Implementation of risk sharing models in access to treatment of rare diseases: an integrative review

Puopolo, Giovanna Renelo; Rodrigues, Maria de Lara Araújo; Bulgareli, Jaqueline Vilela

doi:10.1590/1413-81232026314.06642024

person Giovanna Renelo Puopolo

study’s conception · methodological design · data collection and organization · analysis and interpretation of results · initial manuscript drafting · critical review of the content · coordinated all stages of the research and writing

schoolFaculdade de Saúde Pública, Universidade de São Paulo. Av. Dr. Arnaldo 715, Cerqueira César. 01246-904 São Paulo SP Brasil. giovanna_puopolo@hotmail.com

0009-0009-2244-8520

person Maria de Lara Araújo Rodrigues

collaborated in the interpretation of the findings · participated in the analysis of the results · contributed with conceptual suggestions · assisted in the drafting and revision of the introduction and discussion sections

schoolFaculdade de Odontologia, Universidade Federal de Uberlândia. Uberlândia MG Brasil.

0000-0002-3610-6611

person Jaqueline Vilela Bulgareli

Supervising author · guiding the study’s conception · methodological design · general supervision of the work · critical analysis of all stages · in-depth revision of the manuscript · approval of the final version

schoolFaculdade de Odontologia, Universidade Federal de Uberlândia. Uberlândia MG Brasil.

0000-0001-7810-0595

Chief editors:

Maria Cecília de Souza Minayo, Romeu Gomes, Antônio Augusto Moura da Silva, Vania de Matos Fonseca

Phenomenon: risk-sharing models
Participação no risco financeiro	Financial risk-sharing	Prorrateo de riesgo financiero
Financiamento da saúde	Healthcare financing	Financiación de la atención de la salud
Custos de medicamentos	Drug costs	Costos de los medicamentos
Reembolso de incentivo	Reimbursement, incentive/ incentive reimbursement	Reembolso de incentivo
Pagamento baseado em performance	Pay for performance	Pago por rendimento
Avaliação de resultados em cuidado de saúde	Outcome assessment, health care	Evaluación de resultado en la atención de salud
Avaliação de resultados da assistência ao paciente	Patient outcome assessment	Evaluación del resultado de la atención al paciente
Population: rare diseases
Doenças raras	Rare diseases / rare disease	Enfermedades raras
Medicamentos para doenças raras	Drugs for rare diseases	Medicamentos para enfermedades raras
Tecnologia de alto custo	High-cost technology / technology, high-cost	Tecnología de alto costo
Medicamento órfão	Orphan drug	Medicamento para enfermedades huérfanas
Medicamento do componente especializado da assistência farmacêutica	Drugs from the specialized component of pharmaceutical care	Medicamentos del componente especializado de los servicios farmacéuticos
Doenças órfãs	Orphan diseases / orphan disease	Enfermedades huérfanas
Context: access to treatment
Acesso aos serviços de saúde	Health services accessibility	Accesibilidad a los servicios de salud
Acesso a medicamentos	Access to medicines	Acceso a medicamentos
Acesso a novas tecnologias	Access to new technologies	Acceso a nuevas tecnologías
Acesso a medicamentos essenciais e tecnologias em saúde	Access to essential medicines and health technologies	Acceso a medicamentos esenciales y tecnologías sanitarias
Acesso ao tratamento	Access to treatment	Acceso al tratamiento

