The pharmaceutical industry's focus on rare diseases has intensified, with 57% of all novel drugs approved in 2025 designated as orphan treatments. This is a continued increase from prior years, indicating a strategic shift towards smaller patient populations with high unmet needs, as exemplified by three different drugs for Hereditary Angioedema (HAE) being approved within ten weeks.

The FDA's new pathway for rare disease drugs, based on causal biology, is scientifically promising. However, the name "plausible mechanism" is a critical flaw. The term sounds weak, creating doubt for patients and giving payers powerful leverage to deny coverage by implying a lower standard of evidence.

For its alpha-1 antitrypsin deficiency program, Beam aligned with the FDA on an accelerated approval pathway based on a surrogate endpoint: restored alpha-1 protein levels. This strategy allows for faster market entry, with a longer-term confirmatory trial measuring clinical outcomes like lung and liver function running in parallel.

A key tension is emerging in orphan drug development. While the FDA's approval standards appear to be rising and becoming more erratic, Congress has simultaneously created a powerful economic incentive by exempting orphan-only drugs from Medicare price negotiation, creating a complex strategic landscape.

The FDA issued guidance supporting minimal residual disease (MRD) as an approval endpoint in multiple myeloma. This directly contradicts the CBER division’s recent rejections of drugs based on single-arm response rates, creating a "schizophrenic" and unpredictable regulatory landscape for developers.

After a decade on the market and multiple shifts in endpoints, Sarepta's definitive Phase 3 study for its DMD drugs failed. This outcome casts doubt on the entire accelerated approval framework for slowly progressive diseases, where surrogate endpoints may not translate to clinical benefit, leaving regulators and patients in a difficult position.

The FDA is predicted to approve new PARP inhibitors from trials like AMPLITUDE only for BRCA-mutated patients, restricting use to where data is strongest. This contrasts with the EMA's potential for broader approvals or denials. This highlights the diverging regulatory philosophies that create different drug access landscapes in the US and Europe.

FDA CBER Director Vinay Prasad is reportedly overriding staff recommendations not just in his own center (vaccines), but also in CEDAR (drugs), as seen in the Disc Medicine case. This consolidation of decision-making power in one individual is making FDA approvals far more unpredictable for drug developers.

The FDA's current leadership appears to be raising the bar for approvals based on single-arm studies. Especially in slowly progressing diseases with variable endpoints, the agency now requires an effect so dramatic it's akin to a parachute's benefit—unmistakable and not subject to interpretation against historical data.