Dolon Publications

Exploring the economics of gene therapy innovation and price

Amanda Whittal, Esther Idicula, Adam Hutchings
January 2022

Gene therapies are revolutionising the treatment of severe conditions, offering previously unattainable advances in health gains. Simultaneously, this therapeutic potential is matched by concerns around price and affordability. Are these fears reflective of reality? To address this question requires an…

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Addressing unmet needs in extremely rare and paediatric-onset diseases: how the biopharmaceutical innovation model can help identify current issues and find potential solutions

Emilie Neez, Arianna Gentillini, Adam Hutchings
July 2021

Although the Orphan and Paediatric Regulations have been successful at stimulating innovation in these previously underserved areas, significant unmet medical needs remain. EFPIA held in May 2021 a workshop, which gathered Senior staff from member company R&D, Clinical, Strategy, and…

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How did we get here and where do we go now? An economist’s perspective on EU orphan drug policy

Adam Hutchings
February 2021

The divergence between the rapid pace of scientific progress in rare diseases and declining sentiment towards orphan medicines reflects a paradox that is at the heart of the European orphan drug debate. While the last twenty years have witnessed a…

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Estimated impact of EU Orphan Regulation on incentives for innovation

Emilie Neez, Arianna Gentillini, Richard Dutton, Adam Hutchings
October 2020

The European Commission is currently reviewing the 2000 Regulation on orphan medicinal products (OMP). It is critical that any consideration of reform of the Regulation should be informed by a robust understanding of the relationship between incentives, investment, innovation and…

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A review of the challenges and proposals for improving patient access to advanced therapeutic medicinal products in 10 EU countries

RARE IMPACT Working Group
January 2020

Gene and cell therapies represent some of the most advanced treatments being employed in biomedical research to improve the length and quality of life of patients with rare and complex diseases. Patients’ access to these therapies has been hampered by…

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External Publications Co-authored by Dolon Staff

Double bad luck: Should rare diseases get special treatment?

January 2022
Adam Hutchings

A thought-provoking and well-written article by Monica Magalhaes (Should rare diseases get special treatment?) proposes that prevalence should be irrelevant to policy for rare disease treatments, and any incentives for development of these medicines should be based instead on severity. This commentary reflects on Magalhaes’ arguments and suggests why they may not fully reflect reality, based on current practice and evidence. It then brings forward the counter perspective that it is essential to consider prevalence, as focusing on severity alone creates the exact situation of neglect for effective rare disease treatment development that we are seeking to avoid. Journal of Medical Ethics 48(2) 99–100 (2022). View
Faciliating More Efficient Negotiations for Innovative Therapies: A Value-Based Negotiation Framework

March 2022
Amanda Whittal, Claudio Jommi, Gérard De Pouvourville, David Taylor, Lieven Annemans, Lies Schoonaert, Sebastian Vermeersch, Adam Hutchings, and Julien Patris

Innovative therapies carry significant promise for patients. At the same time, delays in access frequently arise due to differences in manufacturer and payer perspectives regarding the potential impact of a new product, and concerns around affordability and/or evidential uncertainties. How can such concerns be effectively managed to accelerate access to promising therapies? Managed entry agreements (MEAs) are a possible approach, but lengthy negotiation processes can further delay access and do not balance effectiveness with implementation burden. This paper introduces a value-based negotiation framework to support faster, more structured MEA negotiations for innovative therapies. View
Consideration of quality of life in the health technology assessments of rare disease treatments

September 2021
Elena Nicod, Michela Meregaglia, Amanda Whittal, Sheela Upadhyaya, Karen Facey, Michael Drummond

