Wednesday, April 28, 1999

UC research deaths go unreported


Memos says rules were broken

BY TIM BONFIELD
The Cincinnati Enquirer

        Questions about the supervision of medical research at the University of Cincinnati go beyond an investigation of how veterans and others were treated in a handful of psychiatric studies.

        According to documents provided to The Cincinnati Enquirer, UC researchers failed to report that eight participants in medical experiments died. In addition, officials are concerned that at least some medical studies at UC were started without a required review to protect patients' privacy and ensure that they are properly notified of potential risks.

        These documents have come to light as a federal investigation focusing on psychiatric research at UC and Cincinnati's VA Medical Center continues. In that probe, the Office for Protection from Research Risks (OPRR), an arm of the National Institutes of Health, has required UC to “re-review” all of its federally funded medical research.

        That adds up to at least 98 studies that must be checked again by UC's Institutional Review Board, a 22-member panel that is supposed check out all research projects involving human subjects. Their job is to make sure proposed studies pose no unnecessary risks to patients, to see that approved studies clearly explain all risks and benefits, and to keep watch for unforeseen complications involving experimental treatments.

THE REVIEW BOARD
  All research centers that receive federal funding for medical experiments involving humans must have an Institutional Review Board (IRB). The board is responsible for protecting patients from harm by reviewing research protocols and the wording of consent forms to make sure all risks and benefits are explained.
THE VA CENTER
  This center is part of a nationwide medical system for U.S. veterans. The hospital has 1,180 full-time employees. Physicians are provided from the UC College of Medicine faculty.
UNIVERSITY HOSPITAL
  This hospital, now private, remains affiliated with the UC College of Medicine and serves as a main site of clinical research.
        Two memos — one written in December, the other in February — raise questions about how well UC researchers are following the rules.

        “It has become increasingly apparent that adverse event/death reports are not always being filed with the (Institutional Review Board) in a timely manner, and in some instances not at all,” wrote Dr. Harry Rudney, co-chairman of the UC Institutional Review Board, in a Dec. 4 memo to all clinical investigators.

        Dr. Rudney is ill and was not available for comment about his memo. But another IRB member, Linda Harpster, an associate general counsel for UC, and a UC research coordinator said that the letter was triggered by problems within a single study.

        More than 100 patients since 1996 have participated in a study to test whether doses of nitric oxide can help improve breathing in patients suffering acute respiratory distress. However, last year, investigators failed to file “adverse event” reports for at least eight deaths.

        Researchers thought none of the deaths was connected to the treatment, so they waited to report them as part of an annual progress report on the study, said Rich Branson, clinical research coordinator for the department of surgery at the University of Cincinnati Medical Center.

        But a federal regulation that sets standards for all U.S. research involving human experimentation “clearly states that all deaths and unanticipated or unexpected adverse reactions must be reported to the Chairperson of the IRB immediately and a written summary of the circumstances surrounding the adverse reaction or death be submitted to the IRB office within ten days of the occurrence,” Dr. Rudney wrote.

        UC's 22-member IRB reviews more than 400 proposed research projects every year, including public and privately funded studies and studies in which UC is one of many participating centers around the country. In addition, the board reviews all research projects that go on at the VA Medical Center, which is staffed by UC faculty.

        In recent months, psychiatric studies done at UC and the VA center have become subjects of various investigations and media reports, including a December article by the Boston Globe and a piece aired this month by CBS on 48 Hours.

        Four Ohio members of Congress — U.S. Sens. George Voinovich and Mike DeWine and Reps. Steve Chabot and Rob Portman — wrote a letter April 19 that calls on UC to cooperate with the OPRR investigation.

        “These issues need to be addressed so that Ohioans, particularly our veterans, can have ... peace of mind when receiving medical treatment and care,” the letter states.

        Dr. Rudney's memo de scribed how researchers haven't been following the rules:

        “Often, the accounts (of adverse events) are received months after the occurrence, or are forwarded at the time of the annual progress report. In some cases (the progress report) lists deaths or adverse events as having occurred during the period of the report; however, when the IRB staff examines the file, there is no official previously submitted documentation to support these incidents.”

