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DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE
CLINICAL PHARMACOLOGY SUBCOMMITTEE
Thursday, November 4, 2004
8:05 a.m.
Hilton Washington, D.C. North
620 Perry Parkway
Gaithersburg, Maryland
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C O N T E N T S
PAGE
Call to Order 3
Conflict of Interest Statement 3
Tribute to Dr. Lewis Sheiner 5
Introduction to the Topic, Background
and Project Plan 20
Framing the Issues: What Needs to be
Done and How? 32
What are Industry's Expectations of the
Project and Process? 67
Opportunities, Challenges and Some Ways
Forward: How can Academia-Industry-
Government Collaborations Facilitate the
Development of Biomarkers and Surrogates? 90
Committee Discussions and Recommendations 116
Summary of Recommendations 146
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P R O C E E D I N G S
[8:03 a.m.]
DR. VENITZ: Good morning, everyone. For
the second day of the Clinical Pharmacology
Subcommittee meeting, we have half a day agenda for
today. And I would like to point out that we don't
have anybody signed up right now for the open
hearing. If anyone in the audience wants to do
that, please contact Ms. Scharen as soon as
possible so we can lock you in.
The first order of business is to review
the conflict of interest, and Ms. Scharen is going
to do that for us.
MS. SCHAREN: Good morning.
The following announcement addresses the
issue of conflict of interest with respect to this
meeting and is made part of the record to preclude
even the appearance of such. Based on the agenda,
it has been determined that the topics of today's
meetings are issues of broad applicability, and
there are no products being approved.
Unlike issues before a subcommittee in
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which a particular product is discussed, issues of
broader applicability involve many industrial
sponsors and academic institutions. All special
government employees have been screened for their
financial interests as they may apply to the
general topics at hand.
To determine if any conflict of interest
existed, the agency has reviewed the agenda and all
relevant financial interests reported by the
meeting participants. The Food and Drug
Administration has granted general matter waivers
to the special government employees participating
in this meeting who require a waiver under Title
18, United States Code, Section 208. A copy of the
waiver statements may be obtained by submitting a
written request to the agency's Freedom of
Information office, Room 12A30 of the Parklawn
Building.
Because general topics impact so many
entities, it is not practical to recite all
potential conflicts of interest as they apply to
each member, consultant and guest speaker. FDA
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acknowledges that there may be potential conflicts
of interest, but because of the general nature of
the discussions before this subcommittee, these
potential conflicts are mitigated.
With respect to FDA's invited industry
representative, we would like to disclose that Dr.
Paul Fachler and Mr. Gerald Migliaccio are
participating in this meeting as nonvoting industry
representatives acting on behalf of regulated
industry. Dr. Fachler's and Migliaccio's role at
this meeting is to represent industry interests in
general and not any one particular company. Dr.
Fachler is employed by Teva Pharmaceuticals, USA,
and Mr. Migliaccio is employed by Pfizer.
In the event that the discussions involve
any other products or firms not already on the
agenda for which FDA participants have a financial
interest, the participants' involvement and their
exclusion will be noted for the record. With
respect to all other participants, we ask in the
interests of fairness that they address any current
or previous financial involvement with any firm
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whose product they may wish to comment upon.
Thank you.
DR. VENITZ: Thank you, Hilda.
Before we proceed with the scientific
agenda, we will pay a tribute to one of the seminal
members of this Committee, who passed away earlier
this year, Dr. Lew Sheiner, and Dr. Lesko and Dr.
Blaschke will pay tribute to his contributions in
clinical pharmacology.
DR. LESKO: Thank you and good morning,
everyone. Welcome back. We had a long day
yesterday filled with a lot of heavy duty
intellectual discussions, and it's nice to see you
all back and I think refreshed.
Anyway, we would like to pause at this
moment and remember our colleague, Dr. Lewis
Sheiner, who was what I would call a founding
member of the Clinical Pharmacology Subcommittee.
I remember inviting him to join the Committee a
couple of years ago, and he said to me I'll only
come if it's going to be intellectually
stimulating. And after each meeting, I would ask
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him was that intellectually stimulating? And he
would say yes, and he came back to every meeting.
Dr. Sheiner, as everyone knows, and Jurgen
mentioned, passed away unexpectedly in April of
this year, and Lewis, we all know, was many things
to many people. He had an important role as a
member of the CPSC. He provided us with an
extraordinary dimension of opinions on many
different subject matters, always challenging us to
dig deeper into our intellect.
He was great as a member of this
Committee. He focused on solutions, and he didn't
dwell on the problems very much. I remember last
November, and many of you do, too; we were
discussing the end of phase two-A meeting, and I
think we spent about three or four hours of
discussion, and I still remember his question,
which came at the end of that discussion, and I
think it exemplified his way of spicing up a
Committee meeting. He said Larry, it sounds like a
good idea somehow, but I'm not sure exactly why.
I think that was his way of challenging us
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to think clearly and fully about what we were
proposing at this meeting. And I think the topic
that we will discuss later this morning would have
been very near and dear to his heart. So I know
that I speak for many of you, members and audience
alike, all of us at FDA, when I say that it would
be an understatement of the highest proportion to
state that Lewis is sorely missed today.
I have invited Dr. Terry Blaschke, who was
a close friend and colleague of Dr. Sheiner to pay
him a tribute on all of our behalf.
DR. BLASCHKE: Well, thanks, Larry. This
actually is a harder talk to give than the one I'm
going to give later this morning.
Larry did ask me to pay a tribute to
Lewis, and I think we really did lose a visionary
leader in drug development in April. Lewis died
shortly after receiving the Oscar B. Hunter Award
of the American Society for Clinical Pharmacology
and Therapeutics, which is really one of the
premier awards in clinical pharmacology, and I
think Lewis was very pleased to get that award. I
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had the pleasure of introducing him for that award.
Many of the people, of course, in this
room, not just on the Committee but in the
audience, knew Lewis and had an opportunity to
interact with him, and I think if you had that, you
really knew what a wonderful person, enthusiastic
and exciting as Larry has just expressed.
But one of the things that he really did
want to do and did do, I think, not only in this
Committee but elsewhere was really get involved in
improving the process of drug development. And one
of the things I'd like to do during the next few
minutes is really talk about some of those concepts
that he championed and I think have become very
important in the whole field of clinical
pharmacology and drug development.
But I'll start out with a little bit of a
background about Lewis, for those of you who don't
perhaps know some of his background. He was born
in New York City, and in fact, it took many years
for him to evolve his California-like approach to
discussions like this. Those of you who knew him
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early in his career probably remember that he could
be pretty acerbic as a critic of presentations and
so forth, and certainly, as he grew older, he
became much more of a mellow individual when it
came to his discussions.
Lewis received his bachelor's degree from
Cornell University, his medical degree from Albert
Einstein. He was then an intern and a first-year
resident at Columbia Presbyterian Hospital in New
York City. He then, as many of us did in that era,
go to the NIH, where he was a research associate at
the National Institute of Mental Health.
There, Lewis actually published two papers
in the Journal of Biological Chemistry, and I think
but for a change that I'll tell you about in a
moment, he might have been a molecular biologist or
a molecular pharmacologist. He had planned to
return to Columbia University Medical Center to
finish his residency training and called down to
the chair of medicine when he was about to complete
his tour of duty down at the NIH and was told that
he should have called earlier; that basically, they
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weren't ready to take him back.
So instead of returning to Columbia, he
joined the NIH Division of Computer Research and
Technology, where he, I think, had his first
exposure to computers in medicine and to modeling
and possibly a simulation at that time, but the SAM
program. This actually led to his first
publication, which had to do with the
computer-aided long-term anticoagulant therapy,
which was published in 1969 in Computers and
Biomedical Research.
After completing that additional two years
at the NIH, Lewis came to Stanford, where he
completed his medical residency and then went to
UCSF as a clinical pharmacology fellow, joining the
faculty there in 1972, and spending the rest of his
career there, where he was professor of laboratory
medicine and biopharmaceutical sciences.
Of course, Lewis is widely recognized as a
pioneer in the field of pharmacometrics, and his
career at UCSF really focused on the mathematical
and statistical methods applied to the problems of
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clinical pharmacology. During the early part of
his career, Lewis was involved in the whole area of
therapeutic drug monitoring, which was then
becoming established at many hospitals through the
country.
Through Ken Melman, Lewis was introduced
to Bar Rosenberg, a brilliant statistician at
Berkeley, and this really represented another
pivotal point in Lewis' career and really marking
his entrance into the field of the world of
statistics. And this particular paper, again,
published in 1972 in Computers in Biomedical
Research, represented this first paper, actually, I
think it was the second paper along with Bar
Rosenberg in which the focus on individual
pharmacokinetics and computer-aided drug dosing was
first published.
Now, this introduction to Bar and interest
in computer-aided modeling of drug therapy led to
this paper, actually, two papers: a paper
published in 1973 in the New England Journal of
Medicine on computer-assisted digoxin therapy and
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then this paper with our colleague, Carl Peck,
Lewis Sheiner, Bar Rosenberg and Ken Melman again
that appeared in the Annals of Internal Medicine.
This work really, I think, led, as it
inevitably would, to Lewis' interest in developing
methods for predicting pharmacokinetics of drugs in
individuals using sparse data sets; in other words,
using just a few drug concentrations obtained
during the patient's hospital stay, and I think as
a result of that, together with his colleague
Stewart Beal, Lewis developed and applied the
NONMEM program, which I think is probably most
associated with Lewis' work, and I think most of
you are familiar with NONMEM as a Bayesian
forecasting tool incorporating population
pharmacokinetic information to predict
pharmacokinetics.
This novel program and novel approach has
really led to greatly-enhanced predictions for
dosing regimens, for patients in clinical settings
allowing for individualization of drug therapy and,
of course, I think NONMEM really became the
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standard in the industry and at the FDA for
characterizing population pharmacokinetic data
acquired during clinical drug studies, and, in
fact, I think really greatly expanded the entire
field of population PK over the last decade or two.
Lewis then moved from forecasting of
pharmacokinetics to, I think, another very
important area, again, with our colleague, Don
Stanski, in thinking about pharmacokinetic and
pharmacodynamic modeling. Lewis had a very keen
sense of clinical pharmacology, and he really
pioneered these new methods to simultaneously
analyze pharmacokinetic and pharmacodynamic data,
leading to the concept of the effect compartment.
I'm showing that basically with this slide.
This, I think, is the typical slide that
one would see in many different presentations, both
of Lewis and others. This has really become, I
think, the way in which PK/PD data is handled by
many individuals. As with NONMEM, this worked with
his pharmacodynamic PK/PD modeling that has really
become a standard both for industry and for the FDA
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in analyzing drug response data.
Lewis' overall goal all along was to
improve patient care by individualization of dosing
regimens. And the work that he did really enabled
this to be done in a number of different
therapeutic areas. Lewis worked, as many of you
know, with anesthetic and analgesic drugs, much of
which was done in collaboration with Don and Don's
colleagues; worked with me and many others in
antiretroviral therapy and antiretroviral drugs and
in many other therapeutic areas with many
collaborators.
As I mentioned at the beginning, much of
Lewis' work was really focused on improving the
science of drug development by optimizing clinical
trial designs, and his vision was to develop
methods that allowed more efficient and more
informative clinical trials, optimizing dosage
recommendations and optimizing therapy. And one of
the things which he did, again, with his colleague
Nick Holford was, again, really to focus on
understanding the dose-effect relationship and
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along, again, with Stewart Beal and Nancy Samble of
UCSF, I think this was one of the classic papers of
study designs that could be used for dose ranging,
particularly in phase two studies, and I've seen
this particular study quoted many times at meetings
and in the literature.
And Lewis would always say that this was
one of his signature slides. If you didn't see
this slide, you knew it wasn't Lewis talking. This
was his whole concept of a response surface, with
benefit-risk response surface, and he had many
variants of this slide, but this, I think was one
of his, as he said, signature slides and favorite
slides.
Now, Lewis really, as I mentioned at the
beginning, developed an intense interest in
statistics. And this led him, really, to question
the traditional approaches to data analysis in
clinical trials and this whole concept of--did I
pass one slide here?--well, I'll come to that
slide. This is a little bit out of order. But in
any event, he really got very interested in looking
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at the whole issue of statistical approaches to
analysis of clinical trials, and this review that
was written just a couple of years ago in the
British Journal of Clinical Pharmacology was one
example; another example was this paper written by
Nicholas Johnson and Lewis just a couple of years
ago in Clinical Pharmacology and Therapeutics, and
he had begun to work very closely with a number of
statisticians, including Marie in the audience here
and other statisticians at Harvard really asking
questions about the analysis of clinical trials.
Now, I think perhaps his most important
contribution overall was his paper published in
1997 on the concept of the learn-confirm paradigm
of drug development. And I've heard this
particular paper and this particular concept quoted
again and again as I've talked with people in the
pharmaceutical industry and so forth, and I think
this really does represent a major contribution
that Lewis made to the whole thinking of how one
develops drugs, and I'm going to come back to that;
I won't talk much about that right now, but I'm
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actually going to come back to that later on this
morning in my own presentation.
Lewis was obviously very interested in the
whole area of drug development and in the role of
pharmacokinetic and pharmacodynamic modeling in
drug development and published this review in 2000
in the Annual Review of Pharmacology and
Toxicology, which I think was--again, it's a
highly-cited paper, one that really gives an
excellent overview along with Jean-Louis Stymer, of
the role of modeling in the whole drug development
process.
Now, I'll mention to go on a little bit
about Lewis' specific service on FDA advisory
committees and committees such as this one. Since
1987, Lewis had been an expert consultant to the
FDA Center for Drug Evaluation and Research and had
participated in many meetings. He was, and this
will become important later on again, a member of
the Anti-Viral Drugs Advisory Committee from 1991
to 1994, and as you'll see in my presentation
later, this was a very critical time in that field
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of antiretroviral drugs.
He was very involved in the whole area of
bioequivalents and was a member of an expert panel
on the guidance in population PK/PD as well as this
expert panel on individual and population
bioequivalents at CDER. As well, he was a member,
as one might expect, of the exposure response
guidance panel of CDER, and finally, as Larry has
already mentioned, a member of the Clinical
Pharmacology Subcommittee, in fact, a founding
member of the Clinical Pharmacology Subcommittee.
Lewis' substantial influence on the
science of drug development has, I think, been very
well apparent and documented, and those of us who
knew him will remember him for his passion for this
whole subject, his intellectual curiosity, as Larry
has mentioned; his warmth and engaging personality.
He had a great impact on the people he trained and
the people he collaborated with, even those of us
or those of you who had more limited interactions
with him.
He really established deep and lasting
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relationships with his fellows, friends and a broad
spectrum of scientific and business associates. He
spawned several generations of
quantitatively-oriented clinical pharmacologists
worldwide, not only through his research but also
for his commitment to research and training, which
included a number of, I think, world-renowned
courses in pharmacokinetics and in NONMEM and
modeling, working in many cases with his friend
Malcolm Rowland and his colleague, Les Bennett, at
UCSF.
This is just a list of the many people
that Lewis trained. You can glance up at this
list. You probably see many people that you know
on this list, people who are very influential and
very important in the field of drug, clinical
pharmacology and drug development. This picture
was taken in 1992 at a 60th birthday celebration
that was held for Lewis. You see him down there in
the lower left-hand part of the slide. There were
probably about 100 people. Kathy was very
responsible for helping organize this meeting,
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Kathy and Les Bennett, and I think it really
represents the kind of loyalty and so forth that
Lewis was able to generate.
Lewis served as president of the American
Society for Clinical Pharmacology and Therapeutics.
He authored more than 200 books and chapters; was
on the list of most-cited authors in the area of
pharmacology through ISI; had many honors and
awards, including an honorary doctorate from
Uppsala University; the Hunter Award that I
mentioned, the Rawls Palmer Award that I mentioned
from ASCPT and an honorary fellowship from the
American College of Clinical Pharmacology.
Lewis lectured widely throughout the world
as well as being involved in committees such as
this one, and as Larry said, he certainly will be
sorely missed. And I thought these two final
pictures of Lewis really represented Lewis at his
best: one in Amsterdam and one in Switzerland.
Thanks.
[Applause.]
DR. VENITZ: Thank you, Dr. Blaschke.
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Our first agenda item as far as the
scientific agenda is concerned is a discussion of
surrogate markers, and Dr. Lesko is going to
introduce the topic.
