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

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.

Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development: a conference report.

Biomarkers are increasingly used in drug development to aid scientific and clinical decisions regarding the progress of candidate and marketed therapeutics. Biomarkers can improve the understanding of diseases as well as therapeutic and off-target effects of drugs. Early implementation of biomarker strategies thus promises to reduce costs and time-to-market as drugs proceed through increasingly costly and complex clinical development programs. The 2003 American Association of Pharmaceutical Sciences/Clinical Ligand Assay Society Biomarkers Workshop (Salt Lake City, UT, USA, October 24-25, 2003) addressed key issues in biomarker research, with an emphasis on the validation and implementation of biochemical biomarker assays, covering from preclinical discovery of efficacy and toxicity biomarkers through clinical and postmarketing implementation. This summary report of the workshop focuses on the major issues discussed during presentations and open forums and noted consensus achieved among the participants on topics from nomenclature to best practices. For example, it was agreed that because reliable and accurate data provide the basis for sound decision making, biomarker assays must be validated in a manner that enables the creation of such data. The nature of biomarker measurements often precludes direct application of regulatory guidelines established for clinical diagnostics or drug bioanalysis, and future guidance on biomarker assay validation should therefore be adaptable enough that validation criteria do not stifle creative biomarker solutions.