Orphanet Journal of Rare Diseases | Development of a Managed Entry Agreement Matrix to Address Reimbursement Challenges for Orphan Medicinal Products

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This study developed a systematic Managed Entry Agreement (MEA) matrix to address reimbursement challenges related to clinical effectiveness, cost-benefit, and financial risk for orphan drugs, providing a practical tool for healthcare payers and health technology assessment agencies worldwide.

 

Literature Review
The paper "Drivers of managed entry agreements to reduce reimbursement challenges of orphan medicinal products: the development of a matrix" published in Orphanet Journal of Rare Diseases reviews and summarizes the development of a new matrix tool designed to systematically match different types of Managed Entry Agreements (MEA) with reimbursement challenges of orphan drugs in clinical effectiveness, cost-benefit, and financial risk, thereby facilitating earlier patient access to innovative therapies.

Background
Orphan medicinal products (OMPs) treat rare diseases with extremely low prevalence, yet often face high pricing and reimbursement uncertainty due to development challenges, small clinical trial sample sizes, and limited efficacy evidence. Healthcare payers and health technology assessment (HTA) agencies must balance their high value against high costs. However, implementation of MEAs varies across countries, partially due to differences in evaluating uncertainty types and levels. Based on systematic literature review of 77 articles, this study identified 23 MEA types and constructed a matrix to help stakeholders select appropriate agreements at different stages, reducing reimbursement risks and improving patient access. The matrix was demonstrated through Myozyme® case analysis, showing additional reimbursement strategies to optimize decision-making. The ultimate goal is to provide a structured, operational tool for orphan drug lifecycle management to support effective reimbursement negotiations.

 

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Research Methods and Experiments
This study employed a systematic literature review methodology, searching PubMed, Embase, and grey literature from January 1, 2000 to January 1, 2024. The research team used AI tool Rayyan for deduplication and language screening, followed by full-text screening through Mendeley. The final 77 articles were used to construct the matrix linking MEAs with reimbursement challenges. Myozyme® (Alglucerase alfa) was selected as a case study to demonstrate the matrix's practical application value.

Key Findings and Perspectives

• The systematic review identified 23 MEA types including financial-based models, effect-based models, and combination models.
• Effect-based models like CED (Coverage with Evidence Development) and Pay-for-outcome are widely used to address clinical uncertainty.
• Combination models like Pay-for-outcome with annuity payments can address multiple challenges simultaneously including clinical effectiveness, cost-benefit, and financial risk.
• The case study demonstrated the matrix's ability to provide additional reimbursement strategy recommendations for specific orphan drugs, optimizing decision-making processes.
• The study emphasizes early MEA design intervention, recommending discussions begin at pre-approval stages to manage anticipated reimbursement barriers.
• The matrix supports multi-stage application across different lifecycle phases of orphan drugs, helping national reimbursement agencies optimize strategies.

Research Implications and Future Directions
This study provides a systematic tool for healthcare reimbursement agencies, pharmaceutical companies, and health technology assessment organizations to better address uncertainties during orphan drug approval and reimbursement. Future research could expand to additional therapeutic areas and evaluate the matrix's applicability in real-world healthcare systems. The study also recommends stakeholder analysis to validate the matrix's effectiveness and explore optimal MEA types across different national contexts.

 

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Conclusion
The developed matrix tool provides a systematic classification and matching mechanism for Managed Entry Agreements (MEA) in orphan drug management, enabling more rational reimbursement decisions when facing high pricing, limited clinical evidence, and budget impact challenges. Through case analysis, the study demonstrates practical application for identifying additional MEA options to enhance reimbursement strategy flexibility and patient access. While the tool has certain limitations inherent to literature-based construction, including partial lack of real-world data, it offers a practical reference framework for the orphan drug field. Future work should validate the matrix's applicability across diverse healthcare systems and optimize usage through expert consultation.

 

Marcelien H E Callenbach, Sibren van den Berg, Alisa Hulsbosch, Aukje K Mantel-Teeuwisse, and Wim G Goettsch. Drivers of managed entry agreements to reduce reimbursement challenges of orphan medicinal products: the development of a matrix. Orphanet Journal of Rare Diseases.