DR. LESKO: Thank you, Terry, very much
for the thoughtful comments, and I'm sure Lewis is
looking down smiling and saying I told you so.
I'm here at this point to introduce the
last topic of this meeting, which we call the
transition of biomarkers to surrogate endpoints.
It's somewhat of a difficult introduction to make
because of the broad nature of biomarkers and
because of what's gone before, namely, a large
number of discussions, many of them passionate,
about the topic of biomarkers and surrogate
endpoints.
My colleague, Don Stanski, urged me to be
visionary, and being visionary is not something
that comes naturally to me, so it's difficult to be
visionary. So I looked for inspiration. And I
looked for inspiration to the movie that I was
watching on Sunday with my grandson, Nemo, and
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there's a point in the movie where these two fish,
who you probably recognize, come around the corner
of a coral reef and come face to face with a
menacing shark, and they say something like oh, no,
not him again.
And I thought about that, and I called
this the biomarker fear factor, because we've
talked about biomarkers endlessly for the last 10
or 12 years, and one might be apt to say oh, no,
not that again.
We've talked over the years in workshops
and symposia on the validation of biomarkers as
surrogate endpoints, and again, this is a topic
that ignites a lot of discussion and a lot of
debate, very much passionate debate, with the sides
taking shape.
I happened to look in the Internet, using
Google as a search, and I said I wonder what's
going on in biomarker workshops these days. And I
was able to pull up without a lot of trouble
biomarker symposia that are taking place all over
the world, from France to the Netherlands to South
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America, and including Baltimore this weekend,
where there's a biomarker workshop that precedes
the ACPS meeting.
So a lot has gone before, and I'd like to
begin with definitions. These are definitions that
came from the FDA/NIH 1999 workshop, and you'll
probably see these occasionally throughout our
morning just to set the stage as to what we're
talking about in biomarkers and biological markers
and surrogate endpoints, and you can see that we're
talking about characteristics that are measured or
evaluated as indicators of a whole variety of
things, from normal disease processes to
pharmacological responses to drugs. And a
surrogate endpoint is a subset of biomarkers that's
intended to substitute for a clinical endpoint.
The problem that we have, I believe, with
biomarkers is that the pace of biomarker discovery
keeps increasing at a remarkable pace, with
measurable improvements In the biomarker discovery
area but not necessarily measurable improvements in
predicting the success of drug development. There
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was an article yesterday in the New England Journal
of Medicine about the genetic basis for Parkinson's
Disease, and this type of discovery is so
ubiquitous these days that the genetic basis of
this disease or that disease is sure to spur the
discovery of biological markers that are going to
play a major role in drug development and in
patient monitoring.
But the past focus of biomarkers and maybe
even the emphasis or overemphasis has been on
biomarkers as surrogates, and despite the last 14
or 15 years of debate and discussion, there have
been relatively few successes of biomarkers being,
quote, validated as surrogate endpoints. We've had
discussions of conditions that favor or not favor
surrogate status for biomarker endpoint, things
like the pathophysiology characteristics. We
discussed these in our exposure response guidance
that came out in April of 2003, and if you go back
and read that now, it is not very explicit on
either how you develop a surrogate endpoint or what
the criteria is to specify one as such.
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There's been a subtle resistance, I think,
stemming from the past failures of biomarkers as
surrogate endpoints to consider their development
further. And in some ways, there's been a
paralysis in development of this field related to
the statistical rigor that's been associated with
the biomarker to surrogate pathway.
Furthermore, much of the discussion of
surrogates has been fragmented into individual
therapeutic areas as opposed to an integrated
overview of the entire process. And finally,
there's been many workshops that I think have set
unreasonable expectations for biomarkers and
surrogates.
But putting surrogates aside, I think we
need to refocus again and enhance the integration
and use of biomarkers over the entire course of
drug development as a natural path to the surrogate
endpoint goal.
So with biomarkers, I think a lot has
happened, but it does raise the question about how
things can be improved. For example, have we been
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settling for less in the biomarker area? We think
biomarkers are extremely relevant to efficacy and
safety, aside from them being surrogates or not.
We don't need surrogate markers to gain the full
impact of biomarkers. Just in the past couple of
months, we've had many examples of this, and only
using one of those, the Iressa story. EGFR
mutations and tumor tissues have been reported to
predict a response in eight of nine so-called
responders.
Another question is can we more fully work
up biomarkers from discovery to clinical outcomes
than we currently do? One of the goals of
biomarker development is to begin to reduce, over
the course of time from discovery to clinical
outcome, the uncertainty in what I'll call that
gray zone between preclinical biomarker discovery
and phase three clinical outcomes. By bridging
those two areas, by bridging them in a clinical
pharmacology/biostatistical context, it would seem
that the process would more naturally lead to
acceptable surrogate endpoints, instead of thinking
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of it as a one-step process of going from a
biomarker to a surrogate endpoint.
You're all familiar, I believe, with the
critical path. It's a call to action. The
critical path calls for a collaboration between
academic, industry, patient groups to work with FDA
to help identify opportunities, to modernize the
tools for speeding and making drug development more
efficient and more successful.
The biomarker vision is expressed in that
document. It talks about adopting a new biomarker
or surrogate endpoint for effectiveness that can
drive clinical development, and it gives an example
of the well-known case of CD4 and viral load that
were used as surrogate markers for anti-HIV drug
approvals in the early nineties and from that point
forward.
It talks about the biomarker challenge:
additional biomarkers, which we can think of as
quantitative measures of biological effects that
really link mechanism of action, i.e., preclinical
biomarkers and clinical effectiveness or outcomes,
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and additional surrogate endpoints are needed to
guide product development.
So the document, I think, has laid out the
problem. It's laid out a vision. It's laid out a
challenge. And the question that we're here to
sort of begin to discuss is what do we do next.
And what we do next is very important, I think. We
need a new construct. We need to break the pattern
of the past. I think we need to go down a
different path, with two objectives in mind.
The first objective: can we achieve a
general, agreeable conceptual framework to
continuously reduce the uncertainty associated with
biomarkers over the course of the entire drug
development process: what is that systematic path?
Can we define it in a general way that is not
disease-specific, that is not biomarker-specific
but can be applied to many therapeutic areas?
We're seeing with genomics an increase in
disease progression knowledge. We're seeing that
there's benefit from systematically aggregating
knowledge using modeling and simulation,
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quantitative methods. We've seen that there are
increasing ways of establishing the predictive
nature of biomarkers. We talked about some of that
yesterday when we visited the markers associated
with predicting irinotecan toxicity. And there's a
lot of initiatives that relate to the standards for
biomarker performance. So taken together, these
individual initiatives, I think, bode well for a
general conceptual framework.
The second goal of this initiative would
be to better articulate the standards or
specifications to validate and accept biomarkers
for their intended use, including surrogates for
registration and any extension of those surrogates
for additional applications, for example, in other
drug classes. So it's a twofold goal that I think
we want to strive for in the context of this
initiative.
Now, we're not starting from scratch with
this initiative. The agency has taken steps and
intends to take many steps that move us along this
path, and many of these are hinted at in the
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critical path. We've already implemented the end
of phase 2-A meeting, and we plan to have a
guidance out in 2005. We've invested in resources
at the FDA and are developing a new branch of
pharmacometrics to focus on quantitative methods in
the IND period.
We've begun to develop drug-disease state
models, disease progression models in several
therapeutic areas. We've articulated, and Dr.
Stanski has articulated in front of the Science
Board, a very clear stepwise framework for
model-based drug development. We intend to conduct
an inventory of surrogate markers and look at the
evidence, whether it's epidemiological,
pathophysiology, therapeutic or other supporting
evidence, that allowed them to become surrogate
markers, so that we can learn from our current
situation.
We intend to establish an FDA working
group on this topic, with the goal of moving those
two objectives that I mentioned forward. The
working group itself will explore the development
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of a potential guidance on biomarkers. And we've
initiated this discussion with the Clin Pharm
Subcommittee today.
The critical path document and some of the
presentations today will also reflect upon an
express goal to develop a new form of
FDA-industry-academic collaborations for critical
path opportunities, and some of these are being
discussed as we meet today.
From the industry side, steps taken or to
be taken, I can't really speak to that. But there
are many other examples of consortia of
collaborations that have been successful. And I'm
going to use one of them. There's another one I
could have used; it's in the current issue of
Nature Reviews Oncology that talks about a vision
for the development of biomarkers in oncology drug
development.
But this is one that comes from industry,
and it was provided to me by Chris Webster, who is
associated with the PhRMA Biomarker Working Group,
and it was very appealing as a model for a
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consortium, and it's the Semiconductor Research
Corporation. Very briefly, this is a nonprofit,
precompetitive academic-industry-government
consortium, which is now about 20 years old.
You'll notice some parallels between this
and drug development. It was formed in the 1982
time period because of a concern about decline in
the semiconductor industry. It was geared towards,
as an industry, reliance on huge payoffs from
individual successes and isolated research across
the industry in individual companies. There was a
noted reduction in R&D funding with a limited
success in new semiconductor technology and a shift
towards short-term R&D as opposed to an investment
in long-term successes. There was a talent crisis
at the time, and there were many different
technology challenges.
The consortium came together, with
industry, academia and government, to really lead
the industry's long-term research efforts, advance
problem solving technology, integrate university
research capability across the country and now
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internationally and serve as a hub, as a catalyst
for a large global network of collaborative sites
that were charged with developing technology that
would enable the semiconductor industry. They
developed a central vision and implemented an
action plan.
It wouldn't take a lot of imagination to
see the parallels to what could be possibly the
case for the biomarker situation, and whether we
call it a biomarker consortium or a biomarker
institute, it would have at its heart the same
goals that this Semiconductor Research Corporation
had.
So the goals for the Committee and the
strategies to move forward today: we have no yes
or no questions. We have no preconceived plan as
to how we're going to move forward. We have some
general ideas. And what we're here today to
discuss is to hear your input on the science of
biomarkers, the data that would be necessary,
opportunities in this field, obstacles, whether
they be culture, process, impediments, and also,
35
any thoughts you have on collaborations. What
we're looking for is your input and help to define
a new path forward for biomarkers and surrogate
endpoints.
You're going to hear three presentations
that I think will set the stage for the discussion.
Dr. Woodcock will start off and frame the issues as
one of the principle authors of the critical path
and one of the visionaries for this field. We'll
hear from Dr. Wagner an industry perspective, and
Dr. Wagner will represent the PhRMA Biomarker
Working Group, and he has, again, been working with
the others on a very thoughtful position paper, and
we'll hear some of the principles of that today;
and then, finally, we'll hear an academic
perspective from Dr. Blaschke, who has lived
through over a decade of the biomarker surrogate
endpoint progression, starting with the AIDS
epidemic back in the early nineties and reflect on
that and advise us on some thoughts about moving
forward.
As I say, the discussion today, we'll be
36
listening to very carefully. What we hope to
develop is a foundation for a national critical
path opportunity, which the agency will begin
identifying in terms of a priority near the end of
this year. We realize that this project on
biomarkers is going to be a very ambitious one.
We're very optimistic. And of course, like any
initiative that FDA undertakes, there's always that
specter of progress dependent upon its funding, its
sustained commitment and dedicated staff for such a
project.
So we're not overpromising anything, but
we would like to begin and move forward on this
path, and I'll start by introducing Dr. Woodcock.
DR. WOODCOCK: Good morning, everyone.
I'm really delighted to be able to be here and
begin this discussion about moving the field of
biomarkers in drug development forward.
I've named my talk a framework for
biomarker and surrogate endpoint use in drug
development, because that's really what we're, I
think, discussing here, but obviously, it has much
37
broader implications if we're able to move this
forward. And I'm going to address those as well.
First, I'm going to cover--Larry already
went over the current definitions. I think there
are some self-imposed limitations in the current
definitions, and therefore, I'm going to present
them again and talk about them. Second, I want to
talk about overall the limitations, I think, of our
current conceptual and developmental framework and
the reasons which are multiple why we're not moving
forward more rapidly in this area, and by we, I
mean the biomedical research community overall.
And finally, I want to talk about what potential we
have for moving towards robust use of biomarkers in
drug development and then toward regulatory
acceptance of surrogate endpoints, which would
follow on after the robust use in drug development.
Now, in the late nineties, NIH put
together a definitions working group of which I was
a member and some other folks in this room were to
develop some terms and definitions about biomarkers
and surrogate endpoints and to have an overall
38
conceptual model. There had been a lot of thinking
that had gone into the field about how these
interact. And this was an offshoot of the
consensus conference that was held on this topic,
and this was published in a paper.
The definition the working group had for
biomarkers was that it is a characteristic that is
objectively measured and evaluated as an indicator
of normal biologic process, pathogenic process or
pharmacologic response to a therapeutic
intervention. And I don't have any quarrel with
this definition, this one.
And this is ubiquitous, I think widely
used and accepted, although there might be a few
modifications you could make on this, but in
our--in FDA's draft pharmacogenomics guidance that
we published last year, in order to set up this
structure for regulatory filing or not of
pharmacogenomic information, we had to go further
and define the pharmacogenomic tests as either
possible, probable or known valid biomarkers,
because this type of definition, then, determined
39
whether or not there would be a required regulatory
filing under the law.
And these categories were sorted based on
available scientific information on the marker and
how much confidence you would have the marker
actually represented some real outcome or real
information. And we got a lot of comments on that
to the docket for this guidance, saying that we
needed more specificity on these categories and to
define them more clearly, and we will very soon
issue the final pharmacogenomics guidance, but I
don't know if it's going to shed a whole lot more
light on these biomarker definitions. As Larry
said, that's something we need to take up in this
larger context. So those are some of the extant
definitions out there of biomarkers.
Now, the group put forth a definition of
clinical endpoint, all right? And that is a
characteristic or variable that reflects how a
patient feels, functions or survives. And this
kind of is the crux of the conceptual problem I had
with this whole area. Note, you should note, and
40
this is my editorial comment, except for survival,
all these outcome measures or variables involve
some kind of intermediary measurement. It's really
not possible to know how someone else functions or
survives; we can only measure it in some--I mean,
or feels.
And I think we can all agree with that.
We have some kind of measurement that we interpose
between that person and the numbers, and we somehow
quantify how they feel based on some kind of
measurement.
Now, you can disagree about this, and we
should talk about this later, because this is very
important, I think. But anyway, that's a clinical
endpoint. And those are given in the scheme of
things some kind of fundamental reality.
Now, surrogate endpoint, in contrast, is
defined as a biomarker that's intended to
substitute for these clinical endpoints. And the
surrogate is expected to predict clinical benefit
based on various scientific, you know, studies that
have been done. And there is a feeling about a
41
surrogate, and this is something that we need to
develop more. It actually was presented by Dr.
Rowland at the biomarkers meeting, but there is an
issue about how proximal or distal the surrogate is
to the actual clinical outcome that you're trying
to describe or quantitate and say a blood measure
might be quite far away or might be very close, and
that might be based on mechanistic pathway
proximity or it might be based on a sort of
clinical face validity, so there are a number of
different axes on these surrogate endpoints, and
I'm going to discuss that a little bit more in a
minute.
This is the definition that was put forth
by the working group, and there wasn't a lot of
dispute about this definition. Now, as we all
know, biomarkers are used in clinical medicine.
They're not simply used in drug development. And
that is kind of the larger issue here. They're
used in diagnosis, as a tool for staging disease,
an indicator of disease status and to predict and
monitor clinical response.
42
And I see Rick Pazdur today, who's the
head of our oncology group. He knows very well,
often, the clinical use gets well ahead of the drug
development use. And that's because the clinical
use may be based on, you know, there's less--you
can simply adopt a biomarker and use it without
having an organized set of data and evidence that
you base that adoption on. So sometimes,
biomarkers will be taken up and used in clinical
medicine, at the same time not being used for their
corollary use in regulation or in drug development.
But because biomarkers are critical to
clinical medicine, to the diagnostic tests of the
future, there's more at stake here in this
discussion, in this overall initiative that we're
having than just efficient drug development, and
this can't be stressed enough, especially to the
outside stakeholders. Biomarkers really are the
foundation of evidence-based medicine, because it
is those types of tests that determine who should
be treated, how they should be treated, and what
they should be treated with.
43
And so, those quantitative measurements,
diagnosis should go before treatment, and yet, for
many of our treatments, we have very few
discriminatory markers that we apply. Absent new
markers, our advances in targeting therapy, either
in the traditional ways, which would be according
to drug metabolism and other standard markers, or
in new ways will be limited, and to the extent that
we can't or don't adopt these markers and use them
in drug development, treatment will remain
empirical.
