A Charles River-led study describes the tide of regulatory creep emerging in how we measure CNS toxicity
Arguably, one of the most difficult jobs for the nonclinical research team is identifying off-target effects to the central nervous system induced by drug administrations. Animals cannot tell us if an experimental drug is inadvertently inducing nausea, malaise or agitation, and yet we need to know this information before advancing the drug to human trials.
There is little hope of retaining human subjects in clinical trials if the drug alters or adversely effects their well-being. While we certainly would agree that if any animal is feeling sick following drug administration that behavioral changes seem reasonable. However, for drug regulatory approval we have to frame the issue in objective or measurable terms. If the basis for describing an animal as “sick” is a change in behavior, it becomes a circular argument to explain this change in behavior on the basis of a belief that the sickness itself is that change in behavior.
What we can do is observe how animals behave in their cages and interact with other animals or their human caregivers; we must observe, in novel environments (which assess basal muscle tone, muscle strength, and tremors), and in specialized chambers outfitted with infrared photo beams that enable the quantitative assessment of small-scale navigation and spatial orientation. Together the behavioral data gleaned from these varied approaches can tell us a lot about drug-related disruptions in the CNS.
Yet drug companies are not overwhelmingly supportive of this approach, in part because it requires the investment of more resources, capitol and animals, resulting in a contentious point between the drug development team ordering the studies and the contract research laboratories conducting the safety assessment.
A review paper co-authored by Charles River and Kallman Preclinical Consulting that appeared in the International Journal of Toxicology last month captures how passionately certain investigators feel about any hint of scaling back the preclinical CNS work. They warned that Tier 1 CNS safety studies should be held to the highest industry standards of practice, and proposed that what the industry really needs is to fully comply with the already established set of standards used for risk assessment decisions prior to approval and licensure.
“Reducing group size, limiting observations to only a single sex and excluding parameters of motor function testing using automated LMS chambers are not in the best interest of public health and may provide inadequate safety assessment prior to the first dose of administration in Phase 1 clinical trial volunteers,” the authors said in their review. The review was written by scientists from Charles River’s Safety Assessment site in Mattawan, Michigan, which specializes in neurobehavioral science, and Dr. Mary Jeanne Kallman, CEO and VP of Kallman Preclinical Consulting in Greenfield, Indiana.
Drug developers, however, do not consistently share this perspective. They advance the policy of using smaller study designs and fewer animals in attempts to comply with regulatory standards of efficacy, and safety
Charles River Eureka connected with Dr. David Gauvin, Director of Neurobehavioral Science at the Mattawan site, to discuss the theme of their paper and why the work conducted by CROs matters. Here are his edited responses.
Eureka: You mentioned there has been a tide of “regulatory creep” within the drug development industry. What do you mean by this and how do you think this shift will impact quality of safety studies?
DG: We are usually pressured by Sponsors to reduce the standard ICH S7A safety pharmacology studies (functional observational batteries) to some bare minimum in spite of statistical power analysis and regulatory agency guidelines requiring larger sample (group) sizes. They also purge the FOB of satellite groups assessed in automated locomotor activity assays – trying to be cost-conscious.
Eureka: How did we use to measure motor function in rats and how do we do it now?
DG: The IntraAgency Committee on Neurotoxicity, EPA Neurotox guidelines, and the preponderance of FOB-related reports appearing in peer-reviewed scientific journals lists 10 rats per gender per group for all behavioral assays. Most sponsors currently conduct only one gender (males) and ask for only 6 to 8 rats per group; and most importantly for our paper – they remove the automated locomotor activity monitoring that objectively quantifies drug effects on study.
Eureka: How is the “reduce use” principle and cost-cutting strategies being applied in CNS safety protocols? And by reduce use, are you referring to animals or the people conducting the studies?
DG: Reduce use is being implemented relative to animal census on studies. The use of 6 male rats in a treatment group does not meet statistical power requirements for most subjectively rated parameters in the FOB. Submission of data to the FDA based on weak or unreliable safety studies is not in the best interest of the pharmaceutical industry. When one drug fails the whole industry itself takes a hit. The government regulatory policy is based on an expectation that the industry will police itself; short-cuts are not in our best interest.
Eureka: What are the consequences of this “reduce use” practice on collecting the data?
DG: The total number of animals used in safety assessment studies should not be either too big or too small since both have limitations that can compromise the conclusions drawn from these studies. If the group size is too small it increases the chance of assuming as true a false premise. Chances are that the proposed new drug has no disadvantage compared to traditional therapy. Furthermore, it is assumed that these animals were subjected to the stresses of a study knowing that the goals of the study were not valid or reproducible. In addition, financial and time resources were squandered since ultimately it will contribute absolutely nothing to improve the quality of life of the intended human population. The situation becomes even worse if the research involves private investors. Conversely, too many animals in a group may amplify the detection of differences, emphasizing statistical differences that are not clinically relevant
Eureka: How does this paper highlight the importance of integrating CROs with other industry experts?
DG: Drug development represents an integration of multiple elements of study design. The industry as a whole represents a “meeting of the minds” in developing the most efficient and reliable pathway to drug approval. We all know what questions that need to be answered. Risk-to-benefit analyses and the universal goal of demonstrating safety and efficacy of all new drug products brings all of us to the same table. When we work together to advance the health and well-being of the general public, we all win. Good science brings us together in a common path to drug approval.