Fabry Disease: FDA Drafts Drug Development Guidance
The US Food and Drug Administration (FDA) on Wednesday issued draft guidance providing recommendations to drugmakers on clinical trial design and eligibility criteria for products to treat Fabry disease.Fabry disease is a rare inherited disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (α-Gal A). According to FDA, patients with Fabry disease experience chronic gastrointestinal and neuropathic symptoms and progressive organ damage that eventually causes chronic renal disease, renal failure, cardiovascular disease and strokes.
There are only two products approved by FDA to treat Fabry disease, Sanofi Genzyme’s enzyme replacement therapy (ERT) Fabrazyme (agalsidase beta) and Amicus Therapeutics’ Galafold (migalastat), which was granted accelerated approval in August 2018. A second ERT drug, Shire’s Replagal (agalsidase alfa) is approved in Europe, but was withdrawn from consideration in the US in 2012 after FDA indicated the company would need to conduct additional clinical trials to support approval.
FDA says it hopes the draft guidance will “foster greater efficiency in drug development in this rare disease with the goal of enhancing clinical trial data quality.”
In the 7-page draft guidance, FDA sets out its expectations for clinical trial eligibility criteria and trial design, including considerations for efficacy endpoints for treatments targeting specific manifestations of the disease.
As for eligibility criteria, FDA says that all patients should have a “confirmed diagnosis of [Fabry disease] based on both biochemical testing and molecular testing” and that clinical trials should enroll both male and female patients, providing specific enrolment criteria for patients of each sex. FDA also says that sponsors should consider enrolling pediatric patients “as early as feasible.”
Due to how rare Fabry disease is, FDA says that a single adequate and well-controlled trial “showing a clinically meaningful treatment effect on core clinical aspects” of the disease, plus confirmatory evidence, is sufficient for approval.
FDA also says that sponsors should employ a parallel group design with either a placebo or active control group and consider stratifying patients by age and sex.
For treatments meant to slow or halt disease progress rather than reverse the disease, FDA says sponsors should ensure the trial is conducted over a long enough period to observe disease progression, noting that special consideration should be taken with regards to long-term follow up for gene therapies.
The draft guidance also provides considerations for endpoint selection for products targeting specific aspects of Fabry disease, including drugs to treat neuropathic and gastrointestinal symptoms, renal disease and cardiac disease.
FDA, Federal Register Notice