FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

CLINICAL PHARMACOLOGY SUBCOMMITTEE

OF THE

ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

8:28 a.m.

Wednesday, April 23, 2003

Conference Room

5630 Fishers Lane

Food and Drug Administration

Rockville, Maryland 20857

ATTENDEES

SUBCOMMITTEE MEMBERS:

JURGEN VENITZ, M.D., PH.D., Acting Chair

Associate Professor

Department of Pharmaceutics

Virginia Commonwealth University

School of Pharmacy

Box 980533

410 North 12th Street

Richmond, Virginia 23298-0533

KATHLEEN REEDY, R.D.H., M.S., Executive Secretary

Advisors and Consultants Staff (HFD-21)

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, Maryland 20857

EDMUND V. CAPPARELLI, PHARM.D.

Associate Clinical Professor

University of California, San Diego

9500 Gillman Drive

La Jolla, California 92093

HARTMUT DERENDORF, PH.D.

Professor, Department of Pharmaceutics

University of Florida College of Pharmacy

P.O. Box 100494, Health Science Center

Gainesville, Florida 32610-0494

DAVID FLOCKHART, M.D., PH.D.

Professor, Departments of Pharmacology

and Medicine

Indiana University School of Medicine

Division of Clinical Pharmacology

Wishard Memorial Hospital WP OPW 320

1001 West 10th Street

Indianapolis, Indiana 46202

WILLIAM J. JUSKO, PH.D.

Professor, Department of Pharmaceutics

State University of New York at Buffalo

School of Pharmacy

Buffalo, New York 14260

ATTENDEES (Continued)

SUBCOMMITTEE MEMBERS: (Continued)

MARY V. RELLING, PHARM.D.

Member, Pharmaceutical Sciences

St. Jude Children\'s Research Hospital

332 North Lauderdale, Room D-1052

Memphis, Tennessee 38105

WOLFGANG SADEE, DR.RER.NAT.

Chair, Department of Pharmacology

College of Medicine and Public Health

Ohio State University

5072 Graves Hall, 333 West 10th Avenue

Columbus, Ohio 43210

MARC SWADENER, ED.D., Consumer Representative

2235 Dartmouth Avenue

Boulder, Colorado 80305-5207

FOOD AND DRUG ADMINISTRATION STAFF:

SHIEW-MEI HUANG, PH.D.

PETER LEE, PH.D.

LARRY LESKO, PH.D.

C O N T E N T S

AGENDA ITEM PAGE

MEETING STATEMENT

by Ms. Kathleen Reedy 6

TOPIC 3: PHARMACOGENETICS: IMPROVEMENT OF

EXISTING DRUG TREATMENTS

by Dr. Larry Lesko 8

Committee Discussion 28

TOPIC 4: DRUG INTERACTIONS: METABOLISM

AND TRANSPORT-BASED

by Dr. Shiew-Mei Huang 73

Committee Discussion 99

CONCLUDING REMARKS

by Dr. Larry Lesko 124

OPEN PUBLIC HEARING 126

P R O C E E D I N G S

(8:28 a.m.)

DR. VENITZ: I\'d like to call the meeting to order, please.

Welcome to the second day of the Clinical Pharmacology Subcommittee
meeting. We have two agenda items to discuss today, but before we do
that, I\'d like to introduce all the individuals around the table,
starting with Dr. Derendorf.

DR. DERENDORF: Hartmut Derendorf, University of Florida.

DR. CAPPARELLI: Edmund Capparelli, University of California, San Diego.

DR. FLOCKHART: Dave Flockhart from Indiana University.

DR. McLEOD: Howard McLeod from Washington University.

DR. SWADENER: Marc Swadener, Boulder, Colorado.

MS. REEDY: Kathleen Reedy, advisory committee executive.

DR. VENITZ: Jurgen Venitz, Virginia Commonwealth University.

DR. JUSKO: William Jusko, University at Buffalo.

DR. RELLING: Mary Relling, St. Jude Children\'s Research Hospital,
Memphis.

DR. SADEE: Wolfgang Sadee, Ohio State University.

DR. LESKO: Larry Lesko, FDA.

DR. LEE: Peter Lee from FDA.

DR. VENITZ: Thank you, everybody.

Kathleen Reedy, the Executive Secretary, will read the conflict of
interest statement.

MS. REEDY: Acknowledgement related to general matters waivers, Clinical
Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical
Science, for April 23rd, 2003.

The following announcement addresses the issue of conflict of interest
with respect to this meeting and is made a part of the record to
preclude even the appearance of such at this meeting.

The topics of this meeting are issues of broad applicability. Unlike
issues before a committee in which a particular product is discussed,
issues of broad 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. Because they
have reported interests in pharmaceutical companies, the Food and Drug
Administration has granted general matters waivers to the following SGEs
which permits them to participate in these discussions: Dr. Edmund
Capparelli, Dr. William Jusko, Dr. Gregory Kearns, Dr. Howard McLeod,
Dr. Wolfgang Sadee, Dr. Lewis Sheiner.

A copy of the waiver statements may be obtained by submitting a written
request to the agency\'s Freedom of Information Office, room 12A-30 of
the Parklawn Building.

In addition, Dr. Hartmut Derendorf, Dr. David Flockhart, Dr. Mary
Relling, and Dr. Marc Swadener do not require general matters waivers
because they do not have any personal or imputed financial interests in
any pharmaceutical firms.

Because general topics impact so many institutions, it is not prudent to
recite all potential conflicts of interest as they apply to each member
and consultant.

