The Food and Drug Administration has already halted the study and won't consider allowing it to move forward until an investigation into the death of the patient, Jolee Mohr, is complete.
She had died a few weeks after receiving a proposed treatment for rheumatoid arthritis made by the Targeted Genetics Corp. (TGEN) of Seattle. The Food and Drug Administration halted the study and won't consider allowing it to move forward until an investigation into the death of Jolee Mohr, is complete.
Doctors involved with Mohr's care presented the details of her case to the panel on Monday, which showed she had a fungal infection known as histoplasmosis and was bleeding internally when she died on July 24. But, so far doctors haven't been able to determine what caused the bleeding or whether the fungal infection was severe enough to have caused her death. Mohr also developed various blood disorders while in the hospital.
Mohr was injected with the therapy, which uses a virus to transport a gene that churns out copies of a receptor to block excess amounts of the inflammatory molecule known as tumor necrosis factor that plays a role in rheumatoid arthritis, on July 2. Doctors said she reported feeling ill and had a low- grade fever a few days prior to receiving the injection. Mohr was also on several other prescription medications including Abbott Laboratories' (ABT) Humira, which is used to treat rheumatoid arthritis, doctors said.
'The best answer we have to offer today is we don't know' if the treatment contributed to Mohr's death, said Dr. Howard Federoff, the panel chairman and executive dean at Georgetown Medical School. He said he hoped ongoing testing, including looking at blood samples to see if the product was in Mohr's blood, would be able to provide an answer, although he said he thinks there will always be uncertainty even after those test results are complete.
Initial tests have shown there was only trace amounts of the product, or vector, in tissues outside the joint where it was injected.
'While additional tests are needed to draw final conclusions, we believe the results to date are consistent with preclinical and clinical findings that indicate the level of vector that is present outside the locally treated area is insufficient to have further exacerbated an infection,' said H. Stewart Parker, Target Genetics chief executive.
Robb Mohr, Jolee Mohr's husband, said he thinks his wife would still be alive if she hadn't received the gene therapy. 'Until you figure out what's going on don't let this happen to anybody else,' Mohr urged the panel.
Federoff said Jolee Mohr's death and additional test results will be discussed at a December panel meeting.
Whatever the final word, experts urge abundant caution. University of Pennsylvania bioethicist Arthur Caplan, for instance, said that stem cell researchers ought to pay attention to how the risks of gene therapy were evaluated and perceived.
He said, 'There's big expectations, a lot of hype, and embyronic stem cells have to be put into the body, kind of like gene therapy. You've got to get them to go where you want them to go, if you're trying to repair nerves or build back heart muscle. Maybe you're not doing that many animal studies, because people are pressing to get a shot at treatment for some terrible disease -- and if you get a death, your critics are going to be all over you. If I was interested in embryonic stem cell research, I'd be watching this gene therapy experience very closely in terms of oversight, subject selection, informed consent, maybe having the IRBs do careful subject-by-subject review.'
(An institutional review board/independent ethics committee (IRB/IEC) (also known as ethical review board) is a group that has been formally designated to approve, monitor, and review biomedical and behavioural involving humans.)
The sort of oversight Caplan describes could be applied to gene therapy research on non life-threatening diseases -- taking extra care to make sure it's done as carefully as possible, even excluding people who would like to participate if they have other options, others said.
Of 139gene therapy trials the NIH lists as active, the majority involve terminal illnesses, particularly cancer.
Among these are trials for erectile dysfunction, cholera and intermittent claudication -- a complication of arterial disease that can cause severe, potentially disabling limb pain. In these cases, some researchers say gene therapy is still too risky to test on relatively healthy people.
But Julee Mohr's tragedy is that there were other options before her. The entire project covers a disease which has not progressed much. At least nine other gene therapy researches are in the same league.
Hence indeed Jeffrey Chamberlain, a University of Washington gene therapist who specializes in muscular dystrophy feels, 'Until things are worked out, it seems prudent to limit yourself to serious disorders.'
In principle, gene therapy is a medical miracle waiting to happen: Scientists engineer DNA delivery systems -- usually viruses -- that go straight to genes, add or subtract a bit of code, and nip a disease in its genetic bud.
But after 17 years of trying, scientists are still struggling to make gene therapy work, points out Brandon Keim. Complications include rejection of DNA carriers, causing an immune response like the one that killed Jesse Gelsinger, who died in 1999 during a trial for a rare metabolic disorder. In other cases, new genes end up where they shouldn't, or behave unpredictably. That's what happened in 2003 when a gene-therapy trial for severe combined immune deficiency, or SCID, caused leukemia in three children.
If a patient in any clinical trial, much less a gene therapy safety study, reports a serious side effect, researchers need to have the best possible data. How else can they figure out what went wrong and why?
But in the case of Mohr, doctors don't have the information they need. Biological material -- blood and tissue samples from different parts of her body -- weren't taken at regular intervals through the progression of Mohr's illness. Not until she arrived in critical condition at the University of Chicago Medical Center was this done, and even the samples taken there aren't ideal.
It's not enough just to take some blood and tissue; they have to be taken in a way that will be useful for the researchers looking at them. Different methods of analysis require different sample types, and unless those requirements are anticipated, the samples might not be useful.
In the future, designers of clinical trials -- for gene therapy, and for other treatments, such as stem cells -- should specify beforehand what they need if something goes wrong. And then, as soon as a side effect occurs, they should start taking them.
Studies also need to be specific about exclusion criteria -- i.e., the factors that would cause doctors to stop giving an experimental treatment to a patient. Mohr had been feeling sick before her injection, and had actually been treated for herpes a week earlier -- something that should have been a warning sign, given that she was being injected with an immune system-suppressing drug. However, her doctor was apparently not given instructions about how to deal with this.
Patients themselves should be very cautious when considering enrollment in such a trial, especially if the disease is not life-threatening or is under control with available medication, experts urge.