The FDA has released a new draft guidance describing how sponsors could demonstrate that highly individualized therapies are effective and safe when traditional randomized controlled trials are not practical because too few patients are available to conduct them.
At a high level, the guidance lays out what FDA expects when a therapy is developed for a single patient or a very small group. This includes clear evidence of the biological cause of the disease, proof that the therapy directly targets that cause and supporting data that can help stand in for large, randomized trials.
Titled “Considerations for the use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause,” the draft focuses primarily on genome editing and RNA-based therapies, including antisense oligonucleotides.
Although these approaches are the main examples, the FDA says the same regulatory framework may also apply to other individualized therapies, but only in situations where traditional trials are not feasible because patient populations are extremely small.
How the FDA Defines “Individualized Therapies”
In the draft, individualized therapies are described as treatments designed to correct a specific biological change that directly causes a disease, such as a harmful genetic variant. These therapies are typically intended for severely debilitating or life-threatening conditions that affect very small numbers of patients.
The guidance outlines five core considerations sponsors are expected to address. These include identifying the disease-causing abnormality, developing a therapy that targets the underlying biological pathway, relying on a well-documented picture of how the disease progresses without treatment, confirming that the intended target was successfully addressed and showing improvement in clinical outcomes or disease course.
Generating Evidence Without Traditional Trials
When evaluating evidence for individualized therapies, the FDA says it considers the context of the disease, unmet medical need and the practical challenges of enrolling patients into traditional trials. The guidance also stresses that any observed benefit should not be reasonably explained by how the disease typically progresses or by other treatments the patient may have received.
In some situations, the FDA indicates that comparing outcomes after treatment with well-documented natural history data may be acceptable. The draft also discusses the use of master protocols, such as umbrella or platform trials, to study therapies that target different genetic changes linked to the same disease.
What This Means for Sponsors
For sponsors, the draft outlines several core expectations around how individualized therapies should be developed and supported. FDA says diagnoses should be clearly confirmed and backed by evidence showing that the targeted genetic change directly causes the disease, along with information on whether the variant is unique to the patient or seen more broadly.
Dose selection should be grounded in nonclinical evidence and experience with similar products, while biomarkers may be used to help demonstrate that a therapy is working or to support accelerated approval, provided confirmatory studies are underway.
The guidance also emphasizes the need for appropriate safety monitoring, plans to collect additional safety data after approval and early attention to manufacturing and quality considerations, particularly given the compressed timelines often involved in individualized therapy development.
Recent Rare Disease Updates
In the lead-up to Rare Disease Day on February 28, the FDA has also been engaged in other rare disease-related regulatory activities. The FDA approved Eton Pharma’s new oral liquid treatment for central diabetes insipidus, a rare hormonal disorder, and is currently reviewing investigational therapies for conditions such as autoimmune pulmonary alveolar proteinosis (aPAP).
Biopharma Savara said the FDA filed the Molbreevi BLA for autoimmune PAP for review and granted Priority Review, setting a PDUFA target action date of August 22, 2026, with EU and UK filings planned by the end of Q1 2026.
And outside of regulatory activity, the cast of Pretty Little Liars just released a public service announcement to raise awareness of infantile neuroaxonal dystrophy (INAD), a terminal, ultra-rare neurodegenerative disease that currently has no approved treatment.
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