Database	Final syntax	Findings
BVS - Biblioteca Virtual em Saúde	(“financial risk sharing” OR “healthcare financing” OR “pay for performance” OR “outcome assessment, health care” OR “drug cost” OR “patient outcome assessment” OR “reimbursement, incentive”) AND (“Health Services Accessibility” OR “Access to Essential Medicines and Health Technologies” OR “Access to Treatment” OR “Access to New Technologies” OR “Access to Medicines”) AND (“Rare disease” OR “Drugs for rare diseases” OR “High-cost technology” OR “Orphan drug” OR “Orphan disease” OR “Drugs from the Specialized Component of Pharmaceutical Care”)	36 publications
Embase	(‘financial risk sharing’ OR ‘healthcare financing’/exp OR ‘healthcare financing’ OR ‘pay for performance’/exp OR ‘pay for performance’ OR ‘outcome assessment’/exp OR ‘outcome assessment’ OR ‘drug cost’/exp OR ‘drug cost’ OR ‘reimbursement’/exp OR ‘reimbursement’) AND (‘health services accessibility’/exp OR ‘health services accessibility’ OR ‘access to essential medicines and health technologies’ OR ‘access to treatment’ OR ‘access to new technologies’ OR ‘access to medicines’) AND (‘rare disease’/exp OR ‘rare disease’ OR ‘drugs for rare diseases’ OR ‘high-cost technology’/exp OR ‘high-cost technology’ OR ‘orphan drug’/exp OR ‘orphan drug’ OR ‘orphan disease’/exp OR ‘orphan disease’ OR ‘drugs from the specialized component of pharmaceutical care’)	317 publications
PubMed	((financial risk sharing) OR (healthcare financing) OR (pay for performance) OR (Outcome Assessment, Health Care) OR (drug cost) OR (Patient Outcome Assessment) OR (Reimbursement, Incentive)) AND ((Health Services Accessibility) OR (Access to Essential Medicines and Health Technologies) OR (Access to Treatment) OR (Access to New Technologies) OR (Access to Medicines)) AND ((rare disease) OR (drugs for rare diseases) OR (High-cost technology) OR (Orphan drug) OR (Orphan disease) OR (drugs from the Specialized Component of Pharmaceutical Care))	1,146 publications
Scopus	(“financial risk sharing” OR “healthcare financing” OR “pay for performance” OR “outcome assessment, health care” OR “drug cost” OR “patient outcome assessment” OR “reimbursement, incentive”) AND (“Health Services Accessibility” OR “Access to Essential Medicines and Health Technologies” OR “Access to Treatment” OR “Access to New Technologies” OR “Access to Medicines”) AND (“Rare disease” OR “Drugs for rare diseases” OR “High-cost technology” OR “Orphan drug” OR “Orphan disease” OR “Drugs from the Specialized Component of Pharmaceutical Care”)	73 publications
Total		1,572

Author(s)	Year	Title	Magazine
Morel T et al.¹²	2013	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 Journal of Rare Diseases
Gibson SG, Lemmens T. ¹³	2014	Niche markets and evidence assessment in transition: a critical review of proposed drug reforms	Medical Law Review
Gammie T, Lu CY, Babar ZUD¹⁴	2015	Access to orphan drugs: a comprehensive review of legislations, regulations and policies in 35 countries	PLOS ONE
Degtiar I¹⁵	2017	A review of international coverage and pricing strategies for personalized medicine and orphan drugs	Health Policy
Bae EY ¹⁶	2019	Role of health technology assessment in drug policies: Korea	Value in Health
Van Wilder P, Pirson M, Dupont A¹⁷	2019	Impact of health technology assessment and managed entry schemes on reimbursement decisions of centrally authorised medicinal products in Belgium	European Journal of Clinical Pharmacology
Atikeler EK, Leufkens HGM, Goettsch W¹⁸	2020	Access to medicines in Turkey: evaluation of the process of medicines brought from abroad	International Journal of Technology Assessment in Health Care
Biglia LV et al.¹⁹	2021	Incorporation of drugs for rare diseases in Brazil: is it possible to have full access to these patients?	Ciência & Saúde Coletiva
Blonda A et al.²⁰	2022	Assessing the value of nusinersen for spinal muscular atrophy: a comparative analysis of reimbursement submission and appraisal in European countries	Frontiers in Pharmacology
Blonda A et al.²¹	2022	How can we optimize the value assessment and appraisal of orphan drugs for reimbursement purposes? A qualitative interview study across European countries	Frontiers in Pharmacology
Guarga L et al.²²	2022	Implementing risk-sharing arrangements for innovative medicines: the experience in Catalonia (Spain)	Value in Health
Shengnan D et al.²³	2022	Using 5 consecutive years of NICE guidance to describe the characteristics and influencing factors on the economic evaluation of orphan oncology drugs	Frontiers in Public Health
Simoens S et al.²⁴	2022	How to balance valuable innovation with affordable access to medicines in Belgium?	Frontiers in Pharmacology
Iglesias-López C et al.²⁵	2023	Financing and reimbursement of approved advanced therapies in several European countries	Value in Health
Kim H et al.²⁶	2023	Introduction of managed entry agreements in Korea: problem, policy, and politics	Frontiers in pharmacology
Ng QX et al.²⁷	2024	Comparative policy analysis of national rare disease funding policies in Australia, Singapore, South Korea, the United Kingdom and the United States: a scoping review	Health Economics Review
Douglas CMW, Grunebaum S²⁸	2024	Lessons learned from the Canadian Fabry Disease Initiative for future risk-sharing and managed access agreements for pharmaceutical and advanced therapies in Canada	Health Policy
Nieto-Gómez P, Castaño-Amores C²⁹	2024	Factors influencing the reimbursement of cancer drugs in Europe: a scoping review	Journal of Evaluation in Clinical Practice