So it's imperative for good medicine as
well as cost-effective medicine that biomarker
development be accelerated along with the
development of new therapeutics.
Now, here, just to get people's minds
around this, many of you in the room are experts in
this, but many may not. According to the NIH
definition I just talked about in biomarkers, these
types of measurements would be considered
biomarkers of different kinds. So it isn't just a
blood test. It can be all sorts of imaging
44
technologies or bone densitometry, all sorts of
things. Even an APGAR score is a kind of
biomarker. It's a way of quantifying certain
observations on a newborn.
Now, as opposed to use in medicine,
biomarkers are also used in drug development in a
decision making capacity to try to assess and
evaluate the performance of candidate treatments.
Where we have very good biomarkers, we can have
extremely efficient drug development, because the
performance of candidate therapies can be assessed
in animal models. And by the time we get into
humans, we have a very good idea of the
performance, a very good predictive idea of the
performance of the treatment.
The biomarkers can also be used to bridge
animal and human pharmacology and pharmacologic
effects of therapies by doing proof of mechanism.
And again, I'm stressing here the early acquisition
of information about the safety and effectiveness
of the therapy and bridging the animal knowledge
and the human knowledge.
45
There are safety biomarkers, and most of
those are 50 years old. I will tell you that the
markers we're using in the animal safety evaluation
in general and the human safety evaluation are
truly venerable, and they're tried and true, okay,
but they do not incorporate modern knowledge there.
They're largely empirically based, and they have
reasonable predictive value for major organ system
failure and not very good predictive value for
mechanistic understanding of the safety problem or
predicting more rare types of safety outcomes in
the same organ system. So there are problems with
that.
But the biomarkers, to the extent we have
them, can be used to evaluate human safety and
early development; hopefully predict safety
performance of drugs early.
And right now, we use serum chemistries.
We don't use cell surface protein expression very
much. That would be a target for the drug
intervention. Sometimes, that's used. Drug
pharmacokinetics over the last 15 years due to Dr.
46
Sheiner's efforts and many others, many in this
room, these types of measurements have become much
more standardized within drug development and have
tremendously contributed to our understanding of
drugs.
Serum transaminases and other safety
markers have been used forever. Genomic expression
profiles are used very, very rarely right now, and
imaging is, in specific fields, such as
neuropsychiatric disorders is being used widely,
the biomarker of imaging, but its utility is still
not clear, I think is fair.
In later drug development, this is where
the rubber really starts hitting the road as far as
cost of patient and so forth, and the stakes start
really rising. If you have good biomarkers to do
your dose-response work and develop optimal
regimens, it's extremely helpful before getting in
phase three to have a very good idea. Safety
markers to determine dose-response for toxicity, we
aren't as good there and determine the role, if
any, on differences in metabolism on the above
47
dose-response, and this isn't done as widely--is
that fair, Larry, to say--as it probably would be
optimal to do, for a variety of reasons.
Now, here's where we start getting some
probability areas for dispute or discussion.
Biomarkers used in later clinical development: I
would--psychometric testing or psychometric scales
or whatever are used as clinical outcome measures
in trials of psychiatric disorders. I would argue
to you that's as much of a surrogate as an HIV
viral copy number.
It's just we're used to this, so we don't
think of it as a surrogate. We've used it a lot,
and we're comfortable with it. But we don't know
that it represents a cure or a mitigation,
necessarily, in an individual patient. A lot of
work has gone on, and I think we have great
confidence that the testing and outcome measures
that are done for psychiatric diseases actually
reflect efficacy of the drug and have tremendous
utility in the approval of psychiatric drugs;
however, I don't think people recognize that this
48
is as much of a surrogate as many other types of
surrogate markers that have been discussed.
Pain scale is another thing: I mean, you
can't feel another person's scale of pain. We have
constructed different measures, metrics, and they
have been run through the psychometric testing
algorithm to look at their construct validity and
so forth and so on, and we know their performance
pretty well. But they are surrogates for actual
pain.
Imaging can be done; culture status is
obviously a very important marker, not necessarily
a surrogate for antimicrobials; pulmonary function
tests, serum chemistries, electrocardiogram. And I
think what's striking about many of these is they
are very traditional. They've been used in
clinical medicine a very long time.
Now, what about surrogate endpoints that
substitute for the clinical outcome measure? Well,
obviously, there are surrogates for efficacy that
can be used to assess whether a drug has clinically
significant efficacy, and there are surrogates for
49
safety. And basically, our entire drug development
program and the exposure of patients is, in some
way, a surrogate for the real world safety, because
that's what we're really concerned about is how the
drug will perform when it's marketed and out there
in the real world as far as safety goes, so the
entire development program and the patient exposure
experience and the way we look at that is used to
predict safety.
Right now, known surrogate endpoints and
points that are used include blood pressure,
interocular pressure for glaucoma, hemoglobin A1C;
as I've already said, psychometric testing; tumor
shrinkage for cancer, and there's criteria,
performance criteria around all of these. For
rheumatoid arthritis, the clinical endpoints used
in trials are the American College of Rheumatology
criteria that were worked through by the
rheumatologists with great effort, and then, pain
scales are used for pain.
Now, what I want to turn to after giving
sort of an introduction is what I consider
50
limitations of the current conceptual and
developmental framework for biomarkers and
surrogate markers. And the reason I want to do
this is because I think we have to start there in
rethinking, as Larry said, if we're going to put a
consortium together, if we're going to try and work
on new biomarkers, we all have to be on the same
page conceptually about what we're trying to
accomplish and what are the issues.
I think most people would agree that
biomarkers represent a bridge in many cases between
a mechanistic understanding that has been gained in
preclinical development or in actual basic science,
and what is largely now the empirical clinical
evaluation, and the goal is to bring the
mechanistic understanding more forward into the
clinical evaluation to make it more predictable,
both on safety and effectiveness. And the
hypothesis is we can use biomarkers to do that if
we understand their performance adequately.
Now, because of history, we didn't have
the science in the past, and as regulators and the
51
regulatory system has been focused on empirical
clinical testing. And there are tremendous
limitations to that, but that is the best we have
had. And that has really, though, we have that
historical momentum that is continuing to skew our
approach to the clinical, the human evaluation of
drugs to sort of an all-empirical.
And what do I mean by that? Well, you
just expose them, and you see what happens. You
randomize people, and then, you count whatever you
count at the end of the day, and that's basically
empirical drug development, and that's one of the
reasons it's so expensive and timely and risky, is
because there's a tremendous amount of failure in
this approach, and we don't gain as much knowledge.
This is not a highly informative approach, either.
And of course, the FDA is constantly criticized for
drugs that are on the market postmarketing that we
don't have as much information as would be
desirable about those drugs.
I think all of us in this room know,
nevertheless, how expensive, time consuming and
52
what incredible effort current clinical drug
development is, but this is contrasted with the
fact that at the end of it, we don't know that
much. And we should have a discussion about this
afterwards. That's true. We really don't know
that much at the end of current drug development.
And as a result of this being skewed
toward a more empirical approach, the early
mechanistic clinical evaluation has often been
lacking. And I think Larry can speak to that, our
end of phase 2-A meetings are speaking to that.
There really hasn't been that focus. And this
isn't to blame anyone; the reason we haven't
focused on that in the past is we have not had the
tools to do this, and the question is is now the
time where we are developing these tools, and
should we put a lot of effort into this to develop
those tools, and do we have enough scientific
knowledge to actually make the process a lot more
predictable? And I would say the answer is yes.
But I would say as a result of the
history, the business model for biomarker
53
development is lacking. There was just an article
in Biosentry magazine about this, I think, last
week, about companies who have been trying to get
into the biomarker business, and they say there's
really not that much interest or a model for how
they can move forward and develop these biomarkers
and have them used in drug development. And we've
heard this; I have heard this ubiquitously over the
past six months as I have been going around talking
to people about the critical path.
So a consequence of this that anyone can
easily observe looking at the literature is there
has been no rigorous pursuit of the evidence that
would be needed to qualify a marker, really
assemble the evidence on its performance or to
assemble that evidence at a level where you get
regulatory approval of that marker. That doesn't
happen that much, and there are a tremendous number
of markers out there, and we know very little about
their performance in a rigorous way. And the
exploration of their clinical relevance is
generally ad hoc; it's pursued in an academic
54
manner.
However, I think there's an urgent need to
overcome these obstacles I have just discussed. We
have new opportunities to link biomarker
development to the drug development process,
particularly with a newer genomic proteomic imaging
and other types of markers that have been developed
and with the kind of quantitative modeling that we
can now do.
This requires, though, a clear regulatory
framework, a signal to be sent from the regulators,
I think, of what kind of technical evaluation is
required. And within our pharmacogenomics effort,
we're getting a lot of questions. I think that's
probably one of the major questions that is sent to
us, which is what kind of information has to be
sent to the agency at different stages of
development?
But the need also is to develop some new
business models that are viable, because someone
has to develop these tests: either the drug
developers, device developers, someone has to
55
develop these tests. They can't just be an
academic tool if we're going to use them in this
manner.
Now, I'd like to turn to surrogate
endpoints. And I gave a definition previously
about surrogate endpoints, how they stand in for
clinical outcomes or clinical endpoints. As most
of you know, the current model for use of a
surrogate endpoint is based largely on
cardiovascular and HIV experiences in the 1990s and
sort of the analysis that went on around those
experiences.
The cardiac arrhythmia suppression trial
that was performed in, I think, sometime in the
1990s was done because of widespread use of
antiarrhythmic agents to suppress the ventricular
premature beats post-MI based on the hypothesis
that that would decrease the incidence of sudden
death in that population, because they're at risk
for sudden death, and the surrogate there was the
suppression of VPBs.
What happened when the arms of the trial
56
were unblinded is the mortality was increased in
the treatment arms of this trial. And that was
quite a shock to folks, probably akin to what
happened when they unblinded or they looked at the
postmenopausal estrogen treatment a year or so ago
and found that myocardial infarction was increased
in the treated arms.
This caused some--the cast outcome caused
a lot of skepticism, particularly in the
cardiovascular community, about our ability to rely
on surrogates. This is despite the fact that there
was a fair amount of evidence, I think, if you're
sort of impartial about this, a fair amount of
evidence that certain types of antiarrhythmic
agents can cause sudden death as well as certain
kind of antidepressant agents and everything that
have certain electrocardiographic properties and so
forth.
Nevertheless, this cast outcome was a real
shock. It kind of cast a pall over the adoption of
surrogate area. And the whole discussion about
this effort and everything can be seen in the
57
reference I have here by Bob Temple, who wrote up
in the midnineties some of the experiences that FDA
had encountered around surrogates.
Now, then, we had the HIV epidemic in the
nineties, late eighties, nineties, and there was
again discussion, there was discussion of the use
of surrogate endpoints in this disorder; first,
CD-4 counts, which were obviously not really on the
mechanistic chain as much as some other endpoints,
and as a result of this whole discussion, some
rigorous statistical criteria for assessing the
correlation of the candidate surrogate with the
clinical outcome were published have a reference
here they're called the Prentiss criteria, and it
really called upon a surrogate to really encompass
all the qualities of the clinical outcome, so you
wouldn't learn any new information, basically, if
you substituted the clinical outcome for the
surrogate.
This is probably impossible, and no
surrogate endpoint that is currently adopted has
met these criteria. But again, this has caused
58
concern for people about what do you need to do,
and is this a reasonable criterion? It is a good
postulate of the problem, okay? And it frames the
problem very well, and there are a lot of other
articles which I could provide to people if you're
interested by statisticians, discussing various
performance characteristics of surrogates and the
way you can be misled about surrogates.
But nevertheless, the outcome of this was
that HIV RNA copy number was used as an early drug
development tool. It's now used as a surrogate
endpoint in trials, and it's used for clinical
monitoring and antiviral therapy. There is a lack
of complete correlation of this outcome measure
with clinical outcomes, but my point is this does
not compromise the utility of this measurement for
its use in drug development or in monitoring
patients. And the point is that all of our
measurements are uncertain; there is some
uncertainty and lack of full information associated
with any measurement you might make on any person.
So there has been successful development
59
of antiretrovirals and control of HIV infections,
despite the fact that this particular surrogate RNA
copy number is not perfect and certainly misses
certain parts of the outcome for any given drug.
But I want to move now to what I think is
a more fundamental problem and has been a block in
our discussion, and I alluded to this earlier, and
as I said, people may disagree with my assessment
of this, but as a clinician, I would say there is
no gold standard in clinical outcome measurement.
People always argue with this, and they say
survival. Survival is an absolute.
And I will tell you if you look at the
data, say, of John Wendburg and folks who developed
that about what people would choose, would they
choose longer life? Would they choose better
quality of life? There are many people who would
prefer to live a shorter amount of time if their
longer life would--if they would have to trade off
a very poor quality of life for that prolonged
life.
So any measurement does not always capture
60
all the domains of interest for a patient; even
survival. Now, I realize that's a strong
statement, but obviously, if you survive sepsis or
MI or something, you're left with no sequelae,
you'd much rather be alive, and in those cases,
that's a pretty good sequela.
But the generalizability of any single
outcome measure can also be limited by the trial
parameters. So we aren't really getting to full
truth in a trial, even with a survival endpoint.
As a rheumatologist, I'm very well aware of this
because the rheumatologic diseases generally do not
have a single dimension outcome, and capturing just
one, capturing simply pain or function or whatever
is not adequate for fully describing impact on the
disease.
And therefore, many clinical outcomes and
many diseases are multidimensional, and any single
outcome measure we use may miss domains of
interest. That doesn't mean we should throw up our
hands. We should simply be aware of this, that
there is no single gold standard that we're
61
comparing anything to.
In addition, and this is something the
Prentiss criteria were talking about, because they
were looking at survival, and survival can be
diminished, obviously, by harm as well as prolonged
by treatment effect, but in general, it's very
difficult to capture both benefit and harm within a
single measure. And we don't even attempt to do
that within drug development. We're assembling
information from a wide variety of sources, so that
the concept of ultimate clinical outcome is very
elusive. There's always a longer duration, say,
for chronic disease. You could always follow
people longer. The definition of what is ultimate
is very unclear.
And so, I think we need to move away from
the idea, and maybe I'm beating a dead horse here,
that there's one single piece of knowledge that
everything has to be correlated to. That's just
really not how human beings and disease are. And
knowledge about various dimensions can be acquired
outside of a biomarker or surrogate measurement.
62
We don't have to put all our weight on a single
surrogate measurement.
In addition, and this is becoming very
important in this, I hope, new world of more
individualization of therapy, the per patient view
of outcomes is very different than population mean
view of outcomes. If you are the person who
experience an adverse effect from a drug, the
surrogate means nothing to you, the efficacy
surrogate, because something really bad happened to
you.
And where we have the ability now to more
individualize therapy through biomarkers, either
through pharmacogenomic, genetic testing for
metabolism, enzyme metabolism, where more
sophisticated measures of determining who stands to
benefit from a therapy or who is at high risk for
an adverse event for a therapy, this becomes very
important. So newer and older biomarkers do
provide information at the individual level. And
that's very important.
For the reasons I've just gone over, then,
63
I think our conceptual model should view drug
development more as progressive reduction of
uncertainty about the effects or, if you're the
glass half full type, increasing the level of
confidence about the correlation between treatment
and outcomes, not a single, binary measurement of
the drug is effective, it isn't effective; there
are safety problems; there are not safety problems.
We have to be dealing with, in other words, a
multidimensional set of information, not a binary
decision.
Now, I recognize that the regulatory
decision has this binary quality about it. And I
think what I'm telling you is that you should
suppress the science into a binary box. That's not
the right way to go about this. The regulators
have to figure out when that evidence is enough
separate from the way the evidence is developed and
understood.
So no single measurement contributes all
knowledge, and even if we get to the, you know, the
star--what is that Star Trek, where they wave that
64
thing over people, and they get--they probably got
a series of measurements. They weren't just doing
one measurement with their magic wand. And
population mean findings may not be valid for any
given individual. And that's a very powerful
statement, I think, as far as the fact that this
anyone surrogate measure may not really predict for
a given person a correct outcome.
So in the future, I think we need to move
to more composite outcome measurements, more of a
multidimensional understanding. And I realize--I
mean, this is the Clinical Pharmacology
Subcommittee; I'm preaching to the converted here.
