implemented with the aim of taking into account the disadvantages caused by the rarity of orphan conditions. Requests for changing the orphan drug regulations and for applying the same standards to the assessment of treatments for rare and common diseases need to be accompanied with feasible suggestions on how these inherent disadvantages can be compensated for within the proposed system: Patients with EPP cannot just wait until 600 times more funding has been allocated to their condition, they need access to the only existing approved treatment for EPP now! Standards which are not achievable discriminate against patients with rare diseases and might exclude them from the health care they need and are entitled to.

See also:

Kranz et a. (2023): Reforming EU and national orphan drug regulations to improve outcomes for patients with rare diseases. BMJ 2023; 381 doi: (Published 09 May 2023) Cite this as: BMJ 2023;381:e072796

Kranz et al. (2023): Reply to rapid response by Barman-Aksözen and colleagues. BMJ, 7 June 2023 (Last accessed 18 June 2023)