Policy/Position Statement

NIH FUNDING OF GENE THERAPY TRIALS
Approved by ASGT Board of Directors
September 29, 2006

Introduction

The field of gene therapy is evolving rapidly with a growing number of impressive therapeutic successes, particularly for genetic immunodeficiencies and cancer.  Substantial pre-clinical data have accumulated that support the initiation of new clinical trials for many additional disorders, including sickle cell anemia and the thalassemias, the hemophilias, lysosomal storage disorders, neurologic diseases, retinal disorders, forms of cardiovascular disease and many others.  NIH support for early-stage (phase I/II) gene therapy trials is essential to allow the field to continue to develop. 

At present, there are two major sets of barriers to the initiation of trials in the setting of an academic medical center.  First, there are multiple, overlapping and incompletely harmonized levels of regulatory review, both locally and nationally, that extend the length of time and effort required for protocol development and ultimate approval.  Second, the funding mechanisms available, mainly individual (RO1) and program project (PO1) research grants awarded for 4-5 years, although they are useful  and should remain available,  are increasingly difficult to obtain and are not suited for funding clinical trials that generally need a much longer period for development and implementation.  As a consequence, multiple individual grants are needed to fund various aspects of the process, e.g., vector production, toxicity studies and the actual conduct of the clinical trial.  The multiple and redundant rounds of peer review for these grants may have diverging outcomes, thereby making it difficult to complete all of the steps needed to initiate and complete the trial. These obstacles have seriously dampened the enthusiasm of many academic centers to invest in the infrastructure necessary to carry out sustained efforts in gene therapy. Academic centers have been and continue to be the key source for progress in this field.  We are convinced that, in the absence of more efficient mechanisms of support for gene therapy studies, the field of gene therapy, particularly in the United States, will be increasingly hampered and will result in an increasingly un-competitive role of American investigators. Indeed, most of the recent advances in clinical applications in the field have been made in trials outside the United States.

We intend the following series of recommendations to address the second of these barriers by proposing a new mechanism for funding clinical trials in gene therapy.

A proposed new structure

1. A unified review and funding decision.

The NIH has well-defined mechanisms to support hypothesis-driven research by the RO1 or PO1 mechanisms.  These mechanisms are adequate to support pre-clinical development, including the design and testing of specific vectors and their evaluation in relevant animal models.  Once the pre-clinical data have accumulated, a “go/no-go” decision point is reached. We suggest that a new structure be devised for a funding commitment through which all the resources necessary for product development and initial clinical testing could be made available with a single review decision. The review panel convened to make this key “go/no-go” decision regarding individual trials should be constituted with experts in product development, disease-specific clinicians as well as gene therapy experts so that there is adequate expertise to evaluate the pre-clinical data, the product development plan, which should include realistic milestones that must be reached to release each tranche of funding, and the relevance of the gene therapy approach in the setting of current therapeutic options in a particular disease.  Representatives from relevant institutes/centers should participate in this review group.  Regulatory approval need not be obtained prior to review but is anticipated to be a defined milestone for release of funds for the clinical trial.  The application should identify the entity, which may be an NIH supported CORE, one of the National Gene Vector Laboratories or another source that has been selected to produce the vector.

2. Mechanism of support for clinical trials

Once the pre-clinical development of a study is completed, support is needed for at least three well-defined subsequent phases to successfully initiate a clinical trial: 1) clinical vector production; 2) toxicity testing of the vector backbone, transgene and clinical vector preparation; and 3) conduct of the clinical trial.  These three phases should be evaluated in a single review and funding process, rather than additional and separate rounds of grant applications, review and funding. As noted above, awards should be determined by critical peer review that evaluates the pre-clinical evidence supporting the clinical trial and its design.  A contractual mechanism of funding would seem advantageous in that the full amount of money necessary for conduct of all three phases could be awarded at the onset with money released for each successive phase only when the prior one has been successfully completed and supports proceeding onto the next step.  Formal milestones should be established to ensure appropriate progress, but significant flexibility should be allowed in the timeline, given the complex and arduous process of regulatory review and the possibility that unforeseen events might delay the trial because of the need for additional safety data. Ideally, once awarded, release of funds would not be subject to the vagaries of additional and new peer review, but would be via timely administrative review¹.

3. National Gene Vector Laboratories (NGVLs)

Since their development over a decade ago, the NGVLs have established significant expertise on issues of optimization in vector production and quality control.  Noteworthy is the fact that the labs are rarely presented with a vector that allows immediate production.  Rather, a period of further characterization, derivation of a producer clone, and optimization of vector titers and other production issues are often required. In addition, the NGVL process relies upon completion of the clinical trial by independent investigators for full measured success, a process that is as outlined above, less than assured and over which NGVL has little control. In addition, actual production of clinical vector, even after NGVL study section peer review, requires funding of their effort from the ‘interested’ National Institutes of Health (NIH) Institute.

The strong track record of the NGVL success is impressive in spite of these structural impediments. Over the past 11 years, the NGVL has manufactured 36 gene therapy vectors for use in clinical trials. There are currently 5 vectors in production at NGVL centers with an additional three vectors in production at outside centers under the direction of the NGVL. Eighteen academic institutions have received NGVL-manufactured vectors. To date, 310 subjects have been treated. All academic investigators, not just those receiving NGVL vector services, are eligible to participate in the NGVL Archiving and Repository Program, NGVL Clonality Testing Services, AAV Database, and Pharm/Tox Database. 

Utilizing other programs as a substitute to the NGVLs, such as the RAID program, raises a number of concerns. These include the fiscally and scientifically undesirable duplication of much of the expertise that has already been accumulated in the NGVL program.  An alternative to this course would be to allow each investigator awarded funding to contract directly with academic centers, including NGVL Centers, with proven capabilities to make vectors. At the very least, a cooperative approach that emphasizes timeliness and efficiency would be highly recommended.  This is particular the case in biological product development, due to the high infrastructure investment costs and regulatory oversight burden. 

Thus, the field must continue to have the benefit of and access to core laboratories such as the NGVL, that have infrastructure support that allows on-going and continuing development of specific vector systems, independent of the actual production of individual lots for clinical trials. 

Therefore, we strongly urge that the NGVL program be continued.  However, recognizing that the current system of independent NGVL peer review of proposed projects adds another level of complexity to the initiation of clinical trial, we further propose that NGVL peer review be eliminated.

4. Overall summary

We propose a unified approach to the review and funding of gene therapy clinical trials after preclinical proof-of-principle is completed. This process would focus on the three key areas of clinical trial development outlined above and would allow investigators that are awarded clinical trials funding by the contractual mechanism described above to have available resources to fund production of individual lots of vector in the context of a fully supported, clinical trial development plan that includes the necessary toxicity studies.  Such a unified approach to clinical trial development will address the impediments widely recognized in the current multiple funding mechanisms and will facilitate the sustained and more efficient effort required for successful development and implementation of gene therapy clinical trials. 

¹ Note that the recently developed National Heart Lung and Blood Institute (NHLBI) funding mechanism includes many of the features described here, although multiple rounds of peer review may be required even by that mechanism to fully implement a clinical trial.  Streamlining this process by a single episode of peer review of a proposed clinical trial with milestones for development that allow administrative review and release of funds as the trial evolves would seem to be a more efficient mechanism. In addition, it is not yet clear whether NHLBI intends to fund multiple vector platforms or will limit funding to AAV and lentivirus production.