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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:

A rare disease patient perspective on the proposed changes of orphan drug regulations

Dear Editor

As patient advocates for the porphyrias, a group of rare inborn errors of metabolism, we disagree with the conclusions of Kranz et al., who question the benefit of orphan drug regulations. As a precondition for the recommendation for marketing authorisation of an orphan drug, the authors request “robust evidence” for a “real therapeutic benefit”, demonstrated in randomised controlled clinical trials (RCTs). While we agree with some of the general principles behind these requests, for example that suitable comparators should be chosen, we caution against an indiscriminate application of standards developed for common diseases in a rare disease context.

Firstly, what is the “real therapeutic benefit”? According to the authors, the benefit should be estimated by outcome measures relevant for the patient, i.e., “how a patient feels, functions, or survives.” With this definition in place, one would assume that it is the patients, or alternatively their caretakers or physicians, who can answer the question on whether a treatment provides a therapeutic benefit. In reality, patient involvement in most benefit assessment proceedings is still very limited, and sometimes does not even include patients with the disease, but a proxy patient representative. Moreover, for their evaluations most authorities assessing the benefit of treatments, such as the IQWiG in Germany, only accept outcomes originating from generic instruments such as general quality-of-life questionnaires. Disease-specific instruments more sensitive to the specific disease characteristics and treatment effects are usually not accepted, even when fully validated.

Secondly, the authors argue that in their assessment conducting RCTs is feasible for rare diseases in general and refer to their own analysis of 20 orphan drugs reimbursed in Germany. (1) However, most of the investigated drugs concern treatments for rare cancers. While “survival” is a straightforward assessment measure, the situation is more complex in most rare chronic conditions in which new, disease-specific endpoints need to be developed for conducting a clinical trial, especially when no previously approved therapies exist. In addition, of the 20 drugs analysed only 12 received orphan drug status, which in our view is not sufficient to challenge the progress enabled by orphan drug regulations.

The orphan drug “afamelanotide”, the first approved treatment with demonstrated efficacy for the ultra-rare (1/100,000) disease erythropoietic protoporphyria (EPP), illustrates the challenge (2): Because of the complexity of the condition, the EMA assessed RCTs as not suitable to measure the full benefit that afamelanotide provides. Therefore, during the drug’s approval proceedings the EMA involved patients in the discussions on its risks and benefits. (3;4) Patients under treatment consistently report a near-normalisation of all aspects of their lives, a benefit which can and has been quantified in a real-world setting and is supported by data continuously collected in disease-specific registries. (5-7) However, despite providing meaningful outcome measures, such as treatment adherence rates, these forms of evidence are usually not accepted for the benefit assessment in Germany. While afamelanotide is highly effective, its benefit has been assessed in Germany as “not quantifiable”, based on data collected in RCTs and with generic instruments.

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, and not improve outcomes for patients with rare diseases, as the authors claim, but rather compromise opportunities to address their unmet medical needs. To truly improve the outcomes for patients with rare diseases, we recommend to meaningfully involve them in the benefit assessment of orphan drugs and to accept forms of evidence relevant to them and the health care systems, such as real-world evidence.

(1) Institute for Quality and Efficiency in Health Care. Evidence on orphan drugs. 2021.
(2) EMA (2014): European Public Assessment Report (EPAR) Scenesse.
(3) EMA (2014): Press release.
(4) Falchetto R. The Patient Perspective: A Matter of Minutes. Patient. 2020 Feb;13(1):1-6. doi: 10.1007/s40271-019-00399-2. PMID: 31784882; PMCID: PMC6957536.
(5) Biolcati, G., Marchesini, E., Sorge, F., Barbieri, L., Schneider-Yin, X., & Minder, E. I. (2015). Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria. The British journal of dermatology, 172(6), 1601–1612.
(6) Wensink, D., Wagenmakers, M. A. E. M., Barman-Aksözen, J., Friesema, E. C. H., Wilson, J. H. P., van Rosmalen, J., & Langendonk, J. G. (2020). Association of Afamelanotide With Improved Outcomes in Patients With Erythropoietic Protoporphyria in Clinical Practice. JAMA dermatology, 156(5), 570–575.
(7) Barman-Aksözen, J., Minder, A. E., Granata, F., Pettersson, M., Dechant, C., Aksözen, M. H., & Falchetto, R. (2023). Quality-Adjusted Life Years in Erythropoietic Protoporphyria and Other Rare Diseases: A Patient-Initiated EQ-5D Feasibility Study. International journal of environmental research and public health, 20(7), 5296.

Competing interests: No competing interests

23 May 2023
Jasmin Barman-Aksözen
Elke Hauke, president Selbsthilfe EPP e.V., Germany and Rocco Falchetto, president International Porphyria Patient Network, Switzerland
International Porphyria Patient Network (IPPN)
Zurich, Switzerland