COMMENTS TO THE FOOD AND DRUG ADMINISTRATION, BIOLOGICAL RESPONSE MODIFIERS ADVISORY COMMITTEE

October 10, 2002

Who We Are

The Council for Responsible Genetics (CRG) is the nation’s oldest organization committed to educating the public on issues of biotechnology. Founded in 1983, CRG works to raise public awareness and promote debate on the social, ethical, and environmental implications of new genetic technologies. Our Board of Directors consists of scientists, physicians, lawyers, educators and public advocates, each of whom have been involved in these issues at the community, national, or international levels. Our central concern is that of public involvement and accountability. The public must have access to clear and understandable information on technological innovations, and it must be able to participate in governing the applications of technological developments.

Ever since proposals were first made to use gene modification techniques for potential human therapies CRG has fought to prevent the premature application of these treatments. Our Board members and advisors with experience in the relevant areas were concerned that genetic modification could produce severe and unintended side effects. This has been borne out in recent trials and therefore we are renewing our recommendation to adopt a different approach from the one currently in place. As a first step we propose a moratorium on all human gene modification trials.

The Present Risks

Overall, the effects of both viral and non-viral gene therapy vectors continue to be poorly understood. After over a decade of human trials and more than two decades of animal research, gene therapy is still more of a theoretical concept than a sound medical course of treatment. Techniques for making genetic changes in mammalian somatic tissues are still primitive. The death of 18-year-old Jesse Gelsinger as a result of a University of Pennsylvania trial on in vivo viral intoduction of genes was followed by reports of the resounding lack of success of hundreds of other such attempts.

Using ex vivo techniques the Necker Hospital protocol to treat ADA deficiency hoped to circumvent the potentially fatal complications associated with in vivo methods. Nonetheless, there is insufficient ability to precisely direct gene transfer through the vectors chosen. Retroviruses are difficult to target effectively and, as a result, they often may not reach the intended DNA location. This becomes a safety hazard in two primary ways. First, these viruses integrate randomly into the genome of the host cell. After the transgene is introduced, inappropriate integration could disrupt important gene and cell functioning, precipitating cancer or other forms of biological damage. Second, retroviruses may infect non-targeted cell types. Which of these is responsible for the leukemia-like disease seen in one of the Necker patients is unclear.

Data from model organisms does not justify continuing human gene modification experiments at this time. Indeed the NIH report on the Gelsinger incident acknowledged that there were no good animal models for the viral vectors used in that in vivo trial. With regard to ex vivo protocols animal studies provide a strong basis for precaution. For example, in the April 19 issue of Science this year, a team of researchers led by Zhixiong Li showed that the insertion of foreign genes into mouse bone marrow cells using a replication-defective retroviral vector caused the animals to develop leukemia.

Why, in the face of potential cancer risks (which could have been anticipated, and were by us and other commentators), were retroviral gene therapy trials allowed to proceed? This is a question that the committee will have to answer for any adequate review of the recent adverse event. At this stage, many of the scientists who are pushing the gene therapy agenda forward have financial stakes in moving the trials forward. Careful attention should be paid to the potential conflicts of interest that could lead to premature applications of these techniques and thereby compromise the safety of research subjects.

During the months that followed the Gelsinger incident, under improved reporting procedures, 691 reports of “serious adverse events” in gene therapy experiments were sent to the NIH. Over 98% of these incidents had not been previously disclosed. It should be clear that trials cannot responsibly proceed under conditions of secrecy, commercial or otherwise. Regulatory mechanisms should be put in place to ensure the open distribution of data so that investigators can learn from each other’s experience.

Furthermore, that case highlighted the lack of adherence by university researchers to principles of informed consent and to existing Recombinant DNA Advisory Committee (RAC) and FDA recommendations. In many cases, patients in gene therapy trials had not been made fully aware of the risk of severe immune system response, cancer, and other adverse events. As Abbey Meyers, President of the National Association for Rare Disorders and a past member of the NIH Recombinant Advisory Committee, aptly stated, “In the years that I sat on the RAC, I would see these documents time after time, sometimes eight or ten of them would come in front of us at a meeting, and I saw lies, I saw omissions, I saw exaggerations. Patients were not being told the truth in the informed consent documents.” What is also not being clearly communicated to research subjects is that Phase 1 trials hold out no promise of efficacy—they are solely for safety and toxicity evaluation.

A main purpose of FDA oversight is to maintain controls over research to protect the safety and integrity of human experimental subjects. Genetic modification raises questions qualitatively different from previous drug treatment regimes. As a result, these studies should be reviewed with added care. The implications of gene therapy go far beyond the immediate medical context, potentially changing the relationship of humans to their permanent biological makeup. Such issues make it imperative that the FDA take into account larger ethical questions before permitting gene therapy to move forward.

A Proposal

Faced with new evidence of risk, it is our position that the FDA should establish a moratorium on all future gene therapy trials, awaiting clearer evidence of safety and efficacy. Reevaluation should be undertaken of the Phase 1/Phase 2 framework for gene modification trials.