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FDA Issues Sanfilippo Syndrome Drug Development Guidance

Posted 04 February 2020 | By Michael Mezher 

FDA Issues Sanfilippo Syndrome Drug Development Guidance

The US Food and Drug Administration (FDA) on Tuesday issued draft guidance making recommendations to drugmakers looking to develop products to treat the rare disease mucopolysaccharidosis type III (MPS III), also known as Sanfilippo syndrome.
“There are no approved therapies to treat this disease and we hope that this guidance will foster greater efficiency and consistency among drug development programs, and ultimately benefit patients,” said Center for Drug Evaluation and Research Director Janet Woodcock.
Sanfilippo syndrome is the most common form of mucopolysaccharidosis, a rare and life-threatening autosomal recessive disorder, that is estimated to affect between 0.28-4.1 per 100,000 live births. The condition is caused by an enzyme deficiency in one of four enzymes involved in breaking down glycosaminoglycan (GAG) heparan sulfate (HS) in lysosomes and is broken into four subtypes based on the deficient enzyme.
FDA says that children with Sanfilippo syndrome appear healthy at birth but begin to display symptoms between ages 2 and 6. “As the disease progresses, children typically develop behavioral problems and gradual loss of developmental and cognitive skills. It may take years for children to receive a diagnosis for MPS III due to the rarity of the disease and the nonspecific initial symptoms,” FDA writes.
Within the guidance, FDA makes recommendations for clinical trial eligibility criteria, trial design and endpoint selection for companies looking to develop treatments for Sanfilippo syndrome.
When enrolling patients, FDA says that sponsors should ensure that patients have “clinical signs and symptoms consistent with a diagnosis of MPS III,” that are confirmed through biochemical and genetic testing. FDA also says that patients should ideally be enrolled in the early stages of the disease, “before irreversible neurological damage has occurred.”
FDA encourages sponsors to conduct “appropriately designed and executed” natural history studies, which the agency says, “could provide crucial information to help guide and inform essential aspects of a clinical development program.”
Due to the rarity of Sanfilippo syndrome, FDA says that a single adequate and well-controlled trial along with confirmatory evidence is sufficient to support traditional approval. However, in situations where a large treatment effect is not expected, FDA says it “strongly recommends a randomized, parallel group trial design with an appropriate concurrent control group,” noting that sponsors “should use randomization as early as in the first clinical trial involving MPS III patients to allow for maximal use and most efficient use of efficacy data for regulatory purposes.”
FDA also says that externally controlled trials may be acceptable once natural history information for Sanfilippo syndrome is available or when a large treatment effect size is anticipated.
For efficacy endpoints, FDA says sponsors “should assess multiple, distinct clinical endpoints in trials to provide a global characterization of treatment effects on disease manifestation,” to support traditional approval. For accelerated approval, FDA says additional evidence is needed to “support the use of HS reduction in [cerebrospinal fluid] CSF of other tissues (blood or urine) as a surrogate endpoint likely to predict clinical benefit.”
FDA, Guidance


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