Genome editing products: FDA recommends at least 15 years of follow-up after clinical trials
As Intellia recently unveiled its latest promising data around one in a series of potentially game-changing gene therapies, the FDA on Tuesday sought to further encourage the field with new draft guidance on what should be submitted in a clinical trial application and what potentially concerning safety issues to track for these genome editing products.
The agency is upfront about the risks of genome editing, as Allogene was hit with a clinical hold and preclinical studies suggest potential risks. The draft guidance points to several specific risks associated with genome editing, including off-target editing, unintended consequences of on- and off-target editing, and the unknown long-term effects of on- and off-target editing.
As such concerns linger, sponsors may be on the hook for a long and expensive follow-up to any clinical work. As part of efforts to further ensure the safety of such developing products, the guidance recommends at least 15 years of long-term follow-up after product administration, which is in line with past guidance on gene editing.
The agency also calls for adequate monitoring of any off-target editing and adequate assessment of the outcomes of unintended consequences of on- and off-target editing.
“Additional monitoring should capture AEs related to aberrant cellular proliferation, immunogenicity, and tumorigenicity,” the agency says. “Such AEs should be anticipated from pre-clinical studies, if possible, and toxicity grading and management strategy should be outlined in the clinical protocol.”
And for the smaller companies just starting out, the draft offers a brief guide as to what to expect when it comes to the type and degree of genomic modification, specifics on ex vivo vs. in vivo genomic modifications, and how best to find the optimal delivery method for the edited genes.
“When developing a human GE [genome editing] product, we recommend that sponsors consider: 1) the method by which the DNA sequence change will be achieved; 2) the type of genomic modification needed for the desired therapeutic effect; and, 3) the delivery method of the human GE components,” the 17-page draft says.
On the clinical end, the agency again makes clear that due to the risky nature of these products, first-in-human trials “generally should be designed to enroll only subjects for whom no other treatment options are available or acceptable,” but then later on in the draft, the agency also says that “in some instances, subjects with less advanced or more moderate disease may be appropriate for inclusion in first-in-human clinical studies.”
As far as preclinical objectives, the draft calls for sponsors to identify an adequate dose range and regimen, establish the feasibility and safety of the clinical route of administration, and identify potential toxicities, among a checklist of items to complete.
Meanwhile, in addition to the genome editing guidance, the FDA on Tuesday also released new, 36-page draft guidance on developing CAR-T products.
The FDA offers CMC, preclinical and clinical recommendations for those developing CAR-T products, as well as general considerations on CAR constructs, vector, cellular starting material, and more.