Using patient-reported outcome (PRO) data for rare diseases is challenging because of the small populations and lack of disease knowledge, yet it can provide invaluable understanding about the impact on quality of life (QoL) of these severe diseases when assessing new treatments. To better incorporate QoL into Health Technology Assessment, a clearer understanding of the challenges faced by PRO evidence and health state utility values (HSUVs) in rare diseases is required. Document analysis of NICE appraisal reports of non-oncology treatments with EMA orphan designation was conducted, as well as corresponding output from the Netherlands, France and Germany. Overall, findings suggest that a large proportion of the PRO evidence and HSUVs appraised are either not considered during HTA, or provide inconclusive and uncertain outcomes. Results suggest that lack of QoL evidence doesn’t mean no benefit in QoL. To overcome this, the authors emphasise that patient and clinical expert input are key to help interpret and complement this uncertain and incomplete QoL evidence, and for improved development of QoL evidence. View
Implementing Outcomes‐Based Managed Entry Agreements for Rare Disease Treatments: Nusinersen and Tisagenlecleucel

July 2021
Karen M. Facey, Jaime Espin, Emma Kent, Angèl Link, Elena Nicod, Aisling O’Leary, Entela Xoxi, Inneke van de Vijver, Anna Zaremba, Tatyana Benisheva, Andrius Vagoras, Sheela Upadhyaya

Outcomes-based managed entry agreements (OBMEAs) have gained renewed interest as a potential solution to managing uncertainties surrounding innovative treatments for rare diseases, which have high therapeutic potential but significant uncertainties in clinical evidence. To investigate how OBMEAs are being implemented for innovative therapies, this paper reviewed their application in the case of two orphan medicines (nusinersen and tisagenlecleucel), using data from HTA/payer/academic experts in Europe, Australia and Canada. The findings demonstrate that OBMEAs could play an important role in reimbursement and treatment optimization of rare disease treatments. At the same time, due to the complexities and administrative burden of implementation, it is not recommended that such agreements should become the standard approach. Download
HTA Appraisal Framework Suitable for Rare Disease Treatments

May 2021
K Facey, A Whittal, M Drummond, S Upadhyaya, T Junghans, E Nicod

Clinical- or cost-effectiveness- based HTA appraisals of rare disease treatments (RDTs) are often challenging due to small patient populations, uncontrolled trials and limited disease knowledge. Following consultation with HTA leaders from various country pricing and reimbursement (P&R) systems, this paper seeks to overcome these difficulties by developing recommendations for a RDT appraisal process that extends beyond traditional economic evaluations to better capture RDT specificities. The resulting IMPACT HTA Appraisal Framework, based on the tenets of leniency, flexibility and consistency, offers detailed guidance for HTA’ bodies to conduct fair and consistent evaluations of RDTs.

Examining the impact of different country processes for appraising rare disease treatments: a case study analysis

March 2021
Amanda Whittal, Elena Nicod, Mike Drummond, Karen Facey

Conventional appraisal approaches are often unsuitable for rare disease treatments (RDTs) due to the nature of rare conditions, which makes it more difficult to generate evidence that meets the standards of HTA bodies. The objective of this case study analysis was to examine the impacts of various types of appraisal processes on two contrasting RDTs, nusinersen and vortigene neparvovec, by systematically comparing them. Appraisals from nine selected countries were divided into separate process and adapted process categories, and reviewed for their impact on the selected treatments. Both separate and adapted approaches were found to potentially facilitate more structured, consistent decision-making and better management of RDT specificities. Download
The Use of Patient‐Reported Outcome Measures in Rare Diseases and Implications for Health Technology Assessment

January 2021
Amanda Whittal, Michela Meregaglia, Elena Nicod

Patient-reported outcome measures (PROMs), used in health technology assessment (HTA) to measure patient experiences and quality of life with disease and treatment, can enable a deeper understanding of treatment impact beyond clinical endpoints. These are particularly relevant for rare disease treatments (RDTs) considering they most often aim to improve the very poor quality of life affecting patients living with a rare disease. However, unique challenges to measure PROMs in RDTs exist because of the small populations, disease heterogeneity, or lack of natural history knowledge inherent to rare diseases. This scoping review aimed to identify key factors to consider when using different types of PROMs in HTA for RDTs. In total 32 peer reviewed papers and 12 reports from the grey literature were included. Findings revealed key challenges and advantages of using the different types of PROMs, as well as potential solutions, including pooling data, using computer-assisted technology, or using generic and diseases-specific PROMs in a complementary way. Download
The estimation of health state utility values in rare diseases: overview of existing techniques

