Penn’s Institute for Human Gene Therapy (IHGT), under fire since an 18-year-old man died while participating in a clinical study last September, received another warning letter from the Food and Drug Administration (FDA) in July. This one faulted the animal experiments that were used to justify human research and warned of possible further action if the IHGT’s response—which was sent to the FDA later that month but not released to the public—was not satisfactory.
The FDA’s 15-page warning letter was sent less than six weeks after the University had announced that the IHGT would no longer conduct human clinical trials and would limit its scope to molecular, cellular and animal-model experimentation [“Gazetteer,” July/August]. Addressed to Dr. James M. Wilson, the IHGT’s director and the John Herr Musser Professor and Chair of Molecular and Cellular Engineering, it charged that, based on a recent inspection, the IHGT has “failed to fulfill the obligations of a sponsor of non-clinical studies with investigational vectors, and violated [federal] Good Laboratory Practice regulations” governing those studies.
One such alleged violation occurred in a monkey experiment designed to test the treatment’s toxicity, in which the IHGT had used viruses that were more than two years old and past their expiration date, the FDA claimed. The strength of the vectors would thus have been reduced, the agency noted, and “could result in an under-estimation of toxicity in the animal studies used to establish the dose of vector to be administered to human subjects.”
In addition, the letter said that the IHGT’s pathology report for that experiment “underestimates the severity of the liver damage observed” in two of the monkeys.
Jesse Gelsinger died last September of acute-respiratory-distress syndrome and multiple-organ failure, several days after a modified cold virus carrying corrective genes was injected into his liver. Gelsinger, like the 17 previous participants in the study to determine the safety of the experimental gene-therapy drug, suffered from a hereditary liver disorder known as ornithine transcarbamylase deficiency (OTCD), which prevents the liver from properly processing ammonia.
The FDA also charged that:
• The IHGT “failed to manage the testing facility.” While noting that the IHGT’s response letter to an earlier warning acknowledged that a “limited number” of deviations were “not documented in a timely fashion,” the FDA stated: “We do not agree that these instances were isolated because such deviations were noted in each of the three studies reviewed during the inspection.” The agency also said that the “inadequate level of documentation” for the three studies “casts doubts about the reliability and completeness of the remaining study records.”
• The IHGT’s Quality Assurance Unit (QAU) “does not operate in conformance with applicable regulations,” and its inspections “failed to detect, resolve, or document deficiencies in the three studies reviewed during the inspection.” (Among the hitherto-unnoted deficiencies were that three mice were reported as “found dead” by the study pathologist, while the necropsy and clinical pathology records indicated that they had been “sacrificed as scheduled”; that several “key tissues (i.e. pancreas) were missing” from the necropsy reports; and that some animals “did not meet the protocol-specified weight ranges.”)
• The IHGT had failed to properly store specimens and data. “Raw study data are archived and maintained on open shelves in an unused restroom,” with no one person identified as being responsible for maintaining that data.
• The IHGT “failed to prepare written standard operating procedures” as required by federal regulations.
• The IHGT “failed to conduct the study according to the protocol.”
In conclusion, the FDA noted the IHGT’s claim that since 1998, the IHGT “believes it has made—and continues to make—enormous strides in the manner in which it conducts and documents its toxicology studies.” But based on its
own investigation, the FDA concluded that the three studies were “not conducted in accordance with [federal] regulations” and could not be reconstructed from available records. As a result, it demanded a listing of all animal studies conducted by the IHGT from 1994 to the present.
The IHGT’s response to the charges was sent to the FDA July 25, but according to Ken Wildes, the University’s spokesman, “We have no plans to release the response [to the public] at this time.”