Forschung

Michael Schlander führte einen Großteil seiner Forschungsaktivitäten zu seltenen und sehr seltenen Erkrankungen sowie zum Zugang zu Therapien für seltene und komplexe Krankheiten gemeinsam mit seinem Team vom Institut für Innovation & Evaluation im Gesundheitswesen durch. [Die nachstehenden Inhalte stehen ausschliesslich in englischer Sprache zur Verfügung.]

Two major policy shifts are reshaping the current environment for orphan medicinal products (OMPs).

In Europe, the reformed pharmaceutical legislation (´EU pharma package´) replaces the OMP Regulation. It shortens standard orphan market exclusivity from ten to nine years, introduces (up to) eleven years for breakthrough orphans, and ends separate exclusivity periods for multiple orphan indications of the same active substance. It also ties incentives more closely to timely supply across all Member States (cf. European Parliament / Council of the EU and the European Council).

In the U.S., most-favored-nation (MFN) pricing links U.S. prices to those paid in other developed countries, most of them European. MFN agreements with manufacturers are now tied to tariff relief, though products with exclusively orphan-designated indications are treated separately in the tariff framework, and Congress has widened the orphan exclusion from Medicare price negotiation (cf. Most-Favored-Nation Prescription Drug Pricing Executive Order: Legal Issues).

These developments raise strategic questions for industry, payers and policymakers directly related to topics such as market launch sequencing and pricing, lifecycle strategy, health technology assessment (HTA), evidence generation and patient access.

Rare and ultra-rare diseases pose particular challenges for HTA, pricing and reimbursement: small and heterogeneous patient populations, limited comparative evidence and a lack of meaningful comparators. Building on earlier work on the economic evaluation of interventions for ultra-rare disorders (cf. Ultra-rare disorders (URD) evaluation consensus project), Michael Schlander contributes to current European and German policy discussions on how value assessment can be adapted to these conditions without compromising scientific standards, while simultaneously ensuring the best possible access for patients and sustainable financing.

This includes active participation in (health) policy initiatives and platforms at the national and EU levels, as well as contributions to panel discussions and workshops, and presentations at various international conferences, including, among others …

HLM4RARE
A strategic, mission-oriented platform designed to move beyond political alignment and drive coordinated, measurable delivery for rare and complex diseases across Europe.

Change4RARE
The initiative's goals are to bring together knowledge about rare diseases and to create opportunities for those affected.

European Health Forum Gastein 2026
An independent, non-partisan organization with the aim of providing a neutral and inclusive platform for the discussion and advancement of health, solidarity and equity in the EU and beyond.

Rare Dialogues 2026
Rare Days 2026 / Paris, France, 24-26 September 2026.

Furthermore, (current and past) research on rare diseases examines how health care systems can balance the economic evaluation of drugs with equitable access to treatment. It has been shown that expensive drugs for rare disorders rarely meet widely used cost-effectiveness benchmarks, and that strictly applying standard decision rules would leave patients with very rare conditions without access to effective therapy (cf. Ultra-rare disorders (URD) evaluation consensus project).

At the same time, public policies deliberately encourage orphan drug development, which points to a mismatch between conventional cost-effectiveness logic and societal preferences. To provide an empirical basis for the debate, the budget impact and cost drivers of orphan medicines were analyzed, reviewing studies from 11 countries and finding in German data that a doubling of prevalence is associated with a 43% decrease in annual treatment cost (cf. Schlander et al., 2015, 2017). Additional work related to the topic also covers how coverage decisions for rare disease treatments can be made legitimately, including a systematic exploration of decision-making processes using rare diseases and regenerative therapies as a case study. Another study explored the availability and delivery of EMA-approved orphan medicines for hereditary metabolic diseases across the MetabERN network (cf. Heard et al., 2020).

Some of the weaknesses and limitations of the currently prevailing paradigm in applied health economics, i.e., the calculation of incremental cost effectiveness ratios (ICERs) with quality-adjusted life years (QALYs) – as a purportedly universal and comprehensive measure of benefits for valuation, can be illuminated by exploring the issues that arise when this paradigm is applied in practice. One of the pertinent examples is the evaluation of treatments for rare and ultra-rare disorders using this paradigm.

A key underlying reason for the failure of many drugs for (ultra) rare diseases to meet proposed – and, in some jurisdictions, actually applied – standards for cost effectiveness (i.e., maximum cost per QALY benchmarks) is that manufacturers need to generate revenues that allow them to recoup the cost of research and development (R&D), which also include the costs of gaining regulatory approval, from a small number of patients during limited periods of market exclusivity. This challenge inevitably results in high acquisition costs for these products on a per patient basis – and often high costs per QALY gained. At the same time, the success of regulatory policies that have been adopted to encourage R&D of treatments for “orphan” disorders has prompted concerns among payers about the costs that might arise with an increasing number of expensive treatments for (ultra) rare disorders.

An international group of experts with different backgrounds identified a strong need for alternative health economic evaluation models (not only) for ultra rare diseases (URDs), supported by a comprehensive review of the literature on social preferences regarding the allocation of health care resources that indicated empirical support for several characteristics or "attributes" (beyond clinical effectiveness) of interventions. Furthermore, to address concerns by health care policy makers about potentially escalating costs due to drugs for URDs, a budget impact model was developed to predict the future health care expenses caused by treatments for URDs – and continuous monitoring of the budget impact as an input to rational policy making was recommended.

The URD Consensus Project was initiated to investigate how citizens value selected attributes of health care interventions, and how they weigh them against each other, to compare the valuation results obtained in the project with those based on the conventional logic of cost effectiveness, and, furthermore, to generate learnings and provide a basis for subsequent work, ultimately paving the way towards an exploration of international similarities and differences with regard to the valuation of the attributes tested, including an external validation of results by testing the agreement of respondents between their choices in the experimental setting, their policy implications, and their social preferences.

