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Thread: When does risk over-ride benefit and who decides

  1. #1

    When does risk over-ride benefit and who decides

    I know that this does not seem on the surface to have much to do with cure of spinal cord injury but I hope that after some thought you will agree that the question asked here is at the crux of many decisions including clinical trials.

    Source: The

    Vioxx Fans Have Their Say

    By Melissa Davis
    Senior Writer
    2/17/2005 4:47 PM EST

    Patients who rely on painkillers like Bextra and Celebrex are seeking more relief.

    They long for a day when they no longer have to worry that their medications will be pulled from the market. One after another, pain sufferers -- most with arthritis -- pleaded Thursday with government advisers to consider their conditions when deciding the fate of so-called Cox-2 inhibitors.

    The drugs offer pain relief with reduced stomach problems but have been shown to carry cardiac risks. Merck (MRK:NYSE - news - research) has voluntarily withdrawn its Cox-2 painkiller, Vioxx, but Pfizer's (PFE:NYSE - news - research) Bextra and Celebrex remain available.

    Those who use -- or prescribe -- the drugs urged the FDA to weigh both benefits and risks when reaching its decision.

    "I am that patient you are addressing," one said. "I am a standing benefit in front of you."
    Let me explain.

    • Merck recently pulled Vioxx off the market when a clinical trial they were carrying out to assess whether Vioxx reduced bowel cancer in 2586 patients. The trial unexpectedly showed that 46 of the 1,287 patient taking 25 mg Vioxx daily had a blood clot, chest pain, heart attack, stroke, or sudden cardiac death). By contrast, only 26 of the 1,299 patients taking placebo experienced such an event. The patients in the study had been taking the Vioxx for 2.5 years. Merck stopped the study and pulled Vioxx off the market.

    There was another study going on Celebrex (a COX-2 inhibitor) made by Pfizer, also to see whether Celebrex would reduce the risk of colorectal cancer. That study randomized 2,035 patients to 200 mg, 400 mg, or no celebrex. At 2.8 years of taking the 400 mg dose, only 23 of 671 patients (3.4%) experienced a heart attack, stroke, or heart failure, compared to 16 of 685 patients (2.3%) taking the low dose 200 mg, and 7 of 679 patients (1%). Pfizer stopped the trial.

    By the way, the outcome measures in the two trials were different. In the case of the Vioxx trial, the criterion for a cardiovascular event included anybody getting any kind of clot or even chest pain. In the case of the Celebrex trial, the criterion was heart attack, stroke, or heart failure. In other words, the Celebrex trial counted only more severe events. If one counted only heart attack or stroke, the Vioxx study showed that 1.5% (or 15 patients out of a thousand) had a heart attack or stroke. The increased risk of heart attack or stroke is less than 1 out of 100 patients. Please note that a heart attack or stroke is not usually fatal.

    Merck had carried out an earlier clinical trial called VIGOR, comparing 4047 patients that received Vioxx and 4029 patients who received another anti-inflammatory drug called naproxen. That study showed 5 of 4047 patients who received Vioxx died of heart attacks and 4 of 4029 patients that received naproxen died of heart attacks. In other words, there was only one extra death from heart attack out of 4000 people. At the same time, the VIGOR study showed that patients on naproxen had a much higher incidence of gastrointestinal problems.

    Media coverage of the Vioxx withdrawal and the risk of Celebrex was shrill. Few of the articles in the newspapers pointed out that the drug was being taken much longer than is recommended. The patients received Vioxx for over 18 months and Celebrax for 28 months. Many articles pointed to the VIGOR study as evidence that Vioxx had been shown to have a high risk of heart attack. Legions of lawyers are sharpening their knives and preparing class action lawsuits against Merck and Pfizer. Congress and the FDA are having multiple hearings on the subject.