FDA acknowledges that there may be potential conflicts of interest, but
because of the general nature of the discussion before the committee,
these potential conflicts are mitigated.

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 interest of
fairness that they address any current or previous financial involvement
with any firm whose product they may wish to comment upon.

DR. VENITZ: Thank you, Kathleen.

As we did yesterday, we are going to have an introduction of today\'s
topic by Dr. Larry Lesko. Larry.

DR. LESKO: Thank you and good morning, everyone.

Yesterday during my introductory comments, I had said that we would
discuss today the topic of pharmacogenetics and more specifically how it
applies to improving the existing therapies, and in fact we\'re going to
do that.

Following my introduction to that topic and the subsequent discussion,
we\'ll move into the second topic that I mentioned yesterday which would
be metabolism and transporter-based drug interactions. We\'ll be
discussing some aspects of that that we\'d like the committee to weigh
in on and to discuss as well. And that will be Dr. Shiew-Mei Huang.

Well, as I said, I\'m going to discuss pharmacogenetics in the context
of improving existing drug treatments, and leading up to this discussion
yesterday, I mentioned actually three agency-wide initiatives. I thought
it pertinent to mention a fourth sort of initiative that has been
recently announced in the last day or two and that was a new draft
guidance that\'s been released by our Center for Devices that relates to
pharmacogenetics. The draft guidance from CDRH is entitled Multiplex
Tests for DNA Markers, Mutations, and Expression Patterns.

I think as we look to the future and as we look to the future
possibility of companies developing genetic test kits for consideration
by the agency for approval, this guidance has a significant impact on
that. That, of course, then relates to how such test kits, depending on
which genetic test they might be focused on, would impact the use of
them in improving existing therapies. So I wanted to bring that to your
attention before I move forward with today\'s presentation.

Well, I think it\'s interesting we are in the month of April and it\'s
in April that is filled with milestones related to pharmacogenetics.
We\'ve been bombarded really by celebrations of the 50th anniversary of
the discovery DNA\'s helical structure. While we were all at dinner last
night, there was a terrific show, which I taped and can share with you,
on the discovery of DNA on the Public Broadcast station, and I\'m
looking forward to seeing that.

It\'s also the announcement from Dr. Francis Collins of the completion
of the 10-year human genome project and what the next 10 years is going
to hold. I think it\'s interesting that one of the emphases that he\'s
placed on genomics is the translation of this information into medicine
and therapeutic practice which is really the interest that the agency
has as well.

Finally, a little known fact is it\'s the 50th anniversary of the
revision of the Webster\'s New World College Dictionary, which is a
milestone for that.

It caused one to reflect about DNA and dictionaries because in each
case, there\'s a unique combination of letters that form texts and that
text, in turn, informs us to become more knowledgeable. As the
dictionary brings in its 50th anniversary new uses and meanings of words
that we\'ve commonly held our belief in, the genome with its commonly
thought combination of letters and sequences is really by comparison
only in its infancy and we have a lot to learn about what it all means.

Well, I want to bring everyone back to a discussion we had in October of
2002 at the first meeting of the advisory committee. We opened up the
topic of improving existing therapies with pharmacogenetics picking on
one example from the thiopurine family of drugs, that being
6-mercaptopurine. I didn\'t show this data at the time in October, but I
wanted to share with you today the increase in the number of
prescriptions for 6-MP over the last six or seven years.

It\'s interesting, looking at this slide, you can see where the
prescription use of the drug is in all indications or all off-label
uses, where the growth is in the area of GI use and where 6-MP is used
in terms of prescriptions in the area of oncology. You can see some
trends clearly in the direction of increasing use over the years, and we
don\'t quite know where that will end up.

So I guess the point of this that it\'s not a small issue to look at
existing therapies and how they can be improved in terms of their impact
on public health. However, everyone should recognize that the approved
use for 6-MP is in the area of oncology and in contrast, thinking about
that slide I just showed, much of the use of this drug is off-label for
things like in the GI area, inflammatory bowel disease, and a whole
series of autoimmune diseases ranging from rheumatoid arthritis to
multiple sclerosis.

Well, last time we came together, we talked about the metabolism of 6-MP
by thiopurine methyltransferase, TPMT. This enzyme is actually not well
described in the label for this product. If you look in the clinical
pharmacology section, you would not recognize the information I have on
this slide. What this slide illustrates at the top is all the newly
diagnosed ALL patients, acute lymphatic leukemia patients, both adults
and children that we have each year, and that number is 30,000. It\'s
not a huge number. Obviously, there are other diseases that have greater
prevalence in the population, but nevertheless you have to think about,
in some ways, the off-label use of this drug and the number of
prescriptions being used.

What we do know in the case of ALL patients is that there are three
major genotypes, and the ones that are of concern and are at high risk
for toxicity to this drug are the two on the left, the homozygotes which
have none or low TPMT activity and in the middle the heterozygotes and
intermediate activity. In that box, I\'ve illustrated, based upon the 1
in 100 and the 10 or 11 percent of the population that fall into those
boxes, the number of patients that one might anticipate each year that
would fall into these boxes.

This is a well-established metabolic pathway and polymorphism in the
metabolism. We know that three major SNPs ‑‑ this is a single gene
variant ‑‑ define these mutant alleles, the common ones being \*3A,
\*3C, and \*2. The remaining allele, \*3D is in linkage disequilibrium
with \*3A and travel together so that capturing the major alleles for
predicting or risk stratification is not a difficult task.

