Dr. Mario Sznol, The Cancer Drug Development
Process
June 8, 2008
Welcome to Yale Cancer Center Answers with Drs. Ed Chu and Ken Miller, I am Bruce Barber. Dr. Chu is Deputy Director and Chief of Medical Oncology at Yale Cancer Center and Dr. Miller is a medical oncologist specializing in pain and palliative care. He also serves as the Director of the Connecticut Challenge Survivorship Clinic. If you would like to join the discussion, you can contact the doctors directly at canceranswers@yale.edu or 1-888-234-4YCC. This evening Ken Miller welcomes Dr. Mario Sznol. Dr. Sznol is Associate Professor of Medicine in Medical Oncology, and he is here to talk about the process of drug development and clinical trials.
Miller
Mario, you joined the faculty here at Yale 3 or 4 years ago after
a very long career in oncology, and also in the pharmaceutical
industry. Can you tell us a little bit about your background
in medicine?
Sznol
I started working for the part of the National Cancer Institute
involved in drug development and I spent 12 years with them.
After that I went to a small biotech company and directed their
development of a very novel agent and then returned to Yale.
I had a long experience with drug development in the government and
in the industry.
Miller
Having been in all those different environments, can you give us
an overview of the process of drug development, which people often
refer to as bench to bedside?
Sznol
It is a very long process. It starts first with the
discovery of something that has anticancer activity. There are two
ways to find an agent that has anticancer activity. One is to
take chemical compounds and basically screen them against cancer
cell lines that are growing in test tubes, and something that
actually has activity you take forward in further
development. The more exciting approach over the past 10
years has been the ability to define the mechanisms that drive
cancer progression, the exact molecular mechanisms, and then screen
chemical agents against specific targets to see if any of them have
anticancer activity. The latter approach allows you to define
agents with very specific mechanisms of action and we think those
agents are more likely to work in the clinic than the ones that are
discovered empirically. Once you have an agent that has
anticancer activity, there is a very long process to turn that
chemical into a drug that you can give to patients. Subsequent to
that, there is a very long process of clinical testing to actually
develop the data that will eventually allow you to say the drug
actually works in patients.
Miller
Thinking about drug development, I have heard it referred to like
a funnel. A bunch of new possibilities come into the top of
the funnel and at the bottom comes out a small number. Can you tell
us a little bit about that, how many drugs are looked at originally
for every one drug that is a good one?
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Sznol I am not sure that I can give you an exact number, but
I can tell you that it is many, many drugs leading to a very few
that are ultimately approved at the end. We tend to use the
number that somewhere around 10% of drugs that enter clinical
trials in cancer will ultimately make it for approval by the Food
and Drug Administration. Many drugs fail in the initial
processes of clinical testing, either because they are toxic, or
because they just do not have the right activity.
Miller
Patients often ask why it takes so long for a new treatment to
become available. Why is that?
Sznol
First of all, often we just hear that a gene is active in cancer,
or that a gene drives the cancer, and from just understanding the
biology of developing a drug against that target can take a very
long time, but it is also very important to remember that just
taking a chemical entity and making a drug, in other words putting
it into a vial and making sure that it is safe, being able to
manufacture the drug, and then testing it in the clinic, can take
years and years. For example, it can take a year just to find
out the right dose and schedule for a drug, and it can take 3 to 5
years to do the final clinical trial that determines whether a drug
works or not in patients. If you are thinking about the
initial discovery of the drug in the test tube to final data in a
randomized clinical trial that shows that it works, that could be a
process of 7 to 10 years.
Miller
Which is a very long time and all those safety nets are in place
to assure that it is the best drug for the patient?
Sznol
Absolutely. You do not want to have a drug on the market
that does not work or has unpredictable toxicity. Even if it
has toxicity, you have to understand how to manage that toxicity so
you can give it safely. Of course, you want to know ultimately that
a drug works, and to know that a drug works can take a very long
time, but particularly the safety issues, you need a lot of
information and you need to treat a lot of patients to know how to
manage the drug well.
Miller
What role does the government play in cancer drug development?
