Rare diseases are sometimes referred to as “orphan diseases” because their rarity often means they generate hardly any attention or funding. Patients with orphan diseases suffer the double setback of the inability to live a normal life and a diminished hope for a cure. 

In the United States, a definition adopted in the 1980s described a rare disease as any condition that affected fewer than 200,000 individuals in the country. This roughly constituted about 1 in 1200 people at the time, but this ratio is not considered “rare” by today’s standards. International definitions vary; in 2015, the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Rare Disease Special Interest Group categorized orphan diseases as those affecting fewer than 1 in 2500 individuals.

It is important when discussing patients with rare diseases that we do not imagine them to be a homogenous group lumped together at the perimeters of society. The US Food and Drug Administration states that “over 7000 rare diseases affect more than 30 million people in the United States.” Carlo R. Ferreira of the National Human Genome Research Institute wrote, “Rare diseases, although individually rare, collectively affect a significant proportion of the general population.” In other words, these patients are our family, neighbors, and friends. 

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Much more can be said about the need for the equitable distribution of resources into medical research so that orphan diseases do not lead to “orphan patients”—patients cut off from the support they need to thrive the best they can. However, we will leave that discussion for another day and instead turn our attention towards a more positive angle of this phenomenon: how research into orphan diseases can incidentally drive positive changes in the design of clinical trials of more common neurological disorders. 

Breaking Ground in Neurological Research 

In the world of neurological disorders, whether rare or otherwise, there is a consensus among scientists that the development of new therapies needs to catch up to what is possible to achieve technologically. What hinders this is the fact that clinical trials involving neurological diseases are highly prone to failure. 

Stephenson and colleagues wrote in Clinical Pharmacology and Therapeutics, “Three relentlessly progressive diseases, amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), and Parkinson’s disease are in urgent need of new treatments.” These diseases carry a poor prognosis, with or without treatment. 

Read more about DMD epidemiology 

So we need advancements in the therapeutic options of these diseases quickly, but medical research, by nature, is tedious and bureaucratic (not to mention the approval process from regulatory authorities). However, Stephenson et al pointed to the speedy, record-breaking development of COVID-19 vaccines as an example of what is possible when the medical world is united, research is properly funded, and the government is on board. 

Using the widest possible definition, both DMD and ALS can be classified as orphan diseases. Some might argue that they no longer qualify since so much research has been devoted to both disease areas in recent years. However, a look back at history demonstrates that this was not always the case. Stephenson et al wrote that “just 20 years ago there were few trials being conducted” and that currently “there are insufficient numbers of patients to enroll across these trials.” 

Read more about DMD treatment 

These 2 diseases are unique in that they both cause relatively rapid deterioration in most clinical parameters. In other words, effective drugs need to be administered as soon as possible if we are to offer patients the hope for better survival and quality of life. This, and the fact that the pool of participants is small, have influenced the design of clinical trials. 

This allows scientists who are investigating more common neurological diseases to draw inspiration from how these clinical trials are designed (with all the imposed limitations) and then proceed to design better experiments that yield better data.

“Insights gained from analysis of clinical trial data across the spectrum of success can accelerate research progress that can, in turn, drive the design of innovative clinical trials,” Stephenson et al wrote. ”DMD and ALS clinical trials are paving the way for groundbreaking and collaborative strategies applicable to many other areas and to the benefit of patient communities and public health.” 

A Changing Tide in Clinical Trials 

Let’s talk briefly about clinical trial designs. If you review recent and ongoing clinical trials, it is hard not to conclude that they are changing, slowly and subtly, and adjusting to the opportunities and limitations of our age. 

Kruizinga and colleagues, in their study on the future of clinical trial design, believe that we are transitioning from hard endpoints to value-based endpoints. Their thesis is that hard endpoints can quickly fall out of date with the advent of newer technologies.

In the Handbook of Experimental Pharmacology, they wrote, “Value-based clinical trials will use technology to focus more on symptoms and endpoints that patients care about, will incorporate fewer research centers, and will measure a state or consequence of disease at home or at work.” This will enhance data collection, provide for better inclusion of marginalized groups, and reduce the burden for participants. 


Ferreira CR. The burden of rare diseases. Am J Med Genet A. 2019;179(6):885-892. doi:10.1002/ajmg.a.61124

Stephenson D, Ollivier C, Brinton R, Barrett J. Can innovative trial designs in orphan diseases drive advancement of treatments for common neurological diseases? Clin Pharmacol Ther. Published online January 16, 2022. doi:10.1002/cpt.2528

Kruizinga MD, Stuurman FE, Groeneveld GJ, Cohen AF. The future of clinical trial design: the transition from hard endpoints to value-based endpoints. Handb Exp Pharmacol. 2019;260:371-397. doi:10.1007/164_2019_302

Richter T, Nestler-Parr S, Babela R, et al. Rare disease terminology and definitions—a systematic global review: report of the ISPOR Rare Disease Special Interest GroupValue Health. 2015;18(6):906-914. doi:10.1016/j.jval.2015.05.008

Rare diseases at FDA. US Food & Drug Administration. Accessed March 16, 2022.