Experts address clinical challenges for ultra-rare diseases at BIO

Regulatory NewsRegulatory News | 11 June 2020 |  By 

A panel of experts at BIO Digital on Wednesday discussed some of the challenges and regulatory considerations for sponsors developing treatments for ultra-rare diseases where clinical trials could involve a very small number of patients.
When asked where companies should begin their development for extremely rare diseases, Brad Glasscock, global vice president and head of global regulatory affairs at BioMarin said, “First and foremost I think is understanding whether anybody has been there before. Is there past precedent available, either directly in the disease of interest or a related disease,” and emphasized the importance of natural history data and understanding the patient perspective.
Glasscock said that FDA’s recent guidance on patient-focused drug development has helped integrate the patient perspective into BioMarin’s product development strategy.
“We’re seeing that play a bigger part in our regulatory strategies and bringing it earlier into the process so that we ensure we’re developing drugs and interventions that are most responsive to the needs and desires of the patient community,” he said.
Glasscock pointed to the challenges BioMarin faced in getting its drug Brineura (cerliponase alfa) approved to treat CLN2, a form of Batten disease in 2017. At the time, “A lot of those things didn’t exist. What we saw was a disease for which there were no treatment guidelines, no available therapies, no biomarker available to leverage. What we did have was an animal model which enabled some early preclinical work to give us confidence that we were hitting the right target and available natural history, which we had to do actually quite a lot of work on to get it to the level of the standards in which health authorities found it to be a compelling source of comparison,” he said.
Laurie Halloran, CEO of Halloran Consulting Group, said companies working in the ultra-rare disease space need to work closely with patient groups to develop products effectively.
“The patient foundations are huge. They’re pretty much the place you have to go. You must have their input and their support to get anything done,” she said. Halloran also said that companies often underestimate the resources they’ll need to study a drug and complete postmarketing follow-up studies.
Sudhir Agarwal, founder and president of Arnay Sciences, concurred, saying, “The foundations … bring the patients together, they bring the expert researchers and clinical community together, and then they together generate the data.”
Understanding the underlying cause of a disease and identifying potential clinical biomarkers is key, Agarwal said, adding that the goal at first could be to halt disease progression rather than to improve clinical symptoms. “Many of these rare diseases will go through a process of disease stabilization then to improvement,” he said.
When building a case for regulatory approval, Glasscock said it is especially important to look at the totality of evidence when dealing with small patient populations.
“If you’re lucky you have a statistically significant result on a primary endpoint of clinical relevance,” Glasscock said, but if not, “You really need to draw on all lines of evidence you have available to you to craft that benefit-risk story for regulators and expect that they are going to have a number of questions and pushback.”
Glasscock added that, “With respect to the statistical analysis approach to these things, we also try to employ orthogonal methods and different approaches and different methodologies to show that you didn’t just get lucky because of the method you used or the test you applied, but when you look at these other sensitivity analyses or subgroup analyses that the results are durable and robust and stand up to scrutiny.”
Halloran also emphasized that patient retention is a major factor for maintaining statistical validity in small trials, saying sponsors should “really pay attention to retention, because if patients don’t continue and don’t complete then your dataset might be lost with one or two dropouts.”
Glasscock concurred, adding that, “The best way to deal with missing data is to not have it in the first place.”


© 2023 Regulatory Affairs Professionals Society.

Discover more of what matters to you

No taxonomy