The University of Pennsylvania is grateful to Dr. William H. Danforth,
who chaired the external committee appointed by President Rodin to review
the conduct, oversight and monitoring of clinical trials at the Institute
for Human Gene Therapy ("IHGT"). The University also is grateful
to the members of the committee, a group of particularly distinguished scientists
and researchers, who brought their collective insight and considerable experience
to the task.
The committee examined a number of profoundly complex and interrelated
issues fundamental to the conduct of research, not only at the University
of Pennsylvania, but also throughout the academic research community at
large. We believe that their work provides useful advice on issues that
are of concern to other universities, scientific societies and federal agencies
as well as congressional committees with oversight responsibilities.
The University also is grateful for the ongoing work of an internal committee
of distinguished scientists and researchers, also appointed by President
Rodin, which has been conducting a proactive review of all aspects of research
using human subjects across the University. While this internal committee,
chaired by Provost Robert L. Barchi, M.D., Ph.D., will continue its work
through the summer, its interim findings have been useful as a guide to
many of the actions the University has taken and is taking now.
Response to the Basic Findings
We fully agree with the overall finding of the Danforth Committee that
cutting-edge research--like gene therapy and physician-sponsored clinical
trials using human subjects--requires significant investments, if the research
is to meet the standards of excellence that we expect at the University
of Pennsylvania. We also believe that the Danforth Committee has raised
many of the fundamental questions that the University must address as it
moves forward in a new age of clinical research.
We are encouraged, though, by the Danforth Committee's findings that
the University and IHGT: (i) are committed to compliance with all applicable
regulations and to correct any past deficiencies; (ii) were changing processes
and practices to conform to the FDA's requirements before that agency began
its investigation; and (iii) have already instituted a number of important
Action Taken by the University of Pennsylvania
Many of the issues facing us in the area of research using human subjects
today are the subject of a broader national dialogue concerned with improving
the oversight and compliance process for physician-sponsored clinical research
in an academic setting. The University of Pennsylvania will continue to
participate in that discussion with our colleagues, professional associations
and public officials to search for new national policies. At the same time,
Penn is moving forward, guided by the work of both the Danforth and Barchi
committees, with a range of actions to ensure that clinical research at
the University meets the highest possible standards for academic excellence
and patient safety.
We have taken, and are taking, a series of steps to strengthen oversight
and monitoring of our clinical trials, to enhance the professional management,
organization and focus of IHGT, to address issues of ethical decision making
specific to research using humans, to further reinforce the Institutional
Review Board's role in oversight and patient protection and to comprehensively
review our policies on conflict of interest. These include:
1. The University believes the Danforth Committee is certainly 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
has taken, or will take, the actions listed below. Our goal at Penn is to
ensure the highest possible standard of continuing excellence in all clinical
a. Every clinical trial proposed at Penn in the future will be
assessed by the Office of Regulatory Affairs ("ORA") in concert
with the Institutional Review Board ("IRB") to determine the
level of monitoring it will require for strict compliance with all applicable
regulations. Most clinical trials at Penn have external sponsors, such
as pharmaceutical firms, that are required to professionally monitor the
trials. For the remaining trials at Penn that are sponsored by a physician
or an academic center, monitoring will be provided by professional staff
from ORA or, for studies deemed by ORA and the IRB to involve significant
risk, by a contract research organization under agreement with the University;
b. 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
it may require. The University is presently recruiting firms for this purpose.
c. The University is developing a set of clear standards that
will guide the review and monitoring of all clinical trials; and
d. 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.
2. We have greatly benefited from the Danforth Committee's questions
about the scope of IHGT. 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. Consistent with this conclusion, Penn and IHGT have jointly determined
that IHGT can best serve the important future of gene therapy by resolutely
focusing on a pre-clinical mission of molecular and cellular work and animal
model experimentation. IHGT will not serve as a sponsor of clinical trials
in the future.
3. The University is undertaking a comprehensive review of ethical decision-making
specific to research using human subjects at the University, and future
ethical discussions regarding the testing of gene therapy in human subjects
will be overseen by an IRB with special expertise in evaluating gene therapy.
In addition, the School of Medicine will establish a new, free-standing
Department of Bioethics that will take the place of the Center for Bioethics.
4. The University's internal committee chaired by Provost Barchi has
begun a formal, comprehensive review
of its IRB system. The review will examine how 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 recently initiated
at Penn following an outside review completed in the summer of 1999 and
the hiring of Joseph R. Sherwin, Ph.D., as Director of ORA. Following his
appointment, IRB policies and procedures were strengthened to ensure, among
other things, and include:
a. Strict adherence to all IRB regulatory requirements, including
those governing when expedited review is appropriate, and who has the authority
to perform that review.
b. 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).
c. 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 became available on Feb. 1, 2000).
d. Substantial, regular training and education for IRB members
e. 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
f. 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).
g. Addition of new professional staff in the ORA, and additional
positions are being recruited as of this writing.
h. Development of 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.
5. 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 of 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, the University agrees with the Danforth Committee that
a full review of its policies on conflict of interest should be undertaken
at this time, and the internal review committee, chaired by Dr. Barchi,
has initiated such a review.
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 high standards
and always puts the interests of our patients above all else. We will continue
to work with our colleagues throughout the academic community, with regulators
and with lawmakers to accomplish that task.