Clinical Application of Gene Transfer Technology: Overcoming the Obstacles
Authors: Theodore Friedmann, David A. Williams
Journal: Molecular Therapy (2005)

Early in its short clinical history, the field of human gene therapy was burdened by an undeliverable optimism, like the “glad game” of the orphan Pollyanna in the writings of Eleanor Porter. In response to the growing recognition of the difficulties of the goal of gene therapy and to a number of well-recognized setbacks, that view has now moderated toward a more sober reality. In fact, we as a community may have overcompensated to the point where we are overly diffident about the accomplishments of the field. Like other new medical technologies, gene therapy has moved with an irregular trajectory from concept to clinical application. Such a rapid pace and uneven course is not unusual in clinical research. Think of the early histories of other, now standard-of-care therapies such as tissue transplantation, cancer chemotherapy, and monoclonal antibody therapy. It took decades of incremental advances and reversals, clinical setbacks and even patient deaths to evolve from concept to effective therapy. The false starts and setbacks do not detract from the reality now made so evident by the SCID studies. We have now accomplished gene therapy, not only gene transfer. One doesn't have to be Pollyanna to see that. Of course, there are several major obstacles that currently impede wider, safer and more effective clinical gene transfer applications. By far the most important is the still nascent nature of the underlying science and technologies and our incomplete understanding of the mechanisms of disease pathogenesis. Those barriers are already falling and will continue to fall with increasing speed. Other important obstacles stem from the current funding abyss for support of clinical research in gene therapy. It is dauntingly difficult and expensive to implement clinical studies that are desperately needed for the iterative process of testing and refining preclinical concepts and designing ever better clinical studies. Clinical studies are financially beyond the scope of most NIH grant support and increasingly beyond the dwindling commercial biotechnology resources. The deepest traditional nonfederal pockets for such studies would be large pharmaceutical firms, but big pharma's insistence on demonstrated clinical success before making serious investment in experimental gene therapy studies means that even that source of clinical research support will be increasingly inadequate. Without larger and earlier investment by the private sector, the pace of clinical success will continue to be slow. Recently, some investigators have suggested that the current system of multilayered regulation and oversight currently imposed onto clinical research studies is the major obstacle to progress. There is no doubt that gene therapy studies must jump through more local and federal hoops than other areas of clinical research, particularly with respect to RAC review. Even though many of the overlapping aspects of FDA and RAC oversight have already been harmonized, there certainly are additional ways to reduce the oversight burden by further harmonization of review and reporting requirements. However, to suggest as some have done that the RAC oversight role is an unnecessary obstacle is to ignore the immense added value to the field and to the public that RAC's uniquely open public oversight function has played and continues to play in shepherding the field of gene therapy. The RAC and the FDA have played complementary, but unique and irreplaceably valuable, roles in setting the bar for work in this field. Much more than oversight and regulation, it is the relative immaturity of the technology and the dearth of support for more and better clinical studies that are the most serious frustrations to the desire that we all have to speed the design and implementation of effective clinical gene therapy studies. The NIH has recognized the need for enhanced translational research partly through support from the National Heart, Lung and Blood Institute program for Centers of Excellence in Gene Therapy, from the National Center for Research Resources (NCRR) for the National Gene Vector Laboratories (NGVL) and the General Clinical Research Centers. Furthermore the NIH Roadmap recognizes the need for still further catalysts to translational research. Until the participation of the private sector in clinical studies can be strengthened, a constructive new approach at the federal level would be for the NIH to establish a clinical equivalent of the NGVL to provide the large-scale funds on a competitive basis to carry out clinical studies just as it does to provide the vectors for such studies. We need a committed, targeted and well-funded mechanism through the NIH Roadmap and through the private sector to support clinical studies in gene therapy and many other important areas of translational research. We all stand to benefit. Dr. Friedmann's editorial makes very relevant and timely points about current progress in the infant field of gene therapy. Indeed, as a new post-doctoral fellow in training in Boston in the early 1980s, I clearly remember the days of “uncritical and undeliverable optimism” he speaks about. In spite of cautious voices by many in the field, the more dramatic predictions of disease cures made by some tended to gain the attention of the lay press. As made clear recently by the same sort of hype attached to “stem cell plasticity,” this phenomenon seems to accompany all new technologies. As Dr. Friedmann also points out, despite heightened expectations and well-noted setbacks, it is clear that genetic correction of diseases using gene transfer technology is now a reality. However, I would argue that along with the progress in the science and technology of gene transfer that Dr. Friedmann correctly points out will be the basis of further advancement of the field, we should expect that the regulatory structure assembled over the past two decades will also evolve. At the very least, the overlap and redundancy that is represented by FDA and RAC reviews layered onto local review boards should be better coordinated and made more efficient and timely. While Dr. Friedmann may be largely correct in pointing out that a major impediment to future progress is the science, the complexity and duplication of the review processes is expensive, confusing and overly burdensome. One only needs to look at the size of the required documents and the time required, on average, to traverse the regulatory hurdles to understand the impact the processes have on moving clinical trials forward. The need for streamlining of the clinical research regulatory structure (and its funding) has not been lost on the strategic planners of the “NIH Roadmap” (nihroadmap.nih.gov), who took into account the advice of many leading clinical research organizations and experts. We now need for the recognition of these needs to be replaced by real change. This, along with progress in science, will ensure that the technology is more quickly applied to the treatment of many devastating human diseases. In the end, that's why we do what we do!