Cell and Gene Therapy Trials Face Disproportionate Amount of Clinical Holds


Oncological trials of biologics also face particularly higher rates of clinical holds.

Harish Venkatesh, BS candidate, Department of Regulatory and Quality Sciences, University of Southern California, Los Angeles, California. Credit: Linkedin

Harish Venkatesh, BS candidate

Credit: Linkedin

Clinical trials evaluating cell and gene therapies face a disproportionate prevalence of clinical holds compared with trials evaluating small molecules, according to an analysis of all clinical holds from the past 4 years.

The analysis was presented at the 2024 American Society of Gene and Cell Therapy (ASGCT) Annual Meeting, held May 7-10, in Baltimore, Maryland, by Harish Venkatesh, BS candidate, Department of Regulatory and Quality Sciences, University of Southern California, Los Angeles, California.

“Clinical development of cell and gene therapy trials contain added layers of intricacy compared to small molecule drugs, making them increasingly more demanding and costly. One of the most significant hurdles in the advancement of cell and gene therapy trials is the occurrence of clinical holds... Examining the nature of clinical holds could provide helpful insights into common pitfalls that could help researchers improve the conduct of clinical studies associated with cell and gene therapies. The frequency and nature of these clinical holds not only underscore the intricacies involved in the development of these therapies but also highlight a critical gap in the understanding of how to navigate these hurdles effectively,” Venkatesh and his mentor, Eunkoo Pacifici, PhD, PharmD, wrote in their poster.

Venkatesh and Pacifici compiled a list of all 94 clinical holds between January 2020 to January 2024. They found that there were 48 holds due to clinical data, 27 on biologics and 11 on small molecule drugs; 27 holds due to manufacturing, 18 on biologics and 9 on small molecules; and 19 due to preclinical data, 11 on biologics and 8 on small molecules. Of the biologics category, 62% were cell and gene therapies. Holds were disproportionally placed on oncological trials (43%) although only 22% of all trials were for oncologic indications.

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The clinical holds typically lasted an average of 6.2 months and had negative effects on the biotechnology field. In addition to share values of affected companies immediately falling (data from an anonymous company were shared), the authors also found that the NASDAQ Biotechnology Index (NBI) value decreased significantly during months with continuously high numbers of clinical holds.

“This study underscores the intricate challenges associated with cell and gene therapies, particularly the prevalence of clinical holds…the unproportionally large number of holds placed on cell and gene therapies in comparison to small molecule drugs has gained the attention of both sponsors and researchers. The issue has even caught the attention of legislatives, causing them to demand explanations from the FDA,” Venkatesh and Pacifici wrote. “A reason for the increase in holds may be the lack of harmonization in the regulatory requirements for these therapies. While certain clinical issues leading to holds may be inevitable, effectively addressing preclinical and manufacturing aspects of these studies can significantly streamline the clinical trial process for researchers.

Venkatesh and Pacifici wrote that a major limitation in the study is the lack of available information on clinical holds, since only publicly traded companies are obligated to disclose such information to their shareholders. They listed some possible future research in this vein, including a survey-based approach for both companies and contract research organizations about challenges with manufacturing cell and gene therapies as well as examining FDA review documents to better understand the reasons and deficiencies behind clinical holds and the steps taken to address them.

Click here to read more coverage of the 2024 ASGCT Meeting.

Venkatesh H, Pacifici E. Hurdles in Cell and Gene Therapy Trials: Interpreting Clinical Holds Between January 2020 to January 2024. Presented at: 2024 ASGCT Annual Meeting, May 7-10; Baltimore, Maryland. Abstract #1417
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