The FDA reports that 70% of drugs in Phase I trials ultimately make it to later phases of clinical research1. This number may look impressive until one remembers the primary purpose of a Phase I study: to determine if a treatment is safe and well-tolerated in humans. If 70% of drugs tested in Phase I move on to Phase II, does that mean that the remaining 30% induce harmful reactions in the patients to whom they’re administered? From this perspective, it’s 30%, not 70%, that starts to look like the big number.
Adverse reactions to medications usually aren’t catastrophic, but tragedy has struck in clinical settings on occasion. As recently as this past January, a Phase I clinical trial in France resulted in six patients being hospitalized; one has since died, and three are facing possible brain damage. Elizabeth Baker, a science policy specialist at the Physicians Committee for Responsible Medicine, argues that cases like this demonstrate that data gathered in the animal-focused preclinical phase is insufficient to predict how a treatment will affect humans as a trial moves into Phase I2.
To address this insufficiency, she has called for reform, arguing that preclinical trials should be more human-focused. And she points to some fascinating technological developments to illustrate what this shift might look like. One of these developments comes out of Johns Hopkins Bloomberg School of Public Health, where researchers have used human cells to create what they’re calling “mini-brains.” Baker also cites a project at the University of California at San Diego in which engineers used human cells and a 3D printer to create a model of a human liver. These replicas could be used to test treatments for various conditions in a way that focuses on human biology without putting actual humans at risk2.
Doubts and Possibilities
Of course, these developments raise questions about the viability of such technology. The projects discussed above only replicated individual organs; wouldn’t a truly comprehensive safety test, though, need to be applied to the entire body? And if Baker’s calls for reform are answered, what effect would that have on the paradigms that currently govern how early-phase clinical research is conducted? If researchers have a stronger sense of how humans will tolerate a treatment by the end of preclinical testing, how will that impact Phase I? Will the human-focused research in preclinical relieve some of the workload in Phase I, leading to faster completion times? Recent global health emergencies such as Ebola and Zika virus have led to calls for expedited clinical testing in order to make life-saving drugs available as fast as possible; perhaps such a simplification of Phase I trials would help to achieve this goal. Alternatively, perhaps the change will not be to the duration or complexity of Phase I trials, but to their purpose: doing more to determine drug safety in a preclinical setting could free up time and resources during Phase I for researchers to get a jump start on efficacy research, instead of focusing strictly on safety.
Though serious adverse reactions to treatments in Phase I trials are rare, they are a reality, and people like Elizabeth Baker should be commended for trying to increase protections for Phase I participants. The question is whether the approach she proposes–gathering stronger data in the preclinical phase by shifting from animal testing to human-focused technology–would achieve this objective. It will be interesting to see how her ideas are received, and how other reactions to the trial in France play out in governments and research communities around the globe.
1 The Drug Development Process; U.S. Food and Drug Administration; 6/24/2015
2 Baker, Elizabeth; FDA: accept human-focused preclinical tests to improve drug safety; The Hill; 7/7/2016