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Medelis: It sounds as if preclinical and clinical teams often operate independently in their own silos. True?
Dr. McGarry: Yes, that’s true. Preclinical researchers are extremely technical and scientific; they’re focused on mechanistic details of various tissue or organ side effects. On the other side, the CMO is pushing to move a drug forward while managing costs to meet the company’s targets. That forward momentum can create friction with the conservative, tentative nature of the research scientist who is watching the nuances unfold and has perhaps a very different perspective on the trial. Of course, both sides share the same objective, and close ongoing dialogue can help remove those barriers and prevent the silo effect from derailing a promising drug.
Medelis: Can you discuss the typical preclinical process and the questions a CMO should be asking during this phase?
Dr. McGarry: Let’s say you’re a CMO at a biotech that has been working in partnership with a small laboratory that has isolated a bio-reactive molecule from a mollusk. In vitro testing reveals a growth-arresting effect suggesting anti-cancer potential. You aren’t prepared to spend millions mapping out pathways; you just want to know the extent of the effect on tumor growth.
Since an in vitro assay only shows so much and you need an animal assay to assess organ toxicities, the exploratory would probably include a classically defined tumor model with testing over three weeks to determine efficacy or toxicity. The next step after exploratory and toxicity is tumor sensitivity, again in an animal study.
There are some tumors in which drugs stop working once the tumor gets beyond a certain size. So at each step, look at the data and ask the critical questions: "What can we learn from these results? Is this something that arrests or slows tumor growth? Is the tumor static? Is it tumoricidal? Is there a limit?"
If you see animals living longer, maybe you have something. If you’re using monoclonal antibodies directed against a particular surface antigen in a tumor cell, will that be sufficient to eradicate that tumor, or are other interventions required?
Pharmacokinetics is straightforward, but you also want to probe around tumor uptake because that can affect delivery. "Is there a preferential uptake in specific parts of the tumor or body?"
These lines of inquiry can open interesting channels. Photodynamic therapy is a good example. Photofrin® was found to preferentially accumulate in tumors, and laser light focused to the sensitivity of the Photofrin activated cytocidal activity in the drug. This led to an intervention in which surgery is combined with chemotherapy in patients treated with drug-activating laser light specifically aimed at where the tumor had accumulated.
Medelis: Are there any additional requirements unique to oncology preclinical trials?
Dr. McGarry: Yes -- it goes back to selecting the right model for your preclinical data. In oncology, it’s much more critical because malignant disease is enormously complex. You need to make sure you have the animal model that best represents a particular malignancy and will allow you to tease apart various drug effects.
Medelis: What’s the typical time frame for a preclinical study?
Dr. McGarry: Timing mostly depends on the model and tumor type. Obviously the goal is to make the process as efficient as possible without sacrificing integrity and quality of the data.
There are some spontaneous transgenic tumor models where you may not see a tumor for 45 days. If you want to look at spontaneous tumors and whether your intervention has an effect on them, that could be a lengthy study with high costs including per diems on animal holdings.
Medelis: You have over three decades’ experience conducting animal studies. How important is depth of experience on the part of the preclinical investigator?
Dr. McGarry: Experience gets down to knowing the right animal model for the protocol. In some cases it may be necessary to craft two or three models. For instance, if you have an anti-angiogenesis agent, you need to use a solid tumor to determine whether the agent has an anti-tumor effect. Now that may seem straightforward, but it’s the kind of fundamental question that needs to be asked.
Experience also shows in the attention researchers give to the animals. For example, if an animal dies earlier than anticipated, does the researcher just report the statistic, or does s/he look for metastases or nuances that could provide valuable clues for the CMO?
Also, a preclinical investigator who is a published scientist can provide a major advantage in garnering the respect of colleagues. You might throw a leading question out there, for example, and they suddenly realize that you know something. Next thing you know, you’re engaged in deep dialogue. That level of expertise is extremely valuable.
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