These folks have understood this for a very long
time. However, we need to move this into the
general understanding of drug development and
therapeutics.
This means probably in general, as we move
forward, we need to be looking at responder
analyses and so forth and looking at the data in a
more careful way rather than population mean
analysis. And we also need to be moving towards
65
individualized therapy.
Now, we would expect, and this is kind of
the quid pro quo here, with these evaluations, we
also are going to have to see a larger treatment
effect to provide some face validity here, if you
follow me. But you would expect that if we were
able to predict who is able to respond to drugs and
sort out who is at risk for adverse effects. We
should be seeing larger treatment effects, and in
fact, we are for some of these therapies as they're
moving forward.
A basic problem in a lot of drug
development is the drugs don't work very well,
because they are--a lot of people who are exposed
don't stand to benefit from the drug and aren't
going to benefit. But our empirical method of drug
development causes these apparent, very small
treatment effects.
Now, what should we do? What do I think
we should do? And I think Larry laid out kind of
the spectrum of probabilities or possibilities
pretty well. What I would like to stress is
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biomarkers have to be used to be accepted. We have
lots of surrogate measures that we use in clinical
trials and regulatory, I believe. I believe a lot
of the things we use are surrogate markers. We
just are so used to them, we don't think they're
surrogate markers.
But what part of understanding the
performance of these newer technologies is to use
them, to see how they move with treatment or how
they fail to move with successful intervention, to
see how they perform in various populations and
with a wide variety of drug interventions? With
that kind of knowledge, that's the kind of robust
knowledge we need, then, to have both regulatory
acceptance and, then, wider acceptance in clinical
medicine.
The barrier to this up to this point has
been the add-on costs, and there have been many
barriers, but a major barrier is the add-on cost in
clinical trials. And I've talked to the imagers
about this. Nobody wants to put an imaging arm in
the trial if it's experimental, because it's going
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to cost a lot of money, and not only could it not
be used to support approval, but it might show
things that are new and unknown. And there is
concern that these biomarkers will, and they have,
actually, segregate out the people who are most
likely to respond and thus narrow the target
population intended for that investigational drug.
There's also concern that questions, new
information would be found by these biomarkers;
questions would be raised by the regulators, and
that would slow the regulatory acceptance and
approval of the therapy.
And, you know, we all have to get over
this together, because otherwise, the use of
biomarkers in trials will not occur. And that's
what has to happen for us all to start
understanding these.
Now, as Larry said, to bring all this
about is going to require some kind of
collaborative effort between government, academia
and industry and probably not just the
pharmaceutical industry but diagnostic side of
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industry as well. And we're going to have to
focus.
So I just said this: the diagnostic and
imaging industry sector needs to be fully engaged
in this effort. So it's going to require a lot of
parties. And FDA must provide the regulatory
framework and some reassurance as we move forward
that individuals and firms are not going to be
punished for this, so to speak. And the
pharmacogenomic guidance that we published the
draft last year is an example of that. It provides
a space, an experimental space, where those tests
can be done without the fear of all these
regulatory consequences occurring and where the
information can be shared.
Now, development of new biomarkers, you
know, new biomarkers are going to revolutionize
probably both the development and use of
therapeutics and preventatives. But as I said, it
requires commercial development of the biomarker
technology. Academia's role, I think, is to
identify these technologies, put them forward and
69
assist in their evaluation. But they have to be
commercially developed, and we need regulatory
pathways for the pair, the therapeutic intervention
as well as the biomarker, and that's what we've
tried to lay out for pharmacogenomics, but there
are many other types of technologies that we also
need to have the same pathway made available.
Now, for surrogate endpoints, I think we
need further exploration and discussion of some of
the ideas that I put forth today, and this is sort
of the kickoff, but we're going to have to have
more discussions of this. I could be dead wrong.
I don't think so, but we need to talk about it. I
think we need to get rid of the idea of validation,
and Gerry Migliaccio is here, and we've gone
through this in the last two years for the GMP
initiative.
Validation is a term that, unfortunately,
often conveys an idea of much more assurance and
rigor than is actually attached to the activity,
and we need to use more descriptive terms that
everybody understands what is required or what the
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activity actually is, so I think validation is a
bad word to use in this context, because it doesn't
convey any information.
And we may need to adopt new nomenclature
overall around surrogates or perhaps refine the
nomenclature. We need more emphasis on the fact
that our understanding of disease and disease
interventions is multidimensional. It's not a
single dimension. And I think we need greater
emphasis on safety biomarkers, because safety
problems, obviously, are very prominent in the
news. They're also a tremendous source of loss of
compounds within drug development; maybe compounds
that would be very good and for 99 percent of the
people would actually benefit them and their
disease.
So, we need to replace, I think, the idea
of validation with something about degree of
certainty or progressive reduction in uncertainty
or some concept like that that is more graded. The
problem with validation is it's, like, you're
validated; you're not validated. It isn't like
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that. And we have to recognize and remember that
the usefulness of any surrogate will be disease,
context, and to some extent, intervention-specific.
And that's why one of the dimensions that needs to
be investigated for any surrogate is
generalizability across product classes, across
patient populations, across stages of disease or
what have you. That's why these have to be used in
trials. We can't just have them out there in
papers.
We need to develop a framework for
understanding the usefulness of a surrogate as
evidence, used as part of the evidence that's
submitted to the FDA for approval of a drug or
safety in a context-specific manner.
So in summary--it looks like I'm right on
time here--there's an important public health need,
I think we can all agree, but we need to get this
message out, so that people understand why this is
important. I don't think the general world
understands what's at stake here. There's a need
for the development of additional biomarkers to
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target and monitor therapy.
To do this basically is going to require
that they be used in clinical trials during
development and postmarketing trials as well. The
business model, in other words, who is going to pay
for this, how this is going to happen, and the
regulatory path for such markers is not clear to
industry. And we need both clarification, in other
words, what is the path forward, the technical,
scientific path, as well as some probably stimulus
is needed as well in the economic sense.
There have been definitions. Larry and I
both alluded to those for these various terms. But
I think further development of the model is needed
to get it to a higher level of sophistication in
order to increase the use and utility of markers in
development and enable us all to talk to one
another and know what we're talking about. I think
this further development has to recognize the fact
that single measurements will rarely capture all
dimensions of the clinical outcome for any patient.
So I think that a multidimensional and
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continuous model needs to replace the current model
that we're using for clinical effect, and that's
critical for the targeted therapy of the future,
because this will be multifactorial as far as for
any individual patient, whatever their metabolizer
status or whatever it might be that the state of
elaboration of various proteins, receptor proteins
on their tumor cells, whatever it might be, these
factors will influence their response to therapy,
and many of these factors will not be binary
themselves. You would not elaborate receptors on
your tumor or not; it's going to be a gradation.
FDA is considering development of these
concepts, as Larry said, as part of our critical
path initiative, and this initiative, if we take
this part up, would include a process for refining
the general framework as well as individual
projects on biomarker and surrogate marker endpoint
development, because at the end of the day, the
surrogates in particular are going to be, as I
said, disease specific.
So I look forward to the discussion, and I
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hope that this will lead to really something
getting started in this area. Thank you.
DR. VENITZ: Thank you, Dr. Woodcock. Any
quick questions or comments by the Committee
members?
DR. SINGPURWALLA: Yes. I do have a
comment. First is I find myself agreeing with much
of what you say. Sometimes, I wonder if you're a
doctor or an engineer.
[Laughter.]
DR. SINGPURWALLA: But the problems you've
described are very isomorphic to the problem that
engineers have found, and I'll give you two
examples of what you said: one of your slides
talked about validation, and you said that you
shouldn't have something which is either validated
or not. There's got to be some degree of
uncertainty.
There is a body of knowledge called vague
sets or imprecise sets where the boundary of the
set is not well-defined, and you say there is a
certain degree of membership in that set. It goes
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under an ugly name called fuzzy sets, which the
President sometimes uses.
[Laughter.]
DR. SINGPURWALLA: But I would strongly
encourage you to look into that literature.
Now, as far as the markers are concerned,
the problem again that you are facing is similar to
what engineers face with, say, aircraft structures.
The aircraft structure is degrading, and what they
see is a crack. And they monitor the crack; they
study the crack, and based on the growth of the
crack, they predict the performance of the
aircraft. So there is a large industry which looks
at that. You may want to take advantage of that.
And the correct way to model these things
is through stochastic processes, and these are
bivariate stochastic processes, and that would be
the direction in which you may want to go. One
process is observed; the other process is
unobserved. It's the unobserved process you're
interested in, and the observed process gives you a
clue. So at least I'm telling you that there is
76
some parallel paradigm that you may want to
consider. I strongly encourage you to look into
this.
Thank you.
DR. WOODCOCK: Thank you. I think what we
found in our recently-completed GMP initiative is
that bringing in the engineers and various
other--multidisciplinary look to some of these
problems we're facing provides tremendous power,
because people have faced these problems in other
fields.
DR. VENITZ: Any other comments or
questions?
[No response.]
DR. VENITZ: Then, thank you again.
And our next speaker is going to be Dr.
Wagner, and he's going to give us the industry
perspective on surrogate markers.
DR. WAGNER: Great. So, thanks very much
to the Committee for the invitation to and the
opportunity to discuss a little bit of the industry
perspective on biomarkers and surrogate endpoints.
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And we've been giving quite a bit of thought to
this. I represent PhRMA in this case, and in
particular, the PhRMA Biomarker and Genomics
Working Groups, and my colleagues Steve Williams at
Pfizer and Chris Webster have been very large
co-conspirators in this particular effort. And I
represent, actually, a very large group that is
noted at the very end of the slide.
So I want to step through a couple of
different areas. I want to talk really about what
our objectives and focus is right now, a little bit
about biomarker nomenclature, which Dr. Woodcock
and Dr. Lesko have already covered to some extent,
and then talk about the idea of qualifying
biomarkers as surrogate endpoints and the idea of
it's not--very much along the lines of what Dr.
Woodcock said, it's not really a binary process;
it's actually a continuous process of increasing
certainty and then end with some thoughts, some of
our thoughts on collaboration.
So, there's not a laser pointer, I guess.
That's okay. The landscape, I think we all agree,
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is one that Dr. Woodcock already highlighted, that
there's really a much more intense focus on
biomarkers as aids for decision making in drug
development and the regulatory evaluation of new
drugs. And our objectives within the PhRMA
Biomarker Working Group is really to work towards
an improved framework for regulatory decision
making, regulatory adoption of new biomarkers to
work towards a refined nomenclature that will
enhance the discussion and also to work on an
optimized business model for biomarker research;
again, something--these three things are really
very important necessities in moving biomarker
science and use in drug development along.
So our focus has been on the process, the
process to select suitable biomarkers for potential
regulatory purposes, to define what research is
needed for qualification and regulatory use, to
execute that research in a cost-effective manner
and to review the results and agree on whether a
particular biomarker meets the needs.
So I also would like to go back to the
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FDA/NIH consensus conference in 1990--oh, thank you
very much--and I won't dwell on this, but before
that consensus conference, there really was, well,
there was a lack of consensus. There
was--biomarkers were--the term biomarkers were
bandied about in a very casual way, and there was
really no consensus on what folks were talking
about. And the real seminal contribution to that
FDA/NIH consensus conference was was this
definition that Dr. Lesko and Dr. Woodcock already
read--I won't repeat it--for biomarker and
surrogate endpoint?
And it's really served as the groundwork
for all the efforts that have come since then,
because there really was a far-reaching agreement.
We've done that; now, we can move on to some of the
refinements that are really necessary to the next
stage. And that's been part of the thinking over
the last five years or since that consensus
conference, and that's where we're going to go in
the future.
But I think that we all agree that--or at
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least Dr. Lesko and Dr. Woodcock agree that the
biomarker and surrogate endpoint distinction is
really not optimal for use of biomarkers in drug
development, and there's a couple of guidances that
really highlight that. One is, as has already been
highlighted, that the exposure response guidance
really makes a distinction based on the evidentiary
status of biomarkers going from valid surrogates
for clinical benefit to really remote from a
clinical benefit endpoint.
And then, also, in the pharmacogenomic
data submission draft guidance, there's really a
further--that point is really drummed home even
further, that there is a further distinction based
on the evidentiary status of dividing biomarkers
into probable valid biomarkers and known valid
biomarkers, and that really leads into this idea of
qualifying biomarkers in a way that makes them fit
for the purpose that you intend to use them for.
I also don't like the term validation,
maybe for not quite the same reasons as Dr.
Woodcock, but I don't like the term clinical
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validation, which is often used in the literature,
because this process, I believe, has just as much
to do with biology as it has to do with clinical
outcomes. In the FDA/NIH consensus conference, the
term evaluation was used for the process of
qualifying biomarkers. That's probably okay, too,
but we've settled on a term of qualification; it's
really distinct from validation and captures, we
believe, the idea of a graded process that leads to
the right purpose for the use of the biomarker.
So we have sort of a simple working
definition here, an evidentiary process that links
a biomarker both with biology and with clinical
endpoints. The purpose here, after all, is really
to provide reliable biomarker data that's both
scientific and clinically meaningful, and in the
context that it's being used in.
In these remarks, my focus is very much on
disease-related biomarkers that are intended as
indicators in one way or another of clinical
outcomes. There's, of course, a great deal of
interest in all sorts of other biomarkers,
82
particularly pharmacodynamic biomarkers or
mechanism-related biomarkers, but I think that the
need for the regulatory scrutiny on those sorts of
biomarkers is a little bit less than the
disease-related biomarkers, because really, you
know, the--how we approach the evidence to how hard
a particular therapy is hitting a target is a
little more clear-cut than some of the issues that
relate to qualifying a disease-related biomarker.
So my remarks are a bit more restricted to these
disease-related biomarkers.
And then, the last point I want to make on
this slide is that this fit for purpose biomarker
qualification really is a graded with the accent on
graded evidentiary process of linking the biomarker
with biology and clinical endpoints, and it depends
on the intended application. So this is the
universe of biomarkers that came out of the
consensus conference, biomarkers versus surrogate
endpoints, and I think we can agree that it could
be more useful to provide a little bit more
granularity.
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And one proposal that we've been exploring
is to fill in this spectrum of biomarkers with
graded levels of evidence, stretching from
exploration through demonstration through
characterization and finally through surrogacy.
So, an exploration biomarker would be a biomarker
which is really a research and development tool. A
demonstration biomarker, then, would, in this
proposal, would correspond to a probable valid
biomarker, and a characterization biomarker would
correspond to a known biomarker, and surrogacy has
the same meaning: a surrogate endpoint, a
biomarker that can substitute for a clinical
endpoint.
So just to put a little bit more detail on
there, it is not a lot of detail, because these
really are draft concepts, but an exploration
biomarker, then, again, is a research and
development tool. It's not that there's no
evidence. We wouldn't use a biomarker that had no
evidence associated with it. There wouldn't be any
sense in it. But the evidence is largely
84
restricted to in vitro or clinical evidence, and
there really is no consistent information that
links with clinical outcomes in humans.
A demonstration biomarker, then, one step
up in evidence, again, corresponding to a probable
valid biomarker is something with adequate
preclinical sensitivity and specificity and some
links to clinical outcomes but not really
reproducibly demonstrated or reliably demonstrated
or robustly demonstrated. A characterization
biomarker, again, corresponds to a known valid
biomarker, and this is one, again, that has the
adequate preclinical data associated with it and is
more reproducibly linked with outcomes through one
or more adequately-controlled clinical studies.
And then, surrogacy is, again, has the
same meaning as the NIH consensus conference, a
biomarker that can substitute for a clinical
endpoint. And the evidence, the details of how
that biomarker becomes a surrogate endpoint are
still very much a matter lacking in consensus. You
know, some of the thoughts that we've talked about
85
are having an association and treatment effects
across studies or times to events within studies;
you know, there's other ways to couch the evidence
that leads to surrogacy, and as I said, there's by
no means any consensus there.
So just to give a little bit of a couple
examples of where various biomarkers would fit in
this kind of a scheme, exploration biomarkers
really are only limited by the imagination and the
state of the evidence that exists scientifically.
There's numerous examples. A demonstration
biomarker could be something like adiponectin,
which is a P-par gamma agonist biomarker.
Adiponectin levels increase at P-par gamma
treatment, and they're associated with insulin
sensitization, but the tie to insulin sensitization
is far from perfect. There's also intriguing
associations with cardiovascular outcomes with
adiponectin, but the level of evidence is far from
perfect.
