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Thread: More Gene Therapy Studies Are Suspended

  1. #1

    More Gene Therapy Studies Are Suspended

    More Gene Therapy Studies Are Suspended

    .c The Associated Press

    WASHINGTON (AP) - U.S. officials are suspending 27 more gene therapy studies while they investigate a possible serious risk: A second toddler cured of the deadly ``bubble boy disease'' by gene therapy in France has come down with an apparent leukemia-like side effect.

    It marks the second time in three months that health officials have interrupted gene therapy studies because of the grave side effect.

    Bubble boy disease - an immune disorder formally called severe combined immunodeficiency, or SCID - is the only disease ever to be cured with gene therapy. But three months ago, a boy whose life was saved by a SCID gene therapy experiment in France when he was a baby came down with a leukemia-like syndrome at age 3.

    Scientists have long warned that cancer is a possible risk from any gene therapy, such as that for SCID, that uses retroviruses, a type of virus that permanently invades cells, to deliver new genes into a patient's body. Still, no one given gene therapy for SCID or other diseases had ever had such a side effect.

    That first sick toddler prompted U.S. and French scientists in October to stop gene therapy experiments for SCID, including three in this country.

    Now a second child in the French SCID experiment has come down with that same leukemia-like side effect, Food and Drug Administration scientists announced.

    Quietly notified by French researchers about a month ago, the FDA decided the second serious side effect warranted the more serious response: temporarily stopping about 27 more U.S. experiments that use retroviruses to insert new genes into blood stem cells in hopes of fighting diseases other than SCID.

    The FDA didn't release a list of the experiments but said they include some targeting such diseases as cancer, and include several hundred participants.

    Dr. Alain Fischer, the Paris scientist who led the SCID study, called the FDA's reaction reasonable.

    ``We are continuing our research ... to understand what we can do to remedy this so it doesn't happen again,'' he said Wednesday.

    He declined to release details on the latest sick boy, including his nationality, but an FDA official confirmed the child is being treated at an undisclosed U.S. hospital.

    The FDA said if researchers argue that any of the suspended retrovirus experiments offered a sole option to people with life-threatening illnesses, the agency would work to let them restart on a case-by-case basis, with appropriate warnings to participants.

    The three SCID gene therapy experiments, however, remain on hold for at least a few more months. But the FDA's ultimate hope is to restart them because SCID gene therapy offers so much promise to children without other options. After all, most medical treatments have side effects.

    ``If you have something that works - this is pretty good. We can't throw it away. We have to examine it and deal with it and work forward,'' FDA gene therapy chief Dr. Phil Noguchi said Wednesday.

    The FDA will convene its scientific advisers next month to pore over the research and debate future steps.

    ``It's very unfortunate that with the first real success in a very difficult disease, that there's this downside,'' said American Society for Gene Therapy president Joe Glorioso, a University of Pittsburgh geneticist.

    Preliminary DNA testing is pointing to a specific genetic step that may be to blame for the leukemia-like side effects, evidence that will prove crucial in telling if the apparent risk is unique to gene therapy for SCID, Glorioso said Wednesday.

    Both boys responded well to chemotherapy and are stable, but their long-term outlook is uncertain, Noguchi said.

    SCID babies are born without the ability to produce disease-fighting immune cells. The best known victim was David, Houston's famous ``bubble boy'' who lived in a germ-proof enclosure until his death at age 12 in 1984.

    There are some SCID treatments, including bone marrow transplants that can allow patients to live normal lives. But transplant success varies widely, and many children still die young.

    Fischer generated great excitement when his gene therapy apparently cured nine of the 11 boys he treated who had the most severe SCID-type, called X-SCID. He drew bone marrow from the boys, culled immune cell-creating stem cells from it, and mixed in a virus containing the gene their bodies lacked. Injected back into their bodies, the stem cells worked properly.

    On the Net: FDA announcement:

    01/15/03 15:37 EST

  2. #2
    This is worrisome.

    New cancer case halts US gene therapy trials

    Updated 17:14Â*15Â*JanuaryÂ*03 news service

    Nearly 30 US gene therapy trials were halted on Tuesday following the announcement that a second child in a pioneering French gene therapy trial has developed leukaemia as a result of the treatment.

    The French trial is testing a treatment for "bubble boy" disease, or X-SCID (X-chromosome-linked Severe Combined Immunodeficiency). The initial results of the trial were hailed one of the first great successes for gene therapy.

    But the trial was halted in October 2002 following the first diagnosis of leukaemia in one of the boys. Three similar US gene therapy trials were suspended at the same time. A similar trial in the UK was not halted, as British doctors argued that without the treatment many of patients would certainly die. Cure rates for childhood leukaemia can be 90 per cent, but boys with SCID almost always die within a year without a bone marrow transplant.

