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
08 August 2023
Philip Kranz
researcher
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)
Rapid Response:
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