Four months after the death of a gene-therapy-study participant at Penn, the U.S. Food and Drug Administration halted clinical trials at the Institute for Human Gene Therapy, which oversaw the experiment. Citing “numerous serious deficiencies” in the oversight and monitoring procedures of that study— designed to test a treatment for an inherited liver disorder—the agency placed it and seven other investigational new-drug applications at the IHGT on “clinical hold.” Several weeks later, as the Gazette was going to press, the IHGT released a lengthy response that acknowledged some lapses in protocol but maintained that those deviations did not lead to the death.
In a January letter, the FDA explained that its two-month inspection had prompted concerns that subjects enrolled in other studies at the institute would be “exposed to a significant and unreasonable risk.” The agency also released a list of 18 “observations” from its probe, raising red flags about the lab’s adherence to regulations governing informed consent, patient-eligibility, record-keeping and communications.
The patient, 18-year-old Jesse Gelsinger of Tucson, Ariz., died on Sept. 17 of acute-respiratory-distress syndrome and multiple-organ failure, four days after he was injected with a genetically modified cold virus at Penn’s Medical Center. He had suffered from ornithose transcarbamylase deficiency (OTCD), which hindered his body’s ability to process ammonia and had caused him to go into a coma on three occasions. He had been managing his disease through a restricted diet and large quantities of medicine. The IHGT—headed by Dr. James M. Wilson, the John Herr Musser Professor and Chair of Molecular and Cellular Engineering—had designed a therapy to deliver a potentially corrective gene to the liver of OTCD patients. The trial in which Gelsinger participated was to test the drug’s safety; it was halted immediately after he died [“Gazetteer,” November/December, January/February]. An FDA spokeswoman said the trials will only be resumed when the IHGT proves that it can carry them out with the “proper amount of oversight.”
According to the FDA, the study’s sponsors:
- Didn’t adequately document the process of informed consent for some of the patients.
- Did not submit to the FDA a report of the death of two monkeys in a similar study “in a timely manner.” The paperwork was filed Oct. 27, 1999, nearly a year after the animal study concluded.
- Failed to halt the human study and immediately notify the FDA after two previous patients developed severe toxic reactions.
- Didn’t have documentation for the training of study staff.
- Failed to properly document the eligibility of all 18 patients when they were admitted into the study. Eligibility forms were not developed until the fall of 1999, after Gelsinger’s death.
- Included Gelsinger in the study even though the ammonia levels in his blood were too high to meet the eligibility criteria the day before the drug was administered.
- Admitted Gelsinger to the study even though the protocol required that the next patient be a female.
Responding to the FDA’s action, Dr. Judith Rodin CW’66, president of the University, assembled a committee of six scientists from peer institutions around the country to review the practices at the IHGT. The committee was to report back to her in about eight weeks and recommend remedial steps. “We intend for our research programs, particularly those involving human subjects, to meet the highest standards,” Rodin said. “Nothing less is acceptable.”
On February 14, the IHGT issued a 28-page response to the FDA’s “inspectional observations.” It acknowledged that the FDA “has identified important issues arising out of the OTCD trial,” and that the FDA’s “observations and insights have been of great value” in improving the IHGT’s monitoring efforts. It also vowed to “work closely with the FDA to implement new clinical-trial procedures” to improve its monitoring and provide “additional patient safeguards to the fullest extent possible.” Saying that it believed “from the very outset that complete candor and cooperation with all relevant governmental bodies provided the best hope of learning from this tragedy”—the IHGT pointed out that it had quickly notified the proper authorities of Gelsinger’s worsening condition and death, and “immediately and voluntarily” halted the trial.
But the IHGT also asserted that, “as deeply regrettable as Jesse Gelsinger’s death was, it was simply not foreseeable based on informed medical judgment and the best scientific information available at the time.”
Among the key points in the IHGT’s response were that:
- Gelsinger was “properly enrolled and his plasma-ammonia level did not cause his death,” and that “neither the FDA’s observations nor its public comments have asserted any such causal link.” The day before the drug was administered, Gelsinger’s ammonia level had risen to roughly twice the level recorded at his enrollment in June. However, in “consultation with another investigator who is a recognized OTCD expert,” the IHGT’s investigator “carefully assessed Gelsinger’s condition prior to the vector infusion, and concluded that his plasma-ammonia levels had been transiently elevated and that his clinical condition was consistent with participation in the study, a conclusion supported by plasma-ammonia and glutamine measurements taken after infusion.”
- Every patient “gave informed consent to participate.” In “lengthy meetings” with patients, the investigators “reviewed the novel and experimental nature of vector infusion, and made absolutely clear the risks of the trial, including the possibility of injury and life-threatening liver damage.” They also explained that the study was “explicitly a safety study and not a therapeutic trial.” Those points were “echoed in the clearly written, multi-page” document that formed the basis of these meetings, and which included the statement “We do not expect you to benefit directly from this study” in boldface type.