    However, the second leukaemia case has prompted the US Food and Drug Administration to suspend other trials that use the same type of virus to shuttle therapeutic genes into blood cells.

    "Precautionary measure"

    The FDA has no evidence of leukaemia caused by gene therapy in US studies, but says the suspension of trials using retroviruses is a "precautionary measure". The agency will consider specific requests to allow new patients into gene therapy trials tackling life-threatening disorders for which there are no other treatments.

    The UK's Gene Therapy Advisory Committee says they will maintain their position and not suspend the British X-SCID trial. The five patients in the UK trial have all been assessed in the last month and none shows any sign of leukaemia.

    Norman Nevin, chairperson of GTAC, speculates that the adverse French results may be due to minor differences in the techniques used. "The design of the vector is not quite the same in the UK as in the French study," he told New Scientist.

    Philip Noguchi, head of gene therapy issues at the FDA, remains optimistic about the overall prospects of gene therapy. "We continue to see gene therapy as a promising therapy for all those who have not benefited from current technologies," he says.

    No resistance

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    Boys with SCID have no resistance to infection due to a faulty copy of an X-chromosome gene that makes an immune protein called interleukin-2. The gene therapy corrects the genetic defect by shuttling a correct copy of the gene into the patient's cells using a virus. The treatment appears to have cured a number of boys.

    The two boys with leukaemia are now being treated with chemotherapy and are clinically stable. The leukaemia may have been caused by the fact that the injected DNA cannot be targeted to insert into a specific part of a chromosome.

    Scientists suspect the first child developed the cancer because the gene inserted next to an oncogene, called Lmo2, in a single white blood cell. This could have triggered the cell to proliferate uncontrollably, causing the disease.

    According to Reuters, gene therapy experts called to an emergency meeting on Friday at the US National Institutes of Health have said that the development of leukaemia could be unique to the SCID gene therapy trial.

    Natasha McDowell

  3. #3
    But what position should be adopted if you're treating a 100% fatal disease and possibly giving the patients a difeerent disease that is 90% curable?

    Further to that I suppose as SCI is supposedly not fatal any disease created by an experimental treatment would close the whole trial down and any similar trials, at least in US.

    I can understand the caution taken before going to clinical trials.

  4. #4
    I agree that clinical trials should proceed with caution. However, I am worried that different standards are being applied to gene therapy than to other therapies. Please remember that chemotherapy and radiation therapy for cancers also cause leukemia and other cancers. When I was a medical student at Stanford in the 1970's, we saw secondary cancers developing in people several years after we had put their Hodgkin's disease into remission. If clinical trials of chemotherapy were stopped because several patients had gotten leukemia or some other serious side effects from the chemotherapy, we would not now have chemotherapies for Hodgkin's disease or leukemia today.

    The disease that they are trying to treat (bubble boy disease, i.e. loss of the immune function) is a very serious disease and is much worse than leukemia. It is also not clear that why these two kids developed leukemia. But even if the two cases of leukemia were due to the gene therapy, the answer to the question that you ask is clear. Of course, you would choose to apply a therapy that has a 10% chance of killing you to cure a disease that has a 100% chance of killing you. To choose otherwise is not only illogical but immoral because it is depriving many other kids who have the bubble boy disease the choice of this therapy.

    What is difficult for me to understand is why there is no protest from members of our community who profess the desire for more risk-taking in clinical trials. Suppose embryonic stem cell transplants have a 90% chance of restoring function but a 10% chance of growing out of control and producing a spinal cord tumor. Would you want the FDA to stop the clinical trials not only this particular embryonic stem cell trial but all transplant trials in the United States?

    That is why this decision by the FDA is worrisome to me.


    [This message was edited by Wise Young on 01-15-03 at 23:48.]

  5. #5
    Dr. Young, I dont know if the type of transplants carried out in the trial discussed in the article below would be similar to the type of bone marrow transplants SCI's would receive (Dr. Black but it appears that both heterogenous and autologous adult stem cell transplants carry serious risks. I agree with Chris2, safety needs to be well established before human trials begin. Our community needs to be a little more circumspect when calling for human trials based on limited animal data.

  6. #6

    As most people here probably know by now, I am pretty conservative and critical when it comes to clinical trials. I will be crying when the first person with spinal cord injury dies from a therapy in clinical trial. When we gave high dose methylprednisolone to our first patients in the early 1980's, my heart was in my throat during much of the trial because there was a chance that the treatment might kill somebody. I also know how much harm a single death in a clinical trial can do, that one death can derail development of a therapy. If a single person had died during the phase 1 trials of methylprednisolone or 4-aminopyridine, it would have cast a pall over the therapy, not only for the FDA but for me as well. Having somebody die in a clinical trial from a therapy is traumatic.

    A good clinical trial should fulfill the following criteria.

