Ombudsman or Hotline for Gene Therapy Clinical Trials?
Authors: Inder M. Verma
Journal: Molecular Therapy (2001)

There is an even division between those who believe that gene therapy clinical trials should be treated like any other trial involving small molecules, chemotherapeutic agents, or other biologics and those who contend that gene therapy is “special” because genes are involved which can influence the genetic makeup of the recipient or, worse, their offspring. Not being directly involved in clinical trials, I had not paid much attention to this issue, but it caught my attention during a recent exchange between Dr. Catherine Manno, P.I. of the factor IX clinical trial at Children's Hospital, University of Pennsylvania, and Dr. Michael Coyne, a member of the National Hemophilia Foundation (NHF). Dr. Manno: “To date we have treated eight patients with AAV-factor IX vectors introduced into the muscle and we will finish the trial with a ninth patient as we originally planned.” Dr. Coyne: “Why do you want to include the ninth patient in the muscle trial if the benefits to date are relatively limited and you plan to shift over to using liver as the target tissue for gene delivery?” The implication is that the “muscle trial” is being “abandoned” in favor of the next phase of factor IX clinical trials, i.e., transduction of liver in collaboration with Drs. Mark Kay and Bert Glader at Stanford University. This decision to shift to liver from muscle is supported by the emerging data showing that liver transduction by AAV vectors containing factor IX cDNA transcribed from a liver-specific promoter is more efficient and that liver is the natural tissue producing factor IX protein. At a later panel discussion one affected individual asked about the prospects for the eighth and possibly ninth “muscle” patients since they cannot be candidates for other forms of AAV gene delivery due to neutralizing antibodies against the AAV 2 serotype used in the muscle study. These exchanges led to the usual arguments that these are phase I trials designed to test safety, not efficacy. A 10-fold higher dose of the transducing vector will likely be more efficacious, but can only be done after the results of the lower dose have been properly evaluated. Furthermore, safety data from AAV-2 use could have implications for using other serotypes into muscle. However, what really lies behind these discussions is the notion of “consent.” That is, is the patient fully informed of the outcome, possible adverse effects, and other forms of available treatment? There is every indication that Dr. Manno and her colleagues are using the highest ethical standards and adhering to all established guidelines and accepted clinical practices to conduct the trial. However, perhaps we can improve our current system to give the patient all the relevant information prior to enrolling in the clinical trial—particularly when alternative treatments are available. I propose that we set up a “hotline,” where the patient can call and get all the information. Let's start with hemophilia. The NHF could set up a hotline of knowledgeable and trained volunteers (doctors, informed parents, scientists, ASGT members) who can give the patient impartial information on the delivery system and the success rate in preclinical model systems, any adverse events associated with the delivery system and likelihood of adverse events with increased dosage, alternative treatments available (e.g., protein therapy), including analysis of all delivery vehicles currently available and their risks and benefits, cost of the treatment and attended care, etc. Of course the patient may not be able to fully evaluate all this information, particularly if it is filled with technical jargon. Thus, we will need an “ombudsman” who can give the patient the best advice after sorting through all the available information. Who would the ombudsman be? A trained physician, ideally treating hemophiliacs, or knowledgeable scientists able to explain the information to the patient. In short, a “patient advocate.” One immediate response is that this proposal is impractical, expensive, and perhaps totally utopian. Perhaps so, but let us just examine the actual number over the next year—maybe 10–20 patients for factor IX (hemophilia B) and perhaps twice that number for factor VIII (hemophilia A). This will require maybe one hotline with five or six trained experts and maybe a dozen ombudsmen at most. This situation would not exist forever, only now in gene therapy's infancy, which has been rocked by unprecedented bad publicity. Once gene therapy becomes a routine, hotlines or ombudsmen may not be needed. Until then, we can take this extra step to assure the public and, more importantly, the patients that will harvest the fruits of gene therapy. We need a partnership based on trust and transparency of our primary motive—improving their quality of life.