No Questions Answered, but Targeted Genetics Gene-Therapy Trial to Resume

We previously discussed, most recently here, the unfortunate and unexplained death of young patient after an injection of an experimental gene-therapy agent. To summarize the case thus far, a young woman received a dose of an adeno-associated virus carrying a gene that was meant to have a local immune suppression effect, tgAAC94, made by Targeted Genetics, directly into her joint as part of a phase I study meant to assess the safety of the treatment. Soon after the treatment, she became ill, then very ill, and ultimately died in an intensive care unit.

Whether the treatment had anything to do with her illness and death were initially unclear. A hearing by the US National Institutes of Health (NIH) Recombinant DNA Advisory Committee did not reach any conclusions about what caused the patient's death. (See post and here.) The NIH panel "said it was too early to conclude that the gene therapy had not been a factor, perhaps by suppressing ... [the patient's] immune system," (per the International Herald Tribune.) I should also note that even apparently innocuous viruses sometimes are not. The US Center for Disease Control (CDC) recently warned of cases in which people have died after infection with a type of virus, a type 14 adenovirus, that usually just produces a mild upper respiratory infection.

Nonetheless, now the US Food and Drug Administration (FDA) is allowing Targeted Genetics to restart the trial. The company's CEO, H. Stewart Parker, is claiming "this is a vindication for the product, the company and the field of gene therapy," (per Bloomberg News. There is a similar quote in a Seattle Times article.)

The study will apparently resume with many of its previously identified problems unaddressed. Questions were raised about the conduct of the trial, including:

• whether the patient was lead to believe she might benefit from it, even though the study was meant only as an initial, Phase I, safety assessment;
• whether she was influenced to participate because her rheumatologist was an investigator, and he administered the informed consent form, without disclosing he was paid to participate in the trial;
• whether she found the consent form understandable;
• what institutional review board (IRB) reviewed the trial; and
• whether Targeted Genetics unduly delayed reporting the patient's condition to the US Food and Drug Administration (FDA)?
  

None of these questions have yet been answered, However, Per the Washington Post,

Kyle Hogarth, an intensive-care unit physician at the University of Chicago who cared for Mohr and was involved in the investigation, said yesterday that he feels reasonably certain that the treatment did not kill her. But he is still bothered by the study's design, he said, because it allows participants to keep taking prescription medications that cannot be distinguished from the immune-suppressing protein made by the treatment's gene-modified viruses.

That makes it impossible to fully sort out whether problems that arise during the experiment may be caused by the treatment or the drugs the subjects are taking, he said.

Although conventional arthritis medications can, on rare occasions, make patients especially susceptible to fungal infections, Hogarth and others have questioned whether the gene treatment left Mohr especially defenseless.

'I think they have a horrible design,' Hogarth said. 'It muddies the picture.'

Hogarth also echoed a concern raised by others in the course of the investigation: that Mohr was recruited into the study by her personal physician, who stood to profit from each new patient he enrolled. Medical ethicists have criticized such arrangements as posing a potential conflict of interest.

So, what is the big hurry to resume this trial? We still don't know whether the trial intervention was responsible for the death of a patient who, although she had arthritis, appeared nowhere near chronically ill enough so that her death was expected. The treatment has no claim to be life saving, or likely to be so much better than old treatments that it is worth facing a risk of death to take it. The trial is already known to have multiple design defects. I fear that the hurry is generated, as we said before, by the belief held by many people involved with this trial that their new treatment was safe in the absence of much evidence one way or the other. Such a belief may have partly been influenced by their vested interests in their product's success. As Osagie K. Obasogie wrote, "It's also about how profit motives embedded in the clinical trial process can undermine patient safety."