        Prompt reporting of adverse events is important because it is the IRB's job to decide whether the research project needs to be halted or changed, Dr. Rudney wrote. In addition, when adverse events occur, the IRB must decide whether informed-consent forms must be re-written or whether patients involved in the test must “re-consent” to continued participation.

        UC's “adverse event” definition lists six categories that require reporting:

        • Death of a patient.

        • A life-threatening reaction.

        • A persistent or significant disability or incapacity.

        • Hospitalization or extension of an existing hospitalization.

        • A birth defect in a child born to a parent taking the experimental medication.

        • Any other event that requires treatment to prevent one of the medical outcomes listed above.

        In addition to failing to promptly report adverse events, some researchers haven't been telling the IRB about their studies at all, according to a Feb. 24 letter by Dr. Rudney sent to all clinical investigators.

        The IRB met Feb. 17 to discuss whether studies that use leftover tissues or fluids from medical tests, procedures or autopsies would be exempt from IRB review.

        “The Board was also concerned that there were studies being carried out in which the investigator decided that their interpretation of the regulations concerning exemptions and waivers did not require them to submit a protocol to the IRB, let alone inform the IRB of the study,” Dr. Rudney wrote.

        UC officials say none of the studies in question actually went unreported, and that none involved high-risk treatments. Instead, this memo was sent after several researchers raised questions about whether they needed IRB approval for “no-risk” telephone surveys of patients.

        The answer was: They did need approval. To clarify the situation, the IRB passed a resolution Feb. 17 reaffirming that all studies involving humans require IRB approval, even those with no risk.

        The fact that such memos needed to be sent is disturbing to some patient advocates.

        “This raises a big red flag to me. It says that the IRB doesn't have a handle on the research going on at UC,” said James Coleman, recovery coordinator for the Recovery Initiative, a support group for people with mental illness.

        UC officials, however, say the memos from Dr. Rudney show that UC's IRB is being vigilant at enforcing standards.

        “Dr. Rudney is very conscientious. He used these incidents as an opportunity to clarify and remind people what the rules were,” Ms. Harpster said. “I do not believe there's a widespread problem.”

        However, the OPRR investigation already has criticized the IRB for not providing enough detail about its deliberations in its minutes and for allowing too many studies to receive expedited approval.

        To comply with OPRR findings, the IRB at UC already has added wording to its policy spelling out which documents must be provided to IRB members and how votes must be taken and recorded.

        In addition, the IRB must provide copies of all its meeting minutes from January through May to the OPRR to show they are complying with the findings.

        UC has begun re-reviewing all its federally funded studies to meet a May 20 deadline. The process has turned weekly meetings that normally last one hour into meetings that last several hours, Ms. Harpster said.

        So far, no major problems with the projects have turned up.

        “We are doing the best we can to make sure we are responding to all their requirements,” Ms. Harpster said.

UC Medical Research Highlights
        • UC's most famous research achievements include the oral polio vaccine developed by Dr. Albert B. Sabin that virtually wiped the disease from the planet, and the development of Benadryl, the world's first antihistamine. More recently, UC researchers have played a central role in advancing stroke treatments through the use of clot-busting drugs.

        • UC holds at least 66 patents on medical advances that, combined, provide at least $2 million a year in royalties. At least nine start-up companies have been formed in recent years to move research discoveries at UC into the commercial market, ranging from artificial skin to vaccines to prevent urinary infections to better anti-allergy drugs.

        • UC also has been pumping millions into capital programs to expand medical research, including $10 million last year to install a set of super-microscopes called nuclear magnetic resonance spectrometers; $40 million to build the curvy-walled Vontz Center for Molecular Studies; dedicating $70 million from the French family trust to cancer research; and in January, announcing plans to raise $117 million to rebuild its medical sciences building, which houses the bulk of UC's medical student training and basic research labs.

        • Of the more than 5,000 colleges and universities nationwide, UC is one of 75 designated as a “Research I University” by the Carnegie Commission.

        • UC's departments of environmental health, obstetrics/gynecology, pediatrics and molecular genetics are ranked among the top 10 in the United States in terms of funding from the National Institutes of Health.



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