Regulation of Real‐World Evidence in Rare Diseases in the MENA Region: A Review of Current Guidelines Compared to Global Frameworks

Rare diseases are a group of disorders that have a small incidence rate worldwide. Given their low prevalence, drug development for rare diseases is challenging due to the small sample size and high cost. Consequently, real‐world evidence has emerged as a valuable approach to generate supporting evidence, drawing on data from diverse sources and study designs. This review aims to compare the regulatory guidance for rare diseases in the MENA region with the global standards.

BACKGROUND

Rare diseases are a group of low‐incidence and complex diseases. Recently, real‐world data (RWD) and real‐world evidence (RWE) have been leveraged for evidence generation. However, several barriers were identified, including data quality, bias, confounding, data completeness, and comparability. Therefore, the regulatory authorities have released guidelines for the proper handling of RWD and RWE to support decision‐making. ¹ In the Middle East and North Africa region (MENA), RWD is underutilized, but this is rapidly changing.

FDA leadership in RWE framework development

In 2019, the Food and Drug Administration (FDA) released the first foundational framework, regulating the RWE utilization for drug development in rare diseases. Additionally, another guideline was released in 2024 to support regulatory decision‐making about drug and biological products development based on electronic health records and medical claims. ² , ³

EMA's structured approach

The European Medicines Agency (EMA) provides a detailed methodological guidance for using RWD in regulatory submissions, covering critical aspects such as study design, control arm selection, and analytical methods for controlling bias. ⁴

MENA region development and localization efforts

The MENA region has diverse levels of RWE adaptation, with Saudi Arabia (KSA) and the United Arab Emirates (UAE) being the leading countries. The Saudi Food and Drug Authority (SFDA) has released a comprehensive draft of RWD/RWE for medicine marketing authorizations. ⁵ In 2023, the UAE's Ministry of Health (DoH) established its guidelines on RWD to support regulatory, clinical, and reimbursement decisions, in addition to discussing alternatives for rare diseases when clinical trials are not feasible. ⁶ Other MENA countries currently lack explicit RWE guidance.

Special considerations for rare diseases: Regulatory flexibility and innovation

Regulatory flexibility mechanisms

The FDA's Orphan Drug Act provides specific provisions that facilitate the use of RWE in rare diseases, including the acceptance of smaller study populations and external control methodologies. These provisions provide regulatory flexibility while maintaining scientific standards. ³ The EMA has developed specific considerations for rare conditions, in which patient registries may be the only feasible source of evidence. The agency's registry‐based studies guideline provides detailed methodology for using registry data in regulatory submissions, with particular emphasis on data quality and scientific validity. Moreover, the EMA has developed the European Platform on Rare Disease Registration (EU RD) Platform that includes a set of common data elements for rare disease registration to encourage data harmonization across different data registries. ⁷ In the MENA region, there is no specific guidance on RWE/RWD in rare diseases, but the KSA and UAE outline some recommendations for study designs for rare diseases in their RWE frameworks. ⁵ , ⁶

USE OF RWE IN REGULATORY DECISIONS: CURRENT APPLICATIONS AND FUTURE DIRECTIONS

SFDA's supportive framework

The SFDA considers RWE as a supportive tool in regulatory decision‐making, particularly for drug repurposing, statistical support of clinical trials, or orphan drug development, where traditional RCTs face feasibility challenges. The framework emphasizes using RWE to supplement rather than replace clinical trials, with particular focus on external control applications and global data bridging to local contexts. ⁵

UAE's post‐approval strategy

Similar to SFDA, the DoH's framework considers RWE as a supportive source of evidence to establish drug efficacy or safety when RCTs are not feasible. Local RWE studies focus on supporting healthcare decisions, formulary inclusion, and demonstrating benefit in the local population rather than primary regulatory approvals. ⁶ Recently, the Gulf Cooperation Council (GCC) countries have been aiming for a strategic partnership to develop patient‐centric care and support other stakeholders within the GCC countries using RWE. This partnership is facing several challenges due to data quality and standardization, but they can address these challenges and make the best use of their resources by mimicking the Darwin EU coordination center that supports RWE across Europe. ⁸ , ⁹