August 2020
Michela Meregaglia, Elena Nicod, Michael Drummond

Techniques for estimating health state utility values (HSUVs) in rare diseases come with pros and cons. This paper provides an overview of these and their implications for health technology assessment (HTA). Direct techniques can be demanding for rare disease patients as they are often children or have cognitively impairments, while alternatives like “vignettes” or multi-attribute utility measures may not capture the often heterogeneous nature of these rare diseases. The “rule of rescue” approach is a promising alternative in its ability to prioritise patients with life-threatening or disabling conditions. Generally, there is a lack of agreement on the most appropriate techniques to estimate HSUVs across different rare diseases. There is an urgent need to establish recommendations that inform better selection of the most appropriate technique in any given context, and address implications for HTA in ensuring disease and treatment impact are appropriately valued. Download
Are supplemental appraisal/reimbursement processes needed for rare disease treatments? An international comparison of country approaches

July 2020
Elena Nicod, Amanda Whittal, Michael Drummond, Karen Facey

There is growing recognition that conventional appraisal approaches may be unsuitable for assessing the value of rare disease treatments (RDTs). This study reviews whether countries have implemented separate, ‘supplemental’ appraisal/reimbursement processes for RDTs and what these look like. The appraisal processes for 32 countries were first documented through questionnaires, desk research and iterative interactions with country experts. A cross-country analysis was then conducted to identify and characterise the key features included in the supplemental processes identified for RDTs. Findings revealed that these key features have the ability to increase the likelihood of reimbursement by adjusting and/or foregoing part of the assessment process, or by accepting to pay more for the same added benefit compared to common conditions. Findings suggest that there are preferences to treat RDTs differently compared to conventional medicines, and that supplemental process features can facilitate this through more flexible and consistent decision-making. Download
An analysis of orphan medicine expenditure in Europe: is it sustainable?

January 2020
Mestre-Ferrandiz J, Palaska C, Kelly T, Hutchings A, Parnaby A.

An analysis of orphan medicine expenditure in Europe: is it sustainable?. Orphanet J Rare Dis 14, 287 (2019). Download
Expenditure in EU5 to 2021: Adjusting for the Impact of Discounts and Rebates

August 2018
Espin J, Schlander M, Godman B, Anderson P, Mestre-Ferrandiz J, Borget I, Hutchings A, Flostrand S, Parnaby A, Jommi C.

Projecting Pharmaceutical Expenditure in EU5 to 2021: Adjusting for the Impact of Discounts and Rebates. Appl Health Econ Health Policy 16, 803–817 (2018). View
Dealing with Uncertainty and Accounting for Social Value Judgments in Assessments of Orphan Drugs: Evidence from Four European Countries

May 2017
Elena Nicod, Karen Berg Brigham, Isabelle Durand-Zaleski, Panos Kanavos

Orphan medicinal products (OMPs) are often characterised by lower quality evidence than more conventional medicines. To address this, health technology assessment (HTA) bodies have implemented different strategies in their evaluation process. In order to understand the variation in HTA recommendation outcomes for OMPs across countries, this study aimed to elicit the views of HTA bodies about their approaches to OMP evaluation. A series of semi-structured interviews with HTA representatives from England, Scotland, Sweden, and France were conducted. Interviews were transcribed and analysed using qualitative thematic data analysis. Results highlight general agreement around evidentiary requirements and preferences for OMPs between HTA bodies. Differences were identified around how uncertainty should be considered in terms of, for example, the extent to which it is acceptable or the extent to which key concepts (e.g., unmet need, innovation, or disease severity) have a weight in decisions. Download
HTA programme response to the challenges of dealing with orphan medicinal products: process evaluation in selected European countries