    In the meantime, millions of people who depend on Vioxx or Celebrax for relief of their pain are being left in the dust. As the this article pointed out:

    Consider Dave Ellis, a 66-year-old retired pharmacist from Edmond, Oklahoma. For 30 years, he has had degenerative arthritis in his spine. By about mid-February, he will have run through his supply of Vioxx and will not be able to buy more. He tells The Wall Street Journal he "dreads" that day. As Hayes Wilson, a rheumatologist in Atlanta, put it in a December 21 Journal article, "If you live with intractable pain every day of your life, would you take a chance that you would have a heart attack? A lot of my patients would."
    Why are we not simply telling the doctors and patients the risks of the therapy and then allowing them to judge the risk and benefits? Vioxx had already been approved by the FDA for having beneficial effects on osteoarthritis, rheumatoid arthritis, acute pain, dysmenorrhea, and migranes. By the way, Vioxx markedly (by 57%) reduced the gastrointestinal bleeding compared to other non-steroidal anti-inflammatory (NSAID) drugs such as aspirin, Advil, and Aleve. One study has shown that these NSAID-induced GI-bleeding causes 6000 deaths per year and other studies suggest that NSAID-induced gastric complications caused 16,500 deaths and more than 100,000 hospitalizations per year.

    Now, some media reports (and lawyers) suggested that Merck had evidence that Vioxx was dangerous before the outcome of the trial. Indeed, in 2000, Merck's research chief had suggested that Vioxx has cardiovascular hazards but said that it was low incidence. In fact, in 2000, Merck had updated their label including cardiovascular events in the adverse events section to the FDA. The warning of cardiovascular risk was printed on the label of Vioxx in September 2000.

    Many people are blaming the FDA for not taking action earlier concerning Vioxx. The FDA is an extraordinarily conservative organization. In my opinion, the data concerning cardiovascular risk of Vioxx was not sufficient to warrant a withdrawal of the drug before the most recent trial or even now. At most, it merits a warning. But, Merck withdrew the drug from the market. When they did so, many people assumed that Merck was hiding something and that the FDA had slipped up.

    Let me return back to why this is relevant to spinal cord injury. The concept that a drug must be proven to be safe before they can be approved for human use is applied to human clinical trials. For a long time, the FDA even had a tenfold rule. What is this rule? Well, if a company were to discover that a drug produced a serious side effect in a dog study at dose X, the dose that the company was allowed to try in clinical trial must be X/10. In other words, you can only use one-tenth of the dose that had any side effects. If this arbitrary and nonsensical rule had been applied to aspirin or digoxin, the two most ccommonly used drugs in the world, neither would have been approved. In fact, if this rule were applied to drinking water, the FDA would not allow water in clinical trial. We know that it is safe to drink a liter (about a quart) of water. However, some people would have some bad side effects from drinking 10 liters of water, and some may even die from drinking that amount of water all at once.

    This safety-at-all-costs-regardless-of-benefits attitude has delayed clinical trials and approval of gene therapies. For example, because of a single death (Jesse Gelsinger), most adenovirus mediated gene therapy clinical trials in the United States were stopped for nearly two years. Likewise, in a recent clinical trial of gene therapy to treat young children with a fatal immune-deficiency condition called "Bubble-boy" syndrome (because the kids must live in a plastic bubble to avoid being infected by the environment), 2 boys out of 11 developed a leukemia-like syndrome. Even though the treatment cured 9 of the 11 boys with the fatal immune deficiency, the French government not only stopped this clinical trial but the US FDA stopped 27 other clinical trial involving the same viral vector.

    Imagine the scenario if say two cases out of 11 stem cell transplants resulted in a tumor growing in the spinal cord but 9 of the patients were got substantially better. Should the FDA stop all similar stem cell transplant trials? When does risk over-ride benefit? Who decides?

    [This message was edited by Wise Young on 02-18-05 at 08:54 AM.]

  2. #2
    Wise Young


    Imagine what will happen in spinal cord injury if say two cases out of 200 umbilical cord blood transplants resulted in a cancer but 100 of the patients were got substantially better or were cure. Should the FDA stop all umbilical cord blood transplant trials? When does risk over-ride benefit? Who decides?
    This certainly needs to be looked at. I see your point. But, I think if the Drug companies were a little more upfront, rather than people becoming anguished, they might even understand the need to keep some drugs on the market that otherwise might be banned. So, a little education to the public and a little more info supplied by the drug companies and it might work.

