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  • the dangers of clinical trials

    in the light of the SCI communities natural desire for more and speedier clinical trials, I thought this article may be of interest.

    Philadelphia Inquirer, May 20, 2002
    Paul Gelsinger stood before an audience of thousands of doctors and clinicians who test experimental treatments on humans to make a heartwrenching plea:

    Don't let what happened to my son happen to others.

    Gelsinger's son, Jesse, 18, died in a gene-therapy experiment at the University of Pennsylvania in September 1999.

    Since then, revelations of accidents and abuses at other respected research institutions have made it clear Jesse's tragedy was not an isolated one.

    Step-by-step testing of new treatments on humans is essential to medical progress, and about 3 million Americans a year now sign up for 80,000 "clinical trials." But critics say these experiments have become so numerous, commercialized and hard to monitor that it is too easy for researchers who are arrogant, reckless or just plain sloppy to harm people.

    Enhancing patient safety is crucial because clinical research, by its nature, involves risk, even when scrupulous care is taken. Deaths are rare - only about 1 in 10,000 subjects die. But "serious adverse events" - those that are life-threatening or require hospitalization - happen to 1 in 30 subjects in studies of new drugs, according to an analysis by CenterWatch, a Boston firm that tracks the clinical-trials industry.

    Proposals for reform have come from Congress, the drug industry, academia and government. Still, overhauling the vast, varied clinical-trials system is proving to be tough. The federal Office of Human Research Protections has been reorganized and beefed up under former Harvard researcher Greg Koski. Beyond that, critics say, there has been more debate than decisive action.

    Paul Gelsinger, 49, has become an outspoken advocate of change. He was in Toronto last month to address the Association of Clinical Research Professionals, using his son's story to personalize an often-impersonal process.

    He described Jesse, the second of four children, as an exuberant, good-hearted teenager, despite a rare liver-enzyme disorder, which was controlled with diet and drugs. Jesse was also, Paul said ruefully, an unabashed slacker. One day, while driving Jesse to work at a supermarket near their Tucson, Ariz., home, Gelsinger sternly told him to find a job with health insurance if he wasn't going to college.

    In a huff, Jesse jumped from the moving vehicle.

    "As I cradled him in my arms" afterward, Gelsinger recalled, "I cried, 'You idiot! What were you thinking?' "

    Several months later, the same headstrong teenager made a thoughtful decision, with his father's guidance, to volunteer for the study at Penn.

    Both realized Jesse wouldn't benefit and would likely suffer flulike symptoms. But Jesse wanted to help find a cure for babies with a deadly form of his disorder, ornithine transcarbamylase deficiency.

    "Words cannot express how proud I was of this kid," Gelsinger said, recalling the day Jesse flew to Philadelphia. "Just 18, he was going off to help the world. I gave him a big hug and told him he was my hero."

    That was their last hug.

    Paul Gelsinger had planned to go to Philadelphia a week after the treatment for what he figured would be the most dangerous part, a liver biopsy. Within a day of getting the genes, Jesse was gravely ill. His father and family members rushed to Philadelphia to find Jesse in a coma, his organs failing.

    On the third day, they held a bedside prayer service. Then life support was shut off.

    "Jesse was bloated beyond recognition," Gelsinger said. "The only way to be sure it was Jesse was the battle scar on his elbow" from jumping out of the van, and a small tattoo.

    The researchers, federal investigators found, had violated their own protocol and federal safety rules, while ignoring signs the treatment could be harmful - breaches Gelsinger initially denied.

    "I believed that their intent was nearly as pure as Jesse's. They had promised to tell me everything. I had bonded with these men. We shared personal experiences, spiritual things."

    In the last three years, at least two more healthy volunteers have died in trials at other institutions. The most recent was Ellen Roche, 24, who inhaled a toxic chemical in June as part of an asthma experiment at Johns Hopkins University in Baltimore.

    Penn, Johns Hopkins and at least five other prestigious centers, including Duke University Medical Center and Rush-Presbyterian-St. Luke's Medical Center in Chicago, have had trials temporarily shut down by federal regulators concerned that patients were being endangered. Dozens of other centers have been faulted for lapses.

    Invariably, the wayward institutions have made swift, sweeping changes. Penn set up a $1.5 million, 13-member Office of Human Research to train, assist and monitor researchers.

    Still, the clinical-research industry is leery of proposals for tighter federal control.

    "One of the reasons there hasn't been anything concrete is that no one has come up with a really good solution that's workable," said Leonard Glantz, a professor at Boston University School of Public Health.

