FDA Rare Disease Evidence Principles (RDEP): A CRO’s Perspective on Rare Disease Drug Development

By Maria-Cruz Morillo, MS, Executive Director, Global Operations Head, Rare Disease Center of Expertise at Allucent

As a Contract Research Organization (CRO) deeply committed to advancing treatments for rare and ultra-rare diseases, Allucent welcomes the FDA’s announcement on September 3, 2025, introducing the Rare Disease Evidence Principles (RDEP). This initiative represents an important step toward transforming how therapies for very small patient populations are evaluated and, ultimately, how solutions reach families suffering from devastating conditions with no treatment options. 

What is the RDEP Framework? FDA’s Regulatory Process for Rare Diseases

The FDA is offering a more structured and transparent pathway that acknowledges the inherent challenges of conducting traditional clinical studies in rare and ultra-rare diseases. Now, developers may seek approval based on one adequate and well-controlled study, backed by robust confirmatory evidence such as: 

• Mechanistic or biomarker data 

• Preclinical model evidence 

• Pharmacodynamic responses 

• Case reports, expanded access insights, or natural history studies  

The RDEP framework allows drug developers working in ultra-rare diseases, where traditional trial designs are not feasible, to move forward with greater confidence.  Sponsors can apply before a pivotal trial begins, via a formal meeting request, and are encouraged to engage patients, experts, and the FDA early in the process. With post-approval, the FDA may require additional studies to ensure continued safety and efficacy. 

Strategic Alignment: Why the RDEP Matters for CROs and Sponsors 

1. Clarity and Strategic Alignment 
   The Rare Disease Evidence Principles bring clarity. CROs and sponsors can now align trial design and evidence generation strategies with the FDA from the earliest stages, reducing uncertainty and helping scarce resources go further. 

2. Design Innovation and Operational Efficiency 
   Allowing alternative evidence types, such as biomarkers or real-world data, enables CROs and sponsors  to design scientifically rigorous yet feasible trials for ultra-rare diseases where large, controlled studies are simply not possible.  

3. Strengthening Collaborations and Dialogue 
   The RDEP establishes a more collaborative paradigm. CROs can facilitate dialogues between sponsors and the FDA, supported by patient input, to define acceptable evidence pathways. This co-creation model improves trial design, endpoint selection, regulatory alignment, and ultimately accelerates access to effective treatments. 

4. Balancing Rigor with Practicality 
   While the flexibility is encouraging, CROs must remain vigilant in maintaining scientific and regulatory rigor. The challenge lies in leveraging surrogate or mechanistic endpoints without compromising robustness or patient safety. 

The RDEP Framework Challenges and Areas for CRO Support 

While the RDEP is a welcome advance, it also presents practical and ethical considerations: 

• Interpreting Confirmatory Evidence 
  What qualifies as “robust” mechanistic or nonclinical evidence? Establishing clear, replicable standards will be critical. 

• Post-Approval Commitments 
  Requirements should be meaningful but not overburden the patients.  

• Stakeholder Engagement Complexity 
  Incorporating patient voices and expert insights adds layers of coordination. CROs can support these interactions to produce meaningful input without delaying timelines. 

• Integration with Other Regulatory Tools 
  Sponsors may also take advantage of other FDA initiatives, like orphan designation, Rare Disease Endpoint Advancement (RDEA), or accelerated pathways. Effective integration of these overlapping frameworks requires strategic navigation. 

A Vision Forward: CRO-Driven RDEP Collaboration

From where we stand, the FDA’s Rare Disease Evidence Principles offer hope and momentum for families affected by rare diseases. As a CRO, we at Allucent play a pivotal role in translating regulatory frameworks into practical, actionable programs. There are key areas where Allucent can add value: 

• Advising on Evidence Strategy 
  Navigating the types of evidence to meet FDA standards, be it biomarker validation, natural history modeling, or expanded access use cases. 

• Facilitating Early Dialogue 
  Preparing sponsors for pre-pivotal trial discussions and formal RDEP meeting requests, bridging scientific proposals with regulatory expectations. 

• Designing Hybrid Trial Models 
  Building study designs that seamlessly integrate traditional endpoints with surrogate or mechanistic measures when conventional trials aren’t feasible. 

• Managing Post-marketing Commitments 
  Helping to design feasible, targeted post-approval studies that address safety and effectiveness without overtaxing limited patient populations.

In Summary 

The FDA’s Rare Disease Evidence Principles initiative represents a vital evolution in rare disease regulation, acknowledging the limits of traditional clinical trial models while ensuring rigorous science-based review. For patients and families facing devastating ultra-rare conditions, it offers a new path toward earlier access to safe and effective therapies.  

We embrace additional responsibility to guide the sponsor through this process, foster collaboration, and uphold the highest of ethics and data integrity. Together, we can help deliver what matters most: real solutions to alleviate the suffering of rare disease families.