But I want to think beyond the 6-MP for a moment. We\'ll come back to
it. But it brings us to think about other genetic tests and how we\'re
going to deal with these as the science moves forward. I mentioned the
guidance in my introductory remarks. There are other polymorphic enzymes
that we might think about, not that they\'re similar to 6-MP, but they
pose similar questions and similar issues as we move forward in trying
to improve existing therapies.

One might think, for example, of cytochrome 2D6. 30 percent of
prescription drugs are metabolized by this enzyme. Polymorphism is well
known. There are both retrospective and prospective trials that indicate
poor metabolizers, the so-called phenotype of 2D6, have a higher risk of
adverse events, and I\'ll show some examples of that in recent labels.

So they move forward with at one extreme an example like TPMT, a
relatively small target population, to the other extreme, a cytochrome
2D6 with a large number of drugs and millions of people taking these
drugs. How do we advance the science to improve therapeutics with drugs
that are affected, in terms of their exposure, by the polymorphism in
these enzymes?

That\'s broadly what I\'d like this committee to think about, and at the
end of the day ‑‑ not today, but at the end of thinking about this ‑‑
we\'d like to develop at least a general approach to these
polymorphisms, that we don\'t have to deal with them case by case
necessarily but rather have a broad perspective on what is important in
thinking about these enzymes, the polymorphism, and translating that
into medicine. What\'s the paradigm? What\'s the structure that we can
ask generally, as well as specifically, of these examples?

Well, I\'ve put on a general paradigm here. Is this what we should be
thinking about with TPMT and 2D6? The three important things in my mind
might be analytic validity, the manufacturing, the instrumentation, the
performance of the test. How accurate is it in identifying a DNA
sequence?

The clinical validity. This might refer to the clinical effectiveness of
the test. How accurate is it in producing a clinical outcome. The
clinical outcome might be predicting the genotype.

The third criteria is clinical utility. What is the likelihood that this
test is going to lead to improved health outcome. If I had information
from the test, can I alter treatment in a way that would improve
therapeutics? We don\'t want approve here at FDA. We don\'t want to see
tests in genetics in the marketplace that have no clinical value. And I
think that\'s an important paradigm.

This looks simple, but what are the details that underpin this and what
are the important things that we should be thinking about in assessing
validity and utility and so on? It seems to me the analytical validity
is relatively straightforward, but the validity and utility in a
clinical context may not be. What is the evidence for that? Can it be
retrospective, prospective, circumstantial? We have to think about these
issues to advance it into, for example, product labels.

Now, going back, thinking of these general criteria, let\'s talk about
the screening of the TPMT genotypes. As far as the test goes, it appears
to be reliable and accurate. I won\'t present that data today, so I
guess you\'ll have to rely on what I\'m saying. But there\'s virtually
no false positives or negatives that I can tell from a
homozygous-deficient patient. We\'ve spoken with people who perform
these tests. We\'ve looked at some data that they\'ve provided, and this
seems to be true.

Well, what about evidence of clinical validity and utility? Well, this
is some data that might be representative of the type of information
that would support updating, for example, a product label. This talks to
the clinical effectiveness of a test and its clinical utility. On the
left-hand side is a chart that shows the cumulative incidence of 6-MP
dose reduction due to toxicity, and what\'s impressive is that on the
far left-hand side, with the mutant alleles v/v indicated, that 100
percent of patients would develop toxicity on the usual doses of 6-MP.
That\'s evidence of clinical effectiveness.

As far as clinical utility goes, on the right-hand side, what do you do
about it? Well, the right-hand side shows the average final weekly 6-MP
dosage that would be appropriate for these patients. It shows the dose
reduction. So I have a test that\'s clinically in identifying those
patients who would develop toxicity. I have clinical utility because on
the right I can reduce the dose if I have that information in hand. So I
see a thought process there, and maybe this is the way that we need to
think about this in general.

Of course, there are other issues associated with this example. I
indicate in the box interrupting therapy is an important issue in terms
of recovering from toxicity. That lessens the intensity of treatment
which seems to relate to event-free survival in these patients. And also
the reduction of the 6-MP dose in the face of a poor metabolizing
genotype allows for full dosages of the other chemotherapy.

Well, this is very clear for the homozygous patient. The data on the
heterozygous appears to be important, but there are some questions that
remain and we have to address those as we move forward.

This is further evidence of clinical validity and utility, at least in
my mind, and it shows the percent of weeks that full doses that were
tolerated by patients. Again, you can see color-coded on the left is the
homozygous mutant allele that has no activity of TPMT, and the
toleration in terms of number of weeks is relatively few. That\'s an
issue, of course, in terms of maintaining the intensity of therapy.

So these are data from the literature, and it might cause one to think
about, for example, with other enzymes of 2D6, is the data in the
literature sufficient to to provide evidence that would warrant its use
in improving existing therapies.

At the October meeting, we did discuss this issue. We probably didn\'t
give it enough time in terms of what we had. But as far as screening
goes, we talked about the test very briefly. Today I\'ve shown some data
on the utility and validity, and this might represent the type of
evidence that we think about going forward.

What we did talk about in October as well was to reflect upon the
current label for this product and just imagine how a label might be
improved with the integration of new information about genotyping. I
presented a proposal, an example for people to think about as to how
this information could be incorporated into the clinical pharmacology
section of the label. To appreciate the difference, one would have to
have side by side the current label, which I said is deficient in its
description of the role of TPMT. And I showed this section, clinical
pharmacology. I showed something that might conceivably represent an
effective dosage and administration section for such a label.

