Clinical trials for rare neurological diseases are among the most complex in the industry. Traditional randomized controlled trials often face ethical, statistical, and operational challenges, making them unfeasible. For sponsors working on treatments in this area, natural history studies and external control arms serve not only as alternatives but also as practical, regulatorily accepted approaches to generate valuable evidence.

This blog examines how these strategies can be integrated early in the development process, what regulators expect at each stage, and how experienced partners can help sponsors in managing the increasing demand for real-world and patient-centered evidence. From feasibility to regulatory alignment, the right approach can de-risk development, enhance scientific rigor, and ultimately accelerate access for patients with high unmet needs.

Why Rare Neurological Trials Are So Difficult to Design

Designing clinical trials for rare central nervous system (CNS) disorders requires more than just scientific rigor; it also necessitates a comprehensive understanding of the disease. It demands strategic foresight, careful coordination, and a deep understanding of both the disease and the patient population. These trials are uniquely challenging due to a combination of clinical variability, data scarcity, and operational complexity:

• Patient populations are extremely limited and geographically dispersed, often requiring multinational enrollment efforts.
• Disease progression varies, even within the same diagnosis, making it harder to define consistent endpoints and estimate the sample size needed to demonstrate treatment effects.
• Use of placebo arms can raise ethical concerns, especially in conditions with rapid deterioration or no approved treatments.
• Baseline data for endpoints and eligibility criteria are often missing or inconsistent.
• Trial timelines are extended partly because of limited site experience with the condition.
• Regulatory expectations differ across regions. For example, the FDA has sometimes shown more flexibility (such as with accelerated approvals based on surrogate endpoints). In contrast, the EMA may require more robust data unless tools like PRIME are utilized.
• Outcome assessments are heterogeneous, with a mix of clinician, caregiver, and patient-reported measures that can limit comparability.

Given these realities, traditional randomized controlled trials are often impractical. Sponsors must explore alternative evidence strategies that meet both scientific and regulatory standards, striking a balance between methodological rigor and the flexibility required for the development of rare neurological disease trials.

Natural History Studies: Grounding the Trial in Reality

Natural history studies document the progression of a condition in the absence of treatment. They can be retrospective, such as medical record reviews or historical cohorts, or prospective, like structured observational registries. Both are essential for establishing disease baselines, defining meaningful clinical endpoints, and supporting alternative study designs when randomization is not feasible.

Prospective designs add value by standardizing outcome measures and visit schedules, reducing variability, and enhancing reliability. For example, the Enroll-HD study in Huntington’s disease has become a cornerstone for trial feasibility and endpoint selection in multiple interventional programs.

Collaborations with academic consortia, patient advocacy groups, and networks such as the Rare Diseases Clinical Research Network (RDCRN) and Critical Path Institute (C-Path) help sponsors access higher-quality data and align more closely with patient-centered research goals.

Natural history studies help sponsors:

• Select clinically relevant endpoints based on patient and caregiver experience.
• Benchmark natural disease progressions for comparison to investigational therapies.
• Identify potential biomarkers that could act as surrogate endpoints for accelerated approval pathways and gather preliminary data to support their validity.
• Design eligibility criteria based on observed rather than assumed clinical characteristics.
• Reinforce regulatory arguments when traditional controls are not feasible.

Still, natural history data has its own challenges. Issues like missing information, inconsistent visit timings, and evolving diagnostic standards require careful planning and supervision. Sponsors also need to consider how the data will be utilized later, for purposes such as providing context, adjusting eligibility criteria, or serving as an external control group.

External Control Arms: A Practical, Ethical Comparison

When randomized controls are impractical or unethical, external comparators provide a credible alternative. These are built from sources such as patient registries, medical chart data/EHRs, or even prior trial datasets (real-world data sources) that can be analyzed to generate real-world evidence. Their benefit lies in providing context for interpreting efficacy in single-arm trials, a need that is particularly prevalent in ultra-rare neuromuscular or neurodegenerative disorders.

To satisfy regulators, external control arms must closely match the treated cohort in disease severity, demographics, and outcome measurement. Statistical methods like propensity score matching and covariate adjustment are crucial to address baseline imbalances and minimize bias.

