Globally, more than 7,000 rare diseases affect an estimated 263 – 446 million people (3.5 – 5.9% of the global population), of which approximately 36 million are in the European Union (EU) and over 30 million in the United States (U.S). The U.S. Food and Drug Administration (FDA) defines a rare disease as affecting fewer than 200,000 people in the country. In Europe, a rare disease is defined as one that affects five or fewer per 10,000 persons or is life-threatening, seriously debilitating, or chronic. 80% have identified genetic origins that affect 3–4% of births, while others are due to degenerative and proliferative causes. Although many rare diseases are life-threatening and still lack treatment options, fewer than 1,000 have even a minimal amount of scientific knowledge gathered.

In this article, we will cover the unique challenges and risk-mitigation strategies associated with rare diseases and orphan drug studies.

Rare Disease Clinical Trials

Development of treatment options for rare diseases is often high-risk, slow, and expensive. Challenges faced by scientists and Contract Research Organization (CRO) include complex biology and the need for more information on the natural history of many rare diseases. Further, the inherently small patient population adds to challenges in recruiting patients and conducting clinical trials.

The European Medicines Agency (EMA) plays a central role in supporting developing and authorizing drugs for treating rare diseases or conditions, known as orphan medicines. The Orphan Drug Act, passed in 1983, incentivizes the development of orphan drugs in the U.S. while the FDA plays a similar role as the EMA in encouraging the development of interventions to diagnose and treat rare diseases.

Analysts studying the market for rare disease clinical trials projected a compound annual growth rate (CAGR) of 9.7% from 2023 to 2033 and the market size reaching US$31,715.25 million in 2033. Growth was attributed to an increased focus on gene therapies, growing interest in RNA-targeted therapies, and increasing stakeholder collaboration.

Rare Disease Clinical Trial Challenges

Significant challenges for developing drugs, biologics, and devices to treat rare diseases include the complex biology of rare diseases, limited natural history data, an inherently small population of patients, and the need for standardized endpoints. Lack of epidemiologic information also hinders decision-making at the macro level.

Clinical Trial Readiness

According to the U.S. National Institute of Health (NIH), researchers often need more data on symptoms and biology of rare diseases to design clinical trials. In addition to the gaps in understanding the natural history of rare diseases, more suitable biomarkers or clinical outcome measures need to be used. The NIH National Center for Advancing Translational Sciences supports the progression of candidate therapies or diagnostics toward clinical trials through grants and other initiatives. At the same time, the Rare Diseases Clinical Research Network is a federally-directed research network in the U.S. that helps investigators move closer to rare disease treatments through the advancement of diagnosis, management, and treatment. In addition, the network promotes highly collaborative, multi-site, patient-centric, and translational clinical research in rare diseases.

Diversity and Connecting Patients to Clinical Trials

Among patients with rare diseases, some population groups face disproportionate barriers to inclusion in genetic testing in both clinical practice and research. As indicated by Frazier et al., patients who are historically marginalized are underrepresented in clinical genetic testing and genomic research studies. To improve patient care and outcomes, it is crucial to have representation in rare disease research. A multi-disciplinary approach may shed light on how patients with rare diseases navigate their condition and access care and identify effective means of engagement, e.g., regular meetings with advocacy groups, patient listening sessions, and logistical support to reduce patient burden. To improve clinical trial recruitment, there is growing interest in applying artificial intelligence (AI) to identify patients through claims data and electronic health records (EHR).

Informed Decision-making

The United Nations has made a call to find solutions for the estimated 300 million people living with a rare disease worldwide by collecting, analyzing, and disseminating disaggregated data. With accurate data, scientists can prioritize research and therapeutic development, while policymakers can make policy decisions and health system allocations to help people living with rare diseases. Prevailing methods of identifying, extracting, and using epidemiologic information on the prevalence and incidence of rare diseases are manual, time-consuming, and prone to error. A recent study by Kariampuzha et al. explored precision information extraction of rare disease epidemiology at scale. The AI model developed by the study team demonstrated high performance of epidemiologic information extraction from rare disease literature to enhance manual information management processes.

Trends in Clinical Research for Patients with Rare Diseases

Precision Medicine

Advancements in tech and genomic research enable targeted treatments and precision medicine that tailor treatment to an individual’s genetic and molecular characteristics. In rare disease research, there is a growing trend toward precision medicine in treating patients with rare diseases.

Evolving Clinical Trial Designs

Traditionally characterized by randomization and placebo groups, clinical trial design is evolving to include biomarkers, real-world data (RWD), and adaptive trials. Within a rare disease, many subtypes exist that require personalized treatment, leading to added complexities when attempting to identify and screen patients eligible for a trial. Predicting safety may also be challenging for researchers as potential treatments for rare diseases, e.g., gene editing, require different approaches to demonstrate safety and efficacy.

As the traditional clinical trial design can be ill-suited to rare disease research, modified clinical trials and using RWD are among the most promising alternatives. One of the benefits of adaptive clinical trials is that they allow for changes to the trial design based on interim data, thereby improving the efficiency of rare disease clinical trials.

Real-world Data (RWD) and Real-world Evidence (RWE)

Treatment efficacy may be determined from real-world evidence (RWE), which is increasingly used to complement traditional trial data and provide insights into the real-world effectiveness and safety of interventions across diverse patient populations and settings.

RWD, e.g., from EHRs, patient registries, and everyday metrics from wearable tech, is increasingly used to supplement rare disease clinical trial data. In June 2023, the EMA stated that RWE from regulator-led studies can complement evidence from other sources and that RWE can support pre-authorization and post-approval assessments. The FDA is committed to “realizing the full potential of fit-for-purpose RWD to generate RWE that will advance the development of therapeutic products and strengthen regulatory oversight”.

Growing Emphasis on Patient-centricity

Patient advocacy groups, researchers, and industry are increasingly collaborating to help overcome challenges in running rare disease clinical trials. Patient engagement allows a deeper understanding of the lived experience of patients and their caregivers, and patient perspectives are increasingly included in the design and implementation of clinical trials. Pediatric rare disease studies have several patient-centric approaches. For example, researchers need to consider the evolving requirements of their trial demographic over time, as rare diseases often begin in childhood.

Increasing Use of Decentralized Clinical Trials

Traditional clinical trials require participants to attend in-person visits at centralized clinical research sites for tests and procedures. Participating in clinical research can be especially burdensome for patients with rare diseases who require caregiver assistance and are scattered in distant locations, having to travel to clinical research sites. Inclusive and patient-centric, decentralized clinical trials (DCTs) can reduce participant burden and increase the quality of rare disease clinical trials. Further, researchers can cast a wider net, and provided the trial complies with regulatory and ethical requirements, they can enroll more patients with DCTs.


Contributed by:

TFS HealthScience is a leading global mid-size Contract Research Organization (CRO) that partners with biotechnology and pharmaceutical companies throughout their clinical development. TFS HealthScience Rare Diseases and Orphan Drugs has worked with various compounds, including small molecules and biologics, across all phases of clinical development and real-world evidence studies. We understand these studies unique challenges and have specific strategies to mitigate risks. These include country-specific regulatory strategies, recruitment strategies geared toward rare patient populations, investigator site training, and specialized communications. In the last five years, TFS has been involved in more than 70 studies in multiple indications. Contact us today to learn more.

Categories: Health

Nicolas Desjardins

Hello everyone, I am the main writer for SIND Canada. I've been writing articles for more than 12 years and I like sharing my knowledge. I'm currently writing for many websites and newspapers. I always keep myself very informed to give you the best information. All my years as a computer scientist made me become an incredible researcher. You can contact me on our forum or by email at [email protected].