The Social Preferences for Health Care Interventions (SoPHI) Study Phase I was conducted in Switzerland – with the primary expectation to provide robust evidence on the social preferences of the Swiss population. The approach of the study was a willingness to pay (WTP) design using discrete choice experiment (DCE) methodology. WTP was estimated by introducing a cost attribute from the perspective of the members of mandatory health insurance (Obligatorische Krankenpflegeversicherung, OKP, in Switzerland), i.e., using as payment vehicle (or «cost attribute») the extra premium in exchange for a new intervention added to the package of services covered by OKP.
The list of attributes to be tested further comprised: severity of the initial health state (ex-ante, i.e., before intervention, reduced life expectancy and – separately – impaired health-related quality of life); clinical effectiveness (improvements of life expectancy and – separately – health-related quality of life as a result from adding the new intervention, compared to existing treatment options); age of patients (to capture the «fair innings» perspective); and prevalence of the disorder (or «rarity»), i.e., the number of persons benefitting from adding the new intervention. The experimental design assumed existence of a standard treatment for the condition in question; thus, the elicited preferences relate to an improvement of therapy, not to the existence of therapy in the absence of any other options.
Framing effects were assessed by way of randomization of respondents to one out of four subgroups, depending on the whether or not supplementary information was received on each of the following attributes: rarity – with a view towards the specific challenges posed by the evaluation of OMPs, respondents could be offered information and reflection about the potential implications on cost per patient treated of the fixed (i.e., largely volume-independent) cost for research, development, and certain infrastructure (1:1 randomization); and cost(s) – presented from a citizen’s perspective, i.e., as cost per member of a collectively financed health scheme (i.e., as an increase in mandatory insurance premiums); respondents could receive additional information on the implied incremental cost per patient treated (1:2 randomization).

The main survey consisted of three main parts – (1) an initial preference formation phase (PFP), (2) the DCE itself, and (3) supplementary general questions related to both experiment and respondent characteristics.

The DCE included a sample of 1,501 Swiss respondents in 2017 and assessed the relative importance of selected attributes of health care interventions, capturing social preferences from a citizens’ perspective using marginal compulsory health insurance premiums as the payment vehicle.
All attributes investigated in the SoPHI study had an impact on choice probability and citizens’ (or “social”) WTP. The variables with the highest impact on choice probability are change in remaining life years, quality of life, extra insurance premium per year, and age of patients (to some extent). The relatively small impact of prevalence translated into a profoundly increasing implied WTP per patient (and per life year gained) with decreasing prevalence (or rarity).
Study design, and hence our presented data, focused on the “rarity” attribute. Results should therefore not be interpreted as a comprehensive account of all relevant attributes. This also imposes limits on the precision of the quantitative information provided. In particular, Swiss SoPHI Study was not designed to capture initial severity of disease (i.e., the initial impairment of health in terms of reduced life expectancy and reduced quality of life), and / or urgency of an intervention as independent variables.
The observed impact of rarity on implied (or “social”) WTP per patient (and per life year gained, with or without quality adjustment) will need to be confirmed considering numerous aspects (e.g., Does the observed gradient by prevalence reflect true social preferences? Has there been a potential bias due to “insensitivity to size”?). Finally, a critical follow-up survey to investigate the sensitivity of citizens' WTP on size had to be put on hold, and it is planned to re-initiate the "sensitivity-to-size" study.

In SoPHI Study Phase II, the project shall be rolled out in further European jurisdictions. In general, SoPHI Study findings should support the legitimacy of decisions on fair limits made on behalf of the population covered. The assessment of international similarities and differences further promises important insights into the potential for future European harmonization and integration of HTA and appraisal processes.

Selected Publications:

1. Schlander, M., et al.: The Swiss Social Preferences for Health Care Interventions (“SoPHI”) Study – Briefing on Essential Study Insights & Policy Implications. IV Discussion Paper No. 35 / 2021, ISBN 978 3 941609 33 4
2. Heard, J.M., et al.: Availability, accessibility and delivery to patients of the 28 orphan medicines approved by the European Medicine Agency for hereditary metabolic diseases in the MetabERN network. Orphanet Journal of Rare Diseases (2020), DOI: 10.1186/s13023-019-1280-5
3. Wagner, M., et al.: Moving towards accountability for reasonableness: A systematic exploration of the features of legitimate healthcare coverage decision-making processes using rare diseases and regenerative therapies as a case study. International Journal of Health Policy and Management (2019). DOI: 10.15171/ijhpm.2019.24
4. Schlander, M., et al.: Budgetary Impact and Cost Drivers for Rare and Ultrarare Diseases. Value in Health (2017), DOI: 10.1016/j.jval.2017.10.015
5. Annemans, L., et al.: Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases. Orphanet Journal of Rare Diseases (2017). DOI_ 10.1186/s13023-017-0601-9
6. Schlander, M., et al.: Determining the value of medical technologies to treat ultra-rare disorders: a consensus statement. Journal of Market Access & Health Policy (2016). DOI: : 10.3402/jmahp.v4.33039
7. Schlander, M., et al.: Budget impact analysis of drugs for ultra-orphan non-oncological diseases in Europe. Expert Review of Pharmacoeconomics & Outcomes Research (2015). DOI: 10.1586/14737167.2015.965156
8. Schlander, M., et al.: Incremental cost per quality-adjusted life year gained? The need for alternative methods to evaluate medical interventions for ultra-rare disorders. Journal of Comparative Effectiveness Research (2014). DOI: 10.2217/cer.14.34