Sznol
The government plays many roles in development. First of
all, it funds much of the basic research and much of the clinical
research required to take an agent from the bench to the
bedside. The government does its own drug development, so not
only does it fund it, but it also has a drug development arm.
The National Cancer Institute, for example, has a group that is
very much like groups that are present in pharmaceutical companies
that develop drugs. Finally, the government is involved in
the regulation of both clinical research and ultimately drug
approval.
Miller
There has been a lot of publicity on fast track approval. How does
that differ? People talk about the FDA having a fast track, what
does that mean?
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Sznol All that really means is that the FDA commits to
reviewing an application for approval in a somewhat more compressed
time manner, but it does not really speed the process of drug
development as much as what might be thought in the
community. You still have to do the phase I trials, you still
have to do the phase II trials, and you still have to do the phase
III trials. It is only once you gather all of that
information that the fast track process really kicks in.
Miller
Interesting. So all the work still has to be done, but it
sounds like then the final review is quicker?
Sznol
It can be faster. Yes.
Miller
Can you review with us what is phase I, II, and III?
Sznol
Remember that when a drug comes into the clinic, there is no
information. We do not know what dose to give, we do not know
what schedule to give. So, we have to start at a very low dose and
escalate the dose slowly. The first dose that you want to
give to patients has to be low by definition so that it is safe,
and then you escalate the dose in small groups of patients until
you find what is called the maximum tolerated dose. That is a phase
I trial, where you actually determine a tolerable dose and
schedule. Then, the drug goes into phase II trials, which is
activity testing. You want to know whether the drug has
activity and whether it causes tumors to shrink, or you use other
measures such as improvement in symptoms, but even then it is not
absolutely clear that activity translates into benefit, for benefit
you need to do a phase III trial. Phase III trials are randomized
trials either adding the drug to standard therapy, or comparing the
drug to standard therapy. It is in those randomized trials where
you really determine the two measures of benefit, which for
patients is an improvement in symptoms or increase in their
lifespan.
Miller
The other thing that we hear very frequently from patients and in
the press is that new medicines cost so much money, especially some
of these new targeted drugs. Why are they so costly?
Sznol
The process of drug development is just enormously
expensive. I will give you an example. A patient who
goes into a phase III trial, the final phase of drug testing, it
can cost the company up to $50,000 per patient to enroll the
patient, collect the data and pay for all the other necessary tests
that need to be done in order to develop the data that ultimately
is submitted for registration. So, if you think about a
clinical trial or phase III clinical trial, at the last stage there
might be 1000 patients; a $25 million to $50 million investment
just at this stage. We estimate that it may cost $75 million
to $100 million to get a drug from test tube all the way to
registration at the FDA, and you are not only paying for the
development of that drug, you are also paying for all the costs of
developing the other drugs that failed in the clinic.
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Miller
In your career, have there been drugs that you worked with from
the bench that made it all the way to practice, or close to it?
Sznol
Very few of us have had the privilege of working with a drug from
the test tube all the way to registration. I have been
involved in the registration process. For example, the drug
interleukin-2, I was very involved with the clinical development
and the registration of that agent, but I cannot say that I was
involved from the very beginning to the very end for any drug and
there are very few people who can claim that.
Miller
It also sounds like it is a very, very long process in someone's
career. Many people hear about medical breakthroughs on the
news and then they go to their doctor and they bring the article
with them and then the doctor says that therapy is not available
yet. Any advice for patients who are in that situation, they go to
their community doctor and they are not able to get the drug on the
market. Are clinical trials useful to participate in, in that
situation?
Sznol
It really depends on what the breakthrough is. If the
breakthrough is that the drug cures cancer in a mouse, I can assure
you that that would be many, many years before that drug would be
available to patients. If the drug is already in the clinic,
they may be able to access it through a clinical trial.
Sometimes, for example, if the information comes from a late stage
clinical trial then that drug might actually be available through
compassionate use programs that are usually setup at major cancer
centers. It depends, but the best thing to do would be to check
with an expert in the disease and to see if that drug is currently
available for treatment of patients.
Miller
You mentioned compassionate use, what does that mean?
