Wednesday, August 1, 2007
Paying Attention to the Trees, Not the Forest
BY THEODORE FRIEDMANN

During this past week, media attention focused once again on a serious adverse event in a gene therapy study – in this case, the tragic death of a patient. Very few relevant facts have yet become available, but it seems that one patient enrolled in a large study of people suffering from severe arthritis has died in the course of the study. Whether gene transfer manipulations undertaken as part of the study had any relation to the patient’s death has not yet been revealed.

Since the onset of clinical studies of gene therapy in 1989, several thousand patients with serious diseases have taken part in gene therapy studies. If this death is eventually found to have resulted directly from genetic manipulation, it would be the third patient death in a clinical trial proven to have been directly caused by the gene transfer procedure. In addition, there have been a number of very serious, nonfatal adverse events, including three well-documented cases of leukemia in children.

It is certainly possible that the use of the virus vectors – in this case, an adeno-associated vector – was directly responsible for the death of this patient. However, it is equally possible that the death had nothing whatever to do with genetic manipulation. We do not yet know. Nevertheless, the United States Federal Drug Administration has prudently placed a clinical hold on all gene therapy studies currently underway in this country that use this kind of gene transfer until the reasons underlying this tragedy are discovered.

This terrible event is, of course, news, and the media have legitimately sought to interpret the implications for future gene therapy studies. Because of the paucity of information on the entire event, most reports have been limited to the bare fact of the patient’s death. Still, some have called this the “latest setback” to the field of gene therapy – in one case a reporter even asked me pointedly whether this tragic event “pulls the rug out from under gene therapy.” Is that fair to the field? Or does it reflect some observers’ continued inability to distinguish between the inevitable setbacks and failures in any field of clinical biomedical research and the worthiness of the field itself – in other words, a failure to see the forest for the trees?

Gene therapy is an important, highly experimental, and immature field of biomedicine that, after approximately 17 years of clinical applications, has finally begun to demonstrate incontrovertible therapeutic benefit in treating several serious diseases, including life-threatening forms of childhood immunodeficiency and cancer. Many factors have made gene therapy extremely complex to use at the clinical level. Delivering genes effectively and safely is difficult, and our understanding of many diseases contains enormous gaps. The complicated nature of clinical application suggests to some that gene therapy is still too dangerous to use in human patients. But medicine does not have the luxury of waiting for perfect understanding. Rather, it is morally required, at least in our culture, to apply even imperfect methods to relieve suffering. Because of the incomplete state of our knowledge, we know things will inevitably go wrong even in the best designed and most carefully carried out studies – patients will be harmed, and some patients may even die from unexpected and unpredictable setbacks. Why does this continue to surprise us, and why does it seem to surprise us in particular in gene therapy studies?

Modern medicine relies on many forms of therapy that, during their development, went through long periods of setbacks and failure before the underlying conceptual and technical unknowns were solved. These periods often included patient injury and even death. But today’s medicine would be impoverished if it lacked these important technologies – disease-fighting techniques such as bone marrow transplantation, cancer chemotherapy, and the use of monoclonal antibodies for the design of targeted drugs. Bone marrow transplantation – which now saves so many lives – began clinical trials in 1958. By the early 1970s, the survival rate from the procedure was only around 1 percent. It was 32 years before the technology earned its principal discoverer, Professor Donnel Thomas, a Nobel Prize in medicine. Similarly, chemotherapy for childhood leukemia began in 1948, but the cure rate remained below 10 percent well into the 1960s. It wasn’t until the late 1960s and 1970s that salvage rates of children with leukemia rose to the levels common today – upwards of 80 to 90 percent. In both these cases, about three decades of research were required for the technology to become what we consider to be therapy-ready for wide-scale use;  and that seems a reasonable amount of time to expect these kinds of new technologies to take before they fulfill their promise.

We now have approximately 17 years experience in the clinical application of gene therapy. In the past several years, we have seen incontrovertible and growing evidence of therapeutic benefit to patients with immune defects, certain forms of cancer, and other serious illnesses. At the same time, there have been several very serious setbacks that impress upon us how immature this form of medicine is and how important it is for us continually to improve our methods and tools.

In truth, the setbacks in clinical gene therapy trials have been few – two patient deaths and a handful of other serious occurrences proved to be a direct result of gene transfer procedures. Many of the other adverse events and deaths during these studies resulted from progressive underlying disease – an expected result when including patients who are often so sick they are simply beyond rescue. And so I am puzzled that some few but very influential members of the mass media remain so oblivious to the history of clinical research and so consistently fail to appreciate the magnitude of the advance that gene therapy represents. I am not saying we should be complacent about our current technology or overlook the heartbreaking problems represented by every setback. It is constructive and helpful to be reminded periodically by the media that there are many ways in which the field is deficient, and that we have a long way to go before gene therapy becomes the widespread and effective treatment we hope it will be. Those working in the field should learn from this recent event, and if technical or conceptual inadequacies contributed to this patient’s death, investigators will work to remedy them, as they did in the cases of bone marrow transplantation and leukemia therapy. But we should not hold gene therapy to an unachievable standard of perfection, considering each new failure in the clinic to be a threat to the very concept of the therapy itself.

Theodore Friedmann is Whitehill Chair of Biomedical Ethics, professor of pediatrics, and director of the interdepartmental gene therapy program at University of California, San Diego. He is also a past president of the of the American Society of Gene Therapy.

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