Reforming EU and national orphan drug regulations to improve outcomes for patients with rare diseases
BMJ 2023; 381 doi: https://doi.org/10.1136/bmj-2022-072796 (Published 09 May 2023) Cite this as: BMJ 2023;381:e072796
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Dear Editor
We have read the rapid response by Kranz and colleagues (1) to our own rapid response (2) to their article (3) and would like to contribute a few additional considerations.
We share the authors’ opinion that we need research that leads to better, not just new, orphan drugs, and support their recommendations for clinical trials to include comparisons with standard of care and the use of disease registries to assess a drug’s benefit, keeping in mind that these might not be available for many rare diseases. However, we believe that the stringent requirements proposed by Kranz and colleagues would compromise the progress enabled by the EU Orphan Drug Regulation and make orphan drug development more expensive, time consuming and generally burdensome, causing lags in drugs access or loss of potentially life-changing and life-saving drugs because manufacturers would abandon or not even start drug development efforts under these disincentivizing conditions. While we are by no means championing lowering standards in drug development, we would welcome the adoption of standards which better meet the challenges posed by rare diseases.
The example of afamelanotide is a case in point: Kranz and colleagues write that our claim that afamelanotide is “highly effective” is unclear, and mention that in the 2016 German G-BA assessment none of the used outcomes had statistical significance as compared to placebo (1). This is exactly the issue: The data generated during the pivotal afamelanotide clinical trials, in the way assessed by regulatory and HTA bodies, did not reflect the true value of the treatment but the EMA farsightedly granted approval under exceptional circumstances, asking the manufacturer to create a disease registry and start collecting real-world evidence, hence enabling broader access to afamelanotide and leading to a better understanding of the drug’s value to patients over time. In our first response we have only mentioned the high treatment adherence, but much more has been generated to attest to afamelanotide’s high efficacy. For example, new effectiveness endpoints have been developed such as the time spent outdoors used in the mandatory post-authorisation safety and efficacy study (PASS) commissioned by the EMA (4), time until onset of symptoms, i.e., sunlight tolerance (5,6), and effects on circadian rhythm and sleeping patterns objectively measured with a mechanical device attached to the patients’ and control individuals' wrists (7). All of these additional ways to measure the effectiveness of the afamelanotide treatment showed statistically significant results in favor of afamelanotide. Yet, and although the endpoints measured in the PASS are accepted by the EMA, incomprehensibly these studies are not accepted for the benefit assessment in Germany and by other relevant national authorities. These incoherences highlight how afamelanotide is a case in point: Had the stringent requirements proposed by Kranz and colleagues been applied, the drug would have never become available and many patients with EPP would still languish in the dark, suffering from their condition with no help in sight.
We believe that there are more patient-centric alternatives to what Kranz and colleagues are proposing to address both the pricing issue and the generation of better evidence based on real-world experience as a way to let patients express how they “feel, function, or survive”, and we urge all healthcare stakeholders to go beyond a tokenistic inclusion of the patient perspective in decision-making concerning their health. We know best about our diseases, which outcomes matter most to us, and how we “feel, function, or survive” with a new treatment and how to assess that. As Falchetto already pointed out in 2020 (8), surrogate decision makers should not have the authority to override patient perspectives. Our value judgements ought to be given utmost priority.
(1) Kranz et al. (2023): Reply to rapid response by Barman-Aksözen and colleagues. BMJ, 7 June 2023
https://www.bmj.com/content/381/bmj-2022-072796/rapid-responses(Last accessed 18 June 2023)
(2) 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. https://www.bmj.com/content/381/bmj-2022-072796/rapid-responses (last accessed 18 June 2023)
(3) Kranz et al. (2023): Reforming EU and national orphan drug regulations to improve outcomes for patients with rare diseases. BMJ 2023; 381 doi: https://doi.org/10.1136/bmj-2022-072796 (Published 09 May 2023) Cite this as: BMJ 2023;381:e072796 (auf Englisch)
(4) Wensink, D. et al. (2020): Association of Afamelanotide With Improved Outcomes in Patients With Erythropoietic Protoporphyria in Clinical Practice. JAMA dermatology, 156(5), 570–575. https://doi.org/10.1001/jamadermatol.2020.0352
(5) Barman-Aksözen J. et al. (2020): Increased phototoxic burn tolerance time and quality of life in patients with erythropoietic protoporphyria treated with afamelanotide – a three years observational study. Orphanet J Rare Dis. 2020 Aug 18;15(1):213. Doi: 10.1186/s13023-020-01505-6. PMID: 32811524; PMCID: PMC7437008.
