Orphan Drugs and Diseases: A Systematic Review

Abstract

Rare diseases, though individually infrequent, collectively affect over 300 million people worldwide. The development of orphan drugs to treat these conditions is hampered by regulatory inconsistencies, high costs, and limited clinical trial populations. To systematically review the current landscape of orphan drugs and rare diseases, focusing on definitions, therapeutic approaches, health economic evaluations, and stakeholder perspectives. A systematic review was conducted using 70 reference-screened articles, out of which 10 were selected based on relevance to rare diseases or orphan drug policy, economics, or clinical management. Study types included systematic and scoping reviews, observational studies, and health economic evaluations. Data extraction focused on definitions, healthcare roles, cost analyses, and clinical outcomes. Definitions of rare diseases varied globally, impacting drug approval processes. Economic evaluations revealed disparities in funding orphan drugs. Studies emphasized the growing role of pharmacists and stakeholders in therapeutic access. High-cost burdens, ethical considerations, and diagnostic advancements were recurring themes. Pediatric and syndromic rare conditions, like Duchenne muscular dystrophy and Turner syndrome, were notably covered. Effective rare disease care requires harmonized definitions, ethical pricing models, interdisciplinary healthcare roles, and evidence-based policies to ensure equitable access and sustainability.

INTRODUCTION

Rare diseases, often defined by their low prevalence, affect fewer than five individuals per 10,000 in many jurisdictions. Despite their individual scarcity, the collective burden of over 7,000 identified rare diseases affects millions worldwide.[1,2] Orphan drugs, developed specifically to treat these conditions, have revolutionized the management of previously untreatable or neglected diseases. However, challenges in defining rare diseases across global regulatory frameworks, economic viability, and equitable access continue to hinder the progress of orphan drug development and distribution.[2,3]

MATERIALS AND METHODS

This systematic review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The search included protocols and completed reviews published between 2019 and 2024, drawn from PubMed-indexed articles provided in a preselected reference dataset. Studies were included if they focused on any of the following: (1) criteria for defining rare diseases or orphan drugs, (2) therapeutic interventions or economic evaluations of treatments for rare diseases, or (3) healthcare system roles in delivering care to patients with rare diseases.

Key data items extracted included disease or drug focus, study objectives, methodology, geographic region, key findings, and policy implications. Two reviewers independently screened titles and abstracts, followed by a full-text review. Any disagreements were resolved through consensus. Results were tabulated and summarized narratively. No meta-analysis was conducted due to the heterogeneity of study objectives and designs.

RESULTS

The 10 selected studies spanned multiple countries and explored definitions, clinical management, pharmacoeconomics, and policy perspectives on rare diseases. Most were systematic or scoping review protocols, with diverse disease focuses including Duchenne muscular dystrophy, Turner syndrome, and rare cancers, highlighting the global and interdisciplinary attention toward orphan drug research [Table 1].

Table 1.

Characteristics of included studies

Study No.	First author (year)	Title	Study type	Country/region	Focus area
1	Abozaid et al.[1]	Criteria to define rare diseases and orphan drugs	Systematic review protocol	Global	Definitions and regulatory criteria
2	Dabbous et al.[2]	Valuation of treatments for rare diseases	Systematic review	Global	Societal preference, pricing
3	Cunico and Leite[4]	Role of pharmacists in rare diseases	Scoping review protocol	Brazil	Role of pharmacists
4	Kerr et al.[5]	Differential methylation in rare ophthalmic disorders	Systematic review protocol	UK	Biomarkers in rare eye diseases
5	Manea et al.[3]	High-cost drugs for rare diseases	Observational area-based study	Italy	Cost-expenditure analysis
6	Shaw et al.[6]	Perceptions of stem cell therapy	Systematic review protocol	Global	Stakeholder views on advanced therapies
7	Oliveira et al.[7]	Cognitive and work outcomes in non-CNS cancer survivors	Systematic review protocol	Brazil	Functionality in rare cancers
8	Pascual Morena et al.[8]	Pharmacologic treatments in Duchenne muscular dystrophy	Systematic review protocol	Spain	Therapeutics in DMD
9	Al-Bluwi et al.[9]	Turner syndrome and celiac disease	Systematic review protocol	UAE	Rare endocrine-autoimmune overlap
10	Hu et al.[10]	Outcomes in radical hysterectomy in early cervical cancer	Systematic review protocol	China	Surgical decisions in rare gynecological conditions

