Refine gene therapy follow-up guidance, expert says
It’s time for regulatory agencies, academics and pharmaceutical companies to convene to refine guidance for long-term follow-up of patients receiving gene therapy. That was the message Anne-Virginie Eggimann, senior vice president for regulatory science at bluebird bio, Inc., brought to a policy session at the annual meeting of the American Society of Gene & Cell Therapy.To date, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have provided guidance for gene therapy studies and post-approval commitments. The FDA guidance is both more detailed and more recent, having been issued in January 2020, Eggimann noted. (RELATED: FDA finalizes 6 gene therapy guidances, unveils a new draft, Regulatory Focus 28 January 2020).
Both agencies suggest a risk-based approach to follow-up, with an eye to risk for malignancy from insertional oncogenesis. For gene therapy via integrating vectors, a follow-up period of 15 years is recommended. The testing approach recommended by the FDA is to seek vector sequences via polymerase chain reaction in subject surrogate samples, with testing intervals of 6 months or less for the first five years. If a predominant clone is identified – that is, if an oligoclonal pattern of vector insertion is apparent – then an analysis to pinpoint the vector integration site is warranted, according to the guidance.
If a predominant integration site is identified, then FDA guidance asks for repeating the clonality analysis within 3 months, said Eggimann. The agency’s rationale is that these changes increase risk of malignancy, so closer monitoring is warranted for persistent monoclonality, evidence of vector integration near a locus of known oncogenicity, or clonal expansion.
The FDA definition of clonal expansion is the problematic part of this guidance, said Eggimann. The current guidance regarding oligoclonality, she said, “does not seem fully appropriate in our eyes.”
Eggimann noted that the challenge with the proposed approach is that although dominance may never exceed 33% for an individual integration site in terms of frequency, the total percent if there are, for example, three integration sites per cell may approach 90%. “We believe clonal frequency should be in the total population,” she said, and the agency’s guidance leaves the exact definition of oligoclonality unclear.
If “evidence of oligoclonality or monoclonality is observed,” says the FDA guidance, then that information should be reported within 30 days via an amendment to an investigational new drug application.
Currently, she said, “it is not ideal that every sponsor has to make their own definition.” She added that although the initial flexibility in making these definitions with useful, “we believe the field has advanced and it may be useful to convene a group of all the experts” to refine the guidance.
“We would welcome a workshop organized by the agency for an in-depth discussion with experts in the field on best practices to evaluate oligoclonality in clinical trials and long term follow-up studies, and agree on a state-of-the-art definition,” said Eggimann.
Ideally, she said, a workshop would include representatives from EMA as well as FDA to sort out the oligoclonality question and take a good look at the entire long-term follow-up process. “We also hope that over time, requirements for long term follow-up studies will evolve and be refined, and that the duration of long term follow-up studies will be reduced for integrating vectors as more data becomes available,” she said. “We need more dialog.”