Sznol
Many times, as you know, when a drug is being developed data is
generated that shows that it actually works, or at least a very
strong suggestion that the drug works, but it takes time even from
that information to final registration approval and marketing by
the FDA. So, the FDA has a process in which drug companies
can provide the drug through a clinical trial mechanism essentially
to patients who would not be able to get the drug otherwise, so it
looks like a clinical trial, but in fact it is a treatment
protocol.
Miller
So in a sense it is trying to make the drug available a little bit
quicker for people that have problems.
Sznol
That is exactly right. It is being made available for
treatment as though the drug works, but it is not commercially
available so it is being made available through a compassionate use
clinical trial
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process. Under those circumstances, the eligibility criteria
is much looser, so many more patients can get access to the drug
than might be able to get the drug in a clinical trial.
Miller
Are those drugs provided free of charge in that setting?
Sznol
Almost always they are provided free of charge.
Miller
There are different settings and you have talked a little bit
already about where drug development is taking place, there is the
federal government, there are pharmaceutical companies and academic
medical centers. What are some of the differences in the drug
development process in those settings?
Sznol
Well the government and industry develop drugs in very similar
way. Academic centers do not actually do drug development,
they participate in drug development. Drug development is the
entire process of taking a molecule from the very beginning to the
very end, whereas academic centers are involved in drug discovery
and they are involved in individual clinical trials, but they
usually are not involved with the entire process from beginning to
end.
Miller
It sounds like that portion of it is almost a Herculean effort
with many different people involved in different
laboratories. Is that fair to say?
Sznol
Yes, the collaborations between industry and academics are very
strong and they need each other in order to develop drugs
successfully. It is very important to have drug companies
involved in this process because they are the ones who oversee and
are actually invested in the success of that drug. After all, if
they were not involved, who would be available to manufacture or
produce the drug, put it in a vial and make it available in the
market place so that the patients have access? They are very
important in the process.
Miller
Well we would like to remind you that you can e-mail your
questions to us at canceranswers@yale.edu.
We are going to take a short break for a medical minute. Please
stay tuned to learn more information about drug development with
Dr. Mario Sznol from the Yale Cancer Center.
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early detection, and a healthy lifestyle are the most
important factors in defeating breast cancer. Clinical trials
are currently underway at federally designated comprehensive cancer
centers such as the Yale Cancer Center to make new treatments now
yet approved by the Food and Drug Administration available to
patients. This has been a medical minute and you will find
more information atwww.yalecancercenter.org.
You are listening to the WNPR health forum from Connecticut public
radio.
Miller
Welcome back to Yale Cancer Center Answers. This is Dr. Ken Miller
and I am here today with Dr. Mario Sznol from the Yale Cancer
Center discussing clinical trials and drug development.
Mario, we have been talking a little bit about clinical trials. Why
are they important to patients and why they are important to
medicine in general?
Sznol
First of all, without clinic trials we wouldn't make any advances
in clinical medicine. In cancer the truth is we do okay, but for
the most part our treatments in advanced cancer are not very
effective, so we need clinical trials in order to find better
treatments for patients. For individual patients, often times
standard treatments are not optimal. They may get some
benefit from it but they may not be cured. A clinic trial may offer
them a chance to have even a better outcome in that setting.
Miller
You are very active in clinical trials here at Yale. From the
work that you are doing, what is an example of a clinical trial
that you are excited about here?
Sznol
As an example, we are going to be bringing a drug into clinical
trials. We did not discover it, but we are going to be
collaborating with a pharmaceutical company on an agent that works
specifically in the tumor microenvironment to block the tumors
defenses against immune responses. Essentially it will help enhance
the immune response to attack and kill tumors. Now that drug
is in early clinical testing, so this will be a phase I trial in
which we will look at escalating doses and prolonged treatments
schedules. In that clinic study, we will study the immune
responses of patients and we will observe for antitumor responses.
We are very excited about this drug because both from a biological
perspective and a clinical perspective, the animal model data it is
a very active agent.
Miller
It sounds like a fascinating trial to be able to look at how the
immune system might help defend against cancer. It actually
brings up the topic that I look as modern approaches to clinical
trials. How does your approach differ from what would
have been done 15 years ago?
