ARTICLE

Optimizing Animal Requirements in Pre-Clinical Development: Getting Faster Results with Fewer Resources

Introduction

Early and sophisticated non-invasive multi-modality animal imaging will enable scientists to create strong cohorts of data, quickly identifying outlying information to inform course correction or termination of drug development, and reduce dependence on intensive, costly lab resources. Efficiencies can accelerate animal studies, allowing sponsors to generate the highest quality and most clinically relevant results.

Animal trials are a critical component in the drug discovery process. However, the regulatory environment and the acknowledged high costs of trials require sponsors to do more with less at all phases of a research development project. In the animal preclinical stage, sponsors can optimize results if they can reduce animal requirements.

Specifically, sponsors need to:

  • Reduce the number of animals used through careful and sophisticated study design;
  • Keep animals alive throughout the duration; and,
  • Use multiple study points to measure outcomes.

Efficiencies in these areas can accelerate animal studies, allowing sponsors to generate the highest quality and most clinically relevant results.


Challenges

Success in the animal phase needs to be framed around regulation. Animal research is rigorously controlled by regulatory bodies, and it is imperative that sponsors execute studies with the welfare of animals incorporated into the study design. In the United States, animal research is regulated by the U.S. Department of Agriculture via the Animal Welfare Act (AWA) which designates the following principles for sponsors to uphold:

  1. A justification for using animals, the number of animals to be used, and the species chosen.
  2. The procedures or drugs to be used to eliminate or minimize pain and discomfort.
  3. A description of the methods and sources used to search for alternatives to painful procedures.
  4. A description of the search used to ensure that the experiment does not unnecessarily duplicate previous research.1

Success in the animal phase is challenging. Sponsors must plan for failure. For example, cancer therapies have only an 8% success in the animal trial phase.2 Getting to a “go/no-go” conclusion rapidly is a key to containing costs and accelerating the drug discovery process.

To best meet regulatory conditions and minimize time-to-failure or time-to-success requires a reduction in animal requirements. The subsequent gain in acceleration will allow sponsors, including labs and CROs, to more quickly course correct, declare failure, or move to human trials. To achieve these results, it is imperative that the study design incorporates in vivo analysis as in vitro does not always translate into success in the animal model.


Background

Allow for a sophisticated study design

Addressing efficiencies in animal testing has direct implications, not only on a sponsor’s bottom line, but also as a macro consequence related to the overall cost of treating diseases.

While animal research is particularly suited for testing therapies for difficult-to-treat conditions and diseases such as inflammation and cancer, it is suggested that animal models are needed to treat the top five most expensive diseases including heart disease, diabetes, dementia, cancer, and obesity.3

To bring to market therapies that address these and other conditions and diseases requires preplanning and the development and implementation of sophisticated models designed to optimize animal resources. A trial that is designed with multiple endpoints and readouts and that incorporates noninvasive techniques, will allow for real-time data collection, analysis of and insights into the impact of a drug candidate. The alternative is an invasive design with a heavy reliance on dissection, which can delay views into outcomes.

Sponsors should be motivated to invest in the development of workflows and sophisticated study designs prior to implementing animal testing. These investments translate into a longer set-up but can result in a reduction in the study period from two-to-three years to six months. In combination, these strategies will increase the predictive value of the animal trial, which will allow sponsors to both better select which animals to use and then use fewer of them, saving time and money.4

Prioritize noninvasive in vivo research options

Finding therapeutic benefit as quickly as possible is critical to accelerating results and optimizing the output of animal models. A study design which incorporates noninvasive in vivo imaging and analysis will reduce the need for separate sets of animals required at each time point. Without the requirement of dissection at all time points, the demand on human time and reagents is reduced.

Pathogens via Infectious Diseases and/or Joint Replacement

Pathogen investigation can be optimized with in vivo optical imaging. Pathogens grow slowly in plates or cultures to then be modified to express luciferase. Sensitive optical imaging allows much faster detection of drug effects, both in vitro as well as in vivo.6 Infectious diseases and pathogens infecting wounds after orthopedic surgeries including hip and knee implants, are currently primarily treated with antibiotics.5

With multidrug-resistance marginalizing efficacy of antibiotics, this area of research benefits from multimodal co-registration, optical imaging + µCT. Metal implants and bone are visualized by µCT and the growth or death of the pathogen can be quantified by optical imaging.

Maintain subject integrity

A well-designed study incorporating in vivo imaging can improve statistical significance, reduce the total number of animals required, as well as use each animal to serve as its own control. Noninvasive in vivo testing, including in vivo imaging, helps researchers use fewer animals versus traditional, more invasive pathology techniques.

Typically a set of animals would need to be sacrificed at each time point, dissected, frozen, sliced, mounted onto countless slides, and examined under a microscope. These techniques are labor-intensive and time-consuming. In vivo imaging allows the same set of animals to be kept alive and used throughout different time points in the experiment.

Leverage in vivo imaging to accelerate analysis

Each in vivo imaging modality provides valuable information but not a complete picture of biological processes under investigation.

Multiple modality imaging provides the opportunity to combine results from each modality to obtain a more complete picture. With recent advances in analytic capabilities, MRI, CT, PET, optical, and ultrasound data can be incorporated together. Combining other modalities with optical imaging has been particularly informative. Common pairings include MRI-CT, MRI-optical, PET-CT and optical-CT.

Noninvasive in vivo imaging preserves the individual animal, allowing investigators to evaluate therapeutic benefits over a longer-term within the same study subject. By using optical imaging systems, you can do higher throughput screening, limit the number of subjects, and eliminate much repetitive early-stage research.


Conclusion

Early and sophisticated animal trial design that incorporates noninvasive multi-modality imaging will enable scientists to create strong cohorts of data, more quickly identify outlying information to inform course correction or termination, and reduce dependence on intensive, costly lab resources.

Investments in in vivo optical imaging can help scientists improve workflow, accelerate throughput, and realize cost and animal savings during this critical stage of drug discovery. In vivo optical imaging enables sponsors to meet regulatory requirements by maximizing individual animal subjects which can be kept alive for the duration of the experiment and imaged over several time points, thereby minimizing the number of animals sacrificed.

PerkinElmer provides solutions that allow for thorough and sophisticated study design supported by advanced in vivo imaging tools which reduce animal study time and improve sponsor ROI in the drug discovery process.

Sources:

  1. Science, Medicine, and Animals. National Research Council (US) Committee to Update Science, Medicine, and Animals, Washington (DC): National Academies Press (US); 2004 as referenced at https://www.ncbi.nlm.nih.gov/books/NBK24650/
  2. Mak, Isabella WY; Evaniew, Nathan; Ghert, Michelle. Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res. 2014; 6(2): 114–118. Published online Jan. 15, 2014 as referenced at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902221/
  3. National Association of Biomedical Research as referenced at https://www.nabr.org/animal-research-works-to-lower-healthcare-costs/
  4. Scarborough, Ri. Why animal trial results don't always translate to humans. Medical Xpress. Aug. 30, 2017 https://medicalxpress.com/news/2017-08-animal-trial-results-dont-tohumans.html
  5. Sateriale et al. A Genetically Tractable, Natural Mouse Model of Cryptosporidiosis Offers Insights into Host Protective Immunity. Cell Host & Microbe 26, 1–12 July 10, 2019 as referenced at https://doi.org/10.1016/j.chom.2019.05.006
  6. Cressey, Daniel. Imaging animals for better research. Nature. June 29, 2011 as referenced at https://www.nature.com/news/2011/110629/full/news.2011.391.html