When Does “Access” Become “Established” in Rare Diseases?

With a history in high-cost oncology therapies, the use of managed entry agreements (MEAs) or managed access agreements (MAAs), particularly performance-based MEAs, is increasing in rare diseases.1,2 This is no surprise considering the high degree of uncertainty typically associated with high-price orphan and ultra-orphan products. Excitingly, we are now seeing rare disease products completing their MAAs with the National Institute for Health and Care Excellence (NICE), such as elosulfase alfa in mucopolysaccharidosis type IVA,3 and multiple products under NICE MAAs within the same disease area, such as spinal muscular atrophy (SMA).4-6 Furthermore, the proposals for the Innovative Medicines Fund in the UK alongside the proposed methods and process changes for NICE suggests this approach to managing uncertainty is here to stay.

At this year’s ISPOR Europe, my colleague Naomi van Hest raised the question of how established clinical management should be defined in this era of managed access and what this means for comparator selection in health technology assessment (HTA). Her issue panellists, Jacoline Bouvy (Technical Director for NICE Scientific Advice), Gérard De Pouvourville (Professor of Economics, ESSEC Business School) and Mark Sculpher (Director, Centre for Health Economics University of York) led us through the exclusive approach of NICE, the inclusive approach of the French HTA agency Haute Autorité de Santé (HAS) and the fundamental principles that should be applied when selecting comparators. The panel agreed that discrepancies between systems matter less than failure to offer timely guidance and access, noting that each country should make the “appropriate choice” for that system.

The added challenge in rare diseases, however, is what comparator(s) to select when very little is “established” in clinical practice. Often clinical management will be highly heterogeneous and involve off-label treatment(s). Critically, best practice can change rapidly when a new treatment option that addresses a high unmet need becomes available; with so few patients urgently needing new targeted treatments, a treatment available through a MAA can quickly become the dominant therapy in a rare indication and almost completely displace other products, off-label or otherwise, that were used previously.

With respect to off-label comparators, NICE’s view is that they may be included as comparators if they are “considered to be part of established clinical practice for the indication in the NHS”.7 However, NICE excludes technologies that are only available under a MAA as they are “not considered standard care”.8 Is this a justified difference or an inconsistency worth addressing? In both cases, the potential comparator may have little evidence supporting clinical outcomes in the indication in question, and therefore a high degree of uncertainty. Perhaps another point of similarity between off-label products and those undergoing a MAA is the uncertainty of access. The use of off-label treatments remains at physician discretion in the UK with access therefore often remaining far from routine, whilst a product undergoing a MAA does not have funding for routine commissioning guaranteed. That being said, the price is likely to be far higher for a product undergoing a MAA, which perhaps justifies a different approach.


Considering how quickly the landscape can shift in rare diseases, should we be open to the inclusion of products under MAAs that have quickly become “established”? In doing so, aligning our approach closer to that of off-label products. Or is the branding of “established” too contentious in these cases i.e. does inclusion of that product as a comparator mistakenly pre-empt a positive recommendation? It will be interesting to revisit this as we see more orphan and ultra-orphan products exiting MAAs and learn more about the likelihood of achieving routine commissioning via this route.

For me, in the context of rare diseases, intuitively a more inclusive system seems to better capture the most up-to-date comparator decision needing to be made by the payers, and therefore representing the choice facing patients and clinicians at that point in time. In my mind, the inclusion of MAA comparators could bring us closer to the aim, as outlined by NICE,9 of creating a more flexible and rapid system. The option of including MAA comparators in rare indications could enable decisions that may better reflect the reality of the opportunity costs of our decisions. However, the blanket application of such approach would inevitably increase complexity and burden for the NICE system, running the risk of decisions needing to be re-evaluated when MAA products fail to achieve reimbursement. Perhaps the answer lies in our definition of “established” in the context of rare diseases, and how the time taken to achieve “established” status compares to our realistic rate of re-appraisal.


  1. Morel T, Arickx F, Befrits G et al. Reconciling Uncertainty of Costs and Outcomes with the Need for Access to Orphan Medicinal Products: A Comparative Study of Managed Entry Agreements across Seven European Countries. Orphanet J Rare Dis. 2013;8:198.
  2. Wenzl M, Chapman S. Performance-Based Managed Entry Agreements for New Medicines in Oecd Countries and Eu Member States. 2019.
  3. Stevens B, Kenny T, Thomas S et al. Elosulfase Alfa in the Treatment of Mucopolysaccharidosis Type Iva: Insights from the First Managed Access Agreement. Orphanet J Rare Dis. 2021;16(1):394.
  4. National Institute for Health and Care Excellence (NICE). Nusinersen for Treating Spinal Muscular Atrophy. Technology Appraisal Guidance [Ta588]. 2019. Available here. Last accessed: 14.01.2022.
  5. National Institute for Health and Care Excellence (NICE). Risdiplam for Treating Spinal Muscular Atrophy. Technology Appraisal Guidance [Ta755]. 2021. Available here. Last accessed: 14.01.2022.
  6. National Institute for Health and Care Excellence (NICE). Onasemnogene Abeparvovec for Treating Spinal Muscular Atrophy. Highly Specialised Technologies Guidance [Hst15]. 2021. Available here. Last accessed: 14.01.2022.
  7. National Institute for Health and Care Excellence (NICE). Guide to the Methods of Technology Appraisal 2013. 2013. Available here. Last accessed: 14.01.2022.
  8. National Institute for Health and Care Excellence (NICE). Nice Health Technology Evaluations: The Draft Manual. 2021. Available here. Last accessed: 14.01.2022.
  9. National Institute for Health and Care Excellence (NICE). Nice Strategy 2021 to 2026. 2021. Available here. Last accessed: 14.01.2022.

If you would like any further information on the themes presented above, please do not hesitate to contact Annabel Griffiths, Global Head of Rare Diseases (LinkedIn) or Naomi van Hest, UK Head of Health Economics and Statistics (LinkedIn). Annabel and Naomi are employees at Costello Medical. The views/opinions expressed are their own and do not necessarily reflect those of Costello Medical’s clients/affiliated partners.