    Although most people don't know what clinical trials are, such studies are crucial to evaluating the safety and effectiveness of new treatments. Before trials became standard in the mid-20th century - using control groups, placebos and other mechanisms to prevent distortion of outcomes - the healing arts relied heavily on superstition, folk tradition and doctors' experiences.

    "Clinical trials are not only essential to medical progress, but in the overwhelming majority of cases, they also offer participants the opportunity to receive top-quality care and the best available treatments," said Narberth oncologist Marisa Weiss, president of, an Internet support group.

    The number and complexity of trials have grown as research has shifted from lone scientists testing patients at individual medical centers to global, multicenter studies sponsored by the government, academic institutions and drug firms. In 1985, a new drug approved by the FDA involved 36 trials and 3,200 patients; now, the average is 75 trials and 4,800 patients, according to Parexel, a clinical trials-management company. Only one in five drugs ultimately wins approval.

    Considering the system's sheer size, "you don't hear about many problems with clinical trials. I think it's been one of the great worldwide success stories," said Thomas L. Adams, head of the Association of Clinical Research Professionals.

    Indeed, about 77 percent of patients in trials say they would volunteer again, CenterWatch surveys show.

    On the other hand, even top-notch centers have made news with ethically questionable studies or disastrous errors:

    In 1996 at the University of Rochester, a healthy 19-year-old student had lung cells collected in a study of smoking and air pollution. When she complained of pain, she was mistakenly given a deadly dose of the anesthetic lidocaine.

    In 1999 at Children's Hospital of Pittsburgh, a 9-month-old baby died of a heart arrhythmia after being given an experimental medicine for acid reflux; a coroner blamed the arrhythmia on the drug, which had been linked to adult deaths.

    Last year at Case Western Reserve University, a healthy retired nurse died during tobacco industry-sponsored research. Investigators concluded that she was given a fatal overdose of methionine, a normally harmless dietary supplement.

    Too often, critics say, patients don't understand or aren't told about risks, despite signing a statement of informed consent. At Penn, two volunteers preceding Jesse Gelsinger suffered from temporary liver toxicity that should have halted the trial. They were not informed. The Gelsingers were not told, either, even though Jesse's liver functioning was the weakest and his dose the highest.

    Another problem is that the system is unevenly regulated.

    Drug industry-sponsored trials are regulated by the FDA, which conducts impromptu on-site audits and requires reports of virtually all subject deaths and adverse events.

    But government-funded studies at academic institutions are regulated by the Office of Human Research Protections. The OHRP wants to know about "unanticipated problems involving risks to subjects," a rule that compliance-oversight director Michael Carome said has "ambiguity."

    Moreover, until Koski took over the OHRP, it rarely checked on institutions unless someone complained. Now, his staff of 47 seeks to visit 70 sites each month - although 60 of these will be "quality-improvement consultations," not hunts for violations.

    "We must move from a culture of compliance to a culture of conscience," Koski said.

    Outside FDA and OHRP purview are studies with no regulation, including some infertility, dietary-supplement and stem-cell trials.

    "I could have children inhale lighter fluid, and the OHRP and FDA would have nothing to say about it, if I'm not a drug company and I don't work at an institution," said Glantz.

    When rules are unclear, some researchers err on the side of not reporting. After Jesse Gelsinger's death, "the National Institutes of Health received 652 reports of previously unreported serious adverse events [from gene therapy trials] that sparked a series of congressional hearings on patient safety oversight," noted the CenterWatch analysis.

    Adil E. Shamoo, a University of Maryland biochemist and editor of the journal Accountability in Research, says non-disclosure is common.

    "I'm not accusing them of conspiring not to report," Shamoo added. "I'm saying what happens is, nobody is going to... say, 'Hey, guys, I've read the federal regulations, and we have to report this.' "

    The system is not supposed to be so vulnerable.

    Local institutional panels are supposed to ensure that every trial has proper oversight, an ethical design, and that each patient signs an informed-consent document. Called Institutional Review Boards (IRBs), or ethics boards, the panels were mandated in 1974 by federal law following revelations about abuse of human subjects - including government-sponsored radiation experiments and the notorious Tuskegee syphillis study, in which African American men were secretly left untreated for the venereal disease.

    But ethics boards, which must have at least one community representative, are not trained or paid for what is often a crushing workload. A government report found a typical university medical center IRB had less than two minutes per agenda item during a 21/2-hour meeting - hardly conducive to careful deliberation.

    Under current rules, ethics boards may wind up with boxes full of adverse-event reports from many testing sites, but no way to make sense of them.

