The US Food and Drug Administration (FDA) has issued more information to sponsors regarding its “plausible mechanism pathway”, a new framework to spur the development of therapies for ultra-rare diseases.
In the draft guidance published on 23 February, the FDA specifically discusses genome editing and RNA-based therapies that are highly specific and personalised.
Go deeper with GlobalData
Discover B2B Marketing That Performs
Combine business intelligence and editorial excellence to reach engaged professionals across 36 leading media platforms.
The agency’s commissioner, Martin Makary, and Center for Biologics Evaluation and Research Director (CBER) director, Vinay Prasad, first unveiled the programme in a New England Journal of Medicine article in November 2025.
The aim of the pathway is to remove regulatory barriers, such as large amounts of clinical data, in order to bring more innovative and bespoke therapies to market. At the time, the two FDA leaders were brief on details, though were keen to use Baby KJ as a case study. In May 2025, Baby KJ became the world’s first patient treated with a bespoke CRISPR-based therapy.
The criteria that house the pathway are therapies that identify a disease-causing abnormality, demonstrate an ability to treat the disease’s root-cause, and rely on natural history disease progression in untreated patients. Sponsors with an application must also show that their product successfully drugs or edits the target and a positive clinical outcome.
Health and Human Services (HHS) Secretary Robert F. Kennedy Jr (RFK Jr) said: “We are cutting unnecessary red tape, aligning regulation with modern biology, and clearing a path for breakthrough treatments to reach the patients who need them most.”
US Tariffs are shifting - will you react or anticipate?
Don’t let policy changes catch you off guard. Stay proactive with real-time data and expert analysis.
By GlobalDataThe main feature of the pathway is reducing the reliance on clinical trial data, which is harder to obtain for personalised therapies drugging rare diseases with small patient population sizes.
Within the draft guidance, the FDA said it is open to master protocols such as umbrella or platform trials. Trials must be designed to demonstrate clinical benefit, including symptom improvement, slowing of disease progression and decreases in disease related events. Biomarkers will also be accepted as endpoints if they are established to predict clinical benefit.
Given that many genetic editing technologies are considered modular in their approach, a highly supported “plausible” mechanism of action may used to approve therapy variants that target a different mutation. This effectively means that patients not included in the clinical trial used to support the original approval can still be included in the approved label. For example, a single disease with 150 different genetic mutations would be well suited to the bespoke pathway.
Makary stated: “This guidance is a critical step the FDA is taking to tailor our regulatory approach to patients with ultra-rare conditions. 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.”
While gene editing and RNA-based technology is the focus of the guidance, the concepts could apply to other individualised therapies, as per the FDA. However, the agency has not provided further information on how this might be regulated.
At the time of the initial announcement in November, William Blair analyst Sami Corwin said the pathway has “broad, positive implications” for cell and gene therapy companies.
She added: “However, based on the language in the pathway’s outline, the application of the pathway, particularly beyond rare and ultra-rare diseases is a bit more unclear.”
Advancing personalised therapies has been an aim of the Trump administration as it looks to cut the costs of longer-term treatment. In June 2025, in front of a cell and gene therapy panel, RFK Jr said he was “going to continue to figure out new ways of accelerating approvals for rare disease drugs and treatments”.
Cell & Gene therapy coverage on Clinical Trials Arena is supported by Cytiva.
Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content.
