The Future of Rare Disease Clinical Trials: Trends and Predictions for CROs

Rare diseases are defined by the US Food and Drug Administration (FDA) as conditions that affect no more than 200,000 individuals nationwide (prevalence of approx. six per 10,000) and by the European Medicines Agency (EMA) as conditions that affect fewer than five in 10,000 people. There are over 7,000 distinct rare diseases; most are genetic (80%) and are either life-threatening or severely disabling. Globally, close to 300 million people have a rare disease, yet most rare diseases have no approved treatments.

Current treatments are available for less than 6% of rare diseases and are usually supportive rather than disease-modifying. Scientific advances in the genetics and mechanisms of many rare diseases with previously unknown etiologies are welcome news for patients, clinicians, and research communities running rare disease clinical trials and developing disease-specific treatments. Over the past four decades, the number of rare-disease drugs has increased more than fourfold and is still growing, indicative of the expansion of novel drugs and biologics for rare conditions.

Rare Disease Clinical Trials Market

Commercial interest in rare-disease treatments has increased in light of scientific advances and legislation that incentivizes drug development. The sale of orphan drugs is projected to snowball from US$119 to $217 billion by 2024, with an associated increase in demand for rare disease clinical trials.

A recent report estimated the value of the global rare disease clinical trials market at US$11.5 billion in 2022 and projects a compound annual growth rate (CAGR) of 9.7% from 2023 to 2030. Growth factors include improvements in personalized medicine, availability of cell and gene therapies, and increased funding for rare disease clinical trials from pharmaceutical and biotech companies and non-profit organizations.

The rare disease clinical trial report also attributes market growth to the lack of approved drugs for rare diseases (as mentioned above). Further, the COVID-19 pandemic disrupted rare disease clinical trials resulting in delays in the approval of new treatments and drugs.

Rare diseases by phase

In 2022, Phase II trials constituted the largest share (42.6%) of rare disease clinical trials; however, Phase III trials are expected to grow the fastest (CAGR of 10.3%) over the forecast period (2023 – 2030).

Rare diseases by therapeutic area

Oncology had the largest share (33.9%) of rare disease clinical trials. Growth factors include the high number of approvals for rare cancer drugs, the increase in oncology clinical trials, and the growing interest of researchers in rare cancer treatment. The infectious diseases segment is expected to grow fastest, with a CAGR of 10.6%.

Rare diseases revenue by sponsor

In 2022, the pharmaceutical and biopharmaceutical companies had the largest revenue share of 58.5%. The non-profit organization segment was projected to grow fastest at a CAGR of 9.9% during the forecast period. Non-profit organizations like the National Organization for Rare Disease (NORD) and other public organizations actively fund rare disease clinical research. To this end, the FDA awarded 19 grants for clinical research on rare diseases in October 2022.

Rare diseases revenue by region

In 2022, North America had the largest revenue share (49.3%), attributed to growing expenditure on orphan drugs, favorable reimbursement policies, and major market players developing innovative products. The Asia Pacific region is projected to grow fastest at a CAGR of 10.6% during the forecast period.

Clinical Research Challenges & Opportunities

The design and delivery of rare disease clinical trials have specific considerations for researchers, patients, sponsors, and regulators. The design of rare disease clinical trials requires an appropriately powered sample size, control group, validated biomarkers, and clinically meaningful outcome measures. For rare diseases, Pizzamiglio et al. (2022) presented strategies to address the methodological challenges posed by these constraints.

Trial Design

With limited potential participants and phenotypic heterogeneity in rare diseases, the randomized control trial (RCT) gold standard may not be achievable. Natural history studies help identify patient populations, identify clinical outcome assessments and biomarkers, and design externally controlled studies.

  • Limited or non-existent treatment options – patients usually prefer access to an active intervention instead of potentially receiving a placebo. To address this: cross-over studies and studies with an open-label extension.
  • Diseases with high morbidity and mortality raise ethical considerations about using a placebo. Enrichment approaches can select trial participants most likely to demonstrate any treatment effect.

Pizzamiglio et al. (2022) propose major clinical trial design options for rare diseases.

