Abstract
One important objective of HGT Clinical Development is to publish peer-reviewed papers describing pre-clinical animal and in vitro studies designed to assess the safety of gene and cell therapy products used to support clinical trials. These data are critical in the evaluation of proposals to undertake human clinical trials with investigational gene and cell therapy products. Regulatory bodies responsible for these evaluations such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are obligated to keep the details of these applications confidential. However, the sponsor has the authority to provide public access to their data, although this generally has not happened because there is little opportunity or incentive to do so; the normal mechanism for scientific disclosure - publication in peer-reviewed journals - has not been generally available in traditional journals due to the nature of the studies which are not based on hypotheses and do not define mechanisms.
The opportunity to access pre-clinical safety data across a broad range of clinical trials is important in the context of platform technologies where key components of individual products are shared. The notion of broad technology platforms is more relevant to gene therapy than any novel therapeutic modality that has emerged in the modern era of medicine. Many of us believe that key issues of safety and efficacy are driven by these common components of the platform allowing one to assess the merits of a single application by using the broad base of data previously generated with other applications of the platform.
This is nicely illustrated in the context of adeno-associated viral vectors (AAV). The biology of AAV vectors is largely determined by the structure of the capsid which directs the majority of interactions with cellular proteins thereby dictating key issues such as transduction efficiency and immunogenicity. For example, AAV vectors made with identical capsids show very similar bio-distribution when administered in the same dose and route despite the fact that they may be expressing different transgenes. Another example is in the evaluation of lentiviral vector's for oncogenic potential; it is hoped that primary aspects of genotoxicity are directed by the envelope and genome structure which are shared amongst many different lentiviral products.
One potential outcome of broader access to these data is diminished requirements for pre-clinical safety studies in regulatory submissions for early and late phase clinical trials. This would be particularly attractive in progressing gene therapy for orphan diseases where technical feasibility is high and the unmet need is great, but financial support is low. An important caveat is that the non-platform components of the products such as transgene and promoter and the state of the organ in which the vector or cell is being directed will endow unique properties of safety and efficacy that may warrant independent scrutiny in pre-clinical experiments. Even under these circumstances, one could envision more focused study designs, requiring fewer animals and shorter observation periods. Only time will tell if shared safety data will lead to more streamlined translational programs with vector platforms. Nevertheless, an immediate benefit of peer-reviewed publication of these results will be more informed translational decisions and access to experimental designs.
The format for submitting these papers will be brief manuscripts summarizing the results and conclusions, with more extensive access to the source data through linked databases. Despite failed previous attempts to establish voluntary safety databases, we are confident that the opportunity to publish in a peer-reviewed journal that is part of the HGT franchise will encourage participation.
Another goal of HGT Clinical Development is to publish clinical data even if the study was of insufficient impact to pass through peer review in our parent journal. Included in this category are phase I studies without definitive efficacy data (e.g., direct measures of gene transfer or quantitation of relevant biomarkers) and later stage clinical trials which fail to show efficacy. The bottom line is that all clinical data – positive or negative – are important. In addition, we plan to bring back the tradition of the early days of HGT where we publish actual clinical protocols before subjects are enrolled, focusing on the more groundbreaking protocols.
Finally, HGT Clinical Development will serve as a platform for discussing issues relevant to the commercial and clinical development of cell and gene therapy products through reviews, editorials, and commentaries. We have been delighted with the support and encouragement received from our colleagues at FDA and EMA who have also suggested publication of papers related to regulatory science.
Our goal is to publish the first issue of HGT Clinical Development in early 2013. We anticipate that HGT Clinical Development will appear on Medline and PubMed immediately and will be fully NIH, HHMI, and Wellcome Trust compliant from the start, and will develop its own impact factor. The general feeling is that the types of papers we plan to publish in HGT Clinical Development are of lower scientific merit and therefore less frequently cited, potentially contributing to a lower impact factor for the Journal. We will stay true to our mission and will not be influenced by concerns over citation frequency of individual papers. I suspect, however, that conventional wisdom is wrong and that our new journal will fare very well with time in terms of traditional citation indices.
I look forward to your participation in this important new initiative and welcome comments or suggestions (