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December 2, 2022

Designing successful rare disease clinical trials

An overview of challenges in trials for orphan drugs and how technology can help overcome them.
rare disease clinical trials

Despite their moniker, rare diseases affect about 350 million people worldwide. Patients and families affected by rare diseases can spend years searching for a diagnosis, let alone treatment; on average, rare disease patients see seven doctors over nearly eight years in their search for answers. One of the reasons behind the dearth of available treatments for rare conditions is a lack of successful rare disease clinical research, clinical development, and clinical trials.

In this article, we’ll discuss the primary challenges in rare disease research and clinical trials, how companies can overcome them, and new technologies that can support orphan drug manufacturers in designing clinical research and conducting clinical studies for rare disease treatments.

5 common challenges for rare disease clinical trials

Rare diseases research and clinical trials present many challenges, regardless of the potential new treatment being studied or the patient population involved. However, clinical trials for orphan drugs to treat rare conditions have an additional layer of difficulty, making the process more time-consuming. Related: learn about increased funding for rare disease clinical trials.

Trial design and patient recruitment

The nature of rare diseases research means there is a limited patient population available for study. Designing a feasible, scientifically sound clinical development and trial can be challenging. Because a disease is rare, there might not be a consensus on diagnostic criteria, making it difficult to recruit enough patients to conduct a meaningful study. There are also ethical issues around clinical trials for rare diseases, including the potential to expose a vulnerable population of rare disease patients to potentially harmful treatments.

Lack of data, no standard of care

There is often a limited amount of information available about the natural progression of rare diseases, and therefore, it’s difficult for trial sponsors to determine an appropriate endpoint for a clinical trial.

“In developing therapeutics for orphan diseases, it is critical to ensure that the clinical study endpoints will measure how the drug impacts the patient’s disease progression.” – GlobalForum

For most rare diseases, there is also no generally accepted standard of care or standard treatment for the condition. This makes it challenging to design rare disease research and trials that accurately reflect an experimental drug’s true benefits and compare the new treatment with a control group.


Clinical trials for orphan drugs are expensive due to the limited patient pool, the need for specialized expertise, and the development of unique study designs. There may also be limited funding available to support rare disease trials because the return on investment is not as robust as developing treatments for more common diseases.

Regulatory hurdles

Getting regulatory approval for orphan drugs is even more complex and time-consuming than treatments for more common diseases. This is usually related to the unique nature of the disease and lack of information about it, plus the limited patient population.

Difficulty in scaling production

Even if an orphan drug trial is successfully completed, the drug developer may have difficulties in scaling up the production and distribution of the orphan drug to meet patient needs. This can be affected by the geographic distribution of patients worldwide, some in areas that are outside the reach of a company’s established supply chain. Quality can also be a concern, according to Dr. Ke Chen, VP, Head of API Late-Phase Process R&D for WuXi STA: “Scaling up the processes for a low-volume drug can be challenging…which, in turn, lead to inconsistency in performance and even in quality.”

Overcoming common challenges

Despite the challenging outlook for orphan drug trials, trial sponsors do have options. Some of these include:


To overcome the challenge of limited patient populations, “…collaboration with patient advocacy organizations can provide essential patient education and awareness, and these groups are also often able to identify suitable study investigators.” Forging good relationships with patient and caregiver advocacy groups can also benefit trial sponsors when they are ready to develop educational materials or perform other types of patient engagement. (Related: learn about how one pharma team conducted a rare disease preceptorship.)

Innovative trial designs

Life science companies should look beyond the limitations of traditional randomized clinical trials to overcome challenges related to a limited study population and the ability to measure efficacy. One option is the use of adaptive trials:

“Adaptive designs can make clinical trials more flexible by using results accumulating in the trial to modify the trial’s course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative, and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants.”

Patient registries

Patient registries – databases that contain information about patients and their medical history – are used by HCPs to help inform decisions about treatment pathways for a specific person or a group of people. These registries are useful for rare disease drug development because they include data from a large number of sources.

Registries can be helpful in the development of orphan drugs by providing trial sponsors access to clinical, genetic, and biological data from a patient population, so that sponsors can better understand a rare condition or rare disease, its history, and patient needs – all of which can be used to design more effective clinical trials.


Companies can use technology, like telemedicine, remote monitoring, and insights management platforms to overcome the challenges of limited infrastructure and conduct more efficient and cost-effective clinical trials.

How to design and plan a successful clinical trial

Given the challenging outlook around clinical trials for orphan drugs, it’s critical that pharmaceutical companies create a strategic plan for orphan drug development. It’s in trial sponsors’ best interest to have an effective approach – the orphan drug market is forecast to grow at a rate of 12.3% through 2024, nearly double the rate forecast for the non-orphan drug market.

Here are the key steps that a company should consider when designing an orphan drug trial:

  • Define the patient population
  • Determine the endpoint
  • Select the study design
  • Identify trial sites
  • Obtain regulatory approval
  • Recruit patients
  • Monitor the trial
  • Plan for post-approval

By following these steps and working closely with stakeholders, a pharmaceutical company can design and plan an orphan drug trial that is scientifically rigorous, ethically sound, and optimized for success.

Technology to ensure successful orphan drug clinical trials

Technology can overcome many of the challenges unique to orphan drug trials. Telemedicine can be used during the enrollment process or the trial to negate some of the logistical challenges inherent to rare disease trials, as can electronic data capture (EDC) and electronic patient-reported outcomes (ePRO) systems. Reliance on these technologies can also help to reduce errors and improve data quality overall during rare disease drug development.

Artificial intelligence (AI) has applications in many aspects of drug development for both common and rare diseases. Applying AI to large data sets can support patient identification, trial site selection, and data analysis, and it can also shorten timelines by performing analysis in a shorter amount of time than manual processes.

AI tools are a component within insights management platforms, which can be used to manage nearly all aspects of the insight generation process during drug development, launch, and post-market monitoring. Insights management platforms unify a number of typically disparate processes that support the insights generation process, including identifying trial sites, finding rare disease experts, gathering input on protocol design and desired endpoints, and sharing directional information to drive business decisions.

By centralizing these typically disconnected activities in a single platform, trial sponsors can be more streamlined and focused on saving time and avoiding pitfalls during the trial design and execution process.

Learn more about how life science companies can engage patients to provide valuable information during the rare disease trial design process in our client’s success story.

Express Scripts. Getting to the rare diagnosis: 7.6 years and 7 different doctors.
GlobalForum. Rising to the challenges of developing rare disease treatments.
DCAT Value Chain Insights. CDMO Roundtable: Managing Orphan Drug Products.
BMC Medicine. Adaptive designs in clinical trials: why use them, and how to run and report them.
Biorasi. The power of patient registries: how to collaborate with patients to enhance orphan drug research.

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