2013 Theses Master's

A Review of Genetic Transfer Therapy Trials from a Regulatory Perspective for the Scientific Understanding

Olguin, Arturo

The present work reviews the safety and efficacy concerns of the Recombinant DNA Advisory Committee (RAC) regarding Gene Transfer Therapy (GTT) clinical trials. The RAC, an advisory board established by the National Institutes of Health (NIH) is charged with reviewing and discussing GTT clinical trials and give regulatory guidance to the NIH for further proceedings. Considering the infamous past of GTT clinical trials, where malignancies have been found as a serious adverse event, one of the main concerns among regulators is the possible insertional mutagenesis (IM) caused by the viral vector used in this kind of trials. Many controls have been suggested to decrease this risk like fully characterizing the insertion sites (IS) of the vector used. The rest of the regulatory concerns are related to efficacy and safety of the whole therapy. This is no different from any other type of therapy or drug that is subject to FDA approval, however, there are some specific points for GTT clinical trials that must not be ignored. Based on these concerns, I include two case studies to exemplify how their findings would be reviewed from a regulatory perspective The first is a trial that uses an Adenovirus-associated virus vector to treat adult patients suffering from Hemophilia B. The trial is successful but they did not covered key efficacy and safety aspects that would fully convince a regulator to approve this kind of therapy. The second trial uses a lentiviral vector to transduce ex-vivo hematopoietic cells to correct the condition known as X-linked adrenoleukodystrophy (X-ALD), which affects children from 5-12 years of age and results in mental retardation and if not treated can cause death. The researchers on this trial took a lot of measures and controls to ensure the safety of the therapy however they failed to include a statistically significant population that would describe the efficacy of the therapy over the standard of care. I hope this can serve as a guide to harmonize the understanding of regulatory requirements from the science community and work together for a better drug development process.