    1. A good clinical trial evaluates benefit and risk of a therapy. If the risk is very low, I am willing to overlook lack of evidence for beneficial effects. However, the higher the risk, the greater the need for evidence of benefit from animal studies or a clear rationale for the therapy.

    2. A good clinical trial should randomize therapeutic arms that have similar chances of success or failure. The concept of a "placebo"-controlled trial is misleading in some ways. The placebo is the best standard therapy. Preclinical studies therefore should show that the experimental therapy is equal to or better than best standard therapy.

    3. A good clinical trial should be designed for success. Success means that the trial will yield definitive data that contributes to progress in the field. It is unethical to ask people to undertake the risk of a clinical trial that is poorly designed and unlikely to yield definitive results that contributes to progress in the field.

    4. A good clinical trial must be based on the best evidence concerning risk and benefit to participants. By the way, this is true not only from the perspective of the participants but also for the companies and funding agencies.

    Please note that none of the above assumes that there will be no risk involved in the clinical trial. I am very concerned with the current trend and emphasis on "risk-free" clinical trials. There is no such thing as a risk-free trial or therapy. Every therapy has a dark side. Trials are intended to evaluate risk and benefit.


  7. #7
    Senior Member mk99's Avatar
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    Seneca: "Our community needs to be a little more circumspect when calling for human trials based on limited animal data."

    How much more circumspect can we be? What is a reasonable risk/reward ratio? If the main risk of a therapy (such as nasal mucosa transplant) is only that it doesn't improve function what purpose is served in waiting a few more years?

    Dr. Young: what are the implications for SCI research by this Gene Therapy fiasco? Besides Dr. Mark Tuszynski, is anyone else seriously pursuing this avenue to repair damaged cords?

  8. #8
    Mike, I think the feelings of the parents in the following article echo's your sentiments.

    Regarding OEG's, we don't know what the long term risks will be, if any. This therapy hasn't been in use long enough for 2-3 year follow up evaluations to take place.

    Parents Agonize Over Move to Halt Gene Therapy
    January 16, 2003 08:48:12 AM PST, Reuters
    Your child has an untreatable and fatal genetic disease, but the only hope of a cure might give him cancer. Would you take the chance?

    Parents of boys with a condition called X-linked severe combined immunodeficiency now lack even that unenviable choice.

    After learning that a second French boy apparently cured of SCID by gene therapy has developed leukemia, French and US regulators both suspended trials aimed at using gene therapy to cure the rare condition.

    They will stay closed until scientists can determine what the risk of cancer is and whether the treatment caused it.

    Some parents whose children face death in the interim are furious, said Barbara Ballard of the SCID Alliance, which represents parents of children with the rare disease.

    "One in particular is extremely upset," Ballard, who routinely testifies at government hearings, said in a telephone interview on Wednesday. "It is a case where the child has had several bone marrow transplants and lives in isolation. This was their first true hope."

    X-SCID patients, sometimes called "bubble boys," are born with a genetic defect that leaves them without an immune system. If they have a brother or sister to provide a bone marrow transplant, their chances are good.

    Without treatment, they are vulnerable to any passing infection and usually die before reaching the age of 1.

    Ballard's son, now 9, doesn't have a sibling. She donated her bone marrow for a transplant, but was not a good match and her son still lacks the ability to make antibodies key to fighting infections.

    He cannot be vaccinated and gets monthly infusions of immune globulin, a blood product that itself carries risks.


    "Half the winter he spends on antibiotics," Ballard added. "He was made deaf by one of the antibiotics he had to be on as a baby. It saved his life but he's deaf. That is what you are dealing with when dealing with a chronically ill child."

    Ballard would consider gene therapy for her son if a trial opened for which he was eligible. Three experiments were under way or starting in the United States to treat X-SCID before French researchers reported the first leukemia case in a SCID patient in September.

    On Tuesday, the US Food and Drug Administration ( news - web sites) announced a second child in France apparently cured of SCID by gene therapy had developed leukemia. Both boys are being successfully treated with chemotherapy--leukemia in children is 90% curable--but regulators in both countries halted similar trials until they can decide what the risk is.

    An emergency meeting of government regulators scheduled for Friday has been postponed, and regular hearings on the issue are not scheduled until the end of February.

    "The FDA is being cautious and I think that is good," Ballard said. "We want someone being cautious for us. We want someone looking at the details. But at the same time we don't want to throw the baby out with the bathwater."

    She pointed out that seven children from the French trial are leading apparently normal lives, free of both SCID and of leukemia. "Leukemia is nothing to laugh at--it is horrendous for the families involved. But it doesn't mean that gene therapy can't still work."


    Abby Meyers, president of the National Organization for Rare Disorders, was less optimistic.

    "I think it raises a big alarm and I think it is a big lesson to the scientific community and the patient community that when a new technology arises, it takes years and years," said Meyers, who has three children with genetic disorders.

