The early-stage trial, which began enrolling patients in 2014, involved lymphoma of the central nervous system, which does not have an effective treatment and is often fatal. Researchers were testing a treatment that combined a drug called ibrutinib with a cocktail of chemotherapy medications. In addition, steroids were used to reduce swelling in the patients' brains.
In 2015 and 2016, four patients developed an aggressive version of a common fungal infection called aspergillus; another three possibly had the infection. And in May and December last year, two patients died of infections.
Officials said that after the second death, the principal investigator, Kieron Dunleavy, expressed some concerns to the part of the NCI that was sponsoring the trial and the institutional review board overseeing the study. In addition, he ordered CT scans in other patients in the trial to try to catch fungal infections early, before they became deadly. As concerns mounted, researchers stopped enrolling new patients in April this year. But Dunleavy did not file an official “unanticipated problem” report — discussing the suspected relationship between the infections and the treatment — until May this year.
When researchers suspect there might be a problem caused by the experimental treatment, they are supposed to file a report alerting the sponsor within 24 hours and the institutional review board within a week. The sponsor, in turn, must notify the FDA within a week.
In the lymphoma trial, an unanticipated problem report would likely have triggered, at minimum, a change in the informed-consent forms to let patients know that the additional CT scans were being ordered to check for treatment-related fungal infections. It also might have prompted the FDA, which regulates trials, to order some changes. The agency, after being notified this spring about the connection between the treatment and the deadly infections, conducted a review that concluded there also were several other adverse events that weren't promptly reported.
In an interview during a break in Friday's meeting, Collins called the reporting problems troubling and unacceptable.
The exact cause of the infections remains somewhat murky, though it is clear they were not caused by contaminated medications, a problem that plagued the Clinical Center's drug-manufacturing operation in the past. Collins said that it appeared that the combination of ibrutinib and steroids “seemed to place patients, many of whom have compromised immune systems, at an enhanced risk of infection.”
Aside from the fungal infections, the lymphoma study, which was suspended in the spring, showed impressive results, with “therapeutic responses” in more than 80 percent of the 18 participants, Collins said. Eight patients continue to be in a complete remission, including six whose disease had not responded to previous treatment — a situation that usually causes death within a matter of months. All the patients in the trial have been informed of the delayed reporting, Lowy said.
Dunleavy, who has been suspended from clinical research until he undergoes additional training, did not respond to email and telephone messages requesting comment. To ensure researchers know and comply with reporting requirements, Collins and Lowy said, training sessions for other researchers also will be conducted, as will audits of various trials.
The lymphoma-trial incident is the latest in a series of controversies that has roiled NIH for more than a year. NIH suspended the operation of a drug-production unit at the Clinical Center in 2015 after investigators discovered two vials of a study drug contaminated by aspergillus and a nonhuman pathogen. The contamination did not lead to patient illnesses or deaths, officials said.
It did, however, prompt Collins to order a sweeping review of the hospital's operations by an independent task force. That group concluded earlier this year that patient safety had become “subservient to research demands.” Collins, in response, ordered a shake-up of the hospital leadership and created the outside board to advise him on its operations.
His efforts, praised by some, have drawn fire from some officials at the Clinical Center, who have argued that the task force report was unfair and “demonized” hospital leadership.
Staff writer Lena H. Sun contributed to this report.