Sponsors Should Plan CMC Earlier When a First-in-Human Study Could Be Pivotal, Says Former FDA Reviewer Paz Vellanki

When FDA launched its Rare Disease Framework Initiative on October 14, 2026, it opened a broader question for sponsors of small-population programs. If the first study in humans could support a marketing application, how early does manufacturing planning have to start?

Earlier than many sponsors expect, according to Paz Vellanki, MD, PhD, vice president of clinical development at Precision for Medicine and a former supervisory associate director in FDA's Division of Oncology 2. In the first part of a two-part video interview with BioPharm International®, Vellanki discussed phase-appropriate chemistry, manufacturing, and controls (CMC) requirements and the program elements she said sponsors tend to raise too late.

"So if sponsors are now thinking about a first in human trial, potentially supporting a marketing application, we need to be thinking earlier about the requirements that might be needed from a CMC standpoint," Vellanki said.

She described the difference between the two stages of review. "At the IND stage, we think about can you control the quality or purity of a product, and then at the BLA stage or the NDA stage, we're thinking about additional things such as can we inspect the manufacturing processes? Can we ensure that those are met at very high standards?" she said.

Vellanki said that framing was already familiar inside the agency. "I came from the FDA. There, we thought a lot about seamless drug design, so we didn't always call out phase one, phase two, phase three," she said.

Beyond CMC, she pointed to two other areas that sponsors often leave until the end of phase 2: biomarker development for an assay that might become a companion diagnostic, and dosage selection. "I think these are all things that need to be moved earlier and considered earlier," she said.

How can manufacturing and assay readiness delay a trial?

Vellanki said a protocol that FDA clears can still stall before the first patient is dosed. "We have certainly seen scenarios where [an] IND has been submitted to the FDA. FDA has said that the protocol is safe to proceed, and then there's some delay in initiating the trial, and that might be related to manufacturing delays, or it could also be related to delays with assay development," she said.

The assay risk is greatest, she said, when enrollment depends on identifying a biomarker-selected population.

FDA has committed to risk-based CMC review for rare diseases but has not defined risk. Asked what a reasonable definition would look like, Vellanki began, "I want to preface things by saying that I am not an expert in CMC, but I do want to answer your question." She said CMC requirements were a major topic at FDA's October 28 public meeting on the initiative, but the agency did not define risk there.

"I think right now FDA is really calling for multi-stakeholder and external expertise, and they want input on how to define risk," she said. "Safety is going to be paramount no matter what."

Vellanki applied the same logic to FDA's "fit for purpose" language. "So fit for purpose, I think, acknowledges again that in the rare disease space, you may not have these large randomized trials that you might see in more common disease spaces," she said. "I think it's about trying to understand what evidence is required to be generated, and what risk we're comfortable with understanding what's possible."

FDA is accepting comments on the initiative through December 11, 2026, under docket FDA-2026-N-12214.

About the Speaker

Paz Vellanki, MD, PhD, vice president of clinical development, Precision for Medicine

Paz Vellanki joined Precision for Medicine after nearly seven years at FDA, where she worked in the Division of Oncology 2 from August 2019 to May 2026. She served as a medical officer, then as a clinical team lead, and from May 2024 as supervisory associate director. The division oversees drug development for thoracic and head and neck malignancies, neurologic tumors, pediatric solid tumors, and rare diseases.