So this is a biomarker that I would at
least put into the demonstration bucket: do we
86
need it as a surrogate endpoint? I don't know; but
it's a very intriguing biomarker, especially for
P-par gamma agents, and in particular, because its
response is very rapid as opposed to hemoglobin A1C
and some of the more traditional surrogate
endpoints in diabetes.
Now, a characterization biomarker that I
listed here is HDL cholesterol, and there's
really--there really is a great deal of clinical
data associating HDL cholesterol with clinical
outcomes, but there still is a lot of ambiguity
about what some of those data mean. Some of those
associations are still a little bit murky, and I
think most folks would agree that it doesn't fit
bar of a surrogate endpoint. And then, I listed
LDL cholesterol as an example of surrogacy.
So we would say that there's a number of
potential regulatory uses of qualified biomarkers
in different categories. There's probably--you
could make the argument that there may be less need
for regulatory scrutiny of exploration and
demonstration biomarkers, but we would contend that
87
there's at least some interest in focusing on how
to move the biomarkers through an evidentiary
scheme like this, and there's some potential roles
of at least a demonstration biomarker, for example,
as supporting evidence for primary clinical
outcome.
A characterization biomarker, some of the
regulatory uses that we would assert would include
in dose finding and possibly in secondary and
tertiary claims, and of course, surrogacy, as is
already talked about, one of the examples of a
surrogate endpoint would be in registration.
Now, there is a--this is a graded process
of increasing levels of certainty, increasing
levels of evidence. There's also really a life
cycle for biomarkers. So not only is there a
natural progression that you could imagine that
goes from exploration to demonstration to
characterization to surrogacy and then use in
general medical use decision making; but as Dr.
Woodcock pointed out, it also goes back here:
things that are in general medical use. Not
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everything goes through this data stream. It
comes--many things are used in general medical use
come back and only then become adopted into the use
of in drug development.
Similarly, not all of these things work
out, and we have to accept that as we study
biomarkers, we're going to develop evidence that
impugns their use. And I only put the arrows in
this slide in these top two categories, but in
fact, at any point, a biomarker can fall out of
qualified use. And I think again, we have to
accept that this is a risk of using biomarkers.
There's been much talk about the CAS study
over the last 10 or so years in the biomarker field
and about how that's really an issue, but I would
submit that in drug development, we accept the
risks of withdrawing drugs from the marketplace,
and no one wants to have a drug withdrawal from the
marketplace, but we seem to have a reluctance to
accept the idea that something that we've agreed is
a qualified surrogate endpoint, we're going to
develop evidence that it's no longer a qualified
89
endpoint.
I would submit that it's a risky--the
whole drug development process is a risky
proposition, and we are going to develop in some
cases evidence that surrogate endpoints aren't
going to work out. And that is really a fact of
life in biology and medicine.
The last thing I wanted to point out in
terms of this line about qualification is that this
really isn't the only example of a graded
evidentiary process for qualifying biomarkers. A
number of years ago, the NCI Early Detection
Research Network had come up with this concept for
phases of discovery and validation of cancer
biomarkers, and they have five stages that go from
preclinical exploration, where promising directions
are identified, through retrospective longitudinal,
where a biomarker detects a preclinical disease,
and a screened positive rule can be defined all the
way through cancer control, where the impact of
screening and reducing the burden of disease on a
population is quantified.
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So this is a somewhat similar schema to
the one that I presented, and I think that in
general, this idea of a graded evidentiary scheme
is a useful one. Of course, there was a number of
issues here, and I list only some of them. There's
many different schemes of biomarker nomenclature.
There's many different uses of biomarkers, and I
talked to some extent about that as it relates to
ranging from hypothesis generation to regulatory
decisions.
A particularly difficult issue with
biomarkers is the different technology platforms
for biomarker assays. So they range from
immunologic assays to expression profiling to
imaging to psychometric scales. It's very hard to
talk in a uniform way about biomarkers in general
when the range of the measurements is so wide. And
also, as highlighted by Dr. Woodcock, there's the
potential role for multiplexed biomarkers, but we
really haven't gotten the scientific work done on
how to put those into the right conceptual
framework yet. It's really a very nascent field,
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one that's rapidly developing but still very much
in its infancy.
And I did talk a bit about the different
strategies for qualification. And I didn't really
talk very much about the assay validation side.
But there's equally important issues about how the
assays themselves are validated and then put into
wider use.
And the last issue here is that there is
an obvious need for collaboration in biomarker
development. And that's what I wanted to spend the
remainder of this talk on. So we would be the last
to suggest that a collaboration model is the
solution for all biomarkers. There's many, many
uses of biomarkers that don't need any
collaboration. But there are many instances:
imaging is one example, where the scope of the
project has become so large that a collaboration is
really--it's really the only way to move it
forward.
And there's many options for
collaboration. I listed some of them here. The
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PhRMA-FDA-NIH or other academic governmental
collaboration, that's what we would really think of
as the ideal new independent entity with FDA
collaboration, PhRMA with FDA; without some of
these other folks, PhRMA as a consortium or the
status quo.
If we assume that a more wide-ranging
collaboration is desirable, it really comes down to
the question of how members of PhRMA can work with
FDA, other governmental agencies, academics and
develop qualified biomarkers in regulatory decision
making. How can we do that?
Well, we believe that there are really two
broad issues here. One of the issues is really
deciding what biomarkers to pursue; making a
development plan; executing the development plan;
and maybe even at the onset, putting things into
the right framework. And this is an issue, a group
of issues that benefits from the widest possible
cross-collaboration between groups.
The second group of issues is deciding
what data would really be necessary for the
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qualification of a particular biomarker or
reviewing that data on a biomarker and advising
regulators on its acceptance. And this is
something that we view should be more independent
of industry involvement.
So we would submit that one way to do this
would be to have an executive consortium that would
involve industry, both PhRMA and biotech, as well
as diagnostics, devices, perhaps other areas; the
government, in particular, the FDA, NIH, and
academics.
Then, the other really important group
would be a review and acceptance group, and this
would primarily, in our view, fall on the shoulders
of the FDA. How that would flesh out is something
that could take various forms: a relevant review
division for each biomarker if applicable; a new
intercenter advisory group or a designated FDA
advisory committee. If it were an FDA advisory
committee, we really would recommend powering that
committee appropriately so that the issues could
really be worked on.
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And then, in our proposal, form would
follow function, and these separate groups would
deal with each of these broad groups of issues, so
that the executive consortium would deal with the
group one issues, and the review and acceptance
group would deal with the group two issues.
And then, going back to the executive
consortium, the idea there is really not as the
developer of all biomarkers; the biomarker science
is a very, very large field, but to coordinate
aspects of biomarker research, allowing a wide
membership; ensuring that interested parties and
specific biomarkers are connected and brokering
syndicates, identifying gaps for qualification in
biomarkers and really providing a forum, a one-stop
shopping for sharing biomarker science and then
acting as an expert interlocutor with regulatory
agencies.
Now, we recognize that there's a large
number of issues, some of them very vexing, toward
adoption of a collaboration approach. There's both
incentives and disincentives to industry for
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collaboration. We would submit that a major
incentive would be regulatory predictability and
process. The funding for such an enterprise is an
issue, and it could take various different forms:
intellectual property in this kind of a consortium
idea is an issue, as is antitrust, and governance
is a particular issue. The last thing that we
would want to suggest is to create a new, difficult
bureaucracy that makes things harder to do rather
than easier to do.
So, again, I represent a large number of
people that are working both within the PhRMA
context and some outside of that. And in
particular, I want to acknowledge the Biomarkers
Working Group within PhRMA. It's been in existence
for about a year as well as the Pharmacogenomics
Working Group.
DR. VENITZ: Thank you, Dr. Wagner.
Any quick questions by Committee members?
Yes, Hartmut?
DR. DERENDORF: That was a very nice
overview, and I like your proposal at the end, but
96
I'm a little skeptical if that really will be
embraced by all companies. There's a lot of
biological development going on in most companies
right now. And you could look at it from the other
side that it may be a competitive advantage to do
that, and why would companies be interested in
sharing that with competitors?
DR. WAGNER: That's in part--I agree with
you. That's in part why I emphasize that not all
biomarkers would really be ones that you would want
to put in a collaboration effort. But there are
many biomarker areas that really are
basically--have grown too complicated and large and
expensive for any one even big PhRMA company to
tackle on their own, let alone having, you know, 20
of these companies all working at cross-purposes.
The folks that have been working on these
biomarker efforts within PhRMA would submit that
there's at least a subset of biomarkers that we
could get general agreement that a collaboration
model would benefit, but I agree that it's not
something that is necessarily the case for all
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biomarker research and development.
DR. WOODCOCK: Yes, I would submit,
although I recognize all the work that's going on,
that it has not necessarily been successful in
bringing about either, in particular, more
predictable drug development or regulatory adoption
of these biomarkers. Therefore, when we published
a critical path report, quite a few firms indicated
that they would be willing to share in the
precompetitive area, which is very much like that
semiconductor example that was given. There may be
different areas of precompetitive research where
only a critical mass of effort will produce the,
you know, the results that are needed.
DR. SADEE: Yes, I think such a broad
approach is really necessary, and for those of us
who do work on looking at biomarkers from a
genomics point of view or, let's say, expression
profiling or proteomics, what you find is that you
begin with 20,000 transcripts or proteins, and you
narrow it down to a few hundred, even a few dozen.
And for each application, for, let's say, cancer,
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chemotherapy outcomes, you can identify maybe a
dozen genes or proteins that are predictive.
And the combination of those, you evaluate
the best ones; what you end up with is a panel of
biomarkers that each is just maybe slightly better
than the other. There is no demarcation point.
Some may be totally unrelated to the disease. And
so, that's also coming to you, but it's not a
binary thing. It's just a complete gradation. So
you get a panel of biomarkers that just declines in
validity. And so, if you want to validate it, you
have to have a cutoff point someplace. But you do
not know which ones are going to be most predictive
in most clinical situations.
And so, I think that's really the reason
why this biomarker field has exploded, and there
are no singular solutions, and that's why we need
this type of collaboration on a very broad basis.
DR. WAGNER: I agree. And you're also
very much highlighting some of the issues
surrounding the multiplexing of biomarkers, where
one biomarker isn't worth its salt in a particular
99
prediction; a group of a dozen or so can be put
together in a model where the aggregate is actually
pretty good.
DR. DERENDORF: In your classification, I
think one very important aspect is the
differentiation between first in class or fifth in
class, because obviously, with the first in class
with an unknown mechanism, no clinical data, it's
very difficult to validate a biomarker. It's
impossible, as a matter of fact. And I think that
is the challenge is that you can have so many
different scenarios, it's very difficult to put
them in a systematic one, two, three, four
classification. I think we need to keep that
flexibility an creativity in this field that we can
really go any way that suits the particular case.
DR. WAGNER: Yes, I agree we certainly
want to stay as flexible as possible, but your
point also speaks to the idea that across classes,
there is the possibility of biomarkers as well.
And in diabetes, hemoglobin A1C is a gold standard
example of a biomarker that is a surrogate endpoint
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that's accepted across different classes of
therapeutic agents, and there has really been
acceptance that new agents that, that new molecular
entities that are being--are first in class are
compared on the same standards as agents that have
been in existence for years.
DR. STANSKI: Okay; thank you, Dr.
Woodcock mentioned two important pieces of this
problem. One of them is individualizing and
improving therapy for patients; a second piece is
how do you pay for it, and how do you generate
economic incentives? And if a consortium could be
created whereby, with the right aggregation of
expertise, which included engineers to help us
learn to aggregate complex information and even
using Dr. Sheiner's concepts of multidimensional
response surfaces, because that's really what it
involves, is that this group could then both foster
the development of the research and at some point
be able to make clear recommendations to funding
agencies of what to pay for in terms of CMS or
other agencies as to when some aggregation of
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biomarkers has reached a critical point that allows
improved therapy as demonstrated by clinical trials
and has proper statistical validity and therefore
can improve treatment; therefore, we're willing to
pay for it. That could create an incentive to pool
the intellectual capital, because ultimately, it's
the funding gate that will allow the business model
for this kind of work.
DR. WAGNER: I couldn't agree with you
more about that particular point. The reason why
the semiconductor effort was needed and why it was
successful was they worked on standards that then
could drive the expansion of their business. It's
very much of an analogous situation here, where if
there is agreement on regulatory standards both
for--within drug development and in diagnostics,
that would have a real role in substantiating a
business model.
DR. VENITZ: Okay; thank you, Dr. Wagner.
Our last presenter for today is going to
be Dr. Blaschke, who's going to give us the
academic perspective.
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DR. BLASCHKE: Thanks. Well, when Larry
invited me to speak this morning, he suggested that
one of the things that might be helpful would be to
go into a little bit more depth on the issue of the
surrogate endpoints for HIV. We can learn
something from past experiences, and I think that
there are some important lessons to be learned.
I will say that I am a surrogate. I'm a
surrogate for Lewis Sheiner this morning, and some
of the slides that you're going to see, in fact,
will be Lewis' slides. I think he would have had a
lot of important things to contribute to this
discussion.
I think this is an important concept
cartoon that if you can't read, I'll read it for
you. It says it may very well bring about
immortality, but it will take forever to test it.
And that's a real problem with a lot of the drugs
that we're using now for chronic diseases, and I'll
give you a little bit of an academic perspective.
I'll give you my perspective on the situation.
I've been working in the HIV/AIDS area for about 15
103
years; I've been through a lot of the things that
I'll show you on the next few slides, and there are
a number of people in the audience who have also
been involved in this that I'll acknowledge as I go
through this review.
And we've seen this slide before. This is
the challenge. We need more rapid clinical
development. That was certainly true in the area
of HIV, and you've seen this before. This was the
example that was presented in the critical path
document showing that the adoption of CD-4 cell
counts and measures of viral load really led to a
speedup in the approval of antiretroviral drugs,
and this did result as a cooperative effort
involving the FDA, a number of stakeholders,
academic and industry, as I'll show you as I go on.
So what I want to spend the first part of
this talk discussing is now surrogate endpoints
were used for approval of antiretroviral drugs for
HIV infection. And it's important to go through a
little bit of the history of this, because it's not
as simple as it would like to be. The first
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approval, in fact, based on a surrogate marker
occurred in 1992, with a drug called DDC, a
nucleoside analogue, zalcitabine, from
Hockman-LaRoche, and I've highlighted a couple of
the features of a press release that came out at
the time of that approval, which was on June 19,
1992; DDC was approved.
As noted in this release, it was the first
drug approved since the FDA had announced its
accelerated approval process, and as noted in red
on the slide here, the process incorporates the use
of surrogate endpoints to determine efficacy, and
as you'll see later on, the process allowed for
approval to be withdrawn if further review
determines the therapy was to be ineffective, and
John mentioned that point in his presentation.
So 1992 was really the first time that the
HIV RNA and CD-4 cell count was used as a surrogate
for approval of DDC. And what were the factors
that really accelerated the acceptance of it? At
this point, it was just the CD-4 cell count for
approval of DDC. Well, obviously, it was the
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urgent need for new therapied for this fatal
illness, and one of the things in the position
paper that PhRMA has generated is the environment
here was risk-tolerant. We really didn't have
alternative therapies for HIV. We knew it was an
illness that was a fatal illness, and there was an
urgent need for developing therapies.
There were strong patient advocacy groups,
and most of us lived through that experience back
in the early 1990s, late 1980s of these advocacy
groups that were really pushing very hard for the
development and the approval of new therapies. It
led to Congressional interest in this, and
importantly, it led to some changes in FDA
regulations that allowed surrogate-based approval
when a clinical endpoint was perhaps not what we
were looking for.
I think very importantly, it also
represented a willingness of the FDA to take risks
by requiring a phase four commitment, and I would
point out that Carl Peck, who I think is probably
still in the audience, who was head of CDER at the
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time, was also the acting head of the Division of
Antiretroviral Drugs, and Carl was very forceful in
promoting the approval of drugs based on surrogate
endpoints, and you'll see a paper that I'll allude
to in just a moment that I think represented a very
important effort on the part of the Food and Drug
Administration to look at surrogate endpoints.
And as I mentioned earlier, it really
represented a collaboration among clinical
scientists and statisticians from academia,
industry, and the government, and it wasn't all
that well-organized, as I'll try to show you. It
happened, but it didn't happen in a terribly
organized fashion, but it was a very important
point in making this actually happen.
