Preclinical Trials: A Nuanced Study Process To Get Into The Clinic Faster

Medelis, Inc.
4105 N 20th St Ste 215

Phoenix, Arizona 85016
Phone: 602.840.1101
www.medelis.com
Preclinical Trials: A
Nuanced Approach to
Get Into the Clinic Faster
A Q&A with Dr. Mike McGarry, who describes a

nuanced preclinical process that can help a Chief
Medical Officer 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.
Welcome
This presentation is based on our September

2008 issue of Peer Perspectives in Oncology, a
free Q&A series focused on issues that face
Chief Medical Officers today: rising costs,
optimum patient accrual, targeted
therapeutics, patient safety, FDA regulations,
efficacy, budgets, and timelines.
You can sign up to receive an email notice for

future issues at
www.medelis.com/oncology_abstracts.html.
Medelis provides a full range of oncology contract research & drug
development services from preclinical through NDA. Download our
abstracts or read our blog at www.medelis.com.
Preclinical Trials: A Nuanced
Approach to Get Into the Clinic
Faster
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
clinicala teams.
Medelis provides full range of oncology contract research & drug
About Dr. Mike McGarry, VP of Preclinical
Studies
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.
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?
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
Medelis provides a full range
interventions onceof oncology
the tumorcontract research &adrug
has reached certain size?”
How rigorous is the regulatory assessment at
the preclinical stage?
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
Medelis provides tooncology
a full range of the patient in trials?”
contract research & drug You get the
picture.
How common is it for a company to hit a
regulatory wall at this stage?
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?
How can a CMO work with the preclinical team
to gain a better understanding of these
complexities?
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. a full range of oncology contract research & drug
Medelis provides
So the sooner you bridge any gaps between
preclinical and clinical, the better?
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 achasm.
Medelis provides full range of oncology contract research & drug
It sounds as if preclinical and clinical teams
often operate independently in their own silos.
True?
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.
Can you discuss the typical preclinical process and the
questions a CMO should be asking during this phase?
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?”
Can you discuss the typical preclinical process and the
questions a CMO should be asking during this phase?
[continued]
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.

Are there any additional requirements unique
to oncology preclinical trials?
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.

What’s the typical time frame for a preclinical
study?
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.
You have over three decades’ experience conducting
animal studies. How important is depth of experience
on the part of the preclinical investigator?
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
Medelis provides
expertisea is
fullextremely
range of oncology contract research & drug
valuable.
What would you look for in an outside
preclinical team?
Make sure the group understands your project and has

the necessary facilities and expertise to meet your
needs including the husbandry needs of various animal
models, which can differ greatly. The group should have
a deep understanding of the complexities of how strains
and model characteristics affect the utility of certain
animal tumor models. Special technical skills may be
necessary that aren’t available at all units, such as
gavage or infusion. And finally, they should demonstrate
a thorough knowledge of protocol demands and the
appropriate degree of compliance and documentation
required to fulfill the FDA’s Good Laboratory Practices.
Can you discuss GLPs for preclinical work - are
they always required?
GLP criteria are animal-specific directives addressing good

record-keeping, husbandry, mixing of animals with other
animals, and so on. During the regulatory approval process,
yes, you must adhere to GLPs.
However, if you’re very early stage and are only assessing

general compound parameters, you don’t need the costs
associated with GLP-level studies. You obviously need good
records, but you don’t need the same level of detail as a GLP
study. This scenario is much less expensive and will still give a
CMO or principal investigator enough information to determine
whether a compound has potential.
Many groups have pushed for the elimination of animal-
based studies. Is that a likely scenario down the road?
A variety of circles are advocating the elimination of

animal-based studies, but the likelihood that permission
to initiate clinical trials based on something other than
animal-based data seems remote.
However, with genetic engineering, it’s possible to

develop targeted knockouts and other genetic
alterations that will answer almost any question. That’s
a powerful scientific advance that helps us demonstrate
efficacy as well as the appropriate hosts for
pharmacokinetic and pharmacodynamic studies.