I think the important part of this label, not the exact words per se,
but it conveys to the prescriber and to the patient two important
things. It conveys, number one, a prevalence. It tells me that this is
more than a rare ‑‑ I don\'t know what \"rare\" means in a label, but it
tells me how frequently I might encounter this problem in using the
drug. It also gives me some idea about what to do about it if I identify
such a patient. I think that\'s the hallmark of an effective label. It
completes the information package for the user.

I went back to the transcript to remind myself what the committee ‑‑

DR. SADEE: Is this for prescribers or for patients?

DR. LESKO: This was a proposal as an example of label language, but I\'m
assuming it\'s not only for prescribers, but it\'s also for patients.

DR. SADEE: One may want to have simpler language I think.

DR. LESKO: That\'s certainly another topic.

Going back to our committee meeting, I did want to remind what the
committee discussed at that time. They said for TPMT and 6-MP, there\'s
considerable enthusiasm ‑‑ this was the summary part of our meeting ‑‑
and considerable use for having genetic tests ‑‑ we were talking about
the label ‑‑ although there are some scientific and clinical issues
remaining.

With regard to what I had just shown you, the proposed labeling seems to
be a very logical positioning of the information, as well as the type of
information.

We did discuss relatively briefly the issue of screening and
intervention. This wasn\'t necessarily a specific question to the
committee, but it was intended, using this example, to begin our
discussion of how you position genetic testing in labels for drug dosing
purposes.

For example, one option is to say all patients prior to receiving 6-MP
would receive a test that would identify the genotype, and then a priori
a lower starting dose would be used. A product that falls into this
category a little bit different than this one is herceptin. A test is
done for HER-2 overexpression before the drug is prescribed.

A second option is to think about a test that might be used not a priori
but either concurrent with or following the initiation of therapy. A
test might be used in the case of reason, overt signs of toxicity, and
the issue there is what\'s causing it, and is this, in fact, something I
can do something about in terms of drug dosing or is it perhaps another
drug in the regimen.

We discussed these two issues relatively briefly, and with regard to
that, the committee summarized that by saying mandatory testing in the
absence of clear pharmacoeconomic analysis is too early.

Interestingly, there have been two articles on the pharmacoeconomic
analysis of TPMT testing in the literature. I believe one of the two
came after our October meeting, and that might be worth looking at in a
future meeting.

Further, the committee said that the test for TPMT increases awareness
that there is a problem and that something can be done about it. As one
member said, I don\'t think that\'s too much to ask. I think there\'s
enough data to support that sort of thing.

In terms of trying to generalize this type of consideration, it seems
very likely that it would be done on a case-by-case basis. That\'s
probably very true. But while we think about this on a case-by-case
basis, can we also think about it in a broad paradigm of questions that
we would ask of a genotype of a genetic test for the purposes of drug
dosing and then segue down into the specific case?

So I\'m looking to sort of get input on a broad paradigm and then what
would be important on a specific case-by-case basis, taking into account
obviously the risk-benefit considerations for the drug, the types of
efficacy and toxicity, not unlike what we talked about in yesterday
morning\'s session dealing with different dosing strategies to optimize
therapeutics.

Well, I want to bring you back then to the relevance of this topic, and
it relates to the FDA initiative that I presented yesterday, Dr.
McClellan. Well, he\'s talked about this further, and in the Washington
Drug Letter, reporting on one of his recent presentations on April 13th,
he said that new therapies will be developed with genetic or phenotypic
tests that can identify these populations and detect patients who need
different doses or are prone to certain toxic effects.

We have been conducting informal discovery research of the FDA database,
and this is an example of some of the results of the genotyping or
phenotyping that we\'ve uncovered in our IND and NDA database. The trend
here doesn\'t necessarily indicate increasing usage of genotyping or
phenotyping, but what it does indicate is our increasing discovery of
submissions to the agency that contain this type of information. And you
can see, as of August, it\'s not a small number. We have a fair amount
of INDs and NDAs that have mentioned genotyping or phenotyping.

When you look at how that breaks down, something really jumps off the
page here, and that is most of what we\'ve seen in the submissions are
related to 2D6. Almost three-fourths of the genotyping or phenotyping is
related to 2D6, but not to exclude other applications which are on the
bottom in smaller percentages, and how this will continue to play out in
the future might be very interesting.

Keeping 2D6 in mind, let\'s look at a recent example of pharmacogenetic
information in a product label. I\'ve selected for the example a drug
for attention deficit disorder. It\'s atomoxetine, or Straterra. This
was approved recently by the agency. It is a substrate for 2D6 and based
on the evidence that we had, the label reflects how we\'ve linked 2D6
genotypes with various aspects of the product label. For example, a
fraction of populations are PM resulting, and you can check the label
yourself, but I wanted to give you a sense of where the information
appears. So it appears in the human pharmacokinetic section of the
label. It appears in the drug-drug interaction section of the label.
We\'ve included information on the adverse reactions related to poor
metabolizers and extensive metabolizers, and finally there\'s
information in the laboratory tests section. So relatively speaking,
it\'s a genotypically rich label that hopefully will allow for optimal
use of this particular therapeutic agent.

But it brings me around to the central question that I have. That was a
new drug with new evidence, a new submission. But how can existing
therapies, drugs we\'ve approved in the past 20-30 years, be improved
with the new knowledge that genetics provides us?