    Some parents would want to go ahead with the gene therapy no matter what, said Dr. Jonathan Goldsmith, medical director of the Immune Deficiency Foundation in Towson, Maryland.

    "I think it is up to patients and families to make those tough decisions about the risk-benefit ratio. I will assure you there are families who will assume that risk," Goldsmith said.

    The FDA's Dr. Philip Noguchi said the agency may consider allowing gene therapy experiments to proceed on a "compassionate basis"--when children will die without the treatment.

  9. #9
    Seneca, I am glad that the FDA is considering invoking the compassionate use rule for this therapy.

    Mkowalski, a reasonable risk/benefit ratio is of course in the eyes of the beholder. When the statistics are as skewed as this appears to be, i.e. over 90% efficacy rate and 10% complication rate, I don't think that there is sufficient justification for withholding the therapy and certainly not for stopping all retrovirus gene therapy trials in the U.S. One argument of course is that the FDA is not stopping the trials but simply putting a hold on them until the risk can be properly evaluated. The question then becomes what is the risk of delaying the therapy.

    Let us consider the scenarios for smaller benefit:risk ratio. At what point does the benefit to risk ratio become unfavorable. Say there is a 50% cure and 50% risk. I think that the decision should still lean in favor of continuing the clinical trial because the condition itself has such a poor prognosis. Let us say that the 90% of leukemia is curable. If we treat 20 kids, that means that only 5% or 1 kid will die from the therapy and 50% or 10 of the kids die from the condition. In short, even with a 50:50 benefit-to-risk ratio the risk of death from the condition is 10 times greater than the risk of death from the treatment. Note that the benefit:risk ratio does not approach unity even when the chances of cure is 10% and the risk of leukemia is 90%. In such a situation, if 20 kids were treated, 18 will die of leukemia or of their condition but 2 will be cured compared to death of 20 untreated kids.


    [This message was edited by Wise Young on 01-17-03 at 09:39.]

  10. #10
    mkowalski, I thought that I should expand on the benefit:risk analysis.

    If a disease has a high probability of causing death, the benefit:risk analysis favors application of very risky therapies. For example, 90% of people who get amyotrophic lateral sclerosis (ALS) die within five years of disease onset. Let us apply the benefit:risk analysis to this situation.
    • Let us suppose implanting embryonic stem cells (ESC) has a 50% chance of curing ALS but 10% of the ESC will grow into a teratoma and kill the patients. If we treat 20 ALS patients, we would expect 2 to survive anyway, 9 cured by the ESC, but 1 of the 9 cured patients will die from the ESC transforming into a teratoma, and the rest will die from ALS. In short, 10 of 20 treated people will survive. By comparison, if we don't treat the group, only 2 will survive. This would seem to be pretty compelling in favor of treatment.
    • Let us suppose that implanting ESC has a 50% chance of curing ALS but 50% of the ESC will grow into a teratoma and kill the patients. If we treated 20 ALS patients, we would expect 2 to survive anyway, 9 cured by the ESC, but 4-5 of the 9 cured patients will die from the teratoma. In short, 6-7 of the 20 treated people will survive, compared to only 2 of an untreated group. Thus, the ratio would still favor the treatment even though it has a 50% chance of killing the patient.
    • Let us suppose that implanting ESC has a 10% chance of curing ALS but 50% of the ESC will grow into a teratoma and kill the patients. If we treated 20 ALS patients, we would expect 2 to survive anyway, 2 people to be cured by the ESC but 1 of those people will die. In short 3 of 20 treated people will survive, compared to only 2 of an untreated group. The difference is small and therefore may not be compelling.

    Analysis of benefit:risk ratios become more complicated with non-fatal diseases. The five-year survival rate in spinal cord injury is about 90%.
    • Let us assume that the ESC transplant has a 50% chance of curing "complete" SCI and a 10% chance of producing a fatal teratoma or other fatal complication. In such a case, if we transplant ESC into 20 patients, 10% or 2 of the patients may die from the spinal cord injury but if the transplant cured one of them, and 50% of the remaining 18 patients will be cured but 10% of them will die from a teratoma. Of a treated group of 20 patients, one will die from the spinal cord injury, one will die from teratoma, 9 will be cured, and 9 will not be cured. In comparison, of 20 untreated patients, two will die from the spinal cord injury, and 18 will not be cured. So, this would be a pretty good argument for using the treatment.
    • Let us assume that ESC transplant has a 50% chance of curing "complete" SCI and a 50% chance of producing a fatal teratoma. In such a case, one will die from the spinal cord injury, 10 will die from the teratoma, and 9 will be cured. If one accepts that death is worse than spinal cord injury, this would be an an unacceptable benefit:risk ratio. On the other hand, I know that some people may not be dissuaded by this. It is a much closer call.


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