Risky Business

Risky business
It’s not the technology of gene therapy but the regulation of clinical trials that we should be most afraid of, says Apoorva Mandavilli.
Published online: 21 August 2007; | doi:10.1038/news070820-1

Risky business
It’s not the technology of gene therapy but the regulation of clinical trials that we should be most afraid of, says Apoorva Mandavilli.

Apoorva Mandavilli
Almost exactly seven years after the first death in a gene-therapy trial, another unexpected death hit the field late last month – followed quickly by panic, outrage and some calls for an end to gene therapy altogether.

But to blame and ban all gene therapy because of this would be rash and misguided. And it might risk missing the point. What we should be most outraged and scared by is the way this trial took place — and the similar mis-steps that seem to accompany a vast number of clinical trials, gene therapy or no gene therapy.

On 2 July Jolee Mohr, a 36-year-old woman in Chicago, received an injection she thought would treat her painful — although not debilitating — arthritis. She died on 24 July of multiple organ failure, which was also the cause of death of 18-year-old Jesse Gelsinger in September 1999. In each case, the US Food and Drug Administration responded by suspending the trial and any others that used a similar approach.

But tragic and avoidable as both deaths were, I think we should be more worried about a broken system for clinical trials than of a risky treatment.

Short on science

Gene therapy is an experimental procedure in which an ostensibly harmless virus is used to replace faulty genes in an individual’s body with healthy ones. I say ‘ostensibly’ because Mohr’s treatment involved adeno-associated virus (AAV), which has never caused any problems in humans. But the full cause of Mohr’s death is still unknown and may well be because of the AAV vector.

Here’s what we know about what may have gone wrong: at the time of her death, Mohr’s entire body was fighting a fungal and a cold-sore-virus infection, both of which normally cause only mild symptoms. Mohr’s response to the infections suggests that her immune system, which the gene therapy was supposed to suppress only in her knees, may have been shattered throughout her body.

But Mohr was also taking a drug called Humira, which is known to increase the risk of the fungal infection. We also know that since the trial began in October 2005, more than 70 other people have received the gene-therapy treatment with no ill effects.

At this point, that is about all we know about the science — not enough, by a long shot, to pin the entire blame on gene therapy.

Scary stuff

There’s a lot more we do know about the clinical-trial procedures, and some of these details seem far more frightening to me than any jab.

The federal panel that reviewed the trial, run by Seattle-based Targeted Genetics, questioned the need for gene therapy for a non-life-threatening illness such as arthritis, and expressed concerns about the treatment’s potential effects on the immune system. But the advice given by such panels isn’t legally binding — companies can do what they like with such input.

Mohr was a participant in only an early stage of the clinical trial, designed to test the safety, not effectiveness, of the treatment. But according to Mohr’s husband, she was under the impression that it might help to ease her arthritis.

Mohr’s rheumatologist, who signed her up for the treatment, was being paid by the company to recruit patients into the trial. Experts say that shouldn’t happen; a patient might not listen as closely to a description of risks if advice comes from their own doctor as opposed to a third party.

The rheumatologist and the company say that the risks were clearly explained to Mohr. But it’s worth noting that she signed Targeted Genetics’ informed consent document in the office, instead of taking it home to read carefully, as most clinical-trial protocols require. It was more than 10 pages long, with the disclaimer warning of the risk of death buried deep inside.

Not alone

Every one of these potential problems is of grave concern. But the sad truth is that none is unique to gene therapy, or even very surprising.

It seems to me that conflict of interest, of inadequate informed consent, and shoddy reporting of ‘adverse events’ are endemic to the entire system of clinical trials. For a hit-list of potential problems, just take a look at scandals in recent years over the safety of antidepressants, the painkiller Vioxx and the diabetes drug Avandia. A 2003 review of 37 studies found that one of every four researchers has links to the industry and that industry-financed research is more likely to come to conclusions that are favourable to companies1.

This latest tragedy should serve as a warning and should bring about reform in the system.

Gene therapy has had some successes, albeit modest. A few trials, notably for ‘bubble boy disease’ and Parkinson’s disease, have shown promise.

On 17 September, the National Institutes of Health’s advisory committee on gene therapy will take a hard look at all the evidence in the Mohr case. Mohr’s husband, who plans to attend the hearing, says that until her death has been proven to be a result of the gene therapy, he doesn’t want to lay any blame because, he explains, the approach has the potential to help many people.

If he can be so reasonable, surely so can we.

linkback url: http://www.nature.com/news/2007/070820/full/070820-1.html


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