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Preclinical Trials: A Nuanced Approach to Get Into the Clinic Faster
A Q&A with Dr. Mike McGarry
Introduction
Oncology preclinical studies are commonly viewed as straightforward investigations run exclusively by researchers. Tasked with finding therapeutic interventions that stop cell growth, researchers often operate independently without true integration with the preclinical, regulatory and clinical teams.
In this issue of Peer Perspectives in Oncology, Dr. Mike McGarry, VP of Preclinical Studies at Medelis, describes a more nuanced preclinical process that can help a Chief Medical Officer (CMO) get into the clinic faster. This approach hinges on a strategic, well-defined rodent model, quality data, and ongoing integration between the preclinical, regulatory and clinical teams.
About Dr. Mike McGarry
Dr. Mike McGarry is a preclinical research scientist with over 35 years of experience generating high quality animal-based data. For 30 years, he served as an investigator and Director of the Department of Laboratory Animal Resources at the Roswell Park Cancer Institute working primarily in experimental hematology and immunology with basic scientists and clinical colleagues. He chaired the Institute’s Animal Care and Use Committee and served on the Scientific Review Committee of the Institute’s Human Studies Review Board.
Dr. McGarry served as an IACUC member at both the Mayo Foundation and Arizona State University. While serving on the IACUC he helped numerous colleagues write and execute research protocols in a variety of species for experimental therapeutics, toxicology, pharmacokinetics, photodynamic therapy, immuno- and radiation-adjunct therapies, gene therapies, adoptive cell transfers and other leading edge technologies. He has himself worked with SCID-hu and nude immune deficient animals, many genetically altered (transgenic and knockout) and mutant mice in most common strains of mice. His experience extends to most other larger animal models routinely used in preclinical research.
Preclinical Trials: A Nuanced Approach to Get Into the Clinic Faster
Medelis: Mike, when a sponsor initiates a new preclinical study, what are the most important factors for a Chief Medical Officer to understand / evaluate during this step in the drug development process?
Dr. McGarry: The regulatory requirements, model selection and protocol are critical for transitioning into the application for clinical trials. A CMO who has a clear understanding of the nuances of the preclinical phase can extract more useful information that aids drug development and speeds overall progress to phase I.
Selecting the appropriate model for a particular protocol is perhaps the most important factor in a preclinical trial. Yet some CMOs don’t have a lot of experience with animal-based studies where even seemingly minor considerations – for example, having equal numbers of male and female mice - can have repercussions for getting through regulatory agencies.
Other pivotal issues include “Do we need a spontaneous animal model or can we use a passaged tumor?” and “When we administer the tumor, do we need to assess whether or not pre-treatment prior to inoculation with the tumor is efficacious, or do we only start interventions once the tumor has reached a certain size?”
Medelis: How rigorous is the regulatory assessment at the preclinical stage?
Dr. McGarry: Regulatory groups need to know that you’ve done your due diligence assessing the spectrum of adverse effects and efficacy.
For example, let’s say you used a particular tumor line in a genetically-engineered or mutant mouse. The regulatory agency might regard the data with some suspicion and say, “Well, did you do two other strains? Did you do it with human cells or an immune-deficient animal? What was the course of injections? IV? Infusion? Is that consistent with how this drug will be administered to the patient in trials?” You get the picture.
Medelis: How common is it for a company to hit a regulatory wall at this stage?
Dr. McGarry: It’s not as uncommon as one might think. CMOs are used to thinking of preclinical as one of those necessary steps you simply have to do. They often don’t acknowledge or recognize the complexities of this phase, and that can have far-reaching consequences.
Agencies understand and look for nuances. They might look at the data and say you have the wrong animal model or the wrong tumor line. Or they may say that the drug you’re working on is effective in a disease for which there is already a surgical procedure. So you had better be looking at the right animal model and even the correct placements of tumors. Does it make a difference if it is grown intrascapularly or on the flank? Would the results be more compelling if the tumor were grown orthotopically? Does it matter whether you have measured dimensions of tumor growth or do you want to be measuring life expectancy? Is survival the important parameter or is tumor growth?
Medelis: How can a CMO work with the preclinical team to gain a better understanding of these complexities?
Dr. McGarry: There needs to be ongoing, seamless communication and integration among the preclinical, regulatory and clinical teams. Communication affects the quality of results to be reported and thus the usefulness of the data. Each team should be actively involved in feasibility dialogue at each step in the study.
Ideally, you should also ensure that your preclinical team is knowledgeable about international standards so studies meet regulatory requirements for global registration through the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.
Medelis: So the sooner you bridge any gaps between preclinical and clinical, the better?
Dr. McGarry: Absolutely. I’ve spent most of my career in preclinical experimentation, and it’s an expensive funneling process. You start with thousands of compounds and eventually narrow it down to the one that warrants close scrutiny, hopefully making it into clinical study and application. As you’re narrowing the field, you also have to focus on the end goal or you can easily end up in a place that has no utility.
The best way to prevent this problem is to foster collaboration between the preclinical and clinical teams. Otherwise, what starts off being a crack can easily turn into a chasm.
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