Data sources and quality: Infrastructure and standards

Data quality is a vital aspect for evidence generation based on RWE/RWD. The FDA emphasizes the importance of documenting processes for managing real‐world data (e.g., audit trails and quality control procedures). ² Similarly, the EMA has released a draft guidance on establishing the quality of RWD using quality metrics, offering a valuable and comprehensive framework of quality assurance. ¹⁰ The UAE guidance highlights the importance of data and metadata quality and recommends adherence to “the Guidelines for Good Database Selection and Use in Pharmacoepidemiology Research”. ⁶ Likewise, the SFDA requires data standardization of RWD to ensure its accuracy and reliability. It recommends using data standardization frameworks, such as Common Data Models (CDMs), to obtain consistent and uniform data. ⁵

Bias is also a major barrier to the generalizability and validity of RWE. The FDA recommends a baseline control study design for natural history studies to minimize the risk of bias. Additional recommendations comprise the utilization of valid epidemiological approaches during study design, the use of objective measures of treatment effect, and adapting prospective natural history studies. ³ The EMA identifies five main sources of bias in RWE, including selection bias, information bias, time‐related bias, confounding, and effect modification. Investigators should consider these sources during the study design phase, adapting the necessary measures to reduce bias risks and enhance evidence generalizability. ⁴ According to the SFDA, bias arises from two major sources: uncontrolled confounding and inappropriate data handling. Uncontrolled confounding could be mitigated by the proper selection of study design and applying suitable analysis methods (such as stratification, regression models, propensity scores combined with machine learning). ⁵ The DoH requires complete documentation of procedures to address bias and confounding in RWE study protocols; however, no detailed recommendations or instructions are provided on how to tackle these issues in the guidance. ⁶

TIMELINES AND FEASIBILITY: IMPLEMENTATION CHALLENGES AND SUCCESS FACTORS

The global landscape of RWE implementation shows significant variation in maturity levels, from the FDA's established framework with multiple approved cases to the MENA frameworks still in development phases. Understanding these maturity levels is crucial for pharmaceutical companies planning global rare disease development strategies. The FDA has more than 7 years of experience with RWE regulations, while the EMA released its first guideline on registry‐based studies in 2021. ³ , ⁷ In the MENA region, the first guidance was established by the UAE in 2023, followed by the KSA in 2025. ⁵ , ⁶ Yet, no other country in the MENA region has established a regulatory framework for RWE/RWD.

FUTURE OUTLOOK AND STRATEGIC RECOMMENDATIONS

The trajectory of RWE adoption in rare diseases suggests continued expansion and harmonization across regulatory authorities. The MENA region's development of localized frameworks while maintaining alignment with global standards represents a pragmatic approach to building regulatory capacity while addressing local healthcare needs. For pharmaceutical companies developing rare disease therapies, understanding the maturity spectrum and implementation timelines across different regulatory authorities is crucial for strategic planning. Early engagement with regulatory agencies through scientific advice processes and pilot programs can facilitate successful RWE integration into development programs.

Several regulatory and organizational approaches could be adapted to promote the use of RWE/RWD for evidence generation, including:

‐ Integrate RWE considerations into development planning for orphan drugs.

‐Invest in high‐quality data sources and registry partnerships.

‐Build internal capabilities in RWE study design and analysis.

‐ Global harmonization of regulatory requirements across the MENA countries.

In conclusion, real‐world evidence holds significant potential for the MENA countries to generate evidence for rare diseases and facilitate efficient data utilization. MENA countries should develop standardized frameworks to facilitate the development of evidence tailored to their specific needs and priorities.

FUNDING

No funding was received for this work.

CONFLICTS OF INTEREST

The authors declared no competing interests for this work.

ETHICAL APPROVAL

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