By Lisa Seachrist

Washington Editor

WASHINGTON - With gene therapy protocols under intensified scrutiny ever since an 18-year-old volunteer died from participating in an experiment at the University of Pennsylvania, the FDA has issued a warning letter to Jeffrey Isner, chief of vascular medicine at St. Elizabeth's Medical Center in Boston, documenting deficiencies in gene therapy studies he is conducting with Vascular Genetics Inc.'s angiogenic vector, vascular endothelial growth factor plasmid (VEGF-2).

The warning letter comes in response to deficiencies noted following a March 22, inspection of the studies in cardiac and peripheral artery disease, and addresses Isner's role as a clinical investigator. The agency will address deficiencies of the sponsors - Vascular Genetics, St. Elizabeth's and Isner - in a separate letter. The four gene therapy studies were placed on clinical hold in February.

The letter highlights the failure to enroll only patients who met the protocol eligibility criteria, the failure to report adverse events, including a death, to the institutional review board, irregularities with an informed consent document, and the failure to maintain adequate case histories. The letter notes that the "deviations in these studies appear to be the result of a serious lack of knowledge of your responsibilities as principal investigator including supervision of personnel."

"We are working with all of our sites to ensure they understand their responsibilities," said John Cumming, president of privately held, Durham, N.C.-based Vascular Genetics - a study sponsor. "We've offered all of our resources to help him address any problems."

The warning letter details deficiencies found at St. Elizabeth's for which Isner, as principal investigator, is responsible. The agency highlights a patient who was enrolled in the study despite evidence of potential lung cancer. Because VEGF-2 spurs the growth of new blood vessels, the protocol for the study prohibits patients with any signs of cancer from enrolling, in order to prevent the gene therapy from fueling cancer growth.

The patient in question was diagnosed with lung cancer after treatment with the study vector. Cumming said he doesn't know what happened in the case of this particular patient and why investigators found the former smoker eligible for the study. But he called the event "troubling."

"We are, as the sponsors, very concerned that every patient meets the very strict eligibility criteria in the protocol," Cumming said. "That in no way minimizes what happened to this patient. We are working very hard with all of our trial sites to ensure there are no more problems. When something like this happens you ask yourself, 'have we failed somewhere to educate our investigators?'"

In addition, the letter documents a patient who suffered cardiac arrest in the perioperative period following a direct injection of VEGF-2 into the heart. The patient ultimately suffered multi-system organ failure and died more than four months following the gene therapy procedure. The agency found the death hadn't been reported to the Institutional Review Board (IRB). While not commenting on the IRB matter, Cumming said the death had been reported to the FDA in a timely manner.

In addition, the FDA took issue with Isner conducting an anatomic and histopathologic examination of the heart of this patient when Isner isn't board certified in pathology.

The agency also found the case histories and medical records were incomplete for some of the subjects in a number of the four clinical trials Isner oversaw.

"I've talked to some people who said if this study had been conducted at another time we wouldn't be on clinical hold right now," Cumming said. "I don't know about that. But we are in a period of significant scrutiny - we aren't the only gene therapy company on hold - and we must be sure we are complying with FDA."

As with all FDA warning letters issued to clinical investigators, Isner has 15 business days to respond to the issues raised in the warning letter. If Isner fails to correct the deficiencies identified by the agency, he risks losing his right to investigate new drugs and the termination of the VEGF-2 gene therapy IND.

BioWorld Today was unable to contact Isner. Cumming said Vascular Genetics had completed enrollment for three of the four trials currently on hold, and is working to gather the information necessary to get the hold on the final study lifted.

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