“The episode that brought us here today was the Bial 10-2474 trial,” said William B. Smith, President, New Orleans Center for Clinical Research, addressing the room during a session at DIA 2016 in Philadelphia, Pennsylvania.
The trial, which has since garnered much attention from the industry, left one patient dead and five with serious health problems.
Now, as the industry moves forward and tries to figure out what went wrong, experts are examining the risks of First in Human (FIH) trials and working to formulate a process to better address participant safety.
Smith recalled the pressure the scientific community saw following TeGenero (TGN1412) back in 2007 – a FIH tiral in which six out of eight men experienced “severe and systemic adverse reactions,” as Outsourcing-Pharma.com reported at the time.
“This changed how we approach FIH studies,” explained Smith. Today, how exactly the Bial trial tragedy may or may not change things moving forward has yet to be seen.
“In reviewing the protocol, it was not very different from any of the other protocols,” said Smith. “There weren’t the usual red flags.”
From a sponsor’s perspective,Howard Greenberg, MD, medical safety officer and FIHC operational chair, Janssen and co-chair of DIA's clinical pharmacology community commented that the investigators brochure had errors and inaccuracies. “The preclinical package was questionably adequate,” he added.
Greenberg also questioned if the sponsor was informed by the PI of the SAE before the rest of the cohort was dosed - after which he called into question the level of data sharing among sponsors, asking: “Should sponsors or regulatory authorities inform other sponsors of a similar compound?”
Mary L. Westrick, PhD, adjunct professor at the University of Wisconsin Madison, commented that she doesn’t see data sharing happening any time soon. “Companies have a lot to lose,” she added.
Regardless, “in the light of this tragedy we need to figure out what we can do to keep volunteers safer,” she added.
However, according to Westrick, if you look at the regulations, there are no standards in place for Ph I clinics. “CRUs [clinical research units] are built to hotel or dormitory standards,” she explained. “There are units that are doing FIH studies that frankly have no business doing them.”
Often, these units are off-shoots of a practicing physician running a CRU in conjunction with his or her practice. In many countries, including the US, there are no accreditations or standards for entities conducting FIH trials.
“We really need to think about what safety needs to be in place,” explained Westrick. “CRUs really need to be prepared for whatever is coming.”
But what happened?
“One of the issues we need to understand in the Bial trial is why was remainder of the cohort dosed after one patient was admitted to the hospital? Did the CRU even call in to see test results from the patient?” Westrick questioned before posing three considerations:
- Should there be a receipt of PK [Pharmacokinetics] data prior to initiating next does level?
- Should there be sentinel dosing for all SAD and MAD groups?
- Should there be longer observations period before doing the remainder of the group?
Westrick also asked if there should have been psychological and neurological screens or better histories perhaps on drug use, both licit and illicit.
Ultimately, she said “One of the things I can’t stress enough is that every single AE needs to be considered drug related unless proven otherwise.”