Conducting Clinical Trials for Rare Diseases

By Yuki Agarwala

Clinical trials are designed to understand the clinical outcome of particular drugs by observing human subjects in controlled experimental conditions. Clinical trials are conducted with a variety of subjects whose treatments are randomized to limit the inherent confirmation bias of receiving treatment. This allows scientists to determine causality in randomized controlled trials (RCTs). Due to volunteer availability, clinical trials may not always be representative of the broader population, and this could be due to multiple factors such as health status, attitudes and beliefs, or socioeconomic status. As a result, the efficacy of an experimental treatment during controlled conditions in clinical trials may not always translate into “effectiveness” in the real world. However, clinical trials are often designed to eliminate most confounding variables, and are conducted in multiple stages to determine the safety and efficacy of a treatment (Umscheid et al., 2012). 

In preclinical investigations, animal studies are conducted to determine the purity of the treatment and dosage, the mechanism of drug action, and its link to clinical responses. Based on these results, if the treatment is approved for human trials, drugs then undergo phase I trials, whereby the safety and maximum tolerated dose of the drug as well as pharmacokinetics and pharmacodynamics are determined. During phase I trials, healthy and diseased volunteers undertake the treatment in an open-label study. In phase II trials, a larger number of participants are recruited to better elucidate the safety, mechanism, and dynamics of the drug, but it could also be used to identify the optimal doses, frequency, administration routes, etc. Randomization of the control and drug arms, as well as trials of patients administered with different doses can provide early evidence of the drug’s efficacy. The phase III trials’ main objective is to determine the actual drug efficacy, which requires the recruitment of a more diverse and larger group of subjects. Drug efficacy is often determined by comparing the results of a placebo to that of the drug arm. However, because the size of these trials is limited to 300-3,000 people, phase IV trials are required to determine less common adverse reactions, and to evaluate the costs and drug effectiveness for a range of factors such as different populations and diseases. Most drugs are approved after phase III trials, but some require phase IV trials for approval (Umscheid et al., 2012; Freidman et al., 2015).

Given that the clinical trial process relies heavily on the recruitment of both healthy and diseased volunteers, clinical trials for rare diseases can be particularly challenging. According to the US Food and Drug Administration (FDA), a disease is considered “rare” if its prevalence is less than 200,000 people in the US. Using this definition, there are over 7,000 rare diseases that affect 25-30 million people in the US. The Orpha Drug Act also considers a disease “rare” if the costs of developing and implementing a drug for the disease in the US outweigh the gains from sales, despite over 200,000 people having the disease (Griggs et al., 2009). The European Union considers a disease “rare” if less than 5 per 10,000 people have the disease (IRDiRC, 2013). Thus, trials are challenging because they need to be set up in multiple countries to recruit a large enough number of volunteers. This means that the differing regulations for trials in each country need to be adhered to, which presents more logistical challenges. Due to the limited affected population, it can also be very difficult to maintain anonymity for such clinical trials, and the patients are often prone to discrimination from society, including their employer and insurance company (Griggs et al., 2009; Crow et al., 2018). Because of the sheer lack of patients who suffer from such diseases, conducting RCTs – the gold standard for clinical trials – is often made very difficult because of the challenges in recruiting patients, the extended time required for such studies, and the costs associated with international trials. 

Even if RCTs are conducted, there could be variation in disease severity requiring further categorization and investigation, thus limiting the data available to accurately draw conclusions. As a result, clinicians are often left to rely on observational studies, but an alternative method known as the Bayesian method has been proposed. In this method, RCTs are still conducted to change the level of certainty, despite not being able to yield a definitive answer around drug efficacy. The usual approach results in a P value that determines the probability of an event happening given the null hypothesis is true. The Bayesian approach, however, provides the probability of the range in which the clinical effect lies. For example, a Bayesian trial could conclude that the possibility of a particular treatment reducing mortality by at least 50% is 0.2, 25% is 0.5, and so on. In normal trials, a definitive answer is available for the exact efficacy of a drug based on a distribution created from a drug having no effect (null hypothesis). Due to the fewer numbers of patients recruited for rare diseases, the strength of the Bayesian method lies in its ability to determine the probability of a particular clinical outcome, which can still be used for clinical decisions. Although small clinical trials could lead to misleading results, having RCTs provides confidence that the data is free from any inherent biases, which is critical for making informed decisions (Lilford et al., 1995; Ursino & Stallard, 2021). 

Conducting clinical trials for rare diseases is difficult compared to regular drugs because clinicians need to ensure that the drug undergoes the same degree of thoroughness in testing for implementation in patients. Efforts are underway to facilitate international collaboration for setting up studies for rare diseases, but these require time and coordination amongst many countries. Even then, it is important to consider other approaches such as the Bayesian approach which would allow for RCTs of drugs for rare diseases, while adhering to the same stringent protocol. While the exact drug efficacy cannot be determined through this method, scientists can draw conclusions about the probability of a clinical outcome from the trials, which would be helpful to clinicians in making choices regarding drugs for their patients with rare diseases. 


Umscheid, C.A., Margolis, D.J. & Grossman, C.E. (2012) Key Concepts of Clinical Trials: A Narrative Review. Postgraduate Medicine. [Online] 123 (5), 194–204. Available from: doi:10.3810/pgm.2011.09.2475.

Freidman, L.M. et al., 2015. Fundamentals of Clinical Trials, Switzerland: Springer International Publishing. Available at:

Griggs, R.C. et al., 2009. Clinical research for rare disease: Opportunities, challenges, and solutions. Molecular Genetics and Metabolism, 96(1), pp.20–26.

IRDiRC, 2013. International Rare Diseases Research Consortium Policy Guidelines. Available at: [Accessed June 6, 2021].

Crow, R.A. et al., 2018. A checklist for clinical trials in rare disease: obstacles and anticipatory actions—lessons learned from the FOR-DMD trial. Trials, 19(1).

Lilford, R.J., Thornton, J.G. & Braunholtz, D., 1995. Clinical trials and rare diseases: a way out of a conundrum. Bmj, 311(7020), pp.1621–1625.

Ursino, M. & Stallard, N., 2021. Bayesian Approaches for Confirmatory Trials in Rare Diseases: Opportunities and Challenges. International Journal of Environmental Research and Public Health, 18(3), p.1022.

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