An ultra rare disease company is likely going to die now due to the FDA's absurdly stringent manufacturing requirements. We need to reform them, for Phase I and beyond.

A subproblem within how FDA evaluates manufacturing, illustrated by the Grace Therapeutics case below, is excessively stringent "comparability requirements" for manufacturing. The FDA’s bar for what constitutes a “comparable” process is extraordinarily strict, sometimes to the point of absurdity. If the FDA clears your IND and you run clinical trials on Batch 1, then modify your manufacturing process and produce Batch 2, the FDA can simply decide these are different drugs, even if every analytical measure shows identical results. At that point, the only path forward is more human clinical trials to prove equivalence; no amount of chemistry or analytics gets you out of it.

I can anonymously relay a story of how broken this can get: a biosimilar manufacturer produced a drug of higher purity than the branded reference product, and the FDA deemed it “different.” Rather than run an entirely new clinical trial, the company deliberately made their manufacturing process dirtier to bring purity down to match the branded drug. Basically they had to engineer in imperfection just to satisfy a regulatory standard. This dynamic also creates a massive long-term inefficiency at the commercial level. Once a company figures out how to manufacture a drug at scale, they almost never improve the process even as technology advances, because upgrading risks triggering comparability requirements and potentially new clinical trials.

this is a good example of the gap that exists between the plausible mechanism pathway for n=1 diseases like baby KJ vs other ultrarare diseases. even though only a few dozen US patients have ngly1 deficiency, it is too many to qualify for the pathway, so must meet fda standards for gene therapy manufacturing. the article says the company estimates it will cost them $20-25m and 2+ years (that actually sounds like an optimistically low estimate to me). it is precisely at this point that otherwise promising gene therapies hit a brick wall.

https://endpoints.news/grace-science-says-fda-jeopardizes-rare-disease-therapy/?u=cedfead1-db86-4c3f-b8b6-318432f6608d&s=email&c=524130ce-ff1a7f97-9c070832&utm_medium=email&utm_campaign=An%20ultra-rare%20disease%20drugmaker%20faces%20a%20bottleneck%20Insider&utm_content=An%20ultra-rare%20disease%20drugmaker%20faces%20a%20bottleneck%20Insider+CID_fd962452a2e9cb184049f47edd1ea493&utm_source=ENDPOINTS%20emails&utm_term=A%20father%20built%20a%20gene%20therapy%20for%20his%20daughter%20He%20says%20an%20FDA%20request%20is%20the%20bottleneck