Each phase of tox screening introduces unique variables into the process, demanding agility and expertise from testing teams.
by Susan Thompson, Technical Director at VxP Pharma
Once a drug formulation has demonstrated its viability as a potential candidate for clinical applications, it must be vetted for potential toxicity to animal cells, living tissues, or entire bodily systems.
This vetting is achieved through preclinical toxicology studies, which typically progress from in vitro studies on liver and/or blood cells harvested from live animals, to in vivo studies on rodents, swine, and non-human primates. This progression is necessary because in vitro studies, which are far less costly than in vivo ones, may reveal toxicological issues that require the drug to be redesigned before progressing to in vivo studies, and finally to clinical trials on humans.
But despite the necessity of proceeding through this basic testing framework, unexpected challenges can emerge at any stage of the process, requiring a return to earlier stages of drug design in order to work out toxicological issues. Furthermore, a number of significant complexities underlie the tox screening process itself.
For these reasons, many pharmaceutical developers choose to partner with organizations that have experience navigating these complexities, and can develop cost-effective plans of action for anticipating and addressing difficulties that arise throughout the tox screening process. Here are three challenging complexities these experts often face during the tox screening stage of drug development.
Many biomarkers and disease mechanisms are still poorly understood.
Since in vitro testing focuses on cells isolated from their original donors, the drug’s efficacy must be extrapolated by analyzing biomarkers within the cells. Ideally, analysis of these biomarkers would provide insight into the molecular mechanisms of the disorder the drug treats, and predict the drug’s ability to remedy that disease in living organisms.
The reality, however, is not nearly so straightforward. While the molecular mechanisms underlying many common diseases are indeed well-documented, the biomarkers related to many other disorders (most notably diseases of the nervous system) are still poorly understood. Without a clear chain of chemical evidence linking specific molecular processes to symptoms of a disorder, researchers performing in vitro are in a poor position to predict a drug’s efficacy at treating that disorder.
More worryingly, a lack of clear understanding of many biomarkers means in vitro tests provide very little definitive information about a drug’s cytotoxicity, neurotoxicity, or other toxicities that may not manifest at the unicellular level, but can nonetheless prove extremely harmful to whole living tissues, organs and organisms.
Thus, any organization contacted to perform in vitro tox screening should be able to demonstrate their knowledge of the latest research on biomarkers, as well as an ability to accurately and consistently extrapolate results from individual cells into insights about the drug’s impact on living animals.
In vivo animal tests remain poor predictors of drug efficacy in humans.
Once a drug fails to demonstrate any definite toxicity risks in the in vitro testing stage, the next logical step is to proceed to in vivo testing, typically beginning with cohorts of live rodents, then proceeding to more complex animals. But while in vivo research can certainly provide more accurate insights into a drug’s impact on living animals, it remains a surprisingly poor predictor of a drug’s long-term toxicological effects on human beings.
One key reason for this failure of predictive validity is that animal metabolisms do not always closely mimic their human cousins. Disorders that can affect both humans and non-human animals often take different pathways in humans, and cause different symptoms in non-human subjects. Indeed, many failures to predict a drug’s toxicity in humans point back to a lack of understanding of the related biomarkers. Without a precise model of the molecular underpinnings of a disorder, researchers are in a weak position to attempt to extrapolate toxicological results from animal to human models.
Thus, promising tox results in animal cohorts have been known to collapse in human clinical trials, forcing the drug development team to return to the drawing board, and restart the entire tox screening process with a modified formulation. These redesigns are costly both in financial terms, and in terms of time and laboratory resources invested. Worse yet, they may allow competitors who better understand the tox screening process to bring their drugs to clinical trials first, capturing valuable market share.
In order to avoid these costly delays, forward-thinking pharma developers partner with toxicology researchers who have a proven track record of obtaining meaningful results from in vivo tox tests. The more reliably a team of researchers is able to extrapolate from animal models to human ones, the more likely the drug in question can proceed smoothly to the clinical trial stage.
Overly homogeneous patient populations often fail to reveal human toxicity risks.
Even after a drug has passed the in vitro and in vivo tox screening stages, it may still prove toxic to humans in a range of unpredictable ways. Some of these toxicological risks may not be apparent until the drug is clinically tested on a highly heterogeneous human population, and its toxicity to people of certain ages, genetic traits, and other attributes becomes clear.
For this reason, an overly homogeneous human cohort may initially yield very promising clinical results; and only when the drug is tested on a broader range of the population do its true toxicological characteristics reveal themselves. In more heterogeneous human populations, the drug may display signs on neurotoxicity, reproductive toxicity, or even toxicity to a patient’s genetics.
As with negative tox results in the in vitro and in vivo screening stages, a demonstration of a drug’s toxicity at any stage of human trials necessitates a return to the formulation development stage, and a costly redesign of the drug. But once a drug has reached the clinical trial stage, the stakes are much higher: the manufacturer has already invested in equipment and staff to produce the drug on a clinical scale; as well as in packaging, distribution, and perhaps even marketing for the drug. All this expensive activity must be put on hold, or perhaps even terminated altogether, when a drug reveals itself to be toxic to some segment of the patient population.
In order to avoid these risks, pharmaceutical developers should make sure to partner with tox screening specialists who are adept not only in designing and deriving useful insights from in vitro and in vivo studies, but are equally adept at selecting heterogeneous human cohorts with maximum predictive value of a drug’s toxicity to the patient population as a whole. The best of these partners provide not only a wealth of actionable tox data, but also full support in working with regulatory agencies; ensuring a smooth development pipeline from initial testing all the way to final approval.
In addition to being an author and speaker, Susan Thompson serves as the Technical Director of Indianapolis based VxP Pharma.