April 2017
Elena Nicod, Lieven Annemans, Anna Bucsics, Anne Lee, Sheela Upadhyaya, Karen Facey

Following the Advance-HTA project, various new initiatives have been developed to specifically address commonly encountered issues relating to health technology assessment (HTA) of orphan medicinal products (OMPs). Reviewing these initiatives across England, Scotland and at the European-level, this study aims to understand why they were established and whether they resolved the challenges around OMPs. A literature review was conducted and the new HTA programmes were critiqued against a conceptual framework of clinical, regulatory, and economic challenges for OMPs. The new initiatives acknowledge the need for different approaches for assessing the value of OMPs and employ similar criteria across countries. However, questions still remain about whether they sufficiently capture value and manage uncertainty in clinical practice. Download
Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL)

March 2017
Annemans L, Aymé S, Le Cam Y, Facey K, Gunther P, Nicod E, Reni M, Roux JL, Schlander M, Taylor D, Tomino C, Torrent-Farnell J, Upadhyaya S, Hutchings A, Le Dez L.

Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL). Orphanet J Rare Dis 12, 50 (2017) Download
Scientific and Social Value Judgments for Orphan Drugs in Health Technology Assessment

September 2016
Elena Nicod, Panos Kanavos

Orphan medicinal products (OMPs) are often characterised by uncertain evidence and high incremental cost effectiveness ratios (ICERs). In such cases, health technology assessment (HTA) bodies may factor in “other considerations” beyond more routine measures when judging their relative value. Looking across different publicly available HTA reports, this study sought to better understand the dimensions of value used across countries by systemically identifying the scientific and social value judgements made in England, Scotland, Sweden, and France. The analysis focused on ten orphan drugs, and identified and classified these “other considerations”. Better defining and grouping these value considerations and determinants can help improve HTA transparency, accountability, and consistency across OMP decisions. View
Principles for consistent value assessment and sustainable funding of orphan drugs in Europe

May 2015
Gutierrez L, Patris J, Hutchings A, Cowell W.

Principles for consistent value assessment and sustainable funding of orphan drugs in Europe. Orphanet J Rare Dis 10, 53 (2015). Download
Estimating the budget impact of orphan drugs in Sweden and France 2013–2020

February 2014
Hutchings A, Schey C, Dutton R, Antonov K.

Estimating the budget impact of orphan drugs in Sweden and France 2013–2020. Orphanet J Rare Dis 9, 22 (2014). Download
A Pilot Study of Multicriteria Decision Analysis for Valuing Orphan Medicines

November 2013
Sussex J, Rollet P, Garau M, Hutchings A.

A Pilot Study of Multicriteria Decision Analysis for Valuing Orphan Medicines. Value Health 16, 1163-1169 (2013). View
What Is Wrong with Orphan Drug Policies? Suggestions for Ways Forward

October 2012
Panos Kanavos, Elena Nicod

This article reviews the key criticisms surrounding orphan medicinal product (OMP) policies and compares their weaknesses against the positive outcomes that they have had on encouraging R&D investment. It argues that while there are areas of the current policy framework which would benefit from improvement or refinement, this does not mean it should be replaced or dismissed altogether. Instead, the authors recommend changes around certain aspects, such as addressing data collection issues, more clearly defining the thresholds for excessive OMP profits, and updating assessment strategies to better accommodate OMPs and allow for more realistic, affordable payer pricing to become the norm. Download
Estimating the budget impact of orphan medicines in Europe: 2010–2020

September 2011
Schey C, Milanova T, Hutchings A.

Estimating the budget impact of orphan medicines in Europe: 2010 – 2020. Orphanet J Rare Dis 6, 62 (2011). Download