'N of 1' therapies addressed in draft FDA guidance

Regulatory NewsRegulatory News | 05 January 2021 |  By 

Recognizing the pace at which drug developers are moving ever further into individualized medicine, the US Food and Drug Administration (FDA) has issued a draft guidance addressing submission processes for some hyper-specialized treatments.
The new document, which gives high-level guidance for investigational new drug (IND) submissions of individualized anti-sense oligonucleotides (ASOs), takes into consideration that these “N of 1” therapies come with “a set of challenges and considerations not seen with the typical drug intervention,” according to a statement from Patrizia Cavazzoni, MD, the acting director of FDA’s Center for Drug Evaluation and Research (CDER).
Cavazzoni noted that many of the rare diseases treated by tailored ASOs are rapidly progressive, so time is of the essence if the affected individual is to be helped by the treatment. Also, much ASO research and treatment is carried out in academic settings by investigators who may have less FDA experience than traditional drug developers.
The draft guidance emphasizes the importance of initiating interaction with FDA as soon as possible, to include establishing a communication plan.
Because of the individualized nature of these therapies, patients and family members may function more as collaborators than research subjects and may in some cases attend sponsor-FDA meetings. FDA clarifies in the guidance that “whatever the sponsor or FDA shares at a meeting about the application may be considered a public disclosure of the sponsor’s confidential information.” Accordingly, FDA will ask for written clarification of whether having that attendee present will constitute public disclosure and recommends that the sponsor consider confidentiality agreements with an attendees.
If a confidentiality agreement is in place, “FDA generally would not consider the presence of that outside participant at a scheduled meeting between the sponsor and FDA to trigger uniform access with respect to information discussed at that meeting,” according to the guidance.
The draft guidance also lays out general expectation for IND submissions and the content and format for the pre-IND meeting package for ASO products.
FDA provides direction for sponsors on the content of research IND applications as well. These applications should include a justification for the individualized ASO drug product. FDA acknowledges that “it is unlikely that human data will be available at the time of the initial IND submission.” Accordingly, the primarily nonclinical data and chemistry, manufacturing and controls data will support the IND.
The guidance also addresses ethical and human subject protection considerations, safety reporting, and annual reporting requirements.
FDA notes in the introduction to the draft guidance that only the IND submission process is addressed, and that later considerations including marketing and long-term treatment are excluded from the scope of the guidance. Also, neither nonclinical and clinical data guidelines, nor product quality requirements are within the scope of the guidance.
In an October 2019 New England Journal of Medicine editorial, CDER head Janet Woodcock, MD and Center for Biologics Evaluation and Research (CBER) head Peter Marks, MD, PhD laid out some of the societal and ethical challenges involved in developing a regulatory framework for individualized therapies. In addition to considerations for individual patients and their families, the regulators asked, “On a larger scale, we need to consider how such truncated programs fit into the spectrum of drug development in general: what are the differences between treating one, ten, or thousands of patients?”
The agency must also grapple with scaling issues for these therapies, noted Woodcock and Marks: “Although the FDA and other regulators typically allow streamlined preclinical data generation for rare, serious diseases, programs for a single patient are likely to set the floor for the minimum preclinical evaluation. How should this be escalated for slightly more prevalent diseases of equal seriousness?”
Though these treatments may be tailored to an individual’s genetics, the broader approach may eventually stand to benefit many, said Cavazzoni, who called the draft guidance a “first step” along the way to bringing effective individualized treatments to patients safely. “We also are optimistic that development of these individualized drug products may spur gene sequencing that leads to the development of additional individualized drug products for the same disease (though perhaps caused by a different mutation),” she said.


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Tags: biologics, FDA, US

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