An Emerging Consensus on Recommendations to Facilitate Clinical Gene Transfer
Authors: David A. Williams
Journal: Molecular Therapy (2006)

It has been twenty years since the emergence of the field of human gene therapy, and there is now no doubt that the transfer of recombinant genetic material into human somatic cells can significantly impact human disease. Nevertheless, serious obstacles continue to hamper the clinical translation of the incredible advances being made at the bench (see the report from the 2nd Stem Cell Clonality and Genotoxicity Retreat [1Frederickson R.M. Report from the 2nd Stem Cell Clonality and Genotoxicity Retreat.Mol. Ther. 2005; 12: 379-383Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar] for more specifics). The issues impeding the development of human gene therapy trials and recommendations to address these impediments have recently been discussed by a working group of experts assembled by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. A meeting report prepared by this group, entitled “Critical Resources for Gene Therapy in Heart, Lung, and Blood Diseases Working Group,” is published in this issue of Molecular Therapy [2Woo S.L.C. et al.Critical Resources for Gene Therapy in Heart, Lung, and Blood Diseases Working Group.Mol. Ther. 2005; 13: 641-643Abstract Full Text Full Text PDF Scopus (8) Google Scholar]. This report follows a recent editorial in these pages that discussed the outcome of the 2005 ASGT Stakeholders' Conference [3High K.A. Stakeholders' Conference Sharpens Focus on Challenges of Clinical Gene Transfer.Mol. Ther. 2005; 12: 581-582Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar], which was also convened to address the impediments to clinical trials in gene therapy. The full report of the Stakeholders' Conference can be found on the ASGT website (http://www.asgt.org/member_resources/recent_course_materials/stakeholders/2005_workshop_summary.pdf). Not surprisingly, the reports from these two conferences reach very similar conclusions and make nearly identical recommendations for change. Clearly, a key question now is who will take the lead in trying to effect the changes recommended by both of these groups. This is a critical point, because the large number of disparate agencies and regulatory bodies involved in the oversight of gene transfer studies is a central factor leading to the slow pace of clinical and translational gene transfer research. The report of the NHLBI working group identifies key areas needing change. Among others, these include greater emphasis on the continued support of GMP-grade vector production, better mechanisms to support conduct of pharmacological and toxicological studies, and simplification of complex, often redundant regulatory processes. As any investigator who has tried to develop a human gene therapy trial can attest, these issues are clearly relevant to the efficient and effective development and implementation of gene therapy approaches to treat disease. In addition, the meeting report suggests that the current funding mechanisms for producing and testing vectors does not favor success due to the fragmentation of the review process. The overlapping regulatory requirements of local and federal agencies coupled with the disjointed funding of vector production, toxicology studies, and clinical trial support leaves most investigators in double or often triple jeopardy. This is due to the fact that multiple panels of grant reviewers and regulatory bodies often have very different opinions of the proposed research. Furthermore, there is no current mechanism to resolve disputes between the various reviewers from these different agencies. An example of the problems that can arise follows our recent request for a change to a vector for an Institutional Review Board (IRB)-, Institutional Biosafety Committee (IBC)-, FDA- and Cancer Therapy Evaluation Program (CTEP)-approved, peer-reviewed, funded and open (accruing patients) trial at Cincinnati Children's Hospital. In response to the request for a vector change at the funding agency, a reviewer focused not on the specifics of the vector, but rather on the trial design, which he/she thought was inadequate. This criticism was accompanied by requests for changes in the trial before funding of the substitute vector would be approved. This was over three years after the commencement of the approval process and after all of the above agencies and the original study section had agreed to the trial design. This is not to say that the reviewer might not have been correct in questioning the trial design. However, this experience exemplifies how the number of disconnected review processes and committees almost assures that an investigator will be unable to open a trial in an efficient and cost-effective fashion. This is just one example of the “veritable gauntlet for investigators” that the NHLBI working group cites in the meeting report in this issue. There is clearly an emerging consensus on these issues. However, what is unclear is whether the reports' recommendations could be implemented without a concerted effort by academic and industry investigators. While it is clear that the FDA has made real efforts to help facilitate the initiation of clinical trials as rapidly as possible, the need to review projects and to fund them in their entirety is predominantly an issue for funding agencies. Adding to the problem is the short duration of funding and insufficient resources offered by the NIH funding mechanisms. A logical solution would be the creation of a study section designed to focus on all aspects of gene therapy projects in a coordinated fashion. It will not be easy to effect change at the national and local levels. In a perfect world, the possible solution would also include global synchronization of regulatory requirements. Nevertheless, the current funding and regulatory requirements are a substantial impediment to the transfer of novel therapies from the bench to the bedside. It seems that the ASGT is in a strong position to lead the effort to effect positive change and that it should follow the Stakeholders' Meeting with a concerted effort to do so.