Now, this was the paper that I was
alluding to by Stella Machado, Mitchell Gail and
Susan Ellenberg. As you'll see from the
affiliations, this is really a collaboration
between the NCI as well as the FDA. Stella was
somebody that Carl had really asked to lead this
issue of using laboratory markers as surrogates for
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those clinical endpoints in the evaluation of
treatment of HIV infection. You'll see this was
published in 1990, and as I said, the first
approval based on these surrogate endpoints
occurred in 1992. This was a very important effort
and a very active, very busy effort to look at this
whole question.
The next ARV class that was approved were
the protease inhibitors, and they were approved in
the mid-1990s, 1995. Saquinavir was first,
followed shortly thereafter by ritonavir and
indinavir about six months later, four to six
months later. And this is an important, again,
press release that occurred at the time of the
approval of saquinavir that was provided by David
Kessler, who said that the review of saquinavir is
the fastest approval of any AIDS drug so far and
demonstrates the FDA's flexibility in situations
when saving time can mean saving lives. When it
comes to AIDS and other life-threatening diseases,
we have learned to take greater risks in exchange
for greater potential health benefits. And I think
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again, that's a very important concept that we have
to remember, especially in something like HIV.
Carl has talked about this subsequent to
that in presentations that he has made, and I think
it's important to highlight what this meant for the
development of these protease inhibitors that I
just mentioned; that for saquinavir and indinavir
and nelfinavir, you can see from the top line there
that the development of these compounds really was
very, very short compared to the usual development
times: five, three and less than three years in
clinical development; a relatively small number of
clinical trials that were required prior to the
submission of the NDA; relatively small numbers of
patients in those trials, about 1,000 patients in
each of the NDAs, and accelerated approval, as I
mentioned before, that was based on a surrogate
endpoint and a requirement for postapproval
clinical confirmation. So it really did make a
difference.
The result of using these surrogates for
the antiretroviral drugs meant the rapid approval
109
of new drugs to treat HIV. We now have over 20
antiretroviral drugs on the market; most of them
really have been proved in record time, both the
pre-NDA time frame as well as the, obviously, the
review time for these compounds has also been quite
rapid and quite short.
It's provided, I think, incentives for
companies to develop new drugs for HIV, because the
pathway to approval is really fairly
straightforward. It's now been embodied in an FDA
guidance for antiretroviral drugs. And I would
also say that, in fact, because these drugs are so
efficacious in the treatment of HIV, approval now
without the use of surrogates would, in fact,
neither be feasible nor ethical. It would take
years and tens of thousands of patients in order to
demonstrate efficacy using clinical endpoints for
HIV infection, so this has really been a remarkable
achievement in terms of the development of
surrogate markers.
But let's go back a little bit and look at
the process that actually occurred in qualifying
110
the use of these two surrogates, that is, the HIV
RNA, plasma, CD-4 cells and surrogates, because it
really didn't occur in, as I say, in a nice, simple
fashion.
Let me go back and talk about some general
principles, and then, we'll illustrate how those
principles were, in fact, applied in the use of the
surrogate endpoints for HIV. First, is that a
surrogate endpoints qualification has to begin with
a hypothesis about the pathogenesis of the disease.
It ends with the establishment of its applicability
by using clinical trials, and what happens in the
middle? The important thing is that we have to
have basic and clinical studies of pathogenesis.
We have to have markers that are discovered about
disease progression. We have to collect data from
both preclinical and early clinical studies. I
assert that we need to develop mechanistic and
semimechanistic models and avoid the use of only
empirical models and, again, collaboration and
sharing of information in order to qualify those
biomarkers as surrogate endpoints is certainly what
111
occurred.
And I'll go through these components
pretty quickly, because I think they're fairly
well-known to everybody. We know that HIV is
caused by an infectious agent. That needed to be
discovered. It was discovered and was, I think,
well-documented to be proven as the causative agent
of AIDS, and of course, what we really needed to
show was that suppression and prevention of HIV
replication would really alter the course of the
disease.
A lot of work was put into pathogenesis of
HIV. We learned an enormous amount in a very short
period of time about the nature of HIV replication
and its interaction between HIV and the immune
system. These were extensively studied in vitro,
in animal models, and in vivo. This was largely an
academic endeavor carried out within the NIH and at
a number of different academic centers; really, a
tremendous effort that occurred in order to make
this happen, and it led to a detailed understanding
of viral structure, replication mechanisms,
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interaction of the virus with the CD-4 cells,
involvement of co-receptors and so forth, and this
was all extremely important in the development of
therapies for HIV, and it was largely carried out
that--development of antiretroviral drugs was
largely carried out, as one would expect, within
the pharmaceutical industry, although in this case,
there was significant collaboration that occurred
with the NIH and with academia, and I would note
the role of the NCI in the development of
zidovudine and in protease inhibitor development.
So this really was a very collaborative effort in
terms of pathogenesis as well as in drug discovery.
And then, we had the discovery of these
biomarkers that I will call the biomarkers of
disease progression, and these occurred, really,
because of the efforts of multiple groups, again,
mostly from the academic side who evaluated many
possible biomarkers of the progression of HIV to
AIDS. Along the way, there were a number of
putative biomarkers that were evaluated. P24
antigen was one of the first; then came CD4 cell
113
counts and a number of other measures that were
looked at very carefully to look at disease
progression, and this occurred, really, because of
the availability and the support of a number of
cohort studies, and I've just listed half a dozen
or so here.
There were many others, both large and
small, that contributed enormously to the
information on biomarkers and on disease
progression, and that required these important
steps that John also alluded to, which was the
validation of biomarker assays such as the CD4 cell
count, the HIV RNA assays, and then, the next
important step which occurred essentially in
parallel with many of these was the collection of
that biomarker data from interventional clinical
trials, and Janet alluded to that as well.
And then, subsequent to that was the
creation of mechanistic or semimechanistic models,
which incorporated those biomarkers to see what
interventions might do to those biomarkers and
ultimately then to the qualification of those
114
biomarkers as surrogate endpoints. And this was
one of the very important studies that occurred
relatively early on in terms of trying to
understand mechanistic models for HIV infection, a
study that was done by David Ho and Alan Perelson,
published in Nature in 1995, looking at the rapid
turnover of plasma virions and CD4 lymphocytes in
HIV-1 infection.
This was done in collaboration with Abbott
Pharmaceuticals; John Leonard at Abbott
Pharmaceuticals, and what these investigators were
able to demonstrate was sort of this
multicompartmental location of HIV replication, a
very important observation, a very important
finding in terms of understanding viral
replication, and that, then, because this was an
interventional study as well, then helped
understand the role of antiretroviral drugs in the
treatment of HIV infection.
But as I said, this really didn't occur in
a nice, linear process. So you start looking at
some of those dates that I've shown you; we
115
approved, or we, the FDA, approved the first drug
in 1992, but in fact, a lot of this work with
biomarker development and the evolution and
qualification of those biomarkers into surrogate
markers ultimately or surrogate endpoints, John,
ultimately leading to a guidance on this approval
of antiretroviral drugs really occurred in much,
much later than that first approval in 1992. So
just recognize that when you have a disease like
HIV, where there's a lot of pressure to get things
done, things will happen, and they often happen in
a--as I say, a nonlinear fashion.
And I'm using this to, just, again,
recognize that here in 1997, we have a nice review
of the approach to the validation of markers for
the use of HIV RNA in clinical trials that was
done, again, a collaboration between academic, FDA
and the NIH, and even more recently published in
2000, we have a surrogate marker collaborative
group talking about a meta-analysis of the use of
RNA and CD4s prognostic markers and surrogate
endpoints in AIDS.
116
So there's still a lot of active work
going on in this field to try to really understand,
again, from a mechanistic point of view and a
pathogenesis point of view how these markers can be
used to help us better understand the therapies of
HIV and, in fact, approval of drugs.
And I show this one slide not to--because
you can read it but because I really want you to
see what a large group of people were involved, for
example, in this HIV surrogate marker collaborative
group that published that paper that I just showed
on the previous screen. So listed up here are
actually 55 people as part of that collaborative
group as both international representation from
both industry and academia.
So these kinds of things really do require
a lot of input, a lot of data, and a lot of the
people involved in this were heavily involved in
generating the data that's been used to develop
these biomarkers and surrogates in HIV.
So, now, I'm going to turn around and put
my Sheiner hat on, and I'm going to talk a little
117
bit from an academic perspective about the general
principles of biomarker use and qualification. And
this was, again, one of the slides that perhaps
Lewis showed at one of these earlier meetings; I'm
not sure, but basically, the principles here is
that to establish causality, given an empirical
association, by supporting pharmacological activity
as a mechanism, not by ruling out other causes.
And so, the evidence that would support a
pharmacologic action is that the response
correlates with temporally-varying exposure; that
causal path biomarkers change in a mechanistically
compatible direction, rate and temporal sequence,
and we saw that when we looked at viral RNA and
CD-4 in the HIV area. And as Lewis pointed out,
learning trials and analyses are well-suited to
mechanistic interpretation of time-varying data,
and independent causal evidence is still required.
Causal evidence from the same randomized controlled
trial doesn't rule out some sort of transience or
interaction. So again, the key point that he was
making there is that causal path biomarkers need to
118
change temporally in a mechanistically compatible
direction, rate and sequence.
So what are causal path biomarkers? Well,
that's illustrated on this cartoon here, and we
begin with the pathology that influences the
physiology and ultimately the disease progression.
What is next incorporated into this concept is the
idea that we have an intervention, and here, an
area that both Lewis and I were interested in was
not just to incorporate the drug but in fact
incorporate drug exposure, which represented both
pharmacokinetics as well as patient adherence in
order to get better information, so the model that
was used for the intervention represented, again,
both individual differences in pharmacokinetics as
well as patient adherence.
The pharmacokinetics, of course, lead to
time bearing plasma concentrations, and then, what
we're looking for are biomarkers that change as a
result of the changes in exposure to the drug. And
of course, what is important in terms of really
then understanding whether a biomarker is, in fact,
119
something that we really want to continue to pursue
in more detail is to look to determine whether we
see the correct temporal sequence, which gives us
some confidence that there is a mechanistic
involvement of this biomarker in the physiology and
ultimately in the clinical fact and in the disease
itself.
So let me just go back and talk a moment
about causal path biomarkers as opposed to
biomarkers in general. So causal path biomarkers
are those that serve as indicators of the state or
activity of the mechanisms that connect the disease
to the clinical manifestations. They have to be
scientifically plausible based on our current
understanding of the disease itself, and that was
certainly true with HIV/AIDS.
As knowledge increases, the confidence in
the validity of the biomarker will increase,
especially when drugs in the same class or with the
same indication affect the same biomarker, and I
think this is an important principle. If we have a
biomarker, if we have a disease, and we have a
120
biomarker that's influenced by drugs of different
structures and different class, it really increases
our confidence that this particular biomarker
represents a causal path biomarker, one that's
important in the disease and in the disease
progress itself.
More biomarkers will be useful in
developing models of drug action, and again, causal
path biomarkers need not be surrogate markers when
they're used for drug development decisions or as
confirmatory evidence of efficacy. And I won't get
off on that tangent for awhile; as you know, Lewis
and Carl Peck have been very interested in the
concept of using causal biomarkers as confirmatory
evidence along with fewer clinical trials.
So the credibility of these causal path
biomarkers does depend on the state of scientific
knowledge of the disease mechanisms, consistency of
the association with a clinically-approvable
endpoint and the biomarker; proximity of the causal
path of the clinical endpoint. Obviously, the
closer that biomarker is to the endpoint of the
121
disease, that gives us more confidence in that
biomarker and then multiple biomarkers changing in
the correct temporal sequence, and again, this
alludes to the concept of having perhaps multiple
markers that may be important rather than just a
single marker, and again, similarity of the
biomarker exposure and the clinical exposure
response when both are studied together, and all
that came, as you saw, at the bottom of that slide
from a workshop that was held by CDDS a couple of
years ago, involving Carl and Lewis and Don Rubin
as well.
And this next couple of slides and tables
just was something that appeared in a paper that
was published from that conference by Carl, Don
Rubin and Lewis in Clinical Pharmacology and
Therapeutics about a year ago, just a table of
causal path biomarkers. Just highlight a few here
that are really already either biomarkers or
becoming close to being surrogate endpoints and a
few others on this second part of the table of,
again, biomarkers that might well be those that
122
could be qualified as surrogate endpoints.
So again, establishing pharmacological
causality is really what we're trying to do here,
and what it basically means is that if we start
with an empirical association that we get from
preclinical or clinical studies, we establish
causality by directly supporting pharmacologic
activity as the mechanism and not by ruling out
other causes. It's more demanding, in fact, than
empirical confirmation, and the evidence is this
establishing the credibility of those causal path
biomarkers.
Now, this is, again, a slide from Lewis
that demonstrates that one can, in fact, gather
information about biomarkers and causal biomarkers
during phase two and phase three trials; in
particular, of course, Lewis, as I mentioned
earlier this morning, emphasized the learning
elements of the phase three trials that can be
carried out by looking, for example, as you see
from the slide here, at those surrogate prognostic
covariates, serial biomarkers. PK compliance,
123
again, is emphasized here and then the use of
model-based analysis as part of the process of
analyzing not only phase two trials but also phase
three trials.
One of the important things which I think
Lewis contributed was his concept of learning while
confirming, and I think again, this is a concept
which I hope we will see more of in the whole drug
development process. The point that he wanted to
make here was that when we look at confirmatory
trials, which we usually think of as phase three
trials, we're talking about random assignment,
placebo controls, clinical endpoints, baseline
covariates, homogeneous patients and so forth, and
that's a typical outline of a design for a phase
three trial.
However, if we add some additional
measurements, pharmacokinetic measurements in phase
three, compliance in phase three, but importantly
for the purposes of this discussion, serial
biomarkers or other covariates that we can look at,
we may increase somewhat the work involved and the
124
number of patients involved, but in fact, what we
gain is considerable. And then, if we add to that
heterogeneous patients that we begin to look at,
this individual patient therapy is, as Janet also
mentioned, we begin to have some mechanism for
looking at responders and non-responders rather
than looking at a more homogeneous group.
And then, specifically, an area that Lewis
and I have both been interested in is the use of
multiple different doses and potentially even
individual dose escalation trials to try to really
understand the dose-response relationship. And the
point, again, to be made from this slide is that we
can do this in the context of a phase three trial.
It may produce some increase in the effort involved
in the trial; it may increase some of the time
involved in carrying out those trials, but the kind
of information that we gain from this sort of
approach can really be quite valuable.
So the other point that I think needs to
be made is the issue of when is a surrogate ready.
And I've sort of alluded to that already in terms
125
of the HIV problem, but I think we're all
comfortable with the idea that the empirical
certainty is not highly necessary for drug
development decisions.
In fact, we want pharmacologic activity,
and we want mechanistic activity for those drug
development decisions and for labeling, but I think
the most important one that I want to focus on here
is that when we have great potential benefit along
with a high prior presumption of a positive
risk-benefit ration and the excessive cost of
objective evidence, those are really the kinds of
areas in which we really need to go ahead and look
at the use of alternatives to clinical outcomes in
terms of evidence for approval.
And again, what Lewis talks about is that
confirmatory really should also include learning.
And this goes back even to an APS meeting back in
1998, in which Lewis described the sort of
situation in which empiricism needed to be balanced
with the use of causal models, drug regulation
demand, certainty and information; causal models
126
are inevitably uncertain but highly informative, so
when do we use this sort of model, and when do we
use, in fact, surrogate markers at an early stage,
when lesser certainty is permissible, as in
labeling of the drug so that we can use modeling
and simulation and so forth to improve our
knowledge about labeling, but importantly, about
safety and efficacy when there's great potential
for benefit or high prior presumption, and
basically, again, a plug for the use of modeling,
that modeling certainly can yield high certainty
when we have credible models and the correct
performance of some of these tests under the null
hypothesis, and that sort of gets into this other
area that I mentioned earlier this morning about
use of alternative statistical tests when one is
analyzing trial data.
So, again, just from an academic
perspective, what do I see as some of the next
steps that we need to take? This is actually a
slide that I took from Janet's presentation a
couple of weeks ago at the ACCP meeting and what
127
she said at that meeting about what we need in
biomarker development, data pooling, synthesis,
analysis, identification of what's known and not
known and gap analysis. We heard John talk about
that, identifying what studies are needed to fill
those gaps and then doing the work and not just
standing on our heels.
