Over the past 40 years following the Orphan Drug Act (ODA[DM1] ), rare disease therapeutics have steadily advanced. The introduction of gene therapies has sparked exponential growth, marking the beginning of an accelerated "therapeutic era.

The limited number of participants in the clinical trial and shorter duration of a promising rare (orphan) disease therapeutic can lead to unrecognized adverse events and safety revisions even after initial evidence of safety and efficacy. Despite the FDA's requirement for post-approval monitoring, these trials are often delayed/not initiated. Whether drugs approved under special review pathways are as effective as those approved under standard FDA processes remains unknown. Establishing registries for orphan drugs is essential for ongoing safety and effectiveness monitoring.

This session highlights post-marketing surveillance challenges and solutions.

1. Overview of the Accelerated Approval and Post-Marketing Requirements/Commitments Accelerated approvals, contingent upon surrogate endpoints, represent a regulatory mechanism designed to expedite the approval process for pharmaceuticals demonstrating potential efficacy in treating conditions where conventional efficacy endpoints may require prolonged observation. Subsequently, manufacturers must conduct the integral post-market requirements (PMRs) and commitment (PMCs) studies to substantiate expected clinical benefits. Dr. Mehul Desai, medical officer at the FDA, will provide an overview and examples.

2. Stories on Post-marketing outcomes (PMOs): a look into Agalsidase beta (Fabrazyme) and miglastat (Galafold) Fabry disease is a multisystemic disease due to globotriaosylceramide accumulation. Agalsidase beta (2003) and migalastat (2018) stand as pioneering therapies approved under the FDA's accelerated approval pathway. Agalsidase beta finally achieved full approval after 20 years of follow-up through the Fabry Registry. The Fabry Registry serves as an example for what can be achieved with a registry as well as the significant limitations that could be overcome with a different design. Dr. William Wilcox will share his 20-year experience.

3. Stories on PMOs: tales of Eteplirsen (Exondys 51) and delandistrogene moxeparvovec-rokl (ELEVIDYS) Approved in 2016 under the FDA's accelerated pathway, eteplirsen is the first antisense oligonucleotides-based drug for Duchenne muscular dystrophy (DMD) indicated for patients amenable to exon 51 skipping. Single-dose gene therapy ELEVIDYS was approved in 2023 for DMD patients aged 4-5. While comprehensive PMO data is pending, various publications have described clinical improvement in treated patients. Dr. Kevin Flanigan will discuss his experience on the post-approval impact

Consistent with ACMG's commitment to DEI policy, the collaborative presenters are from varying institutions and stakeholders across the country, of both genders and varying ethnicities, and include senior and junior faculty members.