  • Cross-over maximizes the number of on-treatment participants
  • Delayed start whereby all participants receive active treatment
  • Randomized withdrawal reduces the time of exposure to ineffective treatment and placebo
  • Group sequential reduces the sample size, has the potential for identifying early efficacy, and is a flexible methodology
  • Adaptive trial reduces the sample size, increases the probability of receiving the most effective treatment, and is a flexible methodology

Limited trial participants – to address this challenge

  • Natural history data helps in the identification and stratification of appropriate trial participants
  • Multicentre. For sufficient patient recruitment, many rare disease clinical trials are multicentre, even in phase I and phase II
  • Single-patient studies in rare diseases generate data that can be included in a metanalysis
  • The trial duration was extended to increase events captured per patient
  • Reduce disease heterogeneity by identifying and selecting participants who are likely to respond to treatment
  • Comprehensive patient registries with phenotypic and genotypic data, where relevant

Control groups

  • External controls – when the disease is severe with no alternative treatment or when a placebo is inappropriate. External controls can be either from observation before enrollment or from cohorts from published or registry data. To minimize bias, concurrent external controls are preferred.
  • Natural history data can be used as the control, but only if the two groups have similar disease characteristics.


Selection of meaningful and relevant endpoints requires understanding the disease’s natural history and the expected trajectory with the standard of care or no intervention. According to FDA guidance, natural history studies can benefit rare disease drug development.

Outcome measure selection should reflect relevance and significance for the patient, e.g., reduced requirement for daily care. However, for many rare diseases, the magnitude of change in a parameter that is meaningful for patients has not been explored. Continuous outcome variables are increasingly used over binary or hard clinical endpoints as the percentage change of a continuous measurement is preferred.

Biomarkers and outcome measures

  • Surrogate endpoints. Biomarkers serve as surrogate endpoints and help predict an intervention’s clinical benefit or harm.
  • Natural history data help in the development and validation of biomarkers and clinical outcome measures
  • Time to market. Changes in biomarkers may precede clinical parameters, and their inclusion can shorten the time to market authorization, e.g., biomarkers applied in pivotal studies have led to drug approval.
  • Despite their advantages, biomarkers often reflect a single pathophysiological pathway and overlook other relevant data.

Quantitative Model-based approaches, e.g., disease progression modeling, artificial intelligence (AI) and machine learning (ML), and advanced statistical approaches in natural history data and real-world data (RWD), improve disease understanding, thereby guiding efficient clinical study design.

Rare Disease Clinical Trials Ecosystem

Advancements in technology, regulatory frameworks, and patient advocacy have led to the emergence of a rare disease clinical trial ecosystem that strives to overcome challenges and accelerate the development of therapies for rare diseases. In this section, we will explore the key components of this ecosystem and their impact on rare disease clinical research.

Rare Disease Community

Pizzamiglio et al. (2022) assert that partnerships between academia and industry facilitate optimal trial design through the stratification of patients and optimization of participation and treatment effect measurements. However, Denton et al. (2022) believe that the rare disease community, which includes patients, industry, sponsors, and academic medical centers, has an increasingly fragmented structure. Further, prevailing operating models hamper its ability to fully benefit from advancing genomic and computational technologies. The authors propose steps to cultivate and accelerate innovation through non-proprietary patient registries, greater data standardization, global regulatory harmonization, and business models encouraging data sharing and research collaboration.

International collaboration

International collaboration through organizations like the International Rare Disease Research Consortium (IRDiRC) unites national and international governmental and non-profit funding bodies, researchers, industry, and umbrella patient advocacy organizations to drive progress in rare disease clinical research worldwide.

Patient Advocacy and Engagement

The patient’s voice is vital in determining meaningful outcomes. Patient groups include the Genetic Alliance UK or NORD in the US. Leading rare disease contract research organizations (CROs) invariably have engagement and partnerships with patient organizations.

Collaboration Between Patient Organizations and Sponsors

A recent study examined such associations and found that they helped identify and address the unmet needs of patients and their caregivers, thereby improving participant experience


The Orphan Drug Act of 1983 incentivized pharmaceutical companies to develop treatments for rare diseases, including market exclusivity and tax break. Similar legislation passed in the EU, Asia Pacific, and elsewhere.

Regulatory bodies

Regulatory bodies have begun to acknowledge that endpoint selection for rare diseases may not be straightforward, and a rare disease’s natural history is crucial. The FDA has supported a fast-track program for rapid acceleration of rare disease phase III trials and drug approval.

The Vial Rare Disease CRO

Rare diseases can cause significant emotional and financial strain on affected individuals and their families. Vial is a next-generation CRO that delivers faster, more efficient clinical trials that enable scientists to develop effective therapies to improve patients’ quality of life. The Vial Rare Disease CRO aims to streamline clinical trials to help scientists discover how to slow disease progression, or even cure the disease at affordable rates. For more on the Vial Rare Disease CRO, click here or contact a Vial team member today.

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