    "We get a report, but without context... , we often cannot determine if it is referring to one event in a population of 10 patients or 300 patients," said Erica Heath, president of Independent Review Consulting, a for-hire ethics board. "Was the subject assigned to the study drug or placebo?"

    Ethics boards have not been effective in dealing with another problem - financial conflicts of interest. In the gene therapy trial, for example, both James Wilson, Penn's lead gene-therapy researcher, and the university held stock in Genovo, a company that Wilson founded to develop therapies. Paul Gelsinger says he was not aware of this when Jesse volunteered, although it was disclosed on the informed-consent form.

    A year after Jesse died, Targeted Genetics Corp., of Seattle, acquired Genovo. Wilson got $13.5 million in Targeted stock and the university got $1.4 million in stock.

    (Wilson quit last month as head of Penn's gene-therapy institute, and the FDA has begun a process that could bar him from human research overseen by the agency.)

    Money influences the system in other ways, critics say. Drug companies often pay patients to take part in studies, and pay researchers to recruit them.

    Harvard Medical School faculty member Marcia Angell, former editor of the New England Journal of Medicine, says financial deals that could compromise objectivity should be banned, not just disclosed. Disclosure is "neither fair nor helpful to the patient, who may be both sick and desperate."

    A typical reaction to her unequivocal stance: Get real.

    "I think [a ban] would bring, particularly in biotechnology, a lot of research to a complete halt," said Adams. "And I don't think that would be in the interest of public health."

    In Toronto, a nurse from the University of Texas asked Gelsinger, "How are we supposed to find a balance between the industry pressures... and the patients and advocacy groups on the other side? Patients don't care about the details. They just want the new drug now."

    Gelsinger said he sympathized. An advocacy group for patients with Jesse's disorder had pushed for the Penn trial.

    "People pour so much hope in that they become blind," he said. "But that's why we need independent oversight. Somebody needs to be stepping back, and being careful and unbiased."


  • #2
    #'s in perspective

    "Deaths are rare - only about 1 in 10,000 subjects die. But "serious adverse events" - those that are life-threatening or require hospitalization - happen to 1 in 30 subjects... "

    OK so that means you have roughly a 3.3% risk of serious complications and a .01% chance of death. Conversely, you have a 96.6% chance of NOT having serious complications and a 99.99% of living through the trail.

    If you have SCI you have 10% chance of dying each year plus a shortened lifespan full of misery, suffering & secondary complications.

    I think the risks are very reasonable... and much smaller than the risks of NOT doing trials.
    "Oh yeah life goes on
    Long after the thrill of livin is gone"

    John Cougar Mellencamp


    • #3
      MKowalski, I think that we must distinguish between harm to the individual and harm to the field. As the case of Jesse Gelsinger illustrates clearly, a single death in a trial has severely delayed or may even deprive a field of a treatment that may otherwise be very useful. Unfortunately, this article does not address the other people who have died of severe forms of ornithine decarboxylase deficiency because this particular case stopped the trial. The therapy may have helped some people but we will probably not know for a long time. Wise.


      • #4
        how about

        looking at the number of people that die from mistakes in-hospital for routine care. i'm sure these numbers are probably higher, as was recently reported. the trials just are under a bigger microscope. i think it's all relative.


        • #5
          the rewards of research

          Ethics boards have not been effective in dealing with another problem - financial conflicts of interest. In the gene therapy trial, for example, both James Wilson, Penn's lead gene-therapy researcher, and the university held stock in Genovo, a company that Wilson founded to develop therapies. Paul Gelsinger says he was not aware of this when Jesse volunteered, although it was disclosed on the informed-consent form.

          A year after Jesse died, Targeted Genetics Corp., of Seattle, acquired Genovo. Wilson got $13.5 million in Targeted stock and the university got $1.4 million in stock.
          I wonder if it's common for researchers to reap such large rewards? I guess it would be quite a stimulus to develop cures.


          • #6
            However Dr. Y

            Isn't it better to have tried and failed vs. not trying at all?

            Didn't the doctors in Jesse's cased learn what not to do next time? Aren't they better prepared for the next patient?

            This is a major issue that you and others, imo, seem to not grasp nor fully understand. I mean no disrespect to you and others within the field but to understand the psychology of many sci patients is to understand that we will do or try almost anything to improve our conditions. Further, we understand the risks better than you do, its our lives on the line. We can weigh the risk reward potential individually.

            I understand completely that in a perfect research world, clinical trials go as planned, and people are cured of their ailments. But at what cost? To go from rats to cats to monkeys to humans is ideally the best methodology. But within what time frame? What's reasonable to you and others may be completely unreasonable to us, the injured.

