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FDA lifts ban on trial after investigating death

Posted on: 27 November 2007, source: Nature News
A clinical trial of gene therapy in which a woman died this summer is due to recommence, thanks to a decision from the US Food and Drug Administration (FDA) announced yesterday. The experimental therapy for rheumatoid arthritis was stopped after one of the participants, 36-year-old Jolee Mohr, died in July. Autopsy findings presented in September showed that Mohr died of a massive fungal infection complicated by major internal bleeding, and that the gene therapy itself may not have been to blame (see: Study Clears Gene Therapy in Death of Arthritis Patient). Independently of the gene therapy, Mohr was taking several drugs for her arthritis that suppress the immune system, which is a risk factor for this type of infection.

Further evidence from tests on Mohr's tissues and blood has since supported this conclusion. The FDA has now lifted their hold on the trial. The FDA decision was announced by Targeted Genetics, the small Seattle-based biotechnology company that makes the gene therapy that was injected into Mohr’s right knee three weeks before she died. The company said that FDA had reached its decision after reviewing safety data from all 127 subjects in the trial. “The take-home message [of the FDA’s decision] is that this tragic incident was totally coincidental to her gene therapy, that the gene therapy was not implicated or involved and that this trial should proceed,” says Stewart Parker, the firm’s chief executive officer.

The FDA has not made a statement about the rationale underlying its decision. It declined to comment to Nature except to confirm that it had lifted the hold on the trial. The full results of an investigation into the cause of Mohr’s death are due to be presented at a public meeting of the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health on 3 December.

Robb Mohr, the widower of Jolee Mohr, called the FDA decision “reckless”. The trial will continue to allow subjects taking immunosuppressive drugs to receive the gene therapy, he notes, and the therapy’s protein product is itself immunosuppressive. “If they wanted to fire their testing back up and only test patients who are not on immunosuppressive drugs, I think that’s fine. But to test it on patients who are taking [immunosuppressive drugs] Enbrel or Humira; it’s reckless and very, very dangerous.” Parker defends the decision to allow trial subjects to continue taking the immunosuppressive drugs commonly used in rheumatoid arthritis. “There is no scientific basis for changing [the protocol] based on the extensive preclinical data and the clinical data to date,” she says. She adds that patients who have a fever — as Mohr did — will not be allowed gene therapy until the fever passes.

Thomas Murray, a bioethicist and president of the Hastings Center in Garrison, New York, says that the FDA decision is particularly important in light of the bad publicity that has attended the gene-therapy field in recent years. For instance, several boys in France developed leukaemia in the early 2000s after receiving gene therapy for a rare immunodeficiency disease that is fatal if not treated. “Another really terrible outcome of a gene-therapy trial would have been a significant blow to the field,” says Murray. “This is as close to a full acquittal as the field could have hoped for.”

The therapy in the Targeted Genetics’ trial delivers a gene for an anti-inflammatory protein, TNFR:Fc, which eases the inflammation of rheumatoid arthritis. The gene is delivered using a virus as a vector. Parker says that final molecular tests, the results of which were presented at an American College of Rheumatology meeting earlier this month, found only trace amounts of the virus in tissues outside Mohr's joints. And levels of the relevant anti-inflammatory proteins were well within expected limits, given that Mohr was also taking Humira (adalimumab), an injected drug that works in the same way as the gene therapy.

Chris Evans, a gene therapist and arthritis expert at Harvard Medical School, who is preparing to launch his own gene-therapy trial in patients with osteoarthritis, said that he had spent this autumn worrying that regulators were going to put a moratorium on gene-therapy trials in arthritis. Yesterday’s news brought “relief because there’s not going to be a moratorium”, he said. “And we can all move forward.” Still, he expects that recruiting patients into gene-therapy trials is going to get more difficult. “Once FDA says: ‘It wasn’t the gene therapy after all’, the pendulum swings back, but not all the way. So you lose that segment of the population that is a little bit wary to begin with.”

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