Sznol
Because we now understand the mechanisms of these drugs, or at
least have a better understanding of the mechanisms of these drugs,
there is a great deal more emphasis on early clinical studies, and
in lay clinical studies, to obtain blood and tissue from patients
and to verify
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that whatever effects we were seeing in the test tube and animal
models actually occurs in patients. If we do this early in
the clinical developmental process, we do not know for sure that
the drug works, but we know the drug at least has the right
biological activity and it gives us encouragement to proceed and do
the larger phase II and phase III clinical trials. Sometimes
if a drug does not work when we do these biological studies, we
understand why the drug didn't work and then we can go back to the
lab and develop better drugs for patients.
Miller
So you are saying, in a sense, you know what the target is, and
what are you going after, but if you find very early on that this
drug does not hit the target, you might be able to build a better
drug?
Sznol
Absolutely, sometimes it does not hit the target for simple
reasons, you do not get the right blood levels, we find out that it
has metabolized incorrectly or sometimes we find that maybe that
target is not as important in humans as we thought it might
be. There is another very interesting use for markers, which
is to select the patients that may respond. Remember, even
for a single disease, breast cancer, lung cancer or melanoma, it is
still a very heterogeneous disease. Every patient has their
own molecular biology, their own biology. Say we treat 100
patients with the drug, we might only see 20% of the patients
benefit, so one of the things we are trying to do when we get blood
and tissue is to try and identify those patients that might
respond, so we can turn a drug that is 20% effective into a drug
that has a 60% or 70% response rate.
Miller
You are finding the group of patients that are most likely to
benefit.
Sznol
Exactly, right.
MillerFor example, in melanoma, or any other type of cancer, what
kind of target might you look for that would tell you that this is
a patient who is really going to benefit from my therapy?
Sznol
We will talk about a disease other than melanoma, where we do not
yet have those markers. We can talk about a disease that you
are very familiar with, which is breast cancer. A good example is
Herceptin. In breast cancer you identify patients who might respond
to Herceptin by identifying a specific molecule on the surface of
the breast cancer which Herceptin identifies. We then only
treat those patients who have an expression of that receptor.
Miller
I want to go back a little and discuss the issue of clinical
trials, because it is such a great thing for us to learn
about. What is a randomized clinical trial and why are they
important? Sometimes people say they do not want to be
randomized; they want the doctor to tell them which treatment they
should have.
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Sznol
The reason we do randomized trials, whether we are comparing
standard treatment to new treatment or adding the new treatment to
standard treatment, is that we do not know if the new treatment
actually helps. We have some idea that it may be useful from
the phase II trial, but a phase II trial only tells us that the
drug is active, it does not tell us if it prolongs life, for
example. In order to know that, we have to randomize patients
in an unbiased way to receive standard therapy versus a new
therapy. That, in a very rigorous scientific way, tells us that the
drug works. Otherwise we are guessing. Many times,
based on non-randomized studies, we think that the drug is
beneficial for patients, but when we take that drug to a randomized
trial, we find it is no better than standard treatment.
Miller
If patients participate in a randomized trial, is someone
overlooking the trial to see if one arm is not as good, or if one
arm is clearly better?
Sznol
Absolutely, randomized trials have, by definition, what is called
the data and safety monitoring board. Those people look at the data
intermittently to make sure that the new drug is well tolerated and
that the activity is what it should be. In other words, if
early on in the trial it turns out that the experimental arm is no
better than the standard arm, we will stop the trial early.
On the other hand, if it turns out that the experimental arm is
much, much better than the standard treatment, then we will also
stop the trial early and offer the experimental treatment to the
patients who are receiving the standard treatment.
Miller
For a patient who is thinking about participating in a trial, they
do have a sense that someone is overlooking it?
Sznol
No question about it. This is a very tightly regulated
process to ensure both the safety of the patient and to make sure
that they are getting the best treatment.
Miller
Mario, how should a patient decide if he or she should become
involved in a clinical trial?
