When leadership changes at the FDA, as with Vinay Prasad succeeding Peter Marks, a core tension emerges. The new head isn't obligated to follow prior agreements, but abruptly shifting regulatory expectations for companies mid-development creates industry whiplash and erodes trust in the agency's consistency.

A significant disconnect exists between the FDA leadership's public statements promoting flexibility and the stringent, delay-prone reality faced by companies. For areas like gene therapy, firms report feeling the "rug was pulled out," suggesting investors should be skeptical of the agency's accommodating PR.

Drug developers often operate under a hyper-conservative perception of FDA requirements, avoiding novel approaches even when regulators might encourage them. This anticipatory compliance, driven by risk aversion, becomes a greater constraint than the regulations themselves, slowing down innovation and increasing costs.

The FDA publicly champions rare disease drug development, but its actions—frequent and inconsistent rejections—tell a different story. This disconnect between rhetoric and reality creates significant uncertainty, causing prominent investors like Rod Wong of RTW Investors to reduce their investments in the space.

Despite the FDA leadership co-authoring an editorial supporting single-trial approvals, the industry is skeptical. The agency's recent inconsistent actions mean no executive or investor can confidently build a development strategy or financial model based on this policy, rendering the announcement largely ineffective.

An ideologically driven and inconsistent FDA is eroding investor confidence, turning the U.S. into a difficult environment for investment in complex biologics like gene therapies and vaccines, potentially pushing innovation to other countries.

Patient advocates for a Huntington's therapy are frustrated not just by the FDA's halt, but by its reversal on previously agreed-upon trial design. The agency initially accepted an external control arm but later deemed it inadequate, creating regulatory uncertainty that erodes trust and could chill future development in rare diseases.

Recent events, like Moderna's rescinded 'refusal to file' letter, reveal that alignment with FDA staff on trial design is no guarantee. Senior leaders, notably Vinay Prasad, are reportedly overturning prior agreements, creating extreme uncertainty and making it impossible for companies to trust the regulatory guidance they receive.

The current disconnect between the FDA leadership's public calls for flexibility and its divisions' strict actions is not new. For decades, the agency's hierarchy has acted as a promotional arm to encourage industry, while the review divisions have maintained a more conservative, old-school approach to rigor. This historical pattern is often overlooked.