- Each patient’s eligibility “was documented at the time of his or her enrollment in the study,” despite the FDA’s observation that a patient-eligibility form was developed after the study was placed on clinical hold. “Regrettably, that observation has been misinterpreted to suggest that the IHGT attempted to document eligibility only after the fact,” while those documents were actually “checklists” used as part of the review undertaken after Gelsinger’s death, and were “never intended to substitute for contemporaneous documentation of eligibility …”
- While “comprehensive information” about the side effects suffered by two patients was submitted in January 1999, several months late—and while the IHGT “should have discussed them with the FDA before proceeding”—the FDA “had already had these comprehensive reports in its possession for over six months when, in August 1999, it expressly approved the continuation of the trial into the sixth cohort of patients,” which included Gelsinger.
- The sequence of Gelsinger’s participation in the trial was “appropriate” and “reflected the investigators’ good-faith understanding of the guidelines, as well as their experienced clinical judgment.” At the time of Gelsinger’s infusion, “none of the three previous male patients had exhibited a significantly different response to the infusion than the female patients in their respective cohorts”—and the FDA’s observations do not “assert, and nothing in his medical chart suggests, any causal link” between Gelsinger’s gender and his death.
- While the IHGT maintained “numerous documented procedures governing clinical processes,” they “would have been improved by the adoption of more formal Standard Operating Procedures.”
- The deaths of two monkeys occurred during an unrelated study using different genetic material for the treatment of a different disease, colorectal cancer. A third monkey infused with the same generation of the vector used in the OTCD trial exhibited only signs of mild illness. Furthermore, all three monkeys “received dosages approximately 17 times greater than the highest dose administered in the OTCD trial.”
If the FDA’s allegations prove to be founded, “then the suspension is appropriate,” said Dr. Arthur Caplan, director of Penn’s Center for Bioethics and the Trustee Professor of Bioethics in Molecular and Cellular Engineering, before the IHGT issued its response. But what is really needed, he suggested, “is to have a better system for monitoring human-subjects protection across the board—not just for gene therapy.”
Satisfying the FDA is not the IHGT’s only challenge at this point. The National Institutes of Health is also investigating the OTCD trial to determine whether federal patient-safety regulations were violated.
The entire field of gene therapy, as well as the regulatory process, came under scrutiny at a U.S. Senate hearing in February. Three hours of testimony presided over by Sen. Bill Frist, R-Tenn., chairman of a subcommittee on public health, revealed a system in which scientists are slow to report adverse effects and regulators are too understaffed to pick up on protocol violations. “There is a system-wide problem,” said Frist, “that we may have just touched the tip of the iceberg on.”
In fact, it was revealed that out of 691 reports submitted to the NIH regarding serious adverse events in gene-therapy experiments—from abnormal clotting to plummeting blood pressure —only 39 were filed on time.
The most emotional message at the hearing came in testimony from Jesse Gelsinger’s father, Paul Gelsinger. Although he had been fiercely supportive of the OTCD researchers at first, he now believes he was misled about the risks and benefits of the procedure his son underwent and has hired an attorney. He said that researchers downplayed potential side effects and told him that another participant in the trial had benefited from the treatment, which turned out to be false. Gelsinger said, “We gave consent, but in no way was it informed.”
Gelsinger also criticized the FDA for not doing its part to sufficiently monitor experiments.
“I am all for the continued development of gene therapy, but it must be better regulated,” he said. “The concern [of gene therapy] should not be on getting to the finish line first,” he added, “but on making sure no unnecessary risks are taken, no lives filled with potential and promise are lost forever, no more fathers lose their sons.”
Just before the IHGT’s operations were put on hold by the FDA, the University had announced it was forming a committee of 10 faculty members to review “carefully and completely” all aspects of Penn’s research using human subjects, which received about $213 million in funding in the 1999 fiscal year. Provost Robert Barchi Gr’72 M’72 GM’73, who organized that committee, expects it to complete its work near the semester’s end and report to Rodin soon afterward.
“Although Jesse’s death is of paramount concern to us,” the provost explained, “the internal review committee would have been formed in any case. When I first became provost last January, I stated as one of my goals that a complete review of our research operation was necessary given the extraordinary rate of increase in our research funding over the last decade. We need to make certain that our investigators are doing everything possible to address risks and to protect volunteers in clinical trials.”
Noting the recent suspension of research at a number of other institutions, including Duke University, Caplan said, “Human-subjects protection has gotten lax” in all fields, “and needs to be tightened in every institution in all areas around the entire country.”
In a Feb. 6 commentary in the Inquirer, Rodin discussed the steps Penn was taking to ensure that its research would meet the strictest standards, while explaining that it is impossible to remove all risk from human experiments.
“Penn is committed to continuing to conduct research,” Rodin wrote. “In that light, we will learn from a death while we continue to mourn it. We will share what we have learned … And we will emerge strengthened in our ability to translate what we discover in our laboratories into longer, healthier lives for everyone.”
