In an attempt to get clinical trials reinstated at Penn’s Institute for Human Gene Therapy (IHGT), Dr. James M. Wilson, the institute’s director and the John Herr Musser Professor and Chair of Cellular and Molecular Engineering, announced in March several corrective steps it plans to take. In a 14-page letter to the FDA, which put the IHGT’s clinical trials on hold in January after an 18-year-old patient died last September [“Gazetteer,” November/December, January/February, March/April], Wilson listed a number of actions, including hiring an outside consultant to monitor future studies, implementing formal standard operating procedures and partly reorganizing its staff.
The suspension followed an investigation of the death of Jesse Gelsinger, who was participating in a study on the safety of an experimental gene-therapy drug. Like the 17 previous participants in that study, Gelsinger suffered from a hereditary liver disorder known as ornithine transcarbamylase deficiency (OTCD), which prevents the liver from properly processing ammonia. Scientists at the IHGT had developed a technique for delivering corrective genes into the liver through an injection of a modified cold virus, but several days after receiving the drug, Gelsinger died of acute-respiratory-distress syndrome and multiple-organ failure.
After the FDA found “numerous serious deficiencies” in the oversight and monitoring of the OTCD trial, Wilson and the researchers at the IHGT acknowledged certain lapses in protocol, but asserted in a 28-page rebuttal to the FDA on February 14 that those lapses did not contribute to Gelsinger’s death.
Unsatisfied, the FDA sent the institute a “warning letter” on March 3, turning down its request to resume gene-therapy trials, criticizing its response for being incomplete and requesting substantial amounts of new information.
In his reply to the FDA, dated March 24, Wilson provided detailed data and noted that the institute “takes FDA’s observations, and its warnings, extremely seriously,” adding that “fully regaining FDA’s confidence is a necessary first step in the process of resuming the conduct of clinical trials.” He emphasized that the remedial steps being taken by the IHGT will “result in significant improvements in our monitoring and other oversight activities.”
While the FDA’s warning letter “also contains statements that are critical of IHGT,” Wilson noted, the institute would “not enumerate areas of disagreement” regarding those criticisms that did not seek a response. Given that the institute “has done its very best to be completely candid and thorough in all its communications,” he said, “We now want to focus energy on the future, and we welcome FDA’s continued guidance.”
Among the changes planned:
- The IHGT will transfer primary oversight responsibility to an outside “contract research organization,” or CRO. (It hoped to finalize an agreement with a CRO, identified as Parexel International Corp., in April.) Before each trial begins, the CRO would conduct a site visit and review “all relevant forms and documentation” to make sure they comply with regulations. It would also train the staff to ensure that it was “completely versed in the relevant requirements.” After a trial was underway, the CRO would perform regular, on-site monitoring visits and prepare reports verifying that the site was in regulatory compliance.
- The IHGT has developed standard operating procedures devoted to amending the format of a clinical trial; confirming patients’ study eligibility; documenting informed consent; reporting relevant information to regulatory agencies in a timely manner; and maintaining regulatory records at the study site.
- The IHGT intends to create the new position of scientific chief operating officer. The person selected to fill this post will have “broad responsibility” for overseeing clinical trials, toxicology and vector manufacturing. In addition, the institute is in the process of adding more “senior, experienced” staff.
- Some additional changes may be underway after an external-review committee made up of scientists from peer institutions, appointed by Penn President Judith Rodin in February, delivers its own recommendations for improving practices at the institute.
