Clinical holds for cell and gene therapy trials: Risks, impact, and lessons learned

Abstract

The recent increase in cell and gene therapies being developed has been coupled with a disproportionate increase in Food and Drug Administration (FDA)-mandated clinical holds. Aiming to better understand causes and secondary effects of these clinical holds on biotechnology companies, we analyzed 33 clinical holds that were publicly announced from January 2020 to December 2022. Approximately 80% of the analyzed clinical holds were formally lifted by the close of our study after an average of 6.2 months, and several trials have had significant clinical success following a hold. CAR T cell therapies accounted for nine holds, Lentiviral and AAV-based gene therapies accounted for five and 15 holds, respectively, and other cell and gene therapies accounted for four holds. The most common trigger was an adverse event or patient death. To remove a hold, protocol amendments were the most requested resolution by FDA. While there is no way to guarantee a therapy will not be placed on clinical hold, especially following unexpected adverse events, some deficiencies are avoidable. Utilizing FDA-provided resources on regulations and expectations for cell and gene therapy investigational new drug applications, inclusion of an external safety monitoring board, and a proactive risk assessment plan may prevent a clinical hold or result in a shortened duration.

Keywords

• clinical hold
• cell and gene therapy
• IND
• regulatory submissions
• FDA