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Study on Preclinical Study Outcomes Points to Validity Threats

Study on Preclinical Study Outcomes Points to Validity Threats

Research into preclinical study outcomes published this month blames the poor success rate of medical interventions introduced into clinical development largely on flaws in preclinical research.


Only 11 percent of agents that enter clinical testing are ultimately licensed, a failure rate that translates to higher drug prices and potential harm to human trial participants.

The researchers, based at McGill University in Montreal, reviewed preclinical guideline documents that addressed the design and conduct of in vivo animal experiments that support clinical translation. They found many threats to validity affect preclinical study outcomes, and offered a systemized set of widely shared recommendations designed to better ward off such validity threats during preclinical translation.

The study was published in PLOS Medicine. It was conducted by Valerie Henderson, Jonathan Kimmelman, Dean Fergusson, Jeremy M. Grimshaw and Dan G. Hackam.

Guarding Against Threats to Validity

Thomas Clarkson, DVM, created the Department of Comparative Medicine at Wake Forest more than 45 years ago and is one of the nation’s foremost experts on preclinical research involving animal models. He said that Preclinical Translational Services, Wake Forest Innovations’ specialty CRO, is able to help guard against validity threats during testing because of its unique standing.

“Consequently, our CRO can and does seek advice and participation of faculty experts in the area of animal models and in the interpretation of data resulting from studies,” Clarkson said. “I like to think our CRO differs from others in leaning more to a partnership with sponsors seeking answers rather than a pure contract operation.”

Jeffrey Sites, associate director of Preclinical Translational Services, agreed.

“One significant way to improve the success rate for medical interventions is to incorporate the clinical research team into the preclinical research process,” he said. “There are multiple perspectives which clinicians contribute in depth to the preclinical validation of a critical technology, and often, preclinical developments can aid and improve the launch of a clinical product.”

Why Preclinical Study Outcomes Go Wrong

Vince Mendenhall, DVM, PhD, director of preclinical surgery, has 35 years of experience in CRO work. He said the new study points out weaknesses in the CRO process that affect preclinical study outcomes.

“Most CROs do only what the sponsor says to do and does not question them,” Mendenhall said. “We routinely suggest alternative methods and study designs to what they are initially proposing, and justify our recommendations with available literature as well as our experience.”

The McGill study notes that, for a variety of reasons, preclinical research often supports original hypotheses by sponsoring scientists. Mendenhall said good CROs are more proactive in protecting against the threats to validity that frequently derail what were once promising medical interventions.

The study notes that threats to validity occur in preclinical translational work for both devices and drugs. Sites said quality management of preclinical studies is crucial for either type of work and will likely result in better preclinical study outcomes. And it applies to all types of preclinical Good Laboratory Practice research in particular, he said.