And as a final comment, I think that
basically, the public wants more therapies at
reasonable prices. I think we've heard that over
and over again, and the high cost of drug
development is something that I think all of us
believe could be improved by a number of approaches
that are part of the critical path document,
including the implementation of better surrogate
marker data or surrogate endpoint data.
I don't think the regulatory issues are
necessarily any longer a major impediment. I think
the regulations are in place to approve drugs on a
surrogate endpoint basis, so we don't need to have
a lot of new legislation in order to make this
happen.
128
I think what we're hearing this morning
and what we're hearing in general is that the FDA
is very willing to move forward with new
surrogates, that we don't need to think that
there's a resistance on the part of the FDA to do
this.
Substantial collaboration among academia,
industry, and regulatory bodies will be necessary,
and I think John spoke to that very nicely. All
I'd say about academia is that unlike the FDA and
unlike the industry, we are not organized.
[Laughter.]
DR. BLASCHKE: And when I talk about
academia, who knows what I mean?
[Laughter.]
DR. BLASCHKE: There are a lot of us out
there. But I think that there are mechanisms for
getting people to come together for this kind of
important activity.
And I think what I've tried to illustrate
is that this past history with antiretroviral drugs
for HIV indicates that such collaboration can occur
129
and that it benefits all of the constituencies.
And we've already heard that there are already a
number of meaningful collaborations underway and
that we really need to encourage and support these.
So I'll just finish with this: I think
the goal that we all have is not just another
proprietary bestseller but really to get through
some major breakthroughs, and I think that this
kind of approach that we're hearing about this
morning can help along that path. And I'll stop
here, and I think we'll be ready to open it up.
Thanks.
DR. VENITZ: Thank you, Dr. Blaschke.
Any quick questions before we take a break
and start the--
DR. SINGPURWALLA: I have a comment.
DR. VENITZ: Go ahead.
DR. SINGPURWALLA: I enjoyed your
mentioning of causality, but I wanted to draw your
attention to the fact that there is a body of
knowledge called probabilistic causality which your
colleague at Stanford, Supes, specializes in. And
130
there are different interpretations. There is
something called prima facie cause; genuine cause;
and a spurious cause.
I'm wondering--and a lot of information on
causality is rarely discussed in the literature,
the philosophic literature. And I'm wondering if
the drug community is looking at that particular
angle, and if it's not, I'm recommending it.
DR. BLASCHKE: Well, I'd go back to the
comment that Janet made to your earlier comment,
and that is I think that bringing together people
with different expertise and so forth really does
add to the value, and if there's a reason for
collaboration, it's just exactly that kind of
reason, that we can't all know everything, and
there are plenty of experts out there in various
disciplines that I think we need to bring to bear
on these questions.
And I don't know them all, and I think
that's the kind of input that we need to have.
DR. DERENDORF: Very nice presentation. I
agree with everything you said. I'd like to come
131
back to this definition or desire of a causal path
biomarker. Clearly, that's the most desirable
situation. But I don't think it should be a
prerequisite for biomarkers. There are many
examples where there is no causal or no apparent
causal relationship. Think about developing of
benzodiazepenes based on EEG as a surrogate or
fentanyl derivatives, as Don has done.
So it doesn't necessarily have to be a
causal path, and it can still be operative.
DR. BLASCHKE: Well, I think we start with
empiricism. And what the academics can often
contribute to this is to move that in the direction
of understanding the mechanism or the scientific
basis for the change, whatever it is, whether it's
a change in receptor, et cetera. I certainly don't
think it's a prerequisite, but it's something that
I think we do strive for is to really understand
how something works and why it works and the way it
works.
DR. DERENDORF: I think it has to be
reproducible and predictive. I think--
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DR. BLASCHKE: Ultimately, absolutely.
DR. SINGPURWALLA: I think your point is
very well taken, and that's why I'm drawing
attention to Supes' book on causality, where he
does cite spurious cause as an empirically observed
phenomenon which may not be the real cause, but
that's the best you can do. So again--
DR. BLASCHKE: Point taken. I agree.
DR. VENITZ: Okay; then, let's take our
break. We'll reconvene at 11:00 and start a
general discussion of the topic.
[Recess.]
DR. VENITZ: Okay; before we start the
Committee discussion, I would like to ask Dr. Lesko
to kind of give us our charge, what kind of
feedback you would like to get by the Committee.
DR. LESKO: Okay; thank you, and I'll try
my best to lay out some structure for the
discussion.
A couple of--I mean, we've heard some very
interesting presentations this morning that I think
lay the groundwork and help us tee up what amounts
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to a new initiative in the world of biomarkers and
surrogate endpoints. Some of the thoughts I had
with regard to the Committee discussion would be
knowing what you know from the presentations, what
are your thoughts on what FDA can do to assure that
we gain some momentum behind this project and move
it forward?
Let me continue with a few others that we
can keep on the table: what does the Committee
think industry can do to facilitate the proposal
that we've tried to lay out collectively here this
morning? And finally, what can academia do?
Another issue would be what didn't you
hear today in the area of the biomarkers? What was
missing from the presentations that may be on your
mind with regard to advancing this field in the way
that we've talked about?
Dr. Blaschke in his presentation
mentioned, in a sense, a means to an end, but the
means to the end was not a linear process in the
area of AIDS. It was a process that at the end
worked out. But the question would be, and maybe
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some discussion can occur around this, is that the
way it's going to be? Is that the way it has to
be? Or can there be a more systematic way, if we
were to think of the problem of the AIDS again and
then think about how that could be moved forward?
Is it possible in the current environment to do
that in a systematic way?
We didn't talk about this too much in the
presentations, but there was the list of biomarkers
that was in one of the slide sets that came from
the CDDS workshop on biomarkers, and there were
many biomarkers there listed side-by-side with
clinical outcomes. And one of the thought I had is
does the Committee have any specific ideas on what
we would now call biomarkers that would be in close
proximity either in a causal way or even in an
empirical way to a clinical outcome, and what could
be done to close the gap between the biomarker and
the surrogate endpoint in terms of predicting
clinical outcome?
A couple of examples of what I mean: one
example would be bone mineral density; that is, a
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causal path biomarker for fractures and reduction
in fracture rate. Bone mineral density is used as
an approvable endpoint for a claim of prevention of
osteoarthritis, but it is not used as an endpoint
for an indication of fracture rate reduction. So
there's a gap there. What kind of data would be
needed to move biomarkers in specific therapeutic
areas to further along towards the surrogate area,
and how could those sort of gaps be identified in
terms of what we know and how we might get the
additional data?
A couple other examples: gastric acid, a
causal state biomarker; can it be advanced with
additional data, data mining, new research to
become a surrogate endpoint for additional clinical
approvals. Third example, just to stimulate some
thinking, H pylori eradication and its usefulness
in terms of duodenal ulcer recurrence and things of
that sort.
So anyway, I'll just pause here. I think
there's a couple of things on the table that maybe
we can get some discussion going, and there is no
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boundaries on the discussion. There's a lot of
possibilities, but I just wanted to throw out a few
things for the group to think about and to kick
around.
DR. VENITZ: Okay; any comments by the
group?
Jeff?
DR. BARRETT: Larry, I wanted to address,
you know, the point about the systematic approach
relative to maybe the convoluted path. One of the
things that struck me, and we talked about this
briefly, was a lot of the emphasis is focused on
the early stage discovery processes involving
biomarker identification and evolution through the
development process, but it strikes me that another
area of focus could be from the back end as far as
working with thought weeders relative to the basis
for an approval.
I think we seldom are in areas where it's
completely unknown what is going to constitute the
basis for an approval. So from the standpoint of
looking at those study designs, criteria both
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statistical and clinical that constitute the basis
for an approval, what would those decision makers
at that stage like to see at the earlier stage to
show some level of association between a marker to
be named and that basis for an approval.
So, you know, perhaps there could be a
meeting in the middle of the biomarkers that get
advanced at early stages relative to what is
ultimately going to potentially be a surrogate
marker. So that was one thing that struck me. And
the other thing that I thought was an interesting
point was acceptance criteria on making
generalizations. We talk about empiricism a lot as
perhaps being a dirty word here, but I think the
exploratory nature of the biomarkers has to be
there at the early stages, and it's very rare that
a company will invest in studying a biomarker
without some justification or rationale, so I
simply feel that for the most part, that is in
place, but there has to be some criteria by which
we make those generalizations, when, it's okay,
when it's not.
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So that kind of acceptance criteria on
generalizations will help you, I think,
differentiate compound-specific mechanism-related
biomarkers versus things that may be associated
with a class.
And then, I think the other point I wanted
to make was just to be able to differentiate
between the measurement detection issues relative
to the response measurement issues associated with
observational and exploratory versus a confirmatory
test. Those pieces, I think, really need to be
compartmentalized and focused on if we're going to
move forward.
DR. VENITZ: Comment that I had in my mind
the crux, as far as it relates to coming up with
surrogate markers is this mix of using empiric
evidence and mechanistic evidence in the right mix
to convince ourselves that we have either lots of
empirical evidence on the Prentiss criteria, which
means it's going to be very difficult to actually
do that short of doing clinical outcome studies; at
the same time, what is the level of evidence that
139
you need mechanistically to convince ourselves that
those biomarkers are related to the causal
pathophysiology in the disease?
So I think one of the things to focus on,
in my mind, at least, would be what evidence, what
burden of evidence do we put on mechanistic
information? Just like we classify right now in
clinical treatment, therapeutic treatments, the
evidence to support individual treatments? Let's
come up with criteria to assess what mechanistic
evidence do we need to argue that a biomarker is
more likely than not related to the causal path? I
don't think we have had that discussion, and it may
be a matter of just going through a couple of
examples.
We had a similar discussion last year when
we talked about the pediatric decision tree, where
one of the key questions is is the disease similar?
Well, what evidence do you need to support the
contention that the disease is similar in pediatric
and in adults?
And you're getting back to the same issue:
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short of doing empiric studies, which means it's
very expensive and very long-term doing it, what
mechanistic studies, at what level, in vitro, in
vivo, animals, what have you, do you need to
support that hypothesis? So I think we really need
to think about how we evaluate mechanistic evidence
to support transition from biomarkers to surrogate
markers no matter what the ultimate qualification
would be like.
DR. STANSKI: Yes, I think that's a very
good point. Obviously, at some level, this is
going to be marker and intervention specific.
However, we could, I think, much more exploration
of the general principles on the mechanistic side
could be done to provide a general framework, and I
think that's what we were talking about earlier,
that perhaps we can engage in a discussion about
the general framework for doing this; maybe using
examples is a good idea. What do you actually
mean? And what level of evidence is acceptable
that something is on the causal chain?
There are so many variables that probably
141
even elucidating those variables would be helpful.
I was talking to Rick Pazdur at the break, and we
talked about, you know, for the serious and
life-threatening illnesses, because we have the
accelerated approval mechanism that was spoken
about earlier, then, the tolerable degree of
uncertainty is greater. You accept greater
uncertainty, because you can pull the drug back,
and you're expecting those confirmatory studies.
I think depending on your priors, the
priors that you have are extremely important in
this analysis. And, you know, whatever we did or
did not know about HIV, we were pretty sure it was
an infectious disease, and we have a very good
model about eradication or, you know, suppression
or microbes or viruses and the relationship to
disease progression in many infectious diseases.
And so, we had very strong priors about that doing
that would be successful in helping control HIV
disease.
And that's very different in each kind of
disease area we're talking about. But a general
142
discussion of that would be helpful.
Now, getting to the other end, which was
just raised by the previous comment, on the
acceptance end, the regulatory acceptance end, I
think we also need to write specific guidance,
because a surrogate doesn't stand alone. It has to
be embedded within a trial design. There have to
be quantitative limits on what success means as far
as the duration of the trial, the kind of
observations, the analytic validation that has to
go on for the particular measurement and so forth
and so on. So there are a lot of specific,
condition-specific things that could be talked
about at a disease-specific area as well.
DR. VENITZ: Wolfgang?
DR. SADEE: I think that maybe a
compilation of a few examples would be useful in
where it's becoming very clear what we need to do
and others that are not so clear. And so, one
example would be the growth factor receptors and
tarsin kinases that are increasingly targets for
cancer chemotherapy.
143
And so, you already have--you know about
the mechanism, the expression or the mutations in
these target genes are important. In many cases, y
you can inhibit these target genes, and nothing is
happening. And so, it becomes exceedingly
important to define the criteria by which we go
forward, and that's a whole class of compounds that
comes to the fore, and I think that would be a very
useful mechanism to set up a rational approach from
the beginning, because we are only looking at the
tip of the icebergs in terms of the types of
compounds coming along the line and which ones will
be useful, and with EGFR inhibitors, only 15
percent responds, and that's correlated to certain
mutations.
But maybe not always. And so, that's one
class that requires a clear set of guidelines that
one can use in order to take maximal advantage of
this over the next five years.
DR. VENITZ: Another comment relates to
the fact that you are advocating to find more
safety markers, which I think we all would agree
144
with, but a lot of safety issues are not
necessarily related to the primary mechanism of
action of the drug. So I think most of our
discussion so far has really focused around the
mechanism of the drug and the pathophysiology of
the disease, which may or may not be related to any
safety issues.
So I think there should be a separate
initiative, if you like, to look at potential
safety markers for hepatotoxicity, and things that
are very difficult to, at this stage at least, to
predict. So maybe we can get away from the true
and tried serum transaminases. So safety markers
to me is a different domain to look at, because it
does not relate to the mechanism of action of the
drug. It may or may not relate to the
pathophysiology of the disease.
DR. STANSKI: Yes, we agree with that, and
in fact, safety biomarkers, safety markers in
general have had a different evidentiary threshold
completely than what we're talking about for
evidence of clinical benefit. So it is really a
145
different game entirely and probably can be pursued
separately but probably is equally important.
DR. WATKINS: Just to expand on that, you
could imagine a treatment for osteoporosis that you
could show was effective in 20 people with the
right genotype, with the right surrogate marker.
But until the issue of safety and particularly
idiosyncratic reactions is solved, even if the FDA
were willing to allow that to go to some
postmarketing surveillance, you know,
aftermarketing, the medical-legal environment in
the United States, I think, would be a powerful
argument for the company to go ahead and study
thousands of people for a long period of time
anyway.
So all the advantage of the efficacy
surrogate markers would be lost until there is some
kind of an understanding or progress made in safety
biomarkers.
DR. MCLEOD: Sticking on the theme of
safety, safety does represent an area that all
three of the stakeholders that were mentioned have
146
commonality. And it's probably the only area where
there is commonality across all the companies. I
mean, if you're interested in cancer, you may not
care about bone disease and vice versa. There are
some large companies that try to do everything, but
many do not.
And so, it may be as a proof of principle
for pushing this concept forward that that would be
the right framework, if nothing else to try to
standardize things, because it's starting to happen
to a bit. We, in this Committee, have spent some
time on surrogate safety markers like QT
prolongation, et cetera. And there's some--but
there's also a lot of those areas that are very
different from company to company, and maybe they
want to stay that way. But it is one area of
commonality.
On the efficacy side, people usually care
about a small number of things, and that's going to
make it very hard to get people on the same page,
even just programmatically.
DR. VENITZ: Hartmut?
147
DR. DERENDORF: Well, I'm not so sure if
it's really a difference, at least not
conceptually. I think what we're trying to do with
the biomarkers, we're trying to find something that
is easy to measure to replace it with something
that's hard to measure and do it in a faster way to
predict what we would get if we do the hard thing.
So a good example for a safety biomarker
that fits in that mold is cortisone suppression for
inhaled corticosteroids is a great predictor for
long-term osteoporosis or growth retardation in
children, studies that would take years to do; you
can do it in a single dose study and have a pretty
good idea how that product will perform in
long-term use. So I think conceptually, it's the
same thing. The issues, obviously, are different.
DR. GIACOMINI: Yes, I just want to
amplify on the safety biomarkers, I think it's a
really good model for bringing together a
consortium of people from academia, FDA and
industry. First of all, if it's a rare adverse
event, it requires large populations, large
148
clinical populations. I think Paul is
participating in the drug-induced hepatotoxicity
NIH-sponsored network, right? And that's one that
requires a lot of people together, but this could
bring together industry, academia, and all of that
around safety biomarkers, so I just want to second
that.