Can computational toxicology diminish the
reliance on animal models in the future?
Computational toxicology is based on mathematical and

computer models derived from historical information,
predictive models and in vitro data like expression array
analysis of cell cultures. It holds promise. However, it
still hasn’t achieved a level of acceptance such that it
could satisfy regulatory needs now met with animal
data. Database information on families of molecular
structures and their associated potential adverse
reactions and efficacy still aren’t sufficient to exclude
animal studies.

How might personalized medicine affect
preclinical work?
Personalized medicine started in the early eighties with

profiling a tumor for responsiveness to various
chemotherapeutic agents. So what does this mean for
using animal models? It remains to be seen. Gene
profiling is going to make a big difference, but given the
legal implications, we’re probably quite far away.

So the animal model is here to stay?
Since replacing the bacterium model of the 20th

century, mouse models have become the gold standard
for mammalian genomics and proteomics and, in turn,
the development of therapeutics. It’s a very
sophisticated system; given its wide utility and scientific
power, I can’t see it being replaced anytime soon.

About “Peer Perspectives in Oncology”
In Peer Perspectives in Oncology, Medelis brings together

some of the industry’s most respected researchers to talk
about the issues facing Chief Medical Officers today. They’re
issues we all face on a daily basis: Rising costs. Optimum
patient accrual. Targeted therapeutics. Patient safety. FDA
regulations. Efficacy. Budgets. Timelines. In this Q&A series,
we’ll discuss these challenges with leading experts who
deliver practical, frontline insights gleaned from years of
experience bringing new drugs to market.
To download additional issues in the series, please visit

www.medelis.com/oncology_abstracts.html.
About Medelis
Medelis, Inc. is a single-source provider for

oncology CRO and drug development services, providing a total
solution for biotechnology and pharmaceutical companies seeking
rapid drug development and approval. Medelis' medical founders,
team physicians and clinical trial management physicians are
internationally-recognized oncology thought and opinion leaders who
understand the future of personalized medicine and threshold of
credibility trials. Offerings include strategic plans for regulatory
approval from phase I through NDA and complete clinical trial design,
management and execution.
Medelis is privately-held and located in Phoenix, Arizona with other

U.S. locations in Nashville, Boston and Reno. Medelis Europe oversees
projects for European & Asian sponsors and is headquartered in Port
Medelis provides
Vendres, a full range of oncology contract research & drug
France.

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Medelis, Inc.

4105 N 20th St Ste 215

A Q&A with Dr. Mike McGarry, who describes a

This presentation is based on our September

You can sign up to receive an email notice for

In this issue of Peer Perspectives in Oncology, Dr. Mike

Dr. Mike McGarry is a preclinical research scientist with over 35 years of

The regulatory requirements, model selection and protocol are critical

Selecting the appropriate model for a particular protocol is perhaps the

Other pivotal issues include “Do we need a spontaneous animal model

Regulatory groups need to know that you’ve done your

For example, let’s say you used a particular tumor line

There needs to be ongoing, seamless communication and

Ideally, you should also ensure that your preclinical team is

Absolutely. I’ve spent most of my career in preclinical

The best way to prevent this problem is to foster

Yes, that’s true. Preclinical researchers are extremely

Pharmacokinetics is straightforward, but you also want to probe around tumor

These lines of inquiry can open interesting channels. Photodynamic therapy is a

Medelis provides a full range of oncology contract research & drug

Yes -- it goes back to selecting the right model for your

Medelis provides a full range of oncology contract research & drug

Timing mostly depends on the model and tumor type.

There are some spontaneous transgenic tumor models

Also, a preclinical investigator who is a published scientist can provide a major

Make sure the group understands your project and has

GLP criteria are animal-specific directives addressing good

However, if you’re very early stage and are only assessing

A variety of circles are advocating the elimination of

However, with genetic engineering, it’s possible to

Medelis provides a full range of oncology contract research & drug

Computational toxicology is based on mathematical and

Medelis provides a full range of oncology contract research & drug

Personalized medicine started in the early eighties with

Medelis provides a full range of oncology contract research & drug

Since replacing the bacterium model of the 20th

Medelis provides a full range of oncology contract research & drug

In Peer Perspectives in Oncology, Medelis brings together

To download additional issues in the series, please visit

Medelis, Inc. is a single-source provider for

Medelis is privately-held and located in Phoenix, Arizona with other

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