Transatlantic Consortium Spotlights Need for Changes in Gene Therapy Trials
Authors: David A Williams, Adrian J Thrasher, Christopher Baum
Journal: Molecular Therapy (2010)

The other editorial in this issue, by Roland Herzog, comments on a new clinical trial that represents the culmination of a long-term, highly collaborative effort shortly after the initial trials in X-linked severe combined immunodeficiency (SCID-X1) reported insertional mutagenesis leading to serious adverse events. We believe that the experiences gaining regulatory approval for the trial by the Transatlantic Gene Therapy Consortium (TAGTC) were important in shedding light on the ongoing challenges the field faces in implementing gene transfer trials. The previous trials clearly showed the efficacy of the approach, and the consortium members targeted improvement in the vector's safety profile as the critical goal. The rationale for the use of a self-inactivating gammaretroviral vector was to change the major determinant shown to be responsible for the insertional activation of cellular proto-oncogenes (strong viral enhancer–promoter sequences in the vector's long terminal repeats), leaving all other aspects of the trial unchanged (e.g., the envelope protein, transduction conditions, and repopulating cell dose). Theoretically this would allow direct comparison with the results of the previous trials. There were significant contributions to this effort by all members of the consortium, demonstrating that the new vector has a sufficient titer upon clinical-grade manufacturing, is of sufficient potency, and, importantly, is less genotoxic than the first-generation vector. The consortium members shared data, preclinical work, and the costs of vector production, and they are now sharing the protocol. We believe that this is a model of how rare diseases can be approached by multiple groups with the positive results of reduced costs per center and the ability to meet accrual targets more rapidly. At the same time, these efforts spotlight the weaknesses of our funding and regulatory systems that have been pointed out in numerous previous Molecular Therapy editorials and have led to specific recommendations to the National Institutes of Health (NIH) by the American Society of Gene and Cell Therapy. As noted above, the group adopted essentially the same clinical protocol used in the previous studies but substituted an apparently safer vector. In spite of this, it has taken more than two years for the trial to wend its way through the regulatory and funding agencies in the United States (US). The process in the three US sites alone entailed review by the NIH Recombinant DNA Advisory Committee; the US Food and Drug Administration; the local institutional biosafety committee at each site; the local institutional review board at each site; the Data Safety and Monitoring Board for the trial; the National Institute of Allergy and Infectious Diseases (NIAID) (study section review); and NIAID's Division of Allergy, Immunology, and Transplantation Clinical Research Committee. Thus, a major issue we faced was that each of these seven reviews led to new'and often contradictory'recommendations for protocol amendments. It was therefore nearly impossible to maintain an identical protocol at all sites. In addition, a lack of harmonization of regulatory requirements across the international borders, particularly related to the need for additional animal testing and insertion-site analysis, became problematic. Additional animal studies'requested in spite of increasing information suggesting that such studies do not accurately predict genotoxicity in human trials (Sadat, MA et al., Gene Ther 16: 1452–1464, 2009)'led to significant delays and greatly increased costs. For instance, additional requested studies were completed that directly compared insertion sites of the proposed vector with those of the previously utilized clinical vector in bone marrow cells from serially transplanted mice. These studies required that we follow a large number in primary and secondary transplanted mice for up to 16 months and that we identify genes located near all insertion sites in all animals. In the end, we concluded that these studies, although showing an improved safety profile of self-inactivated vector, provided no definitive insights predictive of leukemogenesis in gene therapy for SCID-X1 (D.A. Williams and C. Baum, unpublished results). At the most recent meeting of the TAGTC, held in Reykjavik, Iceland, these two issues'the lack of harmonization of regulatory agencies across international borders and the design of preclinical animal testing'emerged as the critical roadblocks slowing progress in implementing clinical trials. On behalf of the TAGTC: