Rare diseases (RDs), though individually uncommon, collectively affect an estimated 6-8% of the global population, yet most remain without effective treatment. Even when therapies exist, regulatory bottlenecks often delay or prevent access, especially in low- and middle-income economies. Conventional regulatory systems were designed for large, randomized trials in well-characterized conditions. They are poorly matched to the realities of RDs: very small and geographically dispersed patient populations, heterogeneous phenotypes, limited natural history data, and constrained clinical evidence. The result is a structurally inefficient and inequitable landscape in which patients in many APEC economies wait years for therapies that may already be available elsewhere.

 

          This paper examines how regulatory agencies across APEC economies and globally can optimize the review and approval of RD therapies to accelerate equitable access while maintaining scientific rigor. It identifies four interlocking problems that systematically hinder RD therapy development and availability:

 

• Fragmented concepts and incentives: Definitions of “rare disease” and “orphan medical product” (OMP) vary widely across jurisdictions, as do criteria for incentives and designation. This undermines predictability for sponsors, complicates cross-border collaboration, and constrains coherent policy planning.

 

• Limited data and trial feasibility: Small, heterogeneous populations and poorly understood natural histories make traditional Phase I–III trial structures difficult or impossible to execute, limit statistical power, and increase uncertainty at the time of initial review.

 

• Inefficient, duplicative regulatory processes: Many agencies lack dedicated pathways for RD therapies, apply standard evidentiary expectations without adaptation, or run sequential assessments with little work-sharing or reliance. This is particularly burdensome in smaller markets with limited regulatory capacity.

 

• Underdeveloped life-cycle oversight: Post-market surveillance, registries, and real-world evidence (RWE) systems for RD therapies are often fragmented or weak, reducing the ability of regulators to refine benefit–risk assessments over time.

 

          At the same time, there is a growing body of practice demonstrating that these constraints are not immutable. Leading regulators have begun to deploy a toolkit of regulatory, scientific, and collaborative innovations that better fit the RD context:

 

• Adaptive and flexible pathways, including conditional approvals, accelerated and rolling reviews, and staged authorization with targeted initial indications, have enabled earlier access while evidence matures, particularly where surrogate endpoints are used.

 

• RWE and networked registries are being used to complement small trials, serve as external controls, and underpin approvals under exceptional circumstances.

 

• Collaborative review and reliance mechanisms such as Project Orbis, the ACCESS Consortium, ASEAN Joint Assessment, and EMA OPEN have shown that parallel work-sharing and structured use of reference-agency assessments can significantly shorten timelines and build capacity.

 

• Stakeholder engagement and patient-centric approaches have improved trial feasibility, endpoint relevance, and alignment between regulatory decisions and what patients value.

 

• Regulatory science innovations in biomarkers, pharmacogenomics, modeling and simulation, and natural history modeling have enabled more nuanced and context-appropriate evidentiary standards.

 

          Drawing on these examples, the paper sets out six priority reforms to optimize regulatory review and approval of RD therapies, with a particular focus on feasibility in resource-limited settings and alignment with APEC’s regulatory harmonization agenda:

 

1. Converge definitions and designations: Move toward a harmonized framework for defining RDs and OMPs, including convergence around core definitional elements such as prevalence thresholds, while explicitly not imposing a single universal definition. International forums (WHO, ICH, ICMRA, APEC) should lead workstreams to align methodologies for defining and periodically revising RD criteria and to promote mutual recognition or reliance for orphan designation among trusted regulators. Within APEC, establishing a Priority Work Area on RDs under the RHSC, coordinated with the Health Working Group, would provide a platform to operationalize this convergence.

 

2. Streamline and adapt regulatory requirements: Establish dedicated, proportionate pathways for RD therapies that incorporate accelerated review timelines, rolling submissions, and conditional approvals as standard options where appropriate. Update guidance to explicitly recognize adaptive and innovative trial designs, surrogate endpoints, and the use of historical or external controls, including Bayesian methods for small populations. Apply targeted flexibilities for requirements that disproportionately burden RD products (for example, certain local testing or stability studies) where strong global quality data exist, while maintaining clear, risk-based justifications.

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3. Enhance global and regional regulatory collaboration: Expand multi-agency review and work-sharing initiatives for RD therapies and pilot an “Asia-Pacific OMP Work-Sharing” model in which a single dossier is jointly assessed by interested APEC regulators. Systematically use reliance on WHO-listed authorities to avoid duplicative full assessments and focus local review on context-specific issues. Develop common assessment templates and standardized review-report formats to facilitate information exchange. Promote structured training, secondments, and exchange programs so regulators in emerging agencies can learn directly from more experienced authorities.

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4. Increase transparency and communication: Publish clear, accessible guidance on orphan designation, evidentiary expectations, and RD-specific pathways, including in local languages. Routinely issue public assessment reports that explain the rationale for decisions on RD therapies. Communicate anticipated timelines and milestones and provide non-confidential reasons for delays. Institutionalize early scientific advice procedures, with involvement of patient and clinical experts where appropriate, to clarify expectations and reduce avoidable deficiencies. Use public dashboards and reporting on the use of incentives to strengthen accountability and trust.

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5. Strengthen post-market surveillance and evidence gathering: Make robust post-market evidence generation a core feature of RD regulation. Require and enforce post-marketing studies and registries as conditions of approval where appropriate and prioritize participation in regional or global RD registries to overcome small sample sizes. Modernize pharmacovigilance through digital reporting channels and use of electronic health record data, supported by clear standards for data quality and privacy. Establish collaborative post-market surveillance networks that share responsibilities for signal detection and analysis. Use RWE in structured life-cycle reassessment frameworks to adjust, restrict, or expand indications as evidence evolves.

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6. Engage and empower patients and advocacy groups: Institutionalize patient participation in advisory committees, scientific advice, and decision forums for RD products, including through RD patient advisory councils in APEC economies. Support advocacy organizations to build data capabilities, including registries and patient-preference studies that inform benefit-risk assessments. Convene multi-stakeholder workshops early in development to align trial design and endpoints with patient priorities and feasibility constraints. After approval, partner with patient groups to disseminate accurate information on indications, benefits, and risks to improve appropriate uptake.

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          Taken together, these reforms outline a pragmatic pathway for transitioning RD regulation from a fragmented, reactive system to a more coherent, learning-oriented, and collaborative ecosystem. For APEC economies, the agenda leverages existing regional structures while addressing specific capacity and equity gaps. For regulators globally, it provides an integrated framework for using flexibility, collaboration, and patient engagement to manage uncertainty without lowering standards. Implementing this agenda would help ensure that the promise of scientific innovation in RDs translates more quickly and reliably into meaningful access for patients and families.