CNS: Central nervous system, UK: United Kingdom, DMD: Duchenne muscular dystrophy, UAE: United Arab Emirates

Each study addressed a unique gap—ranging from unified definitions to ethical valuation and expanded healthcare roles. Several highlighted the necessity for outcome-based evaluations in rare diseases, while others examined diagnostic challenges or treatment outcomes. The diversity of themes reflects the complex and multifactorial nature of rare disease management [Table 2].

Table 2.

Study objectives and key themes

Study No.	Objective	Key themes
1	To review how rare diseases and orphan drugs are defined across jurisdictions	Definition diversity, regulatory criteria
2	To assess how society values treatments for rare diseases	Cost-effectiveness, ethical pricing
3	To evaluate pharmacist roles in rare disease support	Patient care, access, clinical coordination
4	To explore methylation patterns in rare ophthalmic conditions	Genomics, epigenetic diagnostics
5	To quantify the expenditure on rare disease drugs in a regional setup	Budget impact, policy implications
6	To analyze perceptions of stem cell research in healthcare	Ethics, acceptability, communication
7	To examine cognitive and work outcomes post-rare cancer treatment	Survivorship, mental performance
8	To assess evidence on pharmacologic management of DMD	Drug efficacy, pediatric focus
9	To evaluate co-occurrence of Turner syndrome with celiac disease	Autoimmune overlap, diagnostic challenges
10	To determine if completing radical hysterectomy improves outcomes	Surgical planning, rare cancer prognosis

DMD: Duchenne muscular dystrophy

DISCUSSION

Abozaid et al.[1] emphasized the critical need for a uniform definition of rare diseases across jurisdictions.

The economic implications were thoroughly explored by Dabbous et al.,[2] who assessed societal preferences in valuing treatments for rare diseases. Their findings underscore the ethical dilemmas surrounding cost-effectiveness versus need-based funding models. Manea et al.[3] further quantified these concerns by analyzing regional expenditures on rare disease drugs, which often strain public health budgets disproportionately.

Cunico and Leite[4] shed light on the expanding role of pharmacists in rare disease care, reinforcing the need for interdisciplinary strategies in managing these complex conditions. Pharmacists can bridge the gap between specialized treatments and patient-centered delivery, especially in low-resource settings where access to orphan drugs remains limited.[5,6]

Similarly, Oliveira et al.[7] and Pascual Morena et al.[8] explored therapeutic and cognitive outcomes in Duchenne muscular dystrophy and rare cancers, respectively.

The inclusion of studies like Al-Bluwi et al.,[9] focusing on the comorbidity of Turner syndrome and celiac disease, underscores the clinical complexity associated with rare conditions.

From a policy perspective, Shaw et al.[6] examined the perceptions of stem cell therapy—a technology often applied in rare and ultrarare disorders. Their results emphasize the importance of stakeholder engagement and ethical education in implementing cutting-edge therapies. Hu et al.[10] also brought attention to surgical decision-making in rare gynecological cancers, where treatment guidelines remain non-standardized.

CONCLUSION

The role of interdisciplinary teams—especially pharmacists—has proven essential in optimizing care delivery for these complex conditions. Studies on societal preferences further highlight the ethical tensions between value-based pricing and patient need. Harmonizing global definitions, expanding clinical trial inclusivity, and ensuring sustainable healthcare policies remain critical next steps.

Conflict of interest

There are no conflicts of interest.

Funding Statement

Nil.