  3. #3
    Senior Member alan's Avatar
    Join Date
    Jul 2001
    Baltimore, MD
    Patients should be informed of risks, and then get to decide on their treatment.


    There's a fungus among us, and I'm not lichen it!

  4. #4
    Most people do not understand risk and probabilites. That's why lotteries are so popular and people are worried about mad cow disease. They don't get it. And that's just probabilities, don't get me started on correlation vs. causality!

    Unfortunately there is no easy answer. Ideally one could sign a waiver and assume whatever risk they judged as prudent. Basically like we all do with the other decisions we make in life. (smoking, seat belts, diet/exercise, risky behavior, etc.) The litagation industry has shown there is no such thing as an iron-clad waiver. So the bar gets set lower with fewer risks being acceptable. Sad...

  5. #5
    Yea, what Quadfather said.


  6. #6
    Member PapaJoe's Avatar
    Join Date
    Oct 2004
    Grand Rapids, MI, USA
    With all of the complications of simply living with an SCI wouldn't it be impossible to tell what caused a higher amount of problems from clinical trials ? The injury is so debilitative! We must move forward and press the clinical trials cautiously yet aggresively to hopefully increase the quality of SCI life as quickly as possible.Time to pull out the stops and turn the key unlocking the PRISON of paralysis.
    Thank you,

  7. #7

    Most people make thousands of decisions every day and every decision requires balancing of risks and benefits. It is not so very difficult, in my opinion, if they understand the facts. The role of the doctor today is less of a priest and paternalistic figure than it was in yesteryear.

    It is true that when one is in the throes of an acute crisis, you may have to put your trust in the judgment of others. However, people with chronic spinal cord injury have lived with their injury and have the time to think and understand the problem. They should be able to make their decisions with the advice and consent of their doctors.

    It is true that many people don't want to spend the time understanding their treatment and condition. It is these people that require some protection and why doctors must still make the decision in the end. However, the issue is whether the FDA should be making that decision.


  8. #8
    So where do you draw the line Dr. Young?

    There are scores of SCI that would jump at the opportunity to take a potentially promising therapy today (say, OEG + Schwann + C-ABC) with no regard whatsoever to the very real possibility of safety issues.

    There are desperate and sad people who feel there is nothing to lose. That's why shark embryos are being transplanted. This puzzle is complex. Look at the litigation that arose from the University of Florida fetal transplants. It is a conundrum and frankly a most imposing obstacle that I hope the China trial network will be able to eschew.

  9. #9

    The big difference between 20 years ago and now is the Internet. The Physician Desk Reference use to be the only way that a doctor or a patient could find out risk and benefit information on any drug. It use to take hours and days just to figure out what a surgical procedure is and most information was hidden from the public. Now, of course, googles of data are at our fingertips.

    The above is of course the main reason why I formed Carecure. Our members have more up-to-date and comprehensive information about treatments of spinal cord injury than most doctors. The tsunami of information has changed the landscape of medical decisions. The goal of the FDA should be to ensure the accuracy and factual basis of information and not to make paternalistic decisions for patients.

    Egregious cases of misinformation should be vigorously prosecuted and we must increase our efforts to raise the education level of people so that they are not taken in by scams and charlatans. I believe that every family with spinal cord injury should have a computer with a fast connection to internet and that this probably has done more to save and improve lives than any treatment developed.

    I do admit that old habits die hard. For example, I still find myself reluctant to criticize doctors and certain practices because there is a medical fraternity. On the other hand, it is getting easier to criticize bad medical practice because there is a new culture of evidence-based medicine. In other words, medical bullshit is harder to defend today.


    [This message was edited by Wise Young on 02-18-05 at 08:24 AM.]

  10. #10
    I do admit that old habits die hard. For example, I still find myself reluctant to criticize doctors and certain practices because there is a medical fraternity. On the other hand, it is getting easier to criticize bad medical practice because there is a new culture of evidence-based medicine. In other words, medical bullshit is harder to defend today.

    Dr. Young, the above statement you made really touched me in a good way. You truly are a Doctor for the people. That is a powerful statement and only helps increase my motivation to push ahead with our grass roots efforts, knowing we have good Doctors behind us.
    Thanks, bob

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