Gene Therapy as Drug Development
Authors: Barrie J. Carter
Journal: Molecular Therapy (2000)

Gene therapy has exciting potential, but there is much negative discussion currently as a result of the tragic death of a patient in a clinical trial at University of Pennsylvania. At the same time, questions are being raised about the apparent slow rate of progress of gene therapy. Ironically, a report presented last January at a meeting in Keystone, Colorado, described a gene therapy treatment of several patients with an immune deficiency disease that seemed to show a clear clinical benefit for at least a year. This report is a major achievement for the entire field of gene therapy, but it has generated much less public notice than the UPenn death, maybe because it has not yet been published. Nevertheless, much of the recent discussion about gene therapy is thoroughly muddied. This is due largely to its taking place outside the broader context of pharmaceutical development. To focus the ongoing discussion, it is essential to remind ourselves that gene therapy is drug delivery. It is true that gene therapy is more publicly discussed and engenders far more attention than most other clinical trials. It is also true that gene therapy has been held–rightly or wrongly— to be separate and special. However, the development of gene delivery shares many more similarities with drug development than it does differences. Gene therapy must be developed in the same way as for any other drug. Indeed, the 18 separate alleged violations outlined in the recent FDA letter to the UPenn investigators relate to infractions of general regulations and normally observed tenets of conduct for clinical trials: None of the alleged infractions is unique to gene therapy trials. Drug development begins with basic discovery research, which in turn leads to a treatment concept for design of the active component of a drug (in gene therapy this is a polynucleotide sequence). Next, development research requires formulation to design the drug delivery system (or vector) and process development for the manufacturing system. Manufacturing development usually continues throughout the drug development process to provide a scaled-up manufacturing system that produces a high-quality drug in a cost-effective manner. The drug is tested preclinically in in vitro experiments and in vivo in animal models to provide proof-of-concept of the drug delivery system, to assess toxicology, and to analyze pharmacokinetics as a guide to dosing in human subjects. Side effects or toxicity in preclinical studies are not necessarily showstoppers, but are important to the subsequent design of clinical trial design and monitoring of patients. Clinical trials are generally conducted in three phases, and safety evaluation is key to all three phases. In Phase I a small number of patients are administered the drug. The primary goal of a Phase I trial is to assess safety and toxicity and, potentially, to obtain pharmacokinetic data. Phase II trials are conducted in a larger number of subjects to assess dosing and to evaluate, at least preliminarily, the likely clinical benefit of the drug being tested. Clinical benefit of a drug is demonstrated in Phase III trials, which involve even larger numbers of patients as well as a control group which receives a placebo and/or the current standard of treatment. There is extensive regulatory interaction throughout the entire drug development process (in the United States, this interaction is with the FDA). The regulatory process oversees both the quality of drug manufacturing and the design and execution of preclinical and clinical trials. The goals are to ensure patient safety, to demonstrate clinical benefit, and to determine any restrictions on the use of drug in specific populations of patients or due to side effects. In the clinical testing process, there must be full disclosure, via informed consent, of all risks to the patients. This process is overseen at each clinical testing site by an Institutional Review Board according to Federal regulations. Drugs cannot be developed and tested without performing clinical trials. However, clinical trials should start only when there is a well-designed drug development pathway and a plan to proceed further if the results from Phase I warrant it. Drugs do not show efficacy in Phase I and generally do not fail in Phase I except in cases of significant, unexpected toxicities. There should be a long-term clinical plan to ensure that the early trials are designed to move forward in a useful way. In this respect, perhaps NIH could exercise more caution in announcing funding programs where a clinical trial or two are required as part of the application. The events of recent months emphasize the need for all members of the drug development community to be acutely aware of the need for public education. A continuous, proactive, and reasoned discussion in public forums will be much more useful than reaction after the fact to the sound-bite journalism that characterizes much of the popular press. Industry can and must help this public education on drug development. In presentations at the December meeting of the NIH Recombinant Advisory Committee (RAC) and in testimony at the Senate Public Health Subcommittee hearings in early February, the Biotechnology Industry Organization (BIO) clearly stated its readiness to be involved in the process of public reporting and discussion of gene therapy trials. The FDA has a regulatory authority that is clearly defined but not always well understood by either the public or academic scientists who are not directly involved in drug development. The FDA needs to facilitate further public education and should continue its practice of participating in public meetings such as the RAC and at society meetings such as ASGT. The NIH is now redefining the role of the RAC, which has proven to be a very useful mechanism for public discussion of gene therapy. Initially, this was performed mostly by review of individual protocols. However, the RAC will not be able to continue in this way with the increasing numbers of early gene therapy trials or for large Phase III trials. Several years ago, the Verma committee emphasized the public education role of the RAC to conduct discussion of general topics, examine novel therapies, and assemble a database of information as well as holding public policy meetings. This role was exemplified last year when the RAC conducted meetings on in utero gene therapy, lentiviral vectors, and, at the behest of the FDA, biodistribution of vectors to gonadal tissue. Most recently, in December 1999, RAC addressed the events at the University of Pennsylvania and the general use of adenovirus vectors. In the December meeting, a working group of the RAC listed a number of points to consider for adenovirus gene therapy trials (1Steele F.R. Gene therapy on the RAC.Mol. Ther. 2000; 1: 1-2Abstract Full Text Full Text PDF Scopus (5) Google Scholar). These points included standards to quantitate the vector, end-point measurements of vector activity, vector quality control, preclinical evaluation, routes of administration and biodistribution, patient evaluation and monitoring, and the need for control arms in clinical studies. All of these reiterate basic principles for all drug development of which gene therapy is a subset. However, we have yet to accumulate a large database on knowledge of these types of drugs. On its part, the ASGT must examine its role and must understand that gene therapy cannot be viewed simply as an academic scientific discipline but must be a multidisciplinary approach by many rigorous scientific disciplines involved in applying the principles of drug development to gene delivery. Thus, the end result is to move from discovery research in a predominantly academic setting to drug development in an industrial setting. ASGT has many members from academia, industry, and government and is thus in a position to bring together diverse groups for public education. This is a major challenge for our fledgling society that we must accept and implement. The current focus on and discussion of clinical trials and gene therapy serve as an important, helpful, and timely reminder that development and testing of new therapeutic drugs, including gene therapy, are difficult and not without risk. It is incumbent on all of us to exercise constant and maximum due diligence in the design, conduct, analysis, and reporting of clinical trials.