FDA officials stress natural history studies in supporting rare disease drug development
To promote the development of more treatments for rare diseases, sponsors should leverage data from natural history studies when it is not possible to use data from two adequate and well-controlled trials, officials from the US Food and Drug Administration (FDA) said during a panel discussion sponsored by the National Organization for Rare Disorders (NORD).FDA officials shared insights and best practices for orphan drug development during the panel discussion on 17 October 2023, moderated by Sandra Retzky, director of the agency’s Office of Orphan Products Development (OOPD). Retzky asked the panel members to identify some of the “important gaps” that must be addressed to accelerate orphan product development.
“A lot of the gaps that I see revolve around endpoints,” said Fraser Bocell, a psychometrician in the Office of Strategic Partnerships and Technology Innovation in the Center for Devices and Radiological Health (CDRH).
Getting patients more involved in assessing clinical benefit would go a long way toward developing meaningful endpoints, he said.
But “finding an endpoint when each patient has slightly different trajectories in their disease” is a significant challenge, said Emily Freilich, director of the Office of Neuroscience I in FDA’s Office of New Drugs.
To address this gap, Frelich said it is important to ensure that each patient makes an impact.
“Whenever possible, we try to encourage seamless designs or adaptive designs so that we can start with patients in first-in-human studies,” she said. These patients can then be rolled over and enrolled in pivotal studies “so that every patient counts,” she added.
Level of evidence
Panelists were also asked to address FDA’s expectations for the level of evidence needed to support approval of orphan drugs.
“Substantial evidence is required for any drug that we approve. Substantial evidence really should come from two adequate and well-controlled studies, but we often can’t do that in rare diseases. An option is a large, multicenter trial that has a robust and very persuasive result, but you cannot always get that for a rare disease. The third pathway is single study, plus confirmatory evidence,” Freilich said.
FDA recently published guidance on the types of studies that could supply confirmatory evidence (RELATED: FDA expands types of acceptable confirmatory evidence in new guidance, Regulatory Focus 19 September 2023). This evidence, which can include natural history studies, does not “diminish the quality” of the data to support the drug’s approval, she said.
In 2023, FDA approved two rare drugs where natural history studies were used to support the application -- Skyclarys (omaveloxolone) for Friedreich’s ataxia, a rare inherited degenerative disease that damages the nervous system, and Daybue (trofinetide) for Rett syndrome, a rare genetic disease characterized by profound neurological impairment.
“The importance of natural history studies can’t be minimized,” Freilich said. “It is really helpful to know what happens to patients in the natural course of their disease so that we can identify treatment differences when there is one. The more we know about the natural history, the more we can identify when there is a change.”
Lei Xu, director of the Office of Clinical Evaluation in the Office of Therapeutic Products (OTP) in the Center for Biologics Evaluation and Research (CBER) also supported the use of natural history studies.
Natural history studies can be especially helpful in supporting the development of ultra rare diseases that affect very small patent populations, where it is not possible to conduct randomized trials, Xu said.
FDA grants
FDA officials also discussed the availability of grants to accelerate rare disease development. FDA is now accepting applications for a new round of clinical studies of orphan products addressing unmet needs of rare disease (RO1). The deadline to apply is 24 October 2023. The agency also announced that it will be accepting proposals for innovative natural history studies addressing unmet needs in rare diseases. The deadline to apply is 13 February 2024.
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