More Details and Concerns About the Death of a Gene-Therapy Patient

Details continue to come out about the death of a woman who was participating in a gene-therapy trial of an agent made by Targeted Genetics meant to treat joint symptoms of rheumatoid arthritis. We posted about the case here and here.

Almost two weeks ago, the Seattle Times reported on the company's response to initial news stories about the case.

Chief Executive H. Stewart Parker said in an interview that the company has always applied 'the highest rigor in clinical trials' and that it behaved properly.

The company said it reported the incident to the FDA 'within 24 hours' of determining that the patient's illness was possibly related to the drug. A chronology released by the company shows that occurred 18 days after the patient was injected, in the wake of her admission to a hospital.

Staff at the hospital where Mohr was being treated was the first to alert the FDA, Parker confirmed in the interview.

Targeted Genetics said the patient received a second dose of the arthritis therapy on July 2. On July 10, the company learned that she and another patient suffered nausea, fever and vomiting. The other patient recovered, but Mohr was hospitalized on July 13. The clinical investigator thought it unlikely that the symptoms of both patients were related to the drug, the company said in a statement.

On July 17, the investigator told the company that Mohr's condition 'was deteriorating,' but that it was unrelated to the therapy. The next day, Targeted Genetics notified the chairman of the independent data safety-monitoring board that supervised the study, and on July 19 determined that the incident was possibly related to the therapy.

On July 20, the company informed the FDA.

Last week, the Washington Post reported more details about the demise of the patient.

The 36-year-old Illinois woman who died last month after being treated with an experimental gene therapy was infected with a fungus that usually causes only a mild illness. But the infection spun out of control and ravaged her organs, suggesting that her immune system was seriously impaired, said a doctor who is part of the medical investigation.

The woman's body was also teeming with a cold-sore virus that the body normally keeps in check, another indication of a faltering immune system. And because of a tear inside her abdomen -- perhaps caused by infection, perhaps by injury -- she had an internal blood clot the size of a watermelon.

The picture will be complicated, however, because Mohr was also taking conventional immune-suppressing drugs for her arthritis. One of those in particular, adalimumab, whose brand name is Humira, is known to make patients susceptible to histoplasmosis, the kind of fungal infection that Mohr had. Inexplicably, Mohr suddenly became ill in July even though she had been taking that drug for years and the fungus that causes histoplasmosis is ubiquitous in the area where she lived.

Meanwhile, a columnist in the Seattle Post-Intelligencer wondered about the implications of the case.

Those tragedies reflect one of the more troubling regulatory failures in the U.S. health care system: the inability to develop sensible and enforceable rules to oversee a growing biotech industry that is using humans to test what it hopes will become the next big moneymaker -- all without having much of a clue as to gene therapy's long- or short-term impacts.

When a federal committee charged with reviewing gene therapy trials evaluated Targeted Genetics' arthritis study in 2003, members openly questioned its justification, as it involved patients who were not very ill and evidence from animal studies didn't seem all that promising. They also worried it could trigger dangerous immune responses and questioned the informed consent documents' clarity. But as they have no binding authority or enforcement powers, Targeted Genetics was free to continue as it saw fit.

But this isn't simply about regulatory failure. It's also about how profit motives embedded in the clinical trial process can undermine patient safety. Pharmaceuticals had the fifth-most profitable return on revenues of any industry in 2006; the top five drug companies took home close to $30 billion in profits. Such companies as Targeted Genetics hope gene therapy and other biotech products will help them tap into and expand those markets. To be sure, Targeted Genetics CEO H. Stewart Parker told the P-I in 2005 that arthritis treatment could be 'a $7 billion market ... by 2011' and that the gene therapy used in the clinical trial that may have led to Mohr's death might help the company capture '15 percent to 40 percent of that opportunity.'

Time is money; in the rush to get products to market, patient safety can inadvertently take a backseat. And the fact that Targeted Genetics doesn't currently have any products on the market suggests that it has a significant financial incentive to stop hemorrhaging cash -- financial reports indicate it has lost $8 million this year alone -- and do everything possible to quickly get its products out of the clinical trial phase.

Time will tell whether gene-therapy caused this death. It very well may not have.

However, in my humble opinion, the most troubling aspect of this case so far is how people involved with this trial seem to have believed that their new treatment was safe in the absence of much evidence one way or the other. In particular, they seemed to persist in their disbelief that the new treatment could have had anything to do with the patient's unexplained rapidly deteriorating condition. Why were they so confident that their new treatment could not have been responsible?

This treatment was not merely new, it was a new variant on a broad class of new treatments, genes delivered by viruses, which are not yet in clinical use because no treatment in this class has been proven safe and effective. Furthermore, a few previous attempts at gene-therapy have produced very bad results, most notably in the unfortunate case of Jesse Gelsinger. Thus, one would expect that people setting up a new trial of gene-therapy would be properly cautious, and concerned that the new treatment might have unanticipated kinds of risks.

In my humble opinion, it is all too possible, as suggested by the op-ed above, that financial concerns have pushed manufacturers, researchers, and physicians into believing that the new treatments they are developing just have to be safe and effective.

This is another argument that clinical research, that is, experiments on humans to evaluate new tests or treatments should not be designed, implemented, or reported by people who have a financial stake in the success of the product bying evaluated.