I also want to say on the efficacy
biomarkers, one thing I think that FDA could do is
bring together people from different
disease-related or treatment-related groups to talk
about the issues in those particular
treatment-related groups, because I do feel that
the biomarkers in each group may be very different,
and it would be more conceptual to think about them
in group-by-group, disease-by-disease.
DR. VENITZ: Other comments?
DR. LESKO: Yes, just to throw out another
thought, and it actually somewhat relates to our
discussion yesterday of predictive tests in the
context of irinotecan. At some point in time,
we're going to have to come face-to-face with the
149
statistical issues that revolve around the
biomarker and the predictiveness of it. And
yesterday, when we were talking about a
pharmacogenetic test, we were talking about the
probabilistic nature of the test and attributes of
the test that convey its ability to predict
something. We talked about sensitivity,
specificity, predictive values, likelihood ratios,
et cetera.
And there seemed to be some common ground,
or at least we could probably, with more
discussion, reach a common ground on the
performance of a test that would be generally
acceptable. So it gets me around to the question:
is an approach or a framework that has been used
for the predictiveness of diagnostic screening or
other types of tests appropriate for biomarkers?
Or is the statistical sort of framework for what
we're talking about in place already, or are there
needs for new statistical models to deal with this
problem?
Dr. Woodcock mentioned the Prentiss
150
criteria. That was one model. But do we need to
be thinking about new statistical approaches, new
ways of expressing predictiveness of biomarkers, or
are we sort of satisfied with where we are on that,
and that may be for Marie and David.
DR. DAVIDIAN: Well, there is a lot of
work in the statistical literature; there has been,
in fact, recently, as we speak, in trying to sort
of refine the--the Prentiss criteria are, let's
face it, very stringent criteria, but they do lay
out the, I think, what's the key issue for a
surrogate, which is that you want the effect of the
treatment on the surrogate to--the effect of the
treatment on the clinical endpoint to be seen when
you paw the treatment, you know, through the
surrogate.
So, I mean, I think that is the key issue
there. Now, how you go about quantifying that and
characterizing that, I think, is what you're
talking about. How do you actually do that? And
there's been various proposals that are out there
to do so. I think to try to get a perfect
151
surrogate is impossible, as has already been
mentioned.
But I think in the context of this sort of
discussion here and bringing in mechanistic
considerations and so on, I think there would be
additional work to be done, and I think bringing
statisticians in from that point of view would be a
good thing. I mean, most of the work in the
statistical literature now, in fact, all of it is
totally empirical. It's trying to come up with
empirical models and ways of characterizing
surrogacy and based totally empirically.
So I think that's where the new work can
be done.
DR. JUSKO: The discussions this morning
were extremely good and very informative, and as a
member of this Committee, I very much encourage all
of the participants to continue evolving this area.
One thing that is admirable about what companies do
is when they screen drugs, they often use receptor
systems and animal studies, and eventually, they
get to a study commonly called proof of concept, a
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phase 2-A type of study, where they then may try to
utilize a vast array of potential biomarkers to see
whether or not the drug has any activity that's in
concert with its basic mechanism of action that
they understand it to be. And then, many more
studies are pursued after that.
One thing that's frustrating to me in
academia is this huge vault of information
accumulated by companies in diverse areas,
including all of these kinds of biomarkers that
they've measured. The FDA may be aware of part of
it, but there's probably an immense amount of
information that's lost to the general scientific
public that could be better harvested if there was
some concerted activity through this type of
organization that's being proposed here.
So I just want to voice that degree of
frustration and encouragement towards collecting
some of this information in a more systematic
manner.
DR. SINGPURWALLA: I was going to respond
to your question. I think I've already said a few
153
things, and I'm just going to repeat them.
You talked about modeling and simulation
in one of your slides, MNS. That's the kind of
stuff you hear at the Pentagon all the time, and
that's good.
[Laughter.]
DR. SINGPURWALLA: I think one of the
things that you may consider in this context of
markers is the stochastic process models. You
don't want to look at them in a very traditional
statistical framework. You want to look at it in a
dynamic way. Markers evolve dynamically; diseases
evolve dynamically. They're correlated and what
kind of inference you should do and what kind of
confirmatory studies are needed is something that
needs to be researched and worked.
I also hear the word mechanistic models,
mechanistic considerations. I would hope that
you're looking carefully into Bayesian methods,
which combine both the knowledge of medicine and
whatever have you with empirical evidence and try
to put the two together.
154
And lastly, I would suggest that when you
have these panels of people looking at various
things, I would encourage you to go out of the
normal umbrella and look into other disciplines.
And I just don't have in mind engineers. I
strongly suggest you look into the philosophers.
They write a lot on causality; in fact, there are a
lot of books on causality written by philosophers.
I think also, you should look at ethicists
and people who look at moral issues. So I think
you should expand your umbrella of expertise to
include some other cultures and characters.
DR. BLASCHKE: I want to come back to a
question that you raised, Jurgen, and also a point
that Marie made. And that is maybe one of the
principles of surrogate endpoints and part of this
qualification process is that you have an
advantage, in fact, if there are multiple drugs to
treat the same condition. If you're getting the
same effect when you're using drugs, working
through what are believed or hypothesized to be
different mechanisms, yet at some point, their
155
effect on a surrogate is consistent and also then
consistent with a clinical outcome, it gives you a
lot more confidence that this surrogate is, in
fact, not an epiphenomenon of some sort but, in
fact, is a causal path marker that could be used as
a surrogate endpoint.
So perhaps when we're trying to think of
sort of general principles and so forth of things
that make a biomarker more likely to qualify as a
surrogate endpoint, I think the fact that it
could--and that could even work with new chemical
entities. I mean, even if it's a first in class.
I mean, somebody mentioned earlier that maybe it's
hard for a first in class compound to be approved
on the basis of a surrogate endpoint, but in fact,
no. If that surrogate has been proven for several
other drug classes, it may even be a stronger
evidence that this new drug about which maybe has a
new mechanism is ultimately working through that
same pathway to produce the beneficial effect in
the disease.
DR. STANSKI: Bill Jusko mentioned the
156
sequestering of information. I'd like to ask
people who work within the pharmaceutical industry
to what degree is this precompetitive knowledge and
prevention of sharing to do patent issues and
competitive advantage something that can be
overcome? Or is that just a reality of a
for-profit industry, or for the sake of moving this
concept forward and having more efficient drug
development, how can that barrier be broken?
DR. VENITZ: Would anybody care to
comment, or was this a rhetorical question?
DR. STANSKI: Well, someone in the
industry must think of this and to be able to
respond to it, I'd hope.
DR. VENITZ: Go ahead. Can you introduce
yourself?
MR. WEBSTER: I'm Chris Webster. I'm
director of regulatory strategy and intelligence
from Millennium, and I'm speaking for myself here.
I'm not speaking for the industry, but perhaps my
views are, because I've been involved in some of
the working groups, may be useful to you at this
157
point.
Obviously, everybody is very aware of the
topicality of this issue relating to the
publication of clinical trials, and there has been,
as you know, an initiative published by PhRMA to
put up clinical trial data in a public place for
patients and physicians and others to see it.
I think what you're talking about here is
something more far-reaching than that, and it's
not, I think, a--you know, this is not the first
time I think the industry has become aware of it.
I'll refer you, for example, to the comments of Dr.
Kalif at the Science Board last April, where he
again touched on this point, and so I think we are
aware of it.
I think that it's probably not impossible
to be done, but I think that there would need to be
some kind of really high level working group to
really look at very sensitive and difficult issues
related to intellectual property and ways in which
information could be perhaps shared in an anonymous
way, in a generic way so that it wasn't identified
158
with particular companies or particular drugs but
perhaps could be useful for the purposes of
scientific research.
And perhaps some degree of parallel to
that is the creation of voluntary data submissions
for pharmacogenomic data which, of course, was
published by the agency just about a year ago now,
and so perhaps, that might be to some extent a
model for this.
I think it's very difficult, though; I
don't want to project any illusions about this that
it would be easy, but I think perhaps it's a
conversation which the industry might be ready to
have. Thank you.
DR. LESKO: Yes, Chris, while you're
there, you did mention the voluntary genomic data
submission pathway that the agency created, which
was kind of a groundbreaker in many ways, and I
know you were part of that with the working group
and the workshop. SO, really, my question is do
you see a difference between a similar pathway for
nongenomic biomarkers as we set up for that
159
particular reason? We set it up for genomic
biomarkers, but is there any reason why it couldn't
be utilized for getting some of the information
that's sequestered in some of these areas to submit
to a group separate and apart as we've set up the
interdisciplinary pharmacogenomic review group to
do the evaluation of these and begin to synthesize,
really, a greater association with the clinical
outcomes and so on.
MR. WEBSTER: Yes, I think that's why I
suggested it could be a model, and personally, I,
myself, don't think that there is a qualitative
difference there. But I think that in the sense
that genomics is a new science, a new technology;
its application to drug development versus drug
discovery is something that is perhaps newer; and
also, the fact that there was kind of this safe
harbor concept around the submission of data, all
of those were, I think, if you like, material
facts.
Now, as I say, I think it perhaps is a
model which we could explore, and if, perhaps, in
160
the context of this morning's discussion, the
agency were to create some parallel to the IPRG but
which allowed companies to come in and discuss a
broader context of biomarker research with the
agency, and if that was part of the entire, if you
like, game plan, then, I think that might be a
lever to move this forward.
DR. VENITZ: Wolfgang?
DR. SADEE: There are actually companies
out there that make their business to compile vast
amounts of data of that very nature, for instance,
Iconics. And you not only have array data; you
have 500 assays available for the 500 common drugs
used, and so, that's a business model by itself.
And I would strongly suggest that we get this type
of folks involved in the process, because they have
already integrated much of the information one
would like to use, actually.
DR. BARRETT: Larry, I wanted to come back
to your initial question about the statistics. In
the discussion yesterday, when we got to look at
some parameters associated with sensitivity,
161
specificity, and predictive value, my comment to
your question was I don't think I've seen enough of
that across different therapeutic areas to where
you could make an assessment of that, and they seem
to be very reasonable and applied metrics.
The question I had is, you know, it would
seem to be a good example where you could use some
modeling and simulation to look at what would those
metrics look like if you had good association or
bad association, if you had a high prevalence rate
or low prevalence rate, as well as if the
pharmacokinetics were predictive of the biomarker
or not.
It would seem to be that you could look at
the performance of these characteristics almost
independent of their application to define whether
or not they were reasonable to look at. But to
answer your question, I don't think we've seen
enough of it in a standardized manner, which is,
again, part of the problem of having enough of a
data set to look at across therapeutic areas.
DR. DERENDORF: I liked the proposal that
162
we've heard many times this morning on
collaboration between industry, FDA and academia.
But I think there is a big problem coming our way,
and that is that we are not training enough
scientists in this field. There is a shrinkage of
clinical pharmacology programs, pharmacometrics
programs, a lack of funding in academia, and this
will be a problem. And I think industry really--I
feel it's in their own interest to maybe help
academia a little bit in establishing systems, how
we can provide the training. It's going to be a
problem otherwise.
DR. WATKINS: Sorry, just to bounce around
a little bit, but in the issue of getting companies
to cooperate and sharing data, I'm aware of one
initiative which is the International Life Sciences
Initiative that's been going on for several years
where participating companies are submitting
preclinical toxicity data and safety data in man in
a blinded fashion, creating a database to look at,
you know, markers of predictivity from animals into
man, so that there's at least one precedent for
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that.
The other thing I thought I would just
mention is what Cathy brought up, which is the
drug-induced liver injury network as a potential
for collaboration with industry and the agency.
This is funded by the NIH and the NIDDK in
particular. And these five centers, which cover
about 12.5 million lives, are prospectively
enrolling into the study people who have clinically
significant toxicity due to any drug. And in
addition, they're getting genomic DNA and
immortalizing lymphocytes and getting serum and
liver wherever possible; we're also creating a--and
I'm chair of the steering committee--creating a
registry, and the people agree to be contacted up
to 20 years to undergo genotype/phenotype
correlation studies in focused clinical centers so
that, you know, that seems to me a very nice
potential model for industry to participate;
obviously, we'll be finding out things about their
drugs before they know them, and I'm sure we'd be
open to any kind of collaboration that could come
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down the pipe.
DR. D'ARGENIO: Yes, this comment also has
to do with databases and biomarkers. One of the
real challenges in developing these causal paths
that are mechanistic-based biomarkers is
understanding them and disease progression. And
that is a real challenge, but there certainly are
data out there on just general models of disease
progression, at least one would think, in the
postmarket area, and those data would help inform,
you know, the relevance of biomarkers to follow
disease progression.
DR. CAPPARELLI: I think the last two
comments also focus back on the issue of looking at
the surrogate marker going backwards as well. You
know, one of the issues, even with the disease
state, this is a dynamic issue. You know, looking
at HIV as the example, working in pediatrics, the
surrogates don't work exactly the same.
And so, I think there will be sort of an
evolutionary process of understanding the
relationship, and that is a huge data mining and
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iterative process of working that forward, so, you
know, the concept of looking at some key areas,
especially ones where the clinical endpoint takes
so long to develop, and we may have good
mechanistic reasons to think we have something that
occurs rapidly that we can measure.
And that was the other aspect of HIV, that
the whole research really showed that it wasn't
such a static disease that takes a long time, and
we can see the effect of drugs very rapidly, and
that time differential was, I think, extremely
important in bringing that forward from an industry
and academic standpoint to utilize these tools.
DR. VENITZ: Any other comments, perhaps
on the recommendations that Dr. Wagner talked about
with respect to setting up committee structures to
manage the process?
[No response.]
DR. VENITZ: Any other comments?
[No response.]
DR. VENITZ: Then, I guess, I'm looking at
you, Larry, as the final comment.
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DR. LESKO: So, I guess that means it
brings us to the end of the road--
DR. VENITZ: Right.
DR. LESKO: --for this meeting, and the
closure is stated as a summary of recommendations,
and before I do that, I'd like to not be remiss in
acknowledging the people that helped put this
committee meeting together, and I'm specifically
referring to Hilda Scharen, who's sitting next to
Dr. Venitz; Karen Summers, who was behind me for
most of the meeting, I guess keeping me in line;
I'm not sure why, and Bob King, who has been
helpful in getting all these materials out to the
Committee and my colleague to the left, Peter Lee,
who did a lot of the coordination of it.
We didn't make it easy for this crowd this
time around. We really imposed upon their
administrative support, and I really appreciate
their flexibility in meeting deadlines and going
the extra mile to get everyone who participated
cleared appropriately and within the laws.
As far as the summary of recommendations
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goes, I suppose the summary is really captured by
the voting that the Committee did on the yes and no
questions that we posed yesterday in particular,
and there really isn't much more to comment on
those questions, because I think they did speak for
themselves, although the discussion in between the
various questions were very useful to us in
illuminating the vagaries that we're dealing with
in some of these areas, in particular, the area of
transporters and multiple inhibitors.
What was particularly useful to us was
what I said yesterday: voting aside, the value of
this meeting, the added value of this meeting is
really in the areas that surround the discussion of
the issues. And the discussions in this Committee
meeting were very helpful to us in helping shape
our way of thinking about pharmacogenetics, drug
interactions and biomarkers, and I think that's why
we came here together.
I really enjoyed this meeting. It was
quite an interesting intellectual debate. The
members, even late last night until 6:00, were
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fully engaged. I did miss the after-meeting
discussion last night, but I'm sure it was also
very intellectual, but you were willing to work
hard and late night, and I want to express my
thanks on my behalf, and as Dr. Woodcock had to
leave to go downtown, she asked me to express her
appreciation to the hard work that the Committee
did on her behalf as well.
Well, I think this meeting, we really teed
up some new issues and some challenging topics,
some of which, of course, haven't been resolved.
We didn't expect that: transporters, the
biomarkers, the surrogate endpoints, and I hope all
of you really look forward to further meetings,
where we hope to discuss these issues in more
details as our thoughts come together and as more
data become available.
So in closing, I would like to express my
thanks, thanks on behalf of the Clinical
Pharmacology team that worked to bring the topics
to you. Of course, all of the presenters and to
all of you for your time and public service and
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providing us the intellectual firepower that we
need to resolve these issues. So have safe travels
home; thank you, and I'll turn it back to the
chair.
DR. VENITZ: I agree. I thank everybody
for participating; wish everybody a safe trip home,
and the meeting is adjourned.
[Whereupon, at 11:42 a.m., the meeting was
concluded.]
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