Sznol
That is a very difficult question and they need to have a very long
discussion with their physician about all of the options; both
standard treatments and investigational treatments. If their
physician is not terribly familiar with clinical trials for that
specific disease indication, it is worthwhile to get a second
opinion with an expert in that disease who understands all the
clinical trial options for that disease.
Miller
What is the process of informed consent? What does that mean
and how does that translate to day-to-day practice?
Sznol
We have developed, over a very long period of time, a process in
which patients are informed
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completely of the risks and benefits and their rights within a
clinical trial. It is incorporated into often a very long document
that we provide the patients to read so that they know exactly what
they are going to get, what kind of drug they are going to get,
when they are supposed to be in the clinic, how much blood is going
to be drawn, what the risks of the trial are, and their rights too,
for example they can withdraw from the study at any time. The
informed consent also informs them of all the confidentiality
protections that are now in place for patients. It gives them phone
numbers to contact for the physicians and also for the ethics
review board at the institution where they can ask questions or
make complaints if necessary.
Miller
It sounds like it is a pretty thorough document.
Sznol
Very thorough document and in fact one of the things that we are
concerned about is that they have so much information that
sometimes it is hard for the patients to go through at all.
Miller
Do you get a sense, in the United States, of what percentage of
people with cancer are being treated on the protocol?
Sznol
Unfortunately, it is a very low number. It is probably less than
10% and some people have estimated as low as 2% or 3% of all
patients with cancer go on clinical trials. That is a shame because
clinical trials are often the best option for patients and it is
the only way we are going to advance the field.
Miller
In terms of informed consent, there is a lot of discussion about
risks and benefits. What are some of the risks associated with a
clinical trial?
Sznol
The major risk is that you are getting an investigational agent,
and therefore, the full side effect profile is not known.
Even though there is information from animal models and from
patients who received the drug before, there are always unexpected
side effects that may occur. That is really the major
risk.
Miller
And the benefits on the other side would be what?
Sznol
The benefits are unknown. That is why we are doing the
clinical trial. We have an idea about what the benefits might
be, but the fact is it is a clinical trial and that means we really
do not understand the benefits. For many clinical trials, there may
be no benefit at all.
Miller
What is some of the clinical research you are involved with now
that you are excited about?
Sznol
In general, there are early phase clinical trials, so very novel
drugs that are being tested in phase I
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studies. Those are very good option for patients in which
all standard options have been exhausted. There are also
phase II trials in which we know something about the drug and the
drug's range, from drugs that target blood vessels to drugs that
activate the immune system, to very novel drugs that blocks
signaling pathways in cancer cells; a wide variety of mechanisms of
action and very interesting new agents.
Miller
Can you give us an example of any one trial that again you are
particularly excited about?
Sznol
I'll give you an example of two trials. One is at one end of the
range, which is a compassionate use study of a new immune therapy
called anti-CTLA4. This is a very powerful activator of the immune
system, so powerful that it can sometimes cause side effects of
turning the body's immune system against their own tissues, but we
and others have seen some incredible responses. Unfortunately they
are only in a small number of patients, but we've seen incredible
responses in patients who would otherwise have been refractory to
all other kinds of treatment. We are very excited about this
agent. It is in very late stage clinical testing. At the other end
of the spectrum, we are testing a very novel immunotoxin which is
essentially an antibody that binds to the surface of tumor cells
and attached to this antibody is a toxin. It is like a Trojan horse
that enters inside specifically into melanoma cells. Once it
is inside the cells, it releases the toxin and kills the melanoma
cells from the inside. That is an early stage clinical trial but we
are very excited about this kind of an agent.
Miller
On one hand it sounds like Star Wars and on the other end it sounds
like these things may make a big difference for patients.
Sznol
We will certainly have to prove that, but yes.
Miller
Mario, I want to thank you. This has been a terrific
program. This has given us, and myself as well, an improved
understanding of what happens in drug development. I want to
thank you very much for joining us on Yale Cancer Center
Answers.
Sznol
Thanks for having me Ken.
Miller
From all of us here on the program and from the Yale Cancer Center,
we want to wish all of you a safe and healthy week.
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