Inclusion of the patient perspective is currently an “optional” part of the rare disease drug development process, CBER Director Karim Mikhail told BioSpace. Mikhail, along with his CDER counterpart Michael Davis and other agency rare disease leaders, is trying to change that.
The voices of patients with a rare disease are sometimes heard by the FDA—at listening sessions and during advisory committee meetings—but for biologics head Karim Mikhail, it isn’t enough.
These opportunities currently come late in the drug development cycle, as therapies are on the cusp of potential market entry. “We need to have sponsors, experts and patients engaged in the process from early on,” Mikhail, director of the Center for Biologics Research and Evaluation (CBER), told BioSpace in an interview—right from the time companies seek permission to test their assets in humans.
Only then can substantive changes be implemented based on patient feedback. Today, when patients are heard during adcomm meetings, “that’s way too late,” Mikhail said. “The clinical development is already defined. Everything is already set.”
Under the FDA’s new Rare Disease Framework Initiative, unveiled last month, drug sponsors should expect that the patient perspective will be an essential component of the regulatory submission, Mikhail said. Patient input will be used to define several elements of a rare disease development program, he continued, from a clinical endpoint that is “actually meaningful” to an understanding of the benefit-risk ratio. This is a question that should be answered by those who are afflicted, he said, not people who don’t have the disease.
Sponsors will need to come to these early meetings prepared to discuss issues like endpoint selection, based on what’s important to patients, Center for Drug Evaluation and Research (CDER) director Michael Davis told BioSpace in the same interview. Drug developers will also need to define the trial methodology—including number of trials—along with the control group and analysis plan.
This renewed emphasis on the patient voice in rare disease drug development should be music to the ears of many—including patients.
A public meeting held by the FDA on Oct. 28 to solicit feedback on the new framework has already garnered 63 comments. One anonymous writer implored the agency to “give patients and families a formal voice on acceptable risk. People living with a rare, progressive disease are entitled to weigh risks that a regulator might not choose for them.”
The FDA’s journey to incorporate patients
As with many facets of the FDA’s new rare disease framework, inclusion of the patient voice is not a novel concept.
Patient-focused drug development began in earnest across the agency nearly 15 years ago, with the fifth reauthorization of the Prescription Drug User Fee Act (PDUFA V) in 2012. In that legislation, the FDA committed to evolving the benefit-risk framework, Robyn Bent, director of CDER’s Patient Focused Drug Development Program, told BioSpace on the sidelines of the BIO 2026 conference in June.
“We, of course, also agreed that it’s really hard to understand that therapeutic context without hearing from patients,” Bent said. So the FDA set out to hold 24 condition-specific, patient-focused drug development meetings, where patients with rare diseases could share their experiences.
When these meetings began, Bent continued, “we started hearing that, basically, the patient perspective wasn’t really being incorporated. The endpoints that were being measured weren’t endpoints that mattered to patients [and] clinical trial participation excluded too many people.”
Since then, the FDA has seen an increase in sponsors incorporating the patient voice, she added. “A lot of industry has been very responsive and has worked to incorporate the patient perspective.”
Bent has seen patient experience data included in meeting requests and packages and regulatory applications. That said, “obviously there’s more room to go,” she added.
“Patient experience data has a different kind of importance when you’re talking about diseases that are not super well characterized.”
Innovative trial design
One of the most contentious questions in rare disease drug development has been the use of external controls in clinical trials. Externally controlled studies—those using historical or real-world data—have contributed to recent FDA rejections, including of REGENXBIO’s Hunter syndrome gene therapy, and reversals of regulatory guidance, such as for uniQure’s gene therapy for Huntington’s disease.
Yet agency guidance has supported the use of these innovative trial designs. This includes 2023 draft guidance focused solely on the use of external controls. More recently, in September 2025, the FDA published draft guidance for cell and gene therapy trial design that includes externally controlled studies as one option, as well as the novel Rare Disease Evidence Principles (RDEP) program, focused on therapies for ultrarare diseases. Under the RDEP, treatments for diseases affecting very small patient populations—typically less than 1,000 individuals—may only need to provide evidence from a single-arm trial, in addition to “strong confirmatory evidence,” including from case reports and expanded access data, such as natural history.
The FDA’s new framework echoes this sentiment, championing “the use of cutting-edge science, novel methods and clinical trial designs, and innovative statistical approaches in the development of rare disease therapies,” though it stops short of specifically addressing the use of external controls.
Nasha Fitter, co-founder of the FOXG1 Research Foundation and mom of Amara, who has a rare genetic neurodevelopmental disorder called FOXG1 syndrome, implored the FDA to specifically address the use of external controls. She explained that her “clinical advisors pushed back” on a newly curated database of medical records for use in the foundation’s single open-label trial of an investigational gene therapy for the disease.
Natural history data for FOXG1 was “nonexistent,” Fitter explained in a statement following an Oct. 28 public meeting held by the agency to discuss the new framework. This spurred her foundation to create a database from the medical records of more than 100 children with the disease. These data then shaped the foundation’s endpoints and became the external control for the trial. But because the FDA hasn’t clearly stated its position on external controls, the foundation’s advisors balked at their plan, Fitter explained in her statement, which she shared with BioSpace in an email. “There was no regulatory guidance for it and they wanted predictability.”
While the advisors—academic clinicians from various institutions—urged the foundation to conduct an in-person natural history study, the organization stuck with the medical records approach and the trial was accepted into the RDEP program.
Fitter cautioned, however, that as the gene therapy is still investigational, “it is yet to be seen whether our control of medical records will be accepted at the BLA.”
Innovative trial designs are one area where Davis believes artificial intelligence holds “a lot of promise,” particularly when it comes to analyzing volumes of natural history or real-world data that are inherently less controlled than results from a clinical trial.
AI can also play a role in accelerating biomarker and endpoint development, Davis added. “With tens of thousands of rare diseases, with most of them with no treatments, there’s going to be a lot of work for biomarkers and . . . a lot of them will be very specific to the condition being studied.”
Data sharing is another key focus for the agency. This is particularly true when it comes to natural history studies, Amy Comstock Rick, associate director for Rare Disease Strategy and director of Strategic Coalitions for FDA’s Rare Disease Innovation Hub, told BioSpace at BIO. There is a need for “more natural history studies that are in a place where people can access them” to inform rare disease drug development programs more broadly.
The FDA’s new rare disease framework appears to support this approach, as it highlights “building shared resources, robust training, and institutional knowledge on rare disease drug development and review” as a primary focus.
The challenges ahead
The experts who spoke with BioSpace all acknowledged that many challenges remain when it comes to bringing effective therapies to the 1 in 10 Americans currently living with a rare disease. One obstacle the new framework aims to address is the regulatory unpredictability that has recently plagued the space.
“The more predictable the framework is, I think that will help make investors and companies feel more comfortable investing in it because they won’t be thinking about the sort of unpredictability of flexibility exercised at the end, when the program is done,” Davis said.
This is particularly true in the ultrarare disease space, Davis added, where finding partners to support drug development can be difficult.
Fitter spoke to this issue in her statement provided at last month’s public meeting, requesting that the FDA’s guidance also be written for patient groups going it alone.
She asked the agency to “write this guidance for patient advocacy groups as sponsors, not only drug companies. The FOXG1 Research Foundation sponsors our trial. There is no pharma partner. In ultra-rare disease, more programs will look like ours, because no one else is coming. Build the framework for us too.”
Editor’s note: Reporting contributed from Jef Akst at the BIO international convention in June.
