FDA Proposes Speedy “Plausible Mechanism Framework” for Rare Disease Drug Development

One year ago this week, Baby KJ received his very first infusion of a gene therapy made specifically for him.¹ He had a unique mutation that led to carbamoyl-phosphate synthetase 1 (CPS1) deficiency, an ultrarare metabolic disease that only occurs in one in 1.3 million people.² An ambitious collaboration between scientists in academia and industry resulted in a custom base editing treatment for Baby KJ in just six months.

But in the world of ultrarare disease drug development, Baby KJ is the exception not the rule. Biotechnology and pharmaceutical companies typically prefer to focus their research and development time and money on treatments for more common conditions, allowing for higher returns on their investments.

However, on Monday, the Food and Drug Administration (FDA) took the first step toward changing that. The agency released draft guidelines for developing personalized genetic therapies—both genome editing and RNA-based therapies—for ultrarare conditions like Baby KJ’s. While this guidance aims to accelerate rare disease drug development, industry researchers are looking for further clarification on certain aspects of its outlined regulatory process such as manufacturing requirements, data sharing, and incentives for industry investment.

“It is our priority to remove barriers and exercise regulatory flexibility to encourage scientific advances and deliver more cures and meaningful treatments for patients suffering from rare diseases,” said FDA Commissioner Marty Makary in a press release. Industry researchers and others can comment on the draft guidance until April 27, 2026.

In the framework, the FDA explained that researchers must: identify the specific genetic, cellular, or molecular cause of the rare disease; show that their proposed therapy targets that cause or underlying mechanism; integrate natural history data of the disease—the typical course of the disease without any intervention—in their analysis; show data that indicate the therapy successfully targets or edits the cause of the disease; and show that the drug improves clinical outcomes.

The FDA has encouraged the inclusion of natural history data in the development of rare disease therapies before, but in this new guidance, “It seems that they're a bit more open to the types of data that one can include in natural history studies,” said Sadik Kassim, the chief technology officer of Omics Solutions at Danaher Corporation. “I think that's a positive.”

Kassim, who was part of the team involved in manufacturing Baby KJ’s bespoke gene therapy, added that he would like some clarification on the manufacturing expectations for industry researchers included in the guidance.

“One of the reasons that [Baby KJ’s therapy] came to fruition is because of the upfront investment by the government in basic research and translational research. But then, there was a gap in terms of that last mile of manufacturing,” he explained. “That's where companies like Danaher and Acuitas and Aldevron and [Integrated DNA Technologies] came into the picture. We manufacture the drug product at risk.” From the guidance, he said, it was not clear if the FDA expected manufacturers to continue to produce these personalized therapies in this way or via a different process.

The FDA draft guidance also allows for the modular use of a specific genome editing technology: Researchers can develop one technology and modify one part of it to target multiple diseases. For example, the same CRISPR technology platform with different guide RNAs could treat different mutations in the same gene for different patients. Because the “plausible mechanism” of how the CRISPR technology platform works would be the same, companies could theoretically license that same therapy for multiple mutations in the same gene using just nonclinical and clinical data collected for one specific mutation. To Kassim, however, the definition of what exactly is the same technology platform remained undefined in the guidance.

He said that this idea of a platform technology gets even more complicated if researchers want to use the same platform to treat a related but different disorder. “How does that information-sharing take place? And how can they demonstrate that what they're doing at institution Y is comparable to what [researchers] are doing in institution X?”

Finally, an important goal of the guidance, said Tracy Beth Høeg, the acting director of the Center for Drug Evaluation and Research, in the press release is to “inspire industry to place increased focus on individualized therapies, thereby driving innovation, improving safety, lowering costs and offering more patients with ultra-rare diseases a unique shot at a life-saving treatment.”

However, Kassim said that the incentives for industry to pursue ultrarare disease drug development are not fully articulated in the framework. “Industry investment isn't incentivized by having a publication in a top tier journal or getting grant funding, but it's incentivized by, ‘Will you get paid for the thing that you're making?’” he said. He would like to see more information on how the initial investigator, drug developer, and manufacturing partner get reimbursed for the final treatment, for example.

“I think what the guidance today will do will probably encourage more ambitious investigator scientists…across institutions to take this on, which is a good thing. That's what the field needs,” said Kassim. “But I think, in the broader ecosystem to make it sustainable, you need to align the incentives in a way that brings in industry dollars.”