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A sick young girl sits in a hospital bed as her doctor uses a stethoscope to check her heart and lungs. The child's mother is sitting next to the bed and is holding her daughter's hand, providing support and comfort.
The gold standard for evaluating new therapeutics is through randomized clinical trials, where one group of individuals receives treatment while another does not.

Data-Driven Approach May Replace Rare Disease Clinical Trials

Rare diseases may be difficult to study and monitor for long periods due to small sample size and low occurrence

The Hospital for Sick Children

The Hospital for Sick Children (SickKids), affiliated with the University of Toronto, is Canada's most research-intensive hospital and the largest centre dedicated to improving children's health in the country.

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Published:Mar 01, 2024
|3 min read
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Using a novel methodology, researchers at The Hospital for Sick Children (SickKids) are the first in pediatric research to use data from an international real-world cohort to overcome the barriers associated with conducting randomized clinical trials (RCTs) in children with rare diseases. 

The gold standard for evaluating new therapeutics is through RCTs, where one group of individuals receives treatment while another does not. Unfortunately, conducting this type of clinical trial proves challenging for many rare conditions due to the limited number of individuals with the condition, making meaningful comparisons difficult. Additionally, in pediatrics, it can be unethical to give a potential treatment to some children and not others.  

In a study published in Hepatology, a team of SickKids scientists discussed an innovative and robust statistical approach that may eliminate the need for traditional RCTs, demonstrating the effectiveness of a medication in reducing disease progression and liver transplants in children with Alagille syndrome (ALGS).  

“By using a global database, we were able to mimic high-quality clinical trial results by comparing present-day outcomes to historical data,” says Dr. Binita Kamath, MBBChir, MRCP, MTR, senior associate scientist in the Developmental & Stem Cell Biology program and principal investigator and senior author of the study. “Not only do our findings show a marked improvement in liver-related outcomes for children with ALGS treated with this medication, but they also present a path forward for randomized clinical trials for other rare diseases.” 

Existing medication reduces risk of liver-related outcomes 

ALGS is a rare genetic disorder in which a patient has an inadequate number of bile ducts, which usually drain bile from the liver into the intestine. The bile then builds up and causes liver damage. Around 60–75 percent of patients with ALGS undergo a liver transplant before they reach adulthood. 

Due to the rarity and severity of the condition, clinical trials have historically been difficult to conduct, especially over longer durations of time, since it is unethical and not feasible to have children take a placebo for several years.   

In a previous study describing an international cohort of children with ALGS, Kamath and Shannon Vandriel, BSc, program manager, established an international database of clinical, genetic, and laboratory data in children and young adults with ALGS called The Global ALagille Alliance (GALA) study. 

In this study, using the data of 469 untreated patients from GALA, the research team was able to compare their long-term outcomes to 84 children being treated with maralixibat, a medication approved in the US and Europe and recently in Canada for symptomatic relief of the severe itching experienced by patients with ALGS.  

Using this innovative approach, the research team found that over six years, children taking maralixibat showed a 70 percent improvement in event-free survival and a 67 percent improvement in transplant-free survival.  

“While the current indication for maralixibat is for itching, our data showed that over a longer period, the medication actually reduces the rate of liver transplants in patients with ALGS,” says Kamath, who is also a staff physician in the Division of Gastroenterology, Hepatology and Nutrition. 

Laying the groundwork for other clinical trials 

In addition to these benefits, the methodology used by the research team has critical implications for developing and implementing clinical trials for patients with rare diseases. Kamath and Vandriel believe similar approaches could be applied to any rare disease with enough historical data.  

"Our research provides an alternative to the challenges associated with recruiting patients with life-threatening conditions or debilitating symptoms for long-term clinical trials,” says Kamath. “While our study was specific to patients with ALGS, I hope this sparks a renewed interest in international databases of individuals with rare diseases which can provide real-world data that can be used to help evaluate new therapies.”

- This press release was originally published on The Hospital for Sick Children (SickKids) website