Recent approvals illustrate this approach:

• Brineura (cerliponase alfa) was approved for CLN2 Batten disease based on a single-arm trial, whose outcomes were benchmarked against untreated natural history controls (e.g., data from previous cohort studies).
• Eteplirsen, an exon-skipping therapy for DMD, received accelerated approval without a concurrent placebo arm, using increased dystrophin as a surrogate endpoint and supportive functional data from historical controls to suggest a slower disease progression.

Both cases highlight the importance of planning these strategies from the beginning, ensuring the data sources, comparison methods, and documentation satisfy regulatory requirements.

What Regulators Are Saying

Both the FDA and EMA have provided guidance on how natural history data and external controls can be used to support approval pathways, especially in cases where traditional trial designs are not feasible.

The FDA’s 2019 draft guidance on natural history studies and its 2023 draft guidance on externally controlled trials provide clear frameworks for sponsors. The agency has also established a Real-World Evidence (RWE) framework, outlining how RWE can support both primary and supplementary evidence generation.

The EMA, although generally more conservative, has demonstrated flexibility through tools like Scientific Advice and Protocol Assistance, as well as the PRIME scheme for accelerated development in areas of high need. Recent approvals, such as Zolgensma and Skyclarys, show a growing willingness to accept single-arm designs or non-concurrent comparators, especially when there is early dialogue and clear justification. For example, Skyclarys (omaveloxolone) for Friedreich’s ataxia was approved with one controlled trial plus supportive external comparator analysis.

Notably, both agencies emphasize that external controls should be planned in advance, not added later. The sooner sponsors engage in formal discussions, the greater the likelihood of gaining agreement on acceptable methodologies.

How Sponsors Can Move Smartly

Sponsors in rare CNS should adopt a strategic approach, considering both trial design and overall evidence generation. To do this effectively, they need to integrate natural history and external control strategies early on, while paying close attention to data quality, comparability, and regulatory compliance.

1. Start collecting natural history data early, preferably using a prospective design with regular assessments and visit schedules.
2. Develop external comparators with statistical and clinical input, utilizing matched cohorts, documented methodology, and predefined endpoints.
3. Ensure that external control data is of high quality and comparable. Account for differences in diagnostic criteria or standard of care over time to prevent biased comparisons (e.g., through careful cohort selection and covariate adjustment).
4. Engage proactively with regulatory authorities, including pre-IND or scientific advice meetings, to achieve alignment before finalizing the protocol.
5. Engage biostatistics expertise early on, since propensity matching, sensitivity analyses, and missing data strategies require specialized knowledge.
6. Assess data privacy and governance risks early, especially when working with registry or EHR data. Ensure full compliance with GDPR, HIPAA, and relevant data-sharing agreements.
7. Coordinate internally across clinical, regulatory, and data functions to ensure a unified strategy from trial planning through submission.
8. Partner with an experienced CRO that can support not just operations but feasibility modeling, endpoint justification, and regulatory engagement.

With deep experience in rare CNS trials across North America and Europe, TFS supports sponsors at every stage, from early feasibility and natural history strategy to biostatistics, regulatory engagement, and beyond. Learn more about our Neuroscience CRO expertise.

Final Thoughts

Natural history studies and external control arms are no longer seen as unconventional. They are essential tools for building robust, ethical, and regulatorily accepted clinical trial designs, particularly in rare neurological diseases.

As regulatory guidance matures and more successful examples emerge, these strategies are increasingly transitioning from exceptions to more common practices. Sponsors that embrace them early, with proper planning and partners, are better equipped to navigate complexity and reduce uncertainty.

Long-term success also relies on post-approval planning. Natural history platforms can support follow-up studies and safety monitoring, while registry partnerships can help extend trial insights into real-world impact, both essential factors for therapies serving underserved populations. It is important to note that regulators may grant early approvals using these data with the expectation of confirmatory trials or ongoing post-market studies, so sponsors should integrate plans for post-approval evidence generation.

TFS is committed to helping sponsors deliver better neuroscience outcomes through smarter trial design, scientific integrity, and meaningful patient alignment.

Ready to design a smarter rare CNS trial? Let’s connect and discuss how we can support your next step, from feasibility to regulatory success.