So existing therapies. I\'ve defined the therapy. Why is this important?
Well, it\'s important because of the problem of adverse drug reactions.
I\'m not sure if you\'ve seen in the recent edition of the New England
Journal of Medicine a new report that indicates 1 out of 4 patients have
a side effect to drugs. 10 percent of those are serious. 39 percent were
avoided, and a certain percent, which I can\'t remember but relatively
high, was related to too high a dose.

We have a problem of variability in drug toxicity in the population and
it raises the question is some of this attributable to pharmacogenetics,
and if it is, it seems like we have in our hands a tool to apply towards
reducing this problem, not only in terms of human suffering, but also in
terms of pharmacoeconomics of public health care.

We have some evidence that pharmacogenetics is important. This was from
a study in JAMA that looked at 27 drugs frequently cited in the adverse
drug reaction literature. I think what was important here is that 59
percent, or 16, of these drugs were metabolized by at least one enzyme
with an allele that causes poor metabolism. Thinking about the database
at the agency, similarly 69 percent are metabolized by a specific
enzyme, 2D6. And in contrast, we took a randomly selected number of
drugs. Only 7 to 22 percent of those were metabolized. So the
circumstantial evidence points towards pharmacogenetics being a factor,
not the only factor, but a factor that perhaps we can think about doing
something about.

Well, how are things working in translating genetic science into bedside
medicine? I don\'t know, but I did search the new version of the PDR
recently, and I wanted to address the issue of how many labels in the
PDR include pharmacogenetic information. Think about the history that we
have behind us, 20 years since we\'ve identified some significant
polymorphisms. What I found was that 51 labels out of several thousand
contained information on genomics. When you do see this information in
the label, for the most part it\'s not translatable into the bedside
practice of medicine.

There are challenges moving forward, and as we talk about including
genetic information in the label for the purposes of drug dosing, in the
discussion and debate of that, frequently people will ask what is the
evidence. I think the evidence for including information in labels for
older products is something we have to think very clearly about.

Will we need, for example, well designed and well conducted prospective
investigations of analytic validity and clinical utility? That would be
a challenge in terms of previously approved medication. Who would do
that research?

How about a systematic assessment of evidence-based research in
peer-reviewed journals? Would that be a standard of evidence to think
about in terms of including information in product labels?

What about opinions and evaluations professional associations and
consensus groups? Is that evidence that could be considered in
integrating genetics into therapeutics?

Premarket searches for pharmacogenetic factors influencing risk-benefit.
We do that now with currently submitted NDAs. We probably did not ask
the question as much as we do now, say, five years ago.

And we\'ve begun to look at the FDA post-marketing reports of adverse
events for selected drugs that are candidates for improved therapeutics
by the integration of genetic information.

So this is a body of evidence, and it\'s not going to, obviously, apply
to everything, but it\'s going to apply in different cases, and we might
want to ask you to think about this evidence. What are the standards
that we ought to be defining for improving existing therapies using
genetics?

Well, that gets me around to some of the topics for discussion. What\'s
next? I tried to present the current situation as best I can with regard
to the genetic area for drug dosing? \"What\'s next\" means what is the
systematic way of thinking about this question and what are the issues
as we move forward in thinking about substrates for these polymorphic
enzymes and starting to look for evidence that would help us decide
whether this information would be or would not be helpful for drug
dosing and improving therapeutics in public health.

The second question might be what level of detail of genomic data should
be included in the label. Is it enough to simply say poor metabolizers?
Poor metabolizers are simply a phenotype. Would the data be more
informative recognizing that many people read product labels, not just
physicians and not just patients, but people that want to apply
information in many other ways.

So I\'ve indicated there are a couple of options. Is phenotype enough?
Should we be more specific in the alleles that were investigated, say,
within a clinical trial? Should we talk about enzyme activity, a
percentage of activity that might be associated with a wild type
situation? What about the PK information? Is it knowledgeable or
informative to link alleles with area under curve, say, in a table,
allele frequency, mutation? These are different depths of information
about the genotype that we\'ve begun to think about as being appropriate
for a package insert, and we might like your opinion on that.

The third question relates to where you might think this information
should be contained in the package insert. Where would its location be
effective? We already know that location is important, like in real
estate. If it\'s buried somewhere in certain sections of the label,
it\'s not very apparent to people and practitioners. So where should
this information appear to have the impact that it\'s intended to have
in improving drug dosing?

So these are the questions for the committee, and I look forward to your
input and advice on these. Thanks.

DR. VENITZ: Thank you, Larry.

Any comments by committee members?

DR. SADEE: I think you really have defined the problem very well. I am
concerned ‑‑ or not concerned. I think we have to consider that P450 is
not the typical example. So in the case of P450s we have accumulation of
non-mutations in the human population that on top of it directly affect
drug metabolism or drugs in a way that is obvious. I think this is the
most unusual case.

So if we take 2D6 as the star example that we then expand to other
examples, I think we may actually be in trouble. The majority of genetic
variations will be quantitative. The majority will likely be in
regulatory regions where you get a little more or a little less enzyme
or receptor or signaling molecule. So I think that would be an important
consideration to begin with that. If we start out with 2D6, this may not
be the template for the whole field.

DR. FLOCKHART: I guess I\'d make two comments. First of all, in terms of
translating the pharmacogenetic science into bedside medicine. And this
gets to this central issue of its application in clinical practice,
which I think we\'re very close to. I mean we\'re going it a little in
research centers and a little connected to a number of small companies
around the country, but we\'re on the edge of a much wider application
that has really important implications for public health, and I think we
need to think about this very seriously.