            Bottom line. I'm not speaking out of desperation, misery or unrealistic expectations. I'm speaking about making reasonable attempts at curing us. I think we all realize that some experimental treatments are going to result in complications, even death. But won't the community be able to move light years faster than the current pace? The learning becomes exponential when human lives are at stake. Nobody wants to see anybody die. However I think that the majority understand that we may have to pay the ultimate price in order to cure the masses.

            I'm sure you think I'm crazy but this sci is crazy too. And I know that what I've said flies in the face of every ethical, medical and legal law that you're bound to and believe in but I believe that we need to try whatever's available, with scientific merit, on humans - now.

            Many may not like or understand Will Ambler or the Dr's involved with his project but, I for one, completely respect him / them for their right to try. Statistics be damned I want out of sci!

            Onward and Upward!


            • #7
              Clinical Trials: A Guide for Patients


              What is a clinical trial?

              A clinical trial is a research program conducted in patients to evaluate a new medical treatment, drug, or device. The purpose of clinical trials is to find new and improved methods of treating different diseases and special conditions.

              Clinical trials make it possible to apply the latest scientific and technological advances to patient care.

              During a clinical trial, doctors use the best available treatment as a standard to evaluate new treatments. The new treatments are hoped to be at least as effective as -- or possibly more effective than -- the standard.

              New treatment options are first researched in the laboratory, where they are carefully studied in the test tube and in laboratory animals. Only the treatments most likely to work are further evaluated in a small group of humans prior to applying them in a larger clinical trial.

              When a new medical treatment is studied for the first time in humans, scientists don't know exactly how it will work. With any new treatment, there are possible risks as well as benefits. Clinical trials help physicians discover the answers to these questions:

              Is the treatment safe and effective?
              Is the treatment potentially better than the treatments currently available?
              What are the side effects of the treatment?
              Does the treatment have any possible risks?
              How well does the treatment work?
              Phases of a clinical trial

              Clinical trials are conducted in phases, each designed to find out specific information. Each new phase of a clinical trial builds on information from previous stages.

              Participants may be eligible for clinical trials in different phases, depending on their overall condition. Most clinical trial participants take part in Phases 3 and 4.

              What are the different phases of a clinical trial?

              In a Phase 1 clinical trial, a new research treatment is given to a small number of participants. The researchers determine the best way to give the new treatment and how much of it can be given safely.

              Phase 2 clinical trials determine the effect of a research treatment on the particular disease or condition being evaluated.

              Phase 3 clinical trials compare the new treatment with the standard treatment.

              Phase 4 clinical trials apply the new treatment to general patient care. For example, a new drug that was found effective in a clinical trial may be used together with other effective drugs to treat the particular disease or condition in a select group of patients.

              Advantages and disadvantages

              What are the advantages of participating in a clinical trial?

              You may receive a new treatment before it is widely available to the public.
              You can provide researchers with the information they need to continue developing new procedures and introducing new treatment methods.
              Your treatment costs may be decreased, since many of the tests and doctor visits that are directly related to the clinical trial are paid for by the company or agency sponsoring the study. Be sure to discuss your treatment costs with the physicians and nurses conducting the clinical trial.
              Could any problems arise from participating in a clinical trial?

              This will depend on the type of treatment and the patient's condition.

              Because the drug or device being studied is new, all of the risks and side effects of the treatment are not known at the beginning of the clinical trial. Since this is the case, there may be unknown side effects, as well as hoped-for benefits. It is important to note that most treatments, as well as the disease or condition itself, have potential unpleasant effects.

              Patients will be informed of any known side effects they could experience, as well as any side effects that occur or become known while they are participating in the trial.

              How would my treatment be different if I participated in a clinical trial?

              You may receive more examinations and tests than are usually given for your particular condition. The purpose of these tests is to follow your progress and collect study data. Of course, tests can carry certain benefits and risks or discomforts of their own. Although they can be inconvenient, these tests can assure extra observation.
              Depending on the type of clinical trial, you may be asked to stop or change the medication(s) you are currently taking. You may also be asked to change your diet or any activities that could affect the outcome of the trial.
              Some clinical trials are double-blind, placebo-controlled. This means that the clinical trial participants may receive the real drug or an inactive substance that looks exactly like the drug (called a placebo). Neither the participant nor the researcher will know which drug they are receiving. This is done to make certain that the real drug is effective.
              Clinical trial participants are willing volunteers. Even though patients may be asked by their doctors to take part in a clinical trial, it is up to the patient to make the final decision, or to pull out of the trial if they want to.
              Informed Consent

              What is informed consent?

