Gene therapy holds the promise of curing disease and improving the quality of life for millions of Americans who suffer from cystic fibrosis, cancer and other illnesses. In fact, today’s newspapers report that gene therapy offered hope for the thousands of Americans who suffer from hemophilia. Hundreds of clinical trials have been initiated over the years as government and private industry have worked together to research numerous ways for this technology to reach its potential.
Gene therapy is subject to greater oversight than virtually all other technology. The FDA, through its statutory role as the regulator of drug development, and the NIH/RAC as the forum for public discussion, have served to protect patients while ensuring that important research moves ahead.
Recently, however, there have been questions raised about the adequacy of this oversight process. The tragic death of a patient in the University of Pennsylvania (UPenn) clinical trial has led to a re-examination of the roles of the FDA and the NIH. Questions have been raised that must be further addressed in order to safely and efficiently move gene therapy research and development into the 21st century:
What should be the respective and appropriate roles of the FDA and OBA/RAC?
What should be the requirements and mechanisms for reporting serious adverse events to FDA and OBA/RAC?
What information should be publicly disclosed?
This paper represents the views of the Biotechnology Industry Organization (BIO) which represents 850 companies, academic institutions and state biotechnology centers engaged in biotechnology research on medicines, diagnostics, agriculture, pollution control and industrial applications. It presents a brief overview of gene therapy technology and its current regulation and oversight. It also recommends clarifications in the roles and responsibilities of the governmental agencies that currently oversee gene therapy trials to ensure that the best balance is achieved between the continued need for patient safety and the future development of these potentially important new therapies.
Gene Therapy Technology
Since the first clinical trial was initiated in 1990, the area of gene therapy has expanded greatly with an increasing number of sponsors and academic researchers conducting human trials. Thousands of patients have now received experimental gene therapies. Target indications for gene therapies include genetic and metabolic diseases, cancer, acquired diseases such as AIDS, and cardiovascular disease. The field of gene therapy continues to focus its efforts on patients with severe and life-threatening diseases who usually have few treatment options or who have failed all current available therapies.
Gene therapy technology is much more complex than replacing a damaged gene or adding a gene to elicit a direct effect. Research identified as gene therapy has evolved to include cancer immunotherapy; angiogenesis; anti-angiogenesis, the destruction of blood vessels supporting tumor growth; and a host of other potential therapeutic interventions. Similarly, the vectors used in gene therapy continue to be refined. In addition to adenovirus vectors, retrovirus, plasmid DNA/lipid delivery systems, adeno-associated virus (AAV), and other technologies are in clinical use.
Gene therapy researchers still face many of the challenges that existed a decade ago: perfection of vector design and delivery to specific sites; control and persistence of expression once delivered to the target site; elimination of negative immune responses to the vector and the gene product; identification of target sites; and disease heterogeneity. Overcoming these obstacles requires on-going modification of the gene delivery system, which contributes to the lengthy development times for these products. However, with continued pre-clinical and clinical development, researchers move toward the establishment of safe and efficacious gene therapy products designed to treat severe and life-threatening disease.
Even after a decade of research and clinical development, many of the gene therapy clinical trials that are active today are in an early stage of development. These early phase studies (Phase I/II) are specifically designed to evaluate the safety of the vector under investigation. These trials continue to be in early development not due to problems establishing a safety profile, but because researchers are exploring their options with indications, routes of administration, dosing regimes, patient populations, combination therapies, and novel vectors. Many studies also are designed to evaluate the maximum tolerated dose, with the expectation that adverse events will occur at some dose level. This approach is standard in any drug development process. In addition, biological markers of activity, not efficacy, are sometimes evaluated in a combination Phase I/II study to evaluate if the vector is having the desired biological effect.
A high level of scrutiny and evaluation has been focused on gene therapies, more so than for almost any other health care technology. Clinical trials undertaken in the US are reviewed by four separate bodies: the Food and Drug Administration (FDA), local Institutional Review Boards (IRB), local Institutional Biosafety Committees (IBC), and the National Institutes of Health’s (NIH) Office of Biotechnology Activities (formerly Office of Recombinant DNA Activities). Most standard drugs and biologics only receive review by the FDA and IRBs.