External-Committee Recommendations Prompt Changes at IHGT

The Institute for Human Gene Therapy (IHGT) at Penn will no longer conduct human clinical trials, limiting its scope to molecular, cellular and animal-model experimentation. This change was announced by the University on May 24, following recommendations made a month earlier by an external-review panel charged with examining practices at the institute.
    From now on, human-gene experiments will be conducted by individual departments across the University, with oversight by Penn’s Office of Regulatory Affairs. Though the IHGT’s focus will change, Dr. James M. Wilson, the John Herr Musser Professor and Chair of Cellular and Molecular Engineering, will remain director of the institute. In addition, an Institutional Review Board (IRB) with expertise in evaluating gene therapy will be created, and the entire system of IRBs at Penn will be studied to strengthen their ability to protect patients’ “vital interests.”
    Dr. Judith Rodin, president of the University, appointed the committee, composed of scientists from peer institutions, after the U.S. Food and Drug Administration put clinical trials on hold at the IHGT in January, four months after the death of 18-year-old Jesse Gelsinger, a participant in a clinical trial at the Institute. The FDA’s investigation found “numerous and serious deficiencies” in the monitoring and oversight of the trial [“Gazetteer,” November/December, January/ February, March/April, May/June].
    Chaired by Dr. William H. Danforth, a physician and chancellor emeritus of Washington University in St. Louis, the committee met twice; interviewed 20 people associated with clinical trials at IHGT, as well as Rodin and University Provost Dr. Robert Barchi; and reviewed “scores” of documents. In its report, the committee recommended that the University:

  • Evaluate the function and workload of Independent Review Boards at Penn (which oversee issues of ethical decision-making in human experimentation), making sure they include members who are knowledgeable about specialized areas of research and that those boards share information, particularly about adverse events, among different trials using similar therapies.
  • Review its conflict-of-interest policies, keeping in mind that “perceived as well as actual conflicts of interest make clinical trials more open to suspicion and criticism.”
  • Do everything possible to ensure that informed consent is obtained from patients, following “the letter as well as the spirit” of FDA regulations.
  • Consider whether it makes sense for an entire institute to be devoted to gene therapy, and whether some services, such as the production of vectors for clinical testing, would be better performed “extramurally.”

    The committee also made the following observations:

  •  The IHGT scientists and the University appear committed to correcting any deficiencies and complying with all regulations.
  • Detailed surveillance of clinical trials involving novel biologic therapies, such as viral vectors, is essential. (Gelsinger had been injected with a modified cold virus that was designed to deliver corrective genes to the liver.) 
  • To conduct independent clinical trials—that is, trials that are not sponsored and monitored by pharmaceutical companies or performed in conjunction with other centers at other universities —the University must invest “considerably more resources” for regulatory compliance “than has historically been necessary for independent university-initiated clinical research.”
  • Even if all guidelines and regulations are followed, risk cannot be eliminated from a clinical trial.

    Saying that the University was “extremely grateful” to the committee members and praising their “collective insight and considerable experience,” Rodin added: “While we have moved aggressively in a variety of areas, we recognize that we have considerable work to do to ensure that we structure the best possible climate for clinical trials, one that always ensures the interests of our patients are of paramount importance. We will continue to work with our colleagues … and with regulators and with lawmakers to accomplish this task.”
    The University announced steps it has taken or will be taking, guided by the Danforth-committee report and the interim recommendations of an internal-review committee chaired by Provost Barchi. (The internal committee has been examining all research involving human subjects at Penn and will continue its work over the summer.) Among its steps and observations:

  • Though the IHGT was created “in the belief that it made practical sense to combine in one entity virtually all phases of basic science, pre-clinical and clinical work in gene therapy, IHGT and the University have now come to a different view. Experience has shown that it is very difficult to align all required areas of expertise within a single integrated institute or center.” 
  • “As the IHGT was organized, there was considerable consolidation of responsibility and authority in a single individual,” Rodin told the Gazette. “Over time, Dr. Wilson was simply overloaded with regard to responsibility, so one of our initial efforts has been to reduce some of the day-to-day management and oversight responsibilities. Various entities looking at this from many different directions came to the same conclusion—that responsibility and authority needed to be spread out somewhat.”
  • Every clinical trial at Penn will be assessed by the Office of Regulatory Affairs, which will hire additional staff, to determine the level of monitoring required to comply with regulations. The limited number of trials with no external sponsorship will be reviewed by a professional contract research firm to determine if additional monitoring is needed.
  • The University is examining its IRB system to build on changes already in place following an external review last summer, including a 24-hour adverse-event hotline that was set up on February 1.

    Although the University already has conflict-of-interest restrictions in place, it will conduct a full review of its own policies.
    “I am confident that the steps outlined today will help position Penn in the future as a model environment for the conduct and oversight of all types of clinical research, especially gene therapy,” said Wilson, the IHGT’s director, in a written statement. He added that “my colleagues and I will refocus our efforts in the preclinical area—with the goal of developing a foundation of science necessary to assure the ultimate success of this field.”

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