              Informed consent means that as a patient, you are given all available information so you can understand what is involved in a specific clinical trial. The doctors and nurses conducting the trial will explain the treatment to you, including its possible benefits and risks.

              You will be given an informed consent form to read and consider carefully. Before signing, be sure you find out as much as possible about the clinical trial, including what risks you may face. Ask the researchers to explain parts of the form or the trial that are not clear. (See "Important Questions to Ask" below.)

              You are free to decide whether or not you want to take part in the trial. If you decide to participate, you will sign the consent form. If you do not want to participate in the trial, you may refuse. If you choose not to participate in the trial, your care will not be affected in any way.

              Your signature on the informed consent form does not bind you to the study. Even if you sign the form, you are free to leave the trial at any time to receive other available treatments.

              The informed consent process is ongoing. After you agree to participate in a clinical trial, you will continue to receive any new information about your treatment that may affect your willingness to stay in the trial.

              Clinical trial participation

              Who can participate in a clinical trial?

              Every clinical trial is designed to meet a specific set of research criteria. Each study enrolls patients with certain conditions and symptoms. If you fit the guidelines for a trial, you may be able to participate. In some instances, you may be required to undergo certain tests to confirm your acceptability as a candidate.

              What is it like to participate in a clinical trial?

              All patients face a new world of medical terms and procedures. Fears and myths of being experimented upon or being a guinea pig are common concerns of patients who are thinking about participating in a clinical trial.

              Even though there are always going to be fears of the unknown, understanding what is involved in a clinical trial before agreeing to participate can relieve some of your anxieties.

              This may help ease your concerns:

              The personal information gathered about you during the clinical trial will remain confidential and will not be reported with your name attached.
              If at any time throughout the trial you and your physician feel it is in your best interest to exit the trial and use other known treatments, you will be free to do so. This will not in any way affect your future treatment.
              Clinical trial participants typically receive their care in the same places that the standard treatments are given -- in clinics or physician's offices.
              Clinical trial participants are watched closely, and information about you will be carefully recorded and reviewed.
              Important questions to ask

              If you are thinking about taking part in a clinical trial, find out as much as possible about the study before you decide to participate. Here are some important questions to ask:

              What is the purpose of the clinical trial?
              What kinds of tests and treatments does the clinical trial involve, and how are these tests given?
              What is likely to happen in my case with, or without, this new research treatment? (Are there standard treatment options for my case, and how does the study compare with them?)
              How could the clinical trial affect my daily life?
              What side effects can I expect from the clinical trial? (Note: There can also be side effects from standard treatments and unpleasant effects from the disease itself.)
              How long will the clinical trial last?
              Will the clinical trial require extra time on my part?
              Will I have to be hospitalized? If so, how often and for how long?
              If I agree to withdraw from the clinical trial, will my care be affected? Will I need to change physicians?


              • #8
                His father may not have known about things on the disclosure form but Jesse did. At 18 he was able to make his own decisions. I've been in two trials and in both I read the informed consent form from front to back and every line before I signed them. There also has to be personal responsibility for dangers that are disclosed and people agree to take. No one mentions that Gelsinger's father talked about his son finally being able to eat regular food if the trial worked. And the woman who died at Hopkins was a healthy volunteer. While this is a tradgedy for her family and friends, local news reports said that she had waited a couple days after having side effects before contacting the testing center. I wonder if she would still be with us had she gone back immediately..
                Courage doesn't always roar. Sometimes courage is the quiet voice at the end of the day saying, "I will try again tomorrow."

                Disclaimer: Answers, suggestions, and/or comments do not constitute medical advice expressed or implied and are based solely on my experiences as a SCI patient. Please consult your attending physician for medical advise and treatment. In the event of a medical emergency please call 911.


                • #9
                  Harm to individual vs. harm to field

                  Dr. Young you are 100% correct.

                  The effect of having even a SLIGHTLY DISAPPOINTING clinical trial can hammer a company's stock (which in turn makes it nearly impossible to raise funds). The market has been brutal to companies such as Neotherapeutics, Diacrin and lately ImClone. And if the trial is not privately funded, inconclusive results can set things back even more.

                  However, the point of this article was that a Father lost his son and pleads:

                  "Don't let what happened to my son happen to others"

                  I am very sorry that this man lost his son. It is very unfortunate that he found himself in that .001% that die from a trial. I still think that these are extremely acceptable #s and risk %.

                  As a side topic question:

                  What happens if Neutherapeutics and/or Diacrin go belly-up? Will someone pick up their technology or are we going to lose 2 out of very few options where human trials are actually occurring?
                  "Oh yeah life goes on
                  Long after the thrill of livin is gone"

                  John Cougar Mellencamp