There are two general observations I\'d make. One is that I\'m very
concerned as a clinician that the standard of evidence being applied
here for the requirement for a test may well actually be much, much
higher, almost a quantum higher, than is applied to many of the normal
tests that clinicians use in everyday practice. I point out as a doctor
a vast amount of the information one gets as a physician is gray
information. It\'s not black and white. It\'s not an absolutely clear
mandate to do this or to do that. It\'s something that you integrate
into all the other things about an individual patient, the patient\'s
size, the patient\'s gender, the patient\'s disease status, the
patient\'s other drugs that they\'re taking. These are things that you
integrate into a larger picture, and that\'s what medical practice is.

If we try and generate tests that are so pristinely studied and so
carefully economically worked out, A, it\'s going to cost so much that
it\'s going to be impractical to do that with all tests. And B, at the
end of it, you\'re not going to end up with a test that really has any
greater impact on the practice of medicine. There are many tests, like
for example, the PSA which is a test of prostate specific antigen which
is widely used by cancer physicians around the world, but which has
relatively low specificity, relatively low sensitivity. The potential
benefit of some of the pharmacogenetic tests we\'re talking about for
patients is very remarkable when compared to tests put in the same ball
park like the PSA or, indeed, the BRCA testing that we use for a small
minority of patients with breast cancer.

So my first concern is that the committee set a series of standards that
are not only practically but economically and clinically unattainable.
So we need to set standards for these tests in the context of standards
for other tests that are applied.

Now, that gets me directly to the question of what specific information
should be included in the label, because it gets to the quality of the
testing. I think that there are two separate processes here. There are
going to be FDA-approved tests that are not FDA-approved tests at the
moment, but in the description of those tests, it would seem to be
incumbent upon the companies and the research centers involved to
describe the alleles that they\'re testing for and to communicate that
information.

Personally I think the location in the label of specific allelic
information and very specific genetic information that relates really to
how the test is done, what alleles are tested for and so on, would be
overkill. And that partly derives from my concern, the concern we all
have, about there being too much information in labels. And I\'m
cognizant of the fact that people are working on that and that we\'re
moving towards labels where there will be a specific section that is
very clearly, in appropriate language, aimed at patient information.

In that section, there should be something that talks about the
availability of pharmacogenetic tests I think, and there should be
something that talks about the phenotypes. Personally I don\'t think it
should get into allelic detail and that should be information that\'s
provided in terms of a description of the test.

The second concern that I have ‑‑ and I want to just put this on the
table for discussion ‑‑ is in relation to pharmacogenetic counseling. Do
we say anything in the label about a pharmacogenetic test is available?
You should consult or there are people available to provide this kind of
counseling. This derives in part from a major concern that I have
because I think in the gross picture here, what\'s going to happen is
there are going to be a relatively large number of people, relatively
suddenly in the history of things, wanting and using these tests.

Now, if you think about it, what you need to provide counseling ‑‑ I\'m
talking as someone who has tried to do this ‑‑ to a patient for a
pharmacogenetic test is you basically need a lot of information about
the drugs. You need to know the side effects of the drug you\'re dealing
with. You need to know the effects of the drugs you\'re dealing with.
You need to be familiar with the trials involving that drug. You need to
be very familiar with the drug interactions involved. And it is not
simply enough to be a genetic counselor. You can\'t do this without a
lot of information about drugs.

So there\'s a separate discussion I think that needs to take place about
how that needs to be done, and that should not be part of the FDA\'s
concern or something that we would mention in the label I think. But it
is a concern that I have that suddenly we\'re going to have a large
number of patients needing this, and there frankly are not enough
people, by a long shot, to explain this kind of information clearly to
patients.

DR. McLEOD: Going back to some of the general framework that is needed
for this, I think there are two specific issues that we need to come up
with some kind of general language for.

First of all, in my mind the most critical component to any of these
tests, whether they\'re genetic or otherwise, is in genetic parlance the
penetrance. In other words, how often does this variant really result in
the predicted outcome? So, in other words, with TPMT homozygous
mutations ‑‑ how often does that result in a severe or life-threatening
toxicity from standard doses of mercaptopurine? In that particular
example, it\'s nearly 100 percent.

But for many of the other examples, it will not be that. There will be
other components that come into play. As a matter of fact, I think many
of us who are involved with TPMT and other examples have come across
people who were prescribed thiopurines and had a homozygous variant
genotype but did not have toxicity for issues related to things such as
drug adherence. So they weren\'t taking the medicine, therefore they
didn\'t get toxicity even though they were genetically predisposed to
get the toxicity, reflecting that there is an environmental component,
i.e., actually taking the medicine, that contributes to that. So it\'s
not just bad genes. It\'s bad genes with the wrong drug that lead to the
outcome. So that knowledge needs to be there.

That\'s a framework that can be for any genotype, pharmacogenetic or
otherwise. Certainly with the genetic testing for familial disease,
that\'s a big issue, as to how often does this gene really cause the
phenotype. So that needs to be sorted through.

The other part is that I think we need to define ‑‑ I don\'t know the
language we should use ‑‑ the goal much more realistically. The goal in
my mind should be we need tests that allow us to do better, and that
isn\'t very quantitative. It\'s also not very objective. But it really
is where we should be going. So right now, if you\'re prescribed
mercaptopurine, you have testing performed on you. It happens to be a
liver function test, a panel that is performed, in order to decide
whether to go forward. Liver function tests are usually ordered prior to
purine prescription.

So there\'s already testing being performed in order to decide on dosage
to some level and also whether the drug is going to be used at all. So
the concept of using testing for thiopurines is old. Just in this case,
TPMT offers a lot greater precision than something as nonspecific as
liver function tests.

