|
The University of Pennsylvania is taking a series
of actions designed to strengthen oversight and monitoring of its clinical
trials, enhance the organization and focus of its Institute for Human Gene
Therapy, reinforce its Institutional Review Board's role in oversight and
patient protection, address issues of ethical decision making in research
using humans and comprehensively review its policies on conflict-of-interest.
The actions were announced May 24 following the receipt
of a report by an independent review panel, appointed
by President Judith Rodin to conduct a comprehensive review of oversight
and monitoring of clinical trials at the Institute for Human Gene Therapy
("IHGT").
The independent review by distinguished research scientists
unaffiliated with Penn was chaired by William H. Danforth, M.D., chancellor
emeritus and vice chair of the board of trustees at Washington University
in St. Louis, and was designed "to understand the operations of the
IHGT and its handling of clinical trials and to point out areas that [we]
believe require thought, attention, further investigation or correction."
"Our clinical research programs at the University
of Pennsylvania must meet the highest possible standards for academic excellence
and patient safety and care," Dr. Rodin said. "Nothing less is
acceptable."
Actions Penn is taking include:
- Assessing all clinical trials to determine the level
of monitoring necessary for strict compliance with all applicable regulations.
- Focusing the IHGT mission on molecular and cellular work
and animal model experimentation. Consistent with this focus, IHGT will
no longer conduct clinical trials.
- Initiating a comprehensive review of ethical decision-making
specific to all research using humans, and creating an Institutional
Review Board ("IRB") with special expertise in evaluating gene
therapy.
- Conducting a formal, comprehensive review of the IRB
system to strengthen its abilities to protect the vital interests of patients,
building on significant changes in IRB policies and procedures already
in place.
- Reviewing policies and procedures on conflict-of-interest
specific to both perceived and actual conflicts, including those inherent
in investment and funding of provocative medical therapies.
"We are extremely grateful to Dr. Danforth and to
the members of the committee, who brought their collective insight and considerable
experience to the task," Dr. Rodin said, "and we are very encouraged
by the Danforth Committee's explicit findings that the University and IHGT
are committed to compliance with all applicable regulations and to
correct any past deficiencies, that we were changing processes and practices
to conform to the FDA's requirements before that agency began its
investigation and that we have already instituted a number of important
changes.
Focusing the IHGT Mission
"IHGT is a site of important research on a therapy
that may provide great benefits to human beings in the future," she
said, "and we will continue to support it." The University "has
greatly benefited from the Danforth Committee's questions about the scope
of the IHGT," and its role in the conduct of research using human subjects
at the University.
"Penn and IHGT have jointly determined that IHGT can
best serve the important future of gene therapy by resolutely focusing on
molecular and cellular work and animal model experimentation." It will
not, she said, serve as a sponsor of clinical trials in the future.
The decision to discontinue sponsorship of clinical research
by IHGT will not impede the conduct of gene therapy clinical trials that
may take place elsewhere within the University.
Strengthening Oversight of Clinical Trials Involving Humans
Dr. Rodin said that the University believes that the Danforth
Committee is correct in suggesting that clinical trials involving human
subjects at universities across the country will require increasingly stringent
oversight and regulatory compliance. Consistent with the suggestions of
the committee, the University is taking the following the actions:
- Every clinical trial at Penn will be professionally assessed
by the University's Office of Regulatory Affairs ("ORA") to determine
the level of monitoring the trial will require for strict compliance with
all applicable regulations;
- Each of the limited number of current clinical trials
at Penn that have no external sponsorship and monitoring will be reviewed
by a professional contract research firm to determine any additional monitoring
the trial may require. The University is presently recruiting firms for
this purpose.
- The University is developing a set of clear standards
that will guide the review and monitoring of all clinical trials; and
- The University is developing a compendium of Standard
Operating Procedures for research involving human subjects at Penn and
a process for ensuring that all investigators have access to, are cognizant
of and are in full compliance with these procedures.
Initiating a Comprehensive Review of Ethical Decision-making
The University is undertaking a comprehensive review of
ethical decision-making specific to research using human subjects at the
University, and future ethical discussion regarding the testing of gene
therapy in human subjects will be overseen by an Institutional Review Board
with special expertise in evaluating gene therapy. In addition, the School
of Medicine will establish a new, free-standing Department of Bioethics
that will include the current Center for Bioethics.
Conducting a Formal, Comprehensive Review of the IRB System
The University already has begun a formal, comprehensive
review of its Institutional Review Board system to strengthen the IRB's
ability to protect the vital interests of patients as well as other relevant
issues. This review will include examining the proposals being developed
by Congress and others. It also will build on the significant changes already
in place at Penn following an external review completed last summer and
the appointment of ORA Director Joseph R. Sherwin, Ph.D. IRB policies and
procedures have been strengthened to ensure, among other things, and include:
- Strict adherence to all IRB regulatory requirements.
- Implementation and use of a new database tracking system
that identifies primary and secondary reviewers and monitors IRB discussion
of substantive issues and its recommendations for changes in protocols
and consent forms. (This new database tracking system was available on
Oct. 1, 1999.)
- A new 24-hour adverse event hotline that is monitored
on nights and weekends by the IRB Director and Associate Director. (This
new 24-hour adverse event hotline was available on Feb. 1, 2000.)
- Substantial, regular training and education for IRB members
and staff.
- Training for Medical School faculty, which ultimately
will be integrated into a requirement for certification of both principal
investigators and research coordinators before permitting submission of
protocols for IRB review.
- A new ORA
web site and a new brochure that has been distributed to the University's
research community. (The new ORA web site was available on Dec. 15, 1999;
the brochure is in its second printing.)
- Several new professional staff in the ORA; additional
positions are being recruited as of this writing.
- The ORA is in the process of developing new Standard
Operating Procedures for IRB members that clearly delineate the requirement
for continuing review and the responsibilities of the convened IRB, the
chair and the staff.
Reviewing Policies and Procedures on Conflict-of-interest
The University believes that perceived as well as actual
conflicts make clinical trials open to criticism and suspicion, and that
investments in new medical therapies are uniquely controversial.
The proposed new guidelines of the American Society for
Gene Therapy, issued in April 2000, would prohibit all investigators and
team members directly responsible for patient selection, the informed consent
process and/or clinical management in a trial from having equity, stock
options or comparable arrangements in companies sponsoring the trial. These
guidelines are consistent with restrictions that Penn established
five years ago.
"Nevertheless," Dr. Rodin said, " the University
agrees with the Danforth Committee that a full review of our policies on
conflict-of-interest should be undertaken at this time. She said that a
10-person panel of distinguished members of the Penn faculty, chaired by
Provost Robert L. Barchi, has begun a review
of all aspects of Penn's research using human subjects.
"While we have moved aggressively in a variety of
areas," Dr. Rodin said, "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 throughout
the academic community and with regulators and with lawmakers to accomplish
that task."
Joining Dr. Danforth on the independent
review panel were: Joseph B. Martin, M.D., Ph.D., dean of the faculty of
medicine, Harvard Medical School; Edward J. Benz, Jr., M.D., Sir William
Osler Professor and chair of the department of medicine, Johns Hopkins University
School of Medicine; Inder Verma, Ph.D., American Cancer Society Professor
of Molecular Biology, The Salk Institute, La Jolla, California; Rochelle
Hirschhorn, M.D., professor of medicine and cell biology and chief of the
division of medical genetics, department of medicine, New York University
School of Medicine; and Daniel Callahan, Ph.D., director of international
programs, The Hastings Center, Garrison, New York. |