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Rapid response to:


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

Rapid Response:

Reply to rapid response by Barman-Aksözen and colleagues

Dear Editor,
We read with interest the response to our article by Barman-Aksözen and colleagues [1].

Consideration of the patient perspective in HTA:
We concur on the principle that drug assessment (at each level) would benefit from more patient-centred measures of benefit, provided they are valid and robust. Whenever available, the German Institute for Quality and Efficiency in Health Care (IQWiG) considers them: For instance, its benefit assessments are based on patient-relevant outcomes, including those reported by patients. In addition, patients or patient representatives are regularly directly involved in the HTA process.

Acceptance of disease-specific instruments by IQWiG:
Barman-Aksözen and colleagues claim that IQWiG usually does not accept disease-specific instruments [1]. In fact, such instruments are regularly accepted if they have been validated in the specific indication and the data collected are of sufficient quality. Examples accepted in rare diseases include the Cystic Fibrosis Questionnaire-Revised for cystic fibrosis [2] as well as the Hammersmith-Infant-Neurological-Examination-Subscale 2 and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders for spinal muscular atrophy [3].

Type of outcomes and study design used:
IQWiG regularly considers disease-specific outcomes (symptoms, morbidity) investigated in studies. We are open to new developments, but they must truly reflect how a patient "feels, functions, or survives" [4]. Regarding the feasibility of randomised controlled trials (RCTs) in non-oncological diseases, in our analysis, the proportion of RCTs was markedly higher in these indications than in oncological indications (about 75% vs. 50%).

Small sample size :
We mainly focused on the 20 drugs that initially were granted orphan drug status by the European Medicines Agency at approval and were later subjected to regular HTA in Germany. However, we also analysed the 69 orphan drugs in 97 indications that did not undergo regular HTA. In 78% (n=76) of these indications, the Federal Joint Committee (G BA) assigned only a non-quantifiable benefit, which is an indicator of a lack of added benefit due to insufficient data. The problem, therefore, extends far beyond the orphan drugs in our sample.

Example of afamelanotide:
Afamelanotide has not yet been assessed by IQWiG in a regular benefit assessment, as annual sales are below €30 million. Irrespective of this, the evidence supporting the claim by Barman-Aksözen and colleagues that it is "highly effective" [1] is unclear. They only mention one specific outcome to support this claim ("treatment adherence rates" [1]), but no outcomes related to how a patient "feels, functions, survives" [4]. Various disease-specific outcomes were used in the G BA assessment, but for the vast majority, no statistically significant differences were found versus placebo (phototoxic episodes and pain in phototoxic episodes, disease-specific quality of life) [5].

Methodological standards for benefit assessments:
Barman-Aksözen and colleagues state that "applying standards for the benefit assessment developed in common diseases without the appropriate adjustments will make the development and authorisation of new orphan drugs virtually impossible…" [1]. We specifically address this point in our article: To overcome the issue of small sizes, we propose several methodological adjustments to evidence generation, including the use of randomised data from rare disease registries [6]. Unnecessarily lowering established standards of assessment disincentivises the generation of robust evidence in rare diseases and does not solve the current problems.

The problems in rare disease research are not caused by the HTA agencies assessing the evidence – they are just the bearers of bad news – but by the quality deficits of the underlying studies, which are often not comparative and/or do not consider important disease-specific outcomes. The main key to change is to improve the evidence, not to worsen the assessment standards – this is what our analysis article aims to highlight. We therefore need research that leads to better, not just new, orphan drugs.

1 Jasmin Barman-Aksözen, Elke Hauke, Rocco Falchetto. Rapid Response: A rare disease patient perspective on the proposed changes of orphan drug regulations, . BMJ 2023
2 Institute for Quality and Efficiency in Health Care. Ivacaftor (cystic fibrosis, 6 years and older, with G551D mutation) - Benefit assessment according to §35a Social Code Book V.2019. Available from:
3 Institute for Quality and Efficiency in Health Care. Nusinersen (spinal muscular atrophy) - Benefit assessment according to §35a Social Code Book V.2021. Available from:
4 Kranz P, McGauran N, Banzi R, Ünal C, Lotz F, Kaiser T. Reforming EU and national orphan drug regulations to improve outcomes for patients with rare diseases. BMJ 2023;381:e072796. doi: 10.1136/bmj-2022-072796
5 Gemeinsamer Bundesausschuss. Beschlüsse über die Nutzenbewertung von Arzneimitteln mit neuen Wirkstoffen nach § 35a SGB V – Afamelanotid.2016. Available from:
6 Mordenti M, Boarini M, D'Alessandro F, Pedrini E, Locatelli M, Sangiorgi L. Remodeling an existing rare disease registry to be used in regulatory context: Lessons learned and recommendations. Front Pharmacol 2022;13:966081. doi: 10.3389/fphar.2022.966081

Competing interests: No competing interests

07 June 2023
Philip Kranz
Natalie McGauran (IQWiG), Rita Banzi (Mario Negri Institute for Pharmacological Research), Can Ünal (IQWiG), Fabian Lotz (IQWiG), Thomas Kaiser (IQWiG)
Institute for Quality and Efficiency in Health Care (IQWiG)
Im Mediapark 8, D-50670 Cologne, Germany