(6) Wensink, D. et al. (2021): Erythropoietic protoporphyria: time to prodrome, the warning signal to exit sun exposure without pain-a patient-reported outcome efficacy measure. Genetics in medicine : official journal of the American College of Medical Genetics, 23(9), 1616–1623. https://doi.org/10.1038/s41436-021-01176-z
(7) Wensink, D. et al. (2022): Objective light exposure measurements and circadian rhythm in patients with erythropoietic protoporphyria: A case-control study. Molecular genetics and metabolism, 135(3), 215–220. https://doi.org/10.1016/j.ymgme.2021.12.017
(8) Falchetto, R. The Patient Perspective: A Matter of Minutes. Patient 13, 1–6 (2020). https://doi.org/10.1007/s40271-019-00399-2
Competing interests: No competing interests
Dear Editor
Kranz et al. claim that the “superior therapeutic benefit attributed to orphan drugs is often not supported by evidence from clinical trials” and furthermore propose reforms of the orphan drug regulations to remedy the situation.
In response to the points they raised, we would like to clarify some aspects of the EU orphan drug regulation, which aims to encourage the development of medicines for the approximately 30 million patients living with a rare disease in the EU.
First, the authors’ statement that orphan drugs “have risen sharply” does not take into account an impact assessment which concluded that there are still no good treatment options for 95% of rare diseases in the EU.1 Orphan designation provides incentives for the clinical development of orphan medicines, which face particular challenges in view of the small number of patients and heterogeneity of the natural course of the diseases.
Second, “superior therapeutic benefit” is not a legally established criterion in the EU orphan drug regulation.2 The regulation refers instead to “significant benefit” (defined as a “clinically relevant advantage or major contribution to patient care”), which is only required when treatments are already available or authorised for the rare condition and therapeutic indication concerned.3 Currently, approximately a quarter of orphan medicines granted marketing authorisations are the first medicines authorised for their respective conditions.4
Significant benefit can be based either on the entire population suffering from the condition or a particular population subset or a subset that is resistant to the existing treatments.2,3,5 Providing salvage treatment or covering patient subsets not benefitting from existing treatments (e.g. patients with certain molecular subtypes or disease stages) is therefore understood as justifying a significant benefit.5,6 Such improvements in clinical care cannot be equated with therapeutic or clinical superiority, which Kranz et al. use interchangeably with significant benefit.
Third, the authors call for robust evidence of superiority. Putting aside the fact that superiority per se is not legally required, the authors seem to confuse the timing of the assessments of significant benefit. Significant benefit is assessed initially at the time of orphan designation, typically early in development (when assumptions are allowed in the absence of robust data), and then again at the time of marketing authorisation.2 At the time of marketing authorisation, developers must show sufficient proof of significant benefit to maintain the orphan status for the approved therapeutic indication. In the absence of a requirement to justify significant benefit, the designation may be maintained on the basis of the rarity and the severity of the underlying conditions (the other two legally binding criteria).
Fourth, to illustrate the dearth of evidence the authors cite the use of intermediate or surrogate primary endpoints, the lack of a control arm and lack of randomisation in studies supporting the authorisation of some orphan medicines. However, the authors themselves recognise that conducting “adequately powered RCTs can be challenging” for rare diseases and note that there are situations where exceptions would be justified. Currently, approximately two thirds of orphan marketing authorisations are based on randomised controlled trials and the data submitted are considered comprehensive.4
Finally, we agree with the authors’ view that we need the strongest possible evidence to support clinical use of authorised orphan medicines and recognise the need for evidence generation throughout the life cycle of medicines, especially in the setting of rare diseases.
EMA and its scientific committees will continue striving to facilitate the generation of robust data in close cooperation with the EU regulatory network, including health technology assessment (HTA) bodies and the European Commission.
Sincerely,
Kristina Larsson, Frauke Naumann-Winter, Violeta Stoyanova-Beninska and Armando Magrelli
References
1. EC. Orphan medicinal products [Available from: https://health.ec.europa.eu/medicinal-products/orphan-medicinal-products_en accessed 6 June 2023.
2. EMA. Legal framework: orphan designation [Available from: https://www.ema.europa.eu/en/human-regulatory/overview/orphan-designatio... accessed 6 June 2023.
3. Sheean ME, Naumann-Winter F, Capovilla G, et al. Defining Satisfactory Methods of Treatment in Rare Diseases When Evaluating Significant Benefit-The EU Regulator's Perspective. Front Med (Lausanne) 2021;8:744625. doi: 10.3389/fmed.2021.744625
4. Naumann-Winter F, Wolter F, Hermes U, et al. Licensing of Orphan Medicinal Products-Use of Real-World Data and Other External Data on Efficacy Aspects in Marketing Authorization Applications Concluded at the European Medicines Agency Between 2019 and 2021. Front Pharmacol 2022;13:920336. doi: 10.3389/fphar.2022.920336
5. Tsigkos S, Mariz S, Sheean ME, et al. Regulatory Standards in Orphan Medicinal Product Designation in the EU. Front Med (Lausanne) 2021;8:698534. doi: 10.3389/fmed.2021.698534
6. Vreman RA, de Ruijter AS, Zawada A, et al. Assessment of significant benefit for orphan medicinal products by European regulators may support subsequent relative effectiveness assessments by health technology assessment organizations. Drug Discov Today 2020;25(7):1223-31. doi: 10.1016/j.drudis.2020.04.012
Competing interests: No competing interests
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.
