FDA guidance says sponsors should provide 'convincing' proof of concept data to support INDs for individualized medicine

Regulatory NewsRegulatory News | 26 April 2021 |  By 

Recent draft guidance from the US Food and Drug Administration addresses the non-clinical safety data to support investigational new drug applications (INDs) for individualized antisense oligonucleotide (ASO) products, a type of personalized medicine.
The guidance, issued on 26 April, addresses INDs for ASOs that treat a severely debilitating or life-threatening disease caused by a unique genetic variant. Such diseases may be amenable to RNA-directed treatment.
In a 26 April twitter post, acting FDA commissioner Janet Woodcock, MD said that release of the guidance stems from a “broader effort to provide clarity on developing new drug products in the age of personalized medicines.”
Issuance of the draft also follows up on earlier draft guidance setting the agency’s administrative and procedural recommendations for sponsors on IND submissions for ASOs. (RELATED: ’N of 1’ therapies addressed in draft FDA guidance, Regulatory Focus 5 January 2021)
The draft guidance is “expected to facilitate the preparation of adequate pre-IND and IND submissions for review by the agency that will enable prompt initiation of the clinical trial.”
Since drugs will only be administered to a small number of individuals, the draft guidance notes that nonclinical safety packages to support first-in-human (FIH) exposure will be “less extensive” than what is typically recommended for developing these drugs for broader use or in “less severe” clinical circumstances.
FDA said that “to offset a greater assumption of risk due to more limited data,” sponsors should provide “convincing in vitro and/or in vivo proof of concept (POC) data” to support the application.

FDA recommended specific nonclinical safety studies to support the submission. Hybridization-dependent off-target assessments, which should include the use of basic local alignment search tool and other in silico or in vitro assessments.
Safety pharmacology studies should include the “core safety pharmacology battery” such as cardiovascular, central nervous, and respiratory system tests;
General toxicity studies should include a single adequately designed, good laboratory practice- compliant general toxicity study to support first-in-human dosing; such a study can be conducted in a rodent or nonrodent.
The guidance recommends a single three-month toxicity study for initiating human dose studies. Sponsors should also “clearly” describe and justify the method used to select the starting doses.
The deadline for submitting comments is 60 days after the guidance is published in the Federal Register with an expected publication date of 27 April. Submit comments to this docket number: FDA-2021-D-0320.
FDA draft guidance on nonclinical testing of individualized antisense oligonucleotides


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