Real-World Evidence (RWE) is reshaping the way trials are designed, making them more efficient and patient-focused. Traditionally, RWE has been derived from sources like electronic health records (EHRs), insurance claims, and patient registries¹. These datasets reflect the lived experience of patients outside of the controlled environment of clinical trials.2
However, one source of RWE remains critically underused, especially for rare indications - the peer-reviewed literature.
EHRs and claims data can be fragmented or incomplete, especially for rare indications where patients are few in number, are geographically dispersed, and require multi-disciplinary care . The literature, in contrast, captures decades of global patient experience, and is rich with detailed demographic, clinical, and genomic data, even for ultra-rare indications.3
Why Literature Matters for Trial Design - What We’ve Learned in Practice
Our experience working with pharma teams shows that when curated systematically, literature-derived RWE becomes a powerful tool, not just for interpreting what has already happened, but for shaping what happens next.
1. Expand Eligibility Without Sacrificing Precision
Study teams must navigate the tension between expanding inclusion criteria to accelerate recruitment or increase feasibility, while selecting for patients with the highest probability of response. Overly restrictive criteria may safeguard the chances of meeting primary endpoints but can prolong timelines, put enrollment goals at risk, and exclude plausible responders, which is especially detrimental for rare indications.
Literature-derived RWE provides broad insight into a diverse patient cohort. For rare indications especially, this can shift eligibility in meaningful ways. It supports the selection of genomic biomarkers, as for indications where genetic testing is required for diagnosis and/or enrollment, evidence within the literature often supports the reclassification of variants of uncertain significance (VUS) to pathogenic, ensuring selection of the right patients while expanding eligibility. Additionally, it drives optimized inclusion criteria, as the literature helps teams widen criteria without diluting trial quality, optimizing for both faster recruitment and greater likelihood of response.
2. Select Endpoints That Matter to Patients and Regulators
One of the biggest challenges in drug development, particularly for rare indications, is the lack of informative natural history data. Without a clear understanding of how the disease progresses over time and the impact to a patient’s quality of life or survival, it’s difficult to select endpoints that are clinically meaningful.
Too often, endpoints are selected without full consideration of the patient experience, which is a cornerstone of patient-focused drug development (PFDD). Literature-based RWE offers a deeper understanding of the disease burden, unmet needs, treatment response, and real-world patient experiences that aren’t captured anywhere else.These insights can be synthesized to ensure that endpoints reflect what actually matters - to regulators, but also to patients and caregivers.4
This helps teams anchor their endpoints in clinical reality, rather than just statistical convention, and align better with regulatory expectations around meaningful outcomes and patient-focused drug development.
3. Design External or Historical Control Groups
In many rare or high‑risk indications, including a traditional, randomized control arm may be impractical or ethically challenging. The FDA’s guidance on natural history studies emphasises that for rare indications, knowledge about the disease’s progression in the absence of intervention is often insufficient, yet critical for designing trials, including for the use of external or historical control arms.4
Here’s how literature-derived natural history data fits in: published cohorts, case series, and observational studies provide an in-depth understanding of disease characteristics, progression, and outcomes across varied subpopulations and geographies, data that might not exist elsewhere.
Additionally, when this data is systematically curated, it can form the basis of external control arms, as well as serve as a foundation for future prospective studies, helping to define populations, endpoints, and controls in subsequent trial phases, consistent with regulatory expectations.
4. Strengthen the Regulatory Case - From IND to Approval
The FDA is increasingly open to real-world evidence - especially when it’s transparent, traceable, and literature-based. In rare indications, this kind of evidence is needed early in the development process, before the IND submission, where trial design decisions are first reviewed.
Many rare indications lack robust natural history data or precedent endpoints. Literature helps fill these gaps. Curated case reports and observational studies can inform eligibility criteria, support clinically meaningful endpoints, and provide the basis for external or historical controls when traditional, randomized control arms aren’t feasible.
When trial designs are grounded in peer-reviewed evidence - not just internal reasoning - they become more credible, auditable, and aligned with regulatory expectations. For rare indications, every citation adds weight - bridging gaps and strengthening the path from idea to approval.5
Smarter Trials for the Real World
Designing a clinical trial used to mean starting from scratch. Today, it can begin with a map of what’s already known - if you know where to look.
By systematically curating published literature, trial designers can expand eligibility while keeping focus on likely responders, surface endpoints rooted in real patient experience, build external control groups from existing cohorts, and strengthen regulatory packages with transparent, citation-backed evidence.
For rare indications especially, the literature is not just a supporting character, it’s often the most comprehensive source of data available.
The Future: Every Trial Informed by Every Patient Story
As the line between clinical research and real-world care continues to blur, the published record represents a treasure trove of lived patient experience. Harnessing that knowledge does more than make trials faster or cheaper - it makes them better: more inclusive, more ethical, and more aligned with real-world practice.
The future of trial design won’t be built on data alone. It will be built on evidence - and literature ensures that no patient story is left behind.
References
- Food and Drug Administration. (2025). Real-World Evidence. U.S. Food and Drug Administration. https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence
- Clinical Programming Team. (2024). A guide to real-world evidence in clinical trials. Quanticate. https://www.quanticate.com/blog/real-world-evidence-in-clinical-drug-development
- Linder, J. E., Bastarache, L., Hughey, J. J., & Peterson, J. F. (2021). The Role of Electronic Health Records in Advancing Genomic Medicine. Annual review of genomics and human genetics, 22, 219–238. https://doi.org/10.1146/annurev-genom-121120-125204
- U.S. Food and Drug Administration. (2019). Rare Diseases: Natural History Studies for Drug Development – Guidance for Industry. U.S. Food and Drug Administration. https://www.fda.gov/media/133752/download
- U.S. Food and Drug Administration. (2018, October). Rare diseases: Early drug development and the role of pre-IND meetings: Draft guidance for industry. Center for Drug Evaluation and Research (CDER) & Center for Biologics Evaluation and Research (CBER).