References:
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: https://www.iqwig.de/en/projects/a19-65.html.
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: https://www.iqwig.de/en/projects/a20-114.html.
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: https://www.g-ba.de/downloads/39-261-2674/2016-08-04_AM-RL-XII_Afamelano....
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
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.
References:
(1) Institute for Quality and Efficiency in Health Care. Evidence on orphan drugs. 2021. https://www.iqwig.de/download/ga21-01_evidence-on-orphan-drugs_working-p...
(2) EMA (2014): European Public Assessment Report (EPAR) Scenesse. https://www.ema.europa.eu/en/documents/assessment-report/scenesse-epar-p...
(3) EMA (2014): Press release. https://www.ema.europa.eu/en/news/scenesse-recommended-rare-disease-caus...
(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. https://doi.org/10.1111/bjd.13598
(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. https://doi.org/10.1001
(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. https://doi.org/10.3390/ijerph20075296
Competing interests: No competing interests
Reply to rapid response by Larsson and colleagues
Dear Editor,
The response by Larsson and colleagues [1] (from the European Medicines Agency (EMA) / the Committee for Orphan Medicinal Products (COMP)) to our article [2] confirms several unresolved problems in orphan drug research:
Lack of appropriate randomised controlled trials (RCTs):
As Larsson and colleagues note, approximately two-thirds of orphan marketing authorisations (MAs) in rare diseases are based on RCTs. This figure confirms our findings that RCTs are in principle largely feasible. However, it also points to an excessive waste of resources. As we mention in our article, the trials currently conducted often lack comparisons with the standard of care and are therefore mostly unsuitable for informing clinical decision making. Precisely because it can be difficult to conduct RCTs in rare diseases, the aim should be to maximise the knowledge gained for patient care. RCTs conducted for MA purposes should therefore also generate evidence appropriate for the healthcare context.
Unjustified superiority labels:
We use the term “superior therapeutic benefit” as an umbrella term to cover superiority labels granted at the EU and national level (the “significant benefit” label used by the EMA and the “added benefit” label used by German health technology assessment). Whether or not this term is a “legally established criterion” in the EU Orphan Drug Regulation is of minor relevance and misses the point: the consequences of superiority labels resulting from the granting of orphan drug status, namely, negative effects on health policy and clinical decision-making.
Regarding “the fact that superiority per se is not legally required”[ 1]: The absence of a legal requirement does not mean that the current situation is satisfactory. “The mission of the EMA is to foster scientific excellence in the evaluation and supervision of medicines, for the benefit of public and animal health in the EU” [3]. This may include changing legal requirements to improve health care. Proof of superiority must be a prerequisite for a superiority label.
Larsson and colleagues also state that “Providing salvage treatment or covering patient subsets not benefitting from existing treatments …is therefore understood as justifying a significant benefit. Such improvements in clinical care cannot be equated with therapeutic or clinical superiority…” [1]. However, the conclusion that a new drug improves clinical care / shows a significant benefit can only be drawn based on a comparison with the current standard of care, which includes best supportive care (BSC) in indications or subgroups without existing treatments.
Unmet medical needs:
Larsson and colleagues further mention that “Currently, approximately a quarter of orphan medicines granted MAs are the first medicines authorised for their respective condition” [1]. This means that that three quarters of orphan medicines granted MAs are approved for therapeutic indications with existing treatment options, indicating a lack of research in indications with no treatment options. We also address this point in our article “… clustering of products is observable in some areas, while in others, research and development is wholly absent, leaving high unmet needs.” [2].
In summary, we appreciate that the EMA agrees “that we need the strongest possible evidence to support clinical use of authorised orphan medicines…” [1]. However, the MA context is very different from the healthcare context (“authorised” does not automatically mean “better”, e.g. better treatment outcomes or fewer side effects than the standard of care, e.g. existing drugs or BSC).
The EMA only operates within the MA context – extrapolating positive MA decisions to the healthcare context may be misleading. Instead, a common interest should exist in recognising the MA context limitations and the need to either design studies to cover the healthcare context or, at the latest, to generate the evidence required in parallel to the assessment of MA studies.
References
1 Kristina M Larsson, Frauke Naumann Winter, Violeta Stoyanova-Beninska, Armando Magrelli. Rapid Response: Re: Reforming EU and national orphan drug regulations to improve outcomes for patients with rare diseases. BMJ 2023.
2 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.
3 European Medicines Agency. What we do. https://www.ema.europa.eu/en/about-us/what-we-do (accessed 19 July 2023).
Competing interests: No competing interests