Regulatory Science Symposium: Emerging Technologies/Treatments Session 2: Gene Therapy Trials and Tribulations (2017)

In this series, we will discuss regulatory considerations for conducting clinical trials in the era of emerging technologies and treatments.

Course Syllabus/Topics

Definition of Gene Therapy:

  • Medical intervention based on modification of genetic material of living cells
  • Ex vivo for subsequent administration to humans
  • In vivo by delivery directly into subject

Overview of Gene Therapy Procedure:

  • Collect cells
  • Gene Modify Cells
  • Conditioning Chemotherapy
  • Re-administer Cells
  • Monitor patient for adverse events

Gene Therapy to Correct Genetic Deficiency:

  • Gene therapy is used to treat Severe Combined Immune Deficiency (SCID)

Gene Therapy to Activate the Immune System to Attack Cancer:

  • Modify immune cells to kill cancer cells
  • Adoptive Cell Therapy (ACT) Clinical Trial Schematic

Coordination of Teams Required for Administration of Gene Modified Cells:

  • Manufacturing Team
  • Quality Assurance Team
  • Manufacturing Team
  • Physicians and Nurses

Adverse Events Monitoring Following Cell Administration:

  • Local – IRB, ISPRC, DSMB, IBC
  • Federal – FDA CBER/OTAT, NIH/RAC
  • Protocol changes
  • Agreements among regulatory bodies
  • SAE attributions can be unclear and can change as information becomes available

Potential Serious Adverse Events Lessons From History

  • Death of Jesse Gelsinger (1999)
  • X-SCID Patients Developed Leukemia Following Gene Therapy Due to Insertional Mutagenesis (2002)

Risk Assessment for Insertional Mutagenesis Now Required:

  • Preclinical risk assessment of new vectors
  • Monitoring included in trials for assessment of gene insertions and early detection of secondary malignancies
  • Long-term follow up required for gene therapy patients
  • Vectors have been modified to decrease the risk of insertional mutagenesis leading to cancer

Additional Testing Required by FDA:

  • Replication Competent Retrovirus (RCR) testing
  • Replication Competent Lentivirus (RCL) testing
  • Virus tested before introduced into cells
  • Manufactured cells banked for testing before administration
  • Subjects’ blood banked for testing at 3, 6 and 12 months post cell administration and annually thereafter

Three Companies Fought for First Approval of Chimeric Antigen Receptor T (CAR-T) Cell Therapy:

  • Novartis
  • Juno Therapeutics
  • Kite Pharma

New Directions in Gene Therapy

  • “Off the shelf” CAR-T cells
  • Safety switches – turn off genes or kill cells
  • Reduce cost


Accompanying text created by Yelin (David) Hu | Regulatory Science Student Worker |

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