The death of Jesse Gelsinger two years ago sent a shock wave through Penn and the medical community that is still felt today.
Now, one year after the Gelsinger family settled its wrongful death and negligence lawsuit against the University and others involved with Penn's Institute for Human Gene Therapy, doctors across the nation say there have been significant improvements in the way clinical studies are performed.
When news spread in September 1999 that an 18-year-old man involved in a gene therapy trial had died at a high profile university, national media attention was focused on Penn and the safety of clinical trials involving human subjects became an issue of national concern.
The pursuant investigation by the Food and Drug Administration led to a temporary halting of all human gene therapy studies at the IHGT. The University eventually stepped in and reduced the IHGT's mandate
Additionally, the Gelsingers alleged in their lawsuit that IHGT Director James M. Wilson, who ran the Gelsinger study, and then-Health System Chief Executive Officer William Kelley owned several gene therapy patents and stood to gain financially from a successful outcome of the clinical trials, compromising their judgement.
Following the Gelsinger case, Wilson, previously considered the field's premier researcher, was effectively discredited in the medical community.
As a result of this and several other incidents, the world of academic medicine is being faced with a previously unseen level of accountability.
"I think that academic clinical research is being held to the stricter standards the FDA has held to the [pharmaceutical] industry and there is a greater focus on compliance," said John Glick, head of the Penn Cancer Center.
Jerome Halperin, president and chief executive of the Food and Drug Law Institute, a nonprofit organization in Washington, said universities are being forced to pay closer attention to the rules prescribed by the national government.
"I think there is a much heightened sensitivity to the need for very, very careful planning... and very careful attention to what the ground rules are when you do a study like this," he said.
Doctor of Hematology-Oncology Stephen Eck, who is involved in several clinical studies at Penn, said that in the past many doctors failed to consistently document their procedures in accordance with regulation, though they performed other requirements correctly.
"We had these rules and regulations in place," he said. "But the level of compliance was quite variable."
During the past two years, however, the University has taken steps toward improving its clinical research practices, including the creation of the Office of Human Research last April. The office's responsibilities include monitoring the approximately 4,400 human research projects at Penn.
Medical School Vice Dean for Research Glen Gaulton said a major goal of the office is to solidify understanding of the federal guidelines among Penn research physicians.
Members of the office "have to make faculty more aware of what they need to know when they do human research and... do what industry does and inspect ourselves," he said.
The University is also advising researchers on financial conflicts of interest, a major issue in the Gelsinger case, and has created a new policy that prohibits researchers from participating in studies in which they have a financial or political stake on a case-by-case basis.
"The core idea is that if a faculty member is doing a study it doesn't look any good if they tell the patients... they have a financial interest in the outcome of the study," Vice Provost for Research Neal Nathanson said.
The office is also trying to tackle several problems concerning internal institutional review boards. IRBs exist at every major research institution, are made up of medical school staff volunteers and have been historically responsible for reviewing research proposals for possible improvements, safety concerns and compliance with regulations.
"The IRB is primarily concerned that the initiation of human research is conducted in full respect of human right," Gaulton said. "What they have not been doing is policing."
At Penn, IRB staffs have now been increased and new policies have been implemented to increase patient safety throughout a study.
"Every trial that is started now has to have a monitoring and auditing plan, just like an industry trial does," Gaulton added. "The frequency of the inspection depends on the risks."
Jeffrey Kahn, director of the University of Minnesota Center for Bioethics, said that continued monitoring of clinical studies is becoming an issue of greater focus around the country.
"There's been such an emphasis on prospective review of research," he said. "We don't spend enough time, often any time at all after subjects are recruited. Now there's a greater commitment to satisfying the needs of throughgoing approaches in human subjects protection."
Nathanson said that the new costs faced by researchers around the country will be significant.
"It's making it more complicated to perform clinical trials which will make it more expensive," he said. "The agencies that fund these are going to have to spend a lot more money, maybe three or four times as much per trial."
Clearly, he said, this will decrease the amount of studies performed.
Outside of Penn, some have expressed concerns that the additional work now required of IRBs will only add more paperwork to groups already drowning in it.
John Moorhead, associate dean for research affairs at the University of Colorado's medical school, which had all of their human research studies suspended for failure to comply with FDA rules -- primarily those prescribing the proper means of trial documentation -- said the IRBs and review processes were improved by the shutdown, but added that he still has concerns.
"I think there are some who have backed away from doing more clinical research or doing clinical research at all because it is becoming harder and harder to do because the IRBs are asking for more paperwork and documentation," Moorhead said.
Halperin also expressed that the work demanded of the IRBs, even before these new changes were put in place, has been overwhelming.
"I have heard that in some of the larger academic medical centers that if the IRBs were supposed to give [ongoing] appropriate oversight to all the studies... there wouldn't be enough hours in the year," he said.
Department of Health and Human Services spokesman Bill Hall emphasized the importance of safety protocols.
"This is not about a paper process, it's about protecting research volunteers," he said. "The regulations set out are the best way to do that based on years of research."
He added that federal agencies had taken steps to ensure the protection of human subjects.
These steps include the creation last year of the Office for Human Research Protection within the Department of Health and Human Services. The office will monitor research institutions for compliance with regulations. Additionally, on Oct. 26, the FDA announced the creation of the Office for Good Clinical Practice.
At Johns Hopkins University, where the Office for Human Research Protection temporarily shut down all federally funded medical research in response to the death of an asthma study participant, several researchers said they thought the changes made as a result have been beneficial.
Craig Hendrix, a professor of medicine and IRB member at Hopkins, is involved in the re-review of clinical studies being required there by the Office for Human Research Protection.
"There is no question, there is more paper involved in what we do," Hendrix said. "The first look at that was daunting and I was skeptical, but now, after going through the re-reviews, we've found things that are not right. I think the protocols are more complete now."
Hendrix, who is involved in HIV drug research, added that the recent events would not prevent him from continuing patient-oriented research.
"All the research I do is human subject research and we won't change at all what we do and we will use as many human subjects as we can," he said. "I think there is certainly room for innovation and the regulations leave room for that.... We're not backing away."
Several Penn doctors said they believed the changes here would improve their studies.
"I think the more we can demonstrate that we're in compliance with all appropriate regulations and guidance the better for both our patients and the quality of research that we do," Medical School Professor Howard Herrmann said.
Arthur Caplan, director of Penn's Center for Bioethics -- who was also named in the Gelsinger suit -- agrees that Penn has done an excellent job bringing up its compliance with federal regulations, but claims that the entire system needs a major overhauling.
"I think there's starting to be a recognition that the human subjects protection system is completely broken and desperately needs a fix," he said.
Referring to Penn, Hopkins, Colorado and Duke University, which had its human research studies suspended in May 1999, Caplan cited the large numbers as evidence of inherent problems within the system.
"If you have 20 institutions in the past five years suspended or given major penalties, the system doesn't work," Caplan said.
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