So in my mind simplistically TPMT testing, as an example, is much more
precise and useful than liver function testing because it gives you a
more quantitative endpoint, something you can actually do with the
results, rather than a qualitative endpoint such as liver function
tests. If they\'re high, you don\'t give it, that sort of thing.

So if we could somehow, as a committee, come up with that sort of
framework whereby we can decide whether a test really advances the
precision, that is a good thing. The goal of getting 100 percent
predictability every time for every test in my mind is unrealistic
because we\'re talking about polygenic diseases, polygenic metabolic and
transport pathways, and also we\'re in a world where genes aren\'t
everything. There\'s plenty of environmental components that will have
no genetic basis. So I think 100 percent predictive testing is not our
goal, but rather doing better than we\'re currently doing should always
be the goal.

DR. RELLING: I\'d just like to congratulate Larry because I think he did
an outstanding job of summarizing these issues. In fact, he addressed
the issues that you\'re talking about with penetrance and clinical
utility in his slide where he talked about separating out analytical
validity, clinical validity, and clinical utility. So I didn\'t hear any
requests that the tests be 100 percent predictive of the phenotype, and
in fact, including information about just how much of the clinical
variability you think might be accounted for by genetic testing was
exactly what he presented. So it sounds to me like the FDA is already
considering all of the issues that you brought up, and I don\'t see
those as any kind of problem whatsoever. That\'s how penetrance would be
accounted for by any sort of ‑‑

DR. McLEOD: The testing community, though, has the desire of 100 percent
sensitivity, 100 percent specificity. To me that is unrealistic in the
context. If we know that someone has a 6-fold risk of toxicity, that
often is a test that has maybe only a 60 percent selectivity and
specificity. But if we know that someone has 6 times the risk, which is
more than TPMT brings, then we would alter the therapy. I think that\'s
what I meant. I totally agree with you that what Larry has summarized
hits it.

But if we can be very clear on some suggestions on the goal. The goal is
not the usual lab medicine specificity/sensitivity issues, but rather
better guidelines on how to actually use this stuff. So often people
look at genetic tests and look at it in the old lab medicine way and
say, oh, it\'s not sensitive or specific enough. Well, it\'s still
useful. It\'s better than we currently are doing, and our goal should be
to do better and not to meet certain minimum guidelines for a device.
That\'s the point I was trying to make.

DR. RELLING: I see. I agree with that statement.

I think that the issues of separating out how well does a genotypic test
predict observed phenotypes and then how well does the genotypic test
predict the larger clinical outcome question both are the kind of data
that would be useful to have in the label, if available.

I thought that the examples that you gave of where the label information
was were all useful places. Like you say, for a clinician trying to get
at it, having things cross-referenced under multiple sections is good.
The other place where it might be useful to have pharmacogenetic
information would be, I think, under warnings and under the dosage,
especially where there\'s data to indicate the dosage could be
individualized or at least thought to be individualized based on
genotype.

You talked about how to get information for changing labels based on
existing pharmacogenetic data, and I thought those were all good places
and good things. Looking at the peer-reviewed literature, talking to
professional associations, and getting consensus guidelines, asking
specifically as new drugs come to market, whether genetic predictors
have been evaluated and whether there are known polymorphisms in the
targets and the transporters and drug metabolizing enzymes I think would
be helpful.

The last thing that you mentioned, the thorough evaluation of FDA
post-marketing reports of adverse events, I would have more concern that
the lack of information about post-marketing adverse events should not
be taken as evidence that there\'s a lack of a problem because in many,
many cases these things are so well known in the scientific literature
that clinicians don\'t consider them to be reportable events anymore. I
know that that happened in the case of TPMT, that those events may not
have been reported to the manufacturer or the FDA, but they were well
known in the literature and by clinicians.

And at the end, you mentioned where in the label should genomic data
related to drug metabolism be included. Like Dr. Sadee said, I would
just be careful about ‑‑ I think many of the genetic polymorphisms that
we may end up needing to refer to in labels are not going to be just
drug metabolism. So let\'s not limit ourselves to that because I think
there will be examples with transporters and receptors. There already
are examples of targets and receptors that could probably benefit by
being included in labeling, for example, the thymidylate synthase and
the methylene tetrahydrofolate reductase polymorphisms.

Then on the issue of whether TPMT testing should be something that takes
place preventatively prior to patients receiving the first dose or a
posteriori after a patient has exhibited toxicity, I think really
depends on the details of the particular treatment protocol. As an ALL
therapist, I could give you examples of that.

If you were going to give 6-mercaptopurine the first time in a
relatively mild and uncomplicated two-drug regimen, you might be willing
to observe the patient, see if there\'s toxicity, and then do TPMT
testing to see whether it\'s 6-mercaptopurine or the other drug. But
many ALL regimens will have the first time the patient receives
thiopurine in a very complex regimen with five or six or seven
myelosuppressive agents and if a TPMT-deficient patient would receive
those five, six, or seven agents, along with mercaptopurine, they might
have very severe myelosuppression and it would be impossible to figure
out what the cause of that myelosuppression was. It could be
myelosuppression that lasts for weeks or even months, compromising the
initiation of further therapy. So for that particular type of drug
regimen, it might make more sense to test patients a priori. In other
regimens, it might make sense to test them later.

So whether the FDA wants the labeling to get into that level of detail
or not, I don\'t know, but I think that\'s the reason that there\'s
debate in the oncology community about whether to do this proactively or
a posteriori, and it\'s because it really depends on the details of
therapy.

