Three Things I Learned From the Pink Sheet’s Rare Disease Approval Webinar

by Carolyn Hall

Orphan drugs have long since become part of pharma’s mainstream. With over a fifth of the prescription drug market forecast to come from drugs for rare diseases by 2032, it’s an area that demands attention.

The regulatory hurdles facing these therapies are often high, but orphan drugs have accounted for roughly half of all FDA novel approvals since 2016, and 2026 is tracking the same. But the FDA also issued twice as many rare disease complete response letters in 2025 as it had in 2024, and the current landscape has been difficult to read as a result.

This was the subject of our recent  Pink Sheet webinar, which set out to look at how orphan drugs are progressing through the approvals process. Executive Editor Derrick Gingery and Managing Editor Bridget Silverman worked through seven case studies to map where the FDA’s flexibility sits and where it runs out. There was a lot to cover but three things stood out for me.

1. Effect size is doing more work than any other variable: The thread running through every approval in this landscape is the magnitude of the treatment effect. When it’s large, unambiguous, and mechanistically grounded, FDA has shown it will accept single-arm studies, external controls, and biomarker surrogates. When effect sizes are modest, it’s a different story; every methodological limitation has an impact. The FDA’s tolerance for design imperfection is directly related to the robustness of the efficacy signal.
2. Biological plausibility is a starting point, not a finish line: Several complete response letters were based on surrogate endpoints where the mechanistic logic was sound, but the clinical correlation either was not clear or was undermined by the trial data. An example that Bridget highlighted was RGX-121 for Hunter syndrome, which ran into a problem with a novel CSF biomarker that couldn’t be validated against natural history data. Derrick explained that biomarker validation needs to be explicit for the FDA to consider it sufficient evidence.
3. What FDA agrees to in a meeting does not always hold at review: Multiple sponsors described their CRLs as reversals of positions the agency had previously endorsed. Given the turmoil at the agency over the past year or so, this is not hugely surprising. The FDA has explained that agreements in principle may look different as data accumulates and leadership changes. But that does not resolve the practical problem for sponsors making complex, multi-year development decisions. It is partly why the Haystack Project’s petition for rulemaking, backed by more than 160 patient advocacy groups, is gaining legislative traction ahead of PDUFA reauthorization.

With almost 50 rare disease applications under active review and a cluster of PDUFA goal dates arriving in August and September, these questions will be tested again very soon. It is a complex and constantly evolving landscape, so I’d recommend catching the on-demand recording when you can.  Derrick and Bridget get into the case studies in much more detail and it’s well worth listening in.