Convergence: Inadequate testing of cell and gene therapies draws FDA concern

Regulatory NewsRegulatory News | 15 September 2021 |  By 

Kedest Tadesse, Jiwen Chen and Kirsten Messmer discuss cell and gene therapy challenges

The lack of consistent testing in measuring product quality for cell and gene therapies is a major deficiency found by US Food and Drug Administration (FDA) reviewers in its information requests (IRs) to manufacturers in their submission of biologics license applications (BLAs).
This observation was made by Kedest Tadesse, senior research manager for Agency IQ, which recently compiled a survey of deficiencies identified in IR letters in FDA’s review of five approved cell and gene therapies, in presenting the findings on Tuesday at RAPS Convergence 2021. Panelists at the meeting also discussed some of the challenges in developing and manufacturing these products.
Tadesse said these results are reinforcing FDA’s calls to manufacturers to develop more consistent ways to measure product quality for these advanced therapy products.
The survey compiled IRs that were disseminated to Amgen’s Imlygic (talimogene laherparepvec) Novartis’s Kymriah (tisagenlecleucel) Spark Therapeutic’s Luxturna (voretigene neparvovec-rzyl) Gilead and Kite’s Yescarta (axicabtagene ciloleucel), and Novartis’s Zolgensma (onasemnogene abeparvovec-xioi). These deficiencies were addressed and eventually approved.
Tadesse said that the data have limitations: the complete IRs are redacted due to proprietary and confidentiality concerns. Nonetheless, the survey seemed to pinpoint general areas of concern for these products.
The survey showed that the majority of the deficiencies cited in IR letters were in the chemistry, manufacturing and controls (CMC) or quality area, not the clinical domain. Delving down deeper into letters citing CMC issues, the survey found that more than 50% of the deficiencies targeted testing problems.
There were a total of 150 IRs related to testing deficiencies which found inadequate characterization of product quality, including problems with measurement of product purity and potency. Novartis’s Zolgensma received the most questions in this area at 65.
The other quality issues were related to problems with raw materials, final product validation, stability and shipping.
Tadesse said that these findings buttress the agency’s earlier calls for industry to develop more consistent methods for measuring product quality. Tadesse said that FDA's biologics head, Peter Marks, recently commented that developers need to better characterize the quality of these products.
Challenges noted
Speakers at the meeting also noted the ongoing complexity involved in manufacturing these therapies.
Jiwen Chen, the associate director of Nurix Therapeutics, said that these products are “incredibly complex to produce.” “It is a challenge to make it consistently day after day and year after year,” he added.
Some of these complexities, said Chen, were also observed by former FDA Commissioner Scott Gottlieb, who noted that in the traditional drug review, 80% of the focus is on the clinical portion of the process and 20% is on manufacturing and quality issues, while in cell and gene therapy, this general principal is “completely inverted.”
Growing number of applications
These manufacturing challenges are not dissuading developers from entering this space. The number of advanced therapy products under development, including gene therapy, cell therapy, and adoptive cell therapy, has climbed steadily every year.
Kirsten Messmer, a senior research analyst with Agency IQ, said that in 2016, there were 498 gene therapies in development, 499 cell therapies, and 129 adoptive cell therapies. In 2020, these numbers climbed to 1,354 gene therapies, 789 cell therapies and 688 adoptive therapies in development.
RAPS Convergence



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