Author(s)/year	Access barriers	Risk-sharing model
Morel T et al., 2013¹²	Uncertainty about the clinical and economic performance of new orphan drugs in the real world (difficulty in recruiting a sufficient number of patients, generally heterogeneous population, clinical trials based on substitute outcomes, without randomization, and inclusion of control arms); little knowledge about the natural history of the disease; relatively high treatment costs, generating great budgetary uncertainty and/or financial risk if treatment does not work as expected	Managed entry agreements: (1) performance-based risk-sharing schemes, which may be: a) 'performance-linked reimbursement' schemes; or (b) 'coverage with evidence development'; (2) finance-based arrangements, which may adopt: a) patient-level perspective; or b) population-level perspective
Gibson SG, Lemmens T, 2014¹³	Uncertainties regarding clinical evidence (effectiveness/safety) due to limitations of clinical studies; and a high cost per therapy	Performance-based risk-sharing arrangements, where product performance will be tracked in a defined population over a specific period and the continuation or level of reimbursement is based on the health and economic outcomes that have been achieved. Can manage utilization by linking reimbursement to various performance measures: reimbursement may depend on the clinical decision-making process (e.g., only patients who test positive for a particular biomarker will be covered); other schemes may focus on final or intermediate clinical points to determine reimbursement or involve outcome guarantees where the manufacturer receives a lower payment for patients who do not respond to therapy.
Gammie T, Lu CY, Babar ZUD, 2015¹⁴	High costs and insufficient evidence limit orphan drugs from meeting traditional health technology assessment criteria, especially cost-effectiveness	Two types of Managed Entry Agreements: (1) Performance-based schemes (2) Finance-based arrangements (different models, including cost cap, utilization cap, and free and/or discounted initiation)
Degtiar I., 2017¹⁵	Uncertainties regarding efficacy and safety and often high prices	Managed entry agreements with national results registries
Bae EY, 2019¹⁶	High treatment cost and uncertainties of treatment effect	There are four types of risk sharing in Korea: reimbursement of the difference between the listed price and the contracted price; mixing of conditional treatments based on response and reimbursement; global spending limit; and spending limit per patient.
Van Wilder P, Pirson M, Dupont A, 2019¹⁷	Increasing expenditure on health plans (annual increase of around 25 million euros); drugs with high prices; relative effectiveness and/or cost-effectiveness uncertainties; low willingness to pay for health plans	Managed entry schemes
Atikeler EK, Leufkens HGM, Goettsch W, 2020¹⁸	Very high prices for orphan drugs	Alternative access agreements
Biglia LV et al., 2021¹⁹	Scarcity of adequate scientific evidence and high cost of treatments	Risk sharing agreements
Blonda A et al., 2022²⁰	High cost of treatment	Financial-based Managed Entry Agreements, when related to a discounted price, and/or performance-based, where additional data on the efficacy of the drug in the real world will be collected
Blonda A et al., 2022²¹	Drugs at rising prices and uncertainties regarding cost-effectiveness	Managed entry agreements that allow for a temporary refund upon providing a price reduction (on a financial basis) or on the condition that additional data about real-world effectiveness is collected in a record (based on results or performance)
Guarga L et al., 2022²²	Uncertainties about effectiveness, cost-effectiveness or budgetary impact	Performance-linked reimbursements and cost-sharing agreements
Shengnan D et al., 2022²³	High cost of treatment; small population in studies; and uncertainty regarding the clinical evidence of orphan oncology drugs	Managed access agreements
Simoens S et al., 2022²⁴	Failure to identify unmet medical needs in all therapeutic areas; limitations of available clinical evidence (long-term efficacy and safety); high budgetary impact	Managed entry agreements
Iglesias-López C et al., 2023²⁵	Uncertainty in the cost-effectiveness of drugs (high costs and uncertainties regarding clinical evidence)	Managed entry agreements and results-based payment
Kim H et al., 2023²⁶	High cost of drugs; uncertainty about the effectiveness of drugs	Financial-based and outcome-based agreements
Ng QX et al., 2024²⁷	High cost of treatment; difficulties in financing and reimbursing medicines	Agreements between governments or health systems and pharmaceutical companies to manage uncertainty regarding the cost and effectiveness of high-cost medicines
Douglas CMW, Grunebaum S, 2024²⁸	Uncertainty about the effectiveness of therapies; High costs	Agreements between payers and pharmaceutical companies to address uncertainty about the effectiveness of treatments and contain costs. Performance-based, to reduce the uncertainty of effectiveness, or financial-based, to limit expenses
Nieto-Gómez P, Castaño-Amores C., 2024²⁹	High cost of medicines; lack of transparency regarding the criteria used for the price and reimbursement of medicines; uncertainty regarding the clinical benefits and cost-effectiveness of medicines	Performance-based agreements and country-specific adaptations that allow flexible reimbursement strategies while ensuring patient access to necessary treatments

[TFN8n] Source: Authors.