But I think it\'s terrific that you\'re considering this agency-wide,
and it looks to me like you\'re thinking about it in the right way.

DR. FLOCKHART: I have to really congratulate you also, Larry. I think
putting this together ‑‑ and there\'s a lot of information you\'ve
provided us that is new. But I think it also indicates the level to
which the agency is energized about this. The way you have organized the
thinking about it, I totally agree with Mary in congratulating you in
putting it together.

Just two little things to add to try and respond to your questions. I
think that in the label, there has to be something that describes the
size of the change, and this gets to the question ‑‑ it\'s relevant to
Wolfgang\'s first comment I think. And I wouldn\'t agree with you in
that sense that 2D6 is not a good paradigm to go forward with because
the 2D6 size of change is very remarkable, and in that sense, it is
something that promotes a useful example for other drugs and other
polymorphisms.

But the size of the change ‑‑ and this is for thinking about all the
prior drugs, not for new drugs, this huge problem, which ones do we
consider revising the label. And I would say this. If there is not a
clear polymorphic distribution ‑‑ in other words, not a skewed
distribution, but a clear change ‑‑ then that\'s something that\'s
really hard to start upon. It\'s not impossible, but that might be a way
of separating out the drugs and polymorphism combinations that are worth
going after.

Of course, the other way of thinking about that is where there are very
significant clinically important adverse events or, for that matter,
loss of efficacy that occur as a result.

I\'ll stop there.

DR. SADEE: I also wanted to say once more that I\'m very excited about
the prospect of having genetic information brought directly to the
prescribers and to the patients. I think this opens an entirely new era,
if you wish. So this is a very important step, and therefore, like you
said, Larry, we have to be very careful as to exactly what goes into the
labels and actually what does it open up for us.

I fully agree with you, David, about the need for genetic counseling
because once you put a single piece of genetic information into a label,
there are, the more you think about it, multiple implications. Let me
give you just an example. These implications are legal, economic, health
outcomes, et cetera.

If we come back to 2D6 and an example that would be fairly clear, as far
as I know, codeine is an allogenic drug that has to be activated by 2D6
or it won\'t work in patients who do not metabolize it through the
active ingredient. That appears to be fairly clear. So here\'s an
example that\'s nearly an all or none.

What would be important is if we were to include with codeine a
description that if you do not respond, what are the implications? Well,
now we have a situation where we might imply this is a poor metabolizer.
Alternatively, if we would have known or we would have genotyped, this
person doesn\'t have activity for 2D6, then automatically we are obliged
to provide information that actually 20 percent of the drugs this person
may have trouble with. And that\'s a pretty big implication right there.

In addition, if codeine doesn\'t work, oxycodone might not work because,
to my knowledge, it\'s also activated by the same gene. Nevertheless,
physicians will just go to oxycodone, prescribe it. It doesn\'t work
either. The pain is going on and it\'s actually aggravating the
situation.

So each single piece of information that we introduce has a whole host
of further implications that if we phrase it carefully, introduce it
carefully, must then engender a much greater capability of doing genetic
counseling because it will become very, very important very quickly.

There\'s one more aspect to that. The cytochrome enzymes, for instance,
have associated with them disease susceptibility, and so the question
is, is there a responsibility to extend this and to say, if you have
this genotype, you may be at greater risk, for instance, when smoking
and getting lung cancer? We have to have some kind of a clause that if
we introduce the first genetic piece of information, there should be
some kind of a clause in there saying, if there is this type of
information, it\'s important in more ways than one and there may be some
things in terms of genetic counseling.

DR. FLOCKHART: I\'d just say that the word needs to be pharmacogenetic
counseling because everything you said was really related to a drug. I
will put it on the table. I don\'t think simple genetic counseling is
enough for this, but again, it\'s not particularly on the subject.

I have a concern about putting the metabolism of multiple other drugs in
as a consequence of a particular genetic phenotype for two reasons. One
is that 2D6, 2C9, and 2C19\'s experience have all shown us that the same
genetic variant does not mean the same things for all drugs. For
example, 2C19 which has a huge effect, a 10-fold effect, on the exposure
to omeprazole is basically clinically irrelevant. It doesn\'t mean
anything. It\'s not a useful piece of information. It helps a little bit
in terms of treating Helicobacter, but it\'s not something that\'s
become widely used, even though it\'s been carefully examined. But
certainly for a patient taking omeprazole, they wouldn\'t notice any
difference whether or not they\'re a 2C19 poor metabolizer.

On the other hand, it\'s very obvious to an individual patient who\'s
taking diazepam and who\'s heavily dependent on 2C19. They get
completely knocked out for a long period of time when there are genetic
variants. So there are different consequences of an individual variant
for different drugs.

So I think we have to be very cautious about making a statement in the
label like, for example, because you\'re a 2D6 poor metabolizer or
because you carry a TPMT poor metabolizer phenotype, it follows that you
will have sensitivities to a large number of drugs. I think we need to
have specific criteria for what those drugs would be, for obvious
reasons. One is we\'re talking about cross labels here, just as you
would in drug interactions. So if you raise it with one label, you have
to consider it with the other label. That makes the process considerably
more complicated. But I think some criteria for what that list of drugs
should be is something we ought to try and provide.

DR. SADEE: I don\'t think I really wanted to put something specific in
other than to say that knowing this phenotype has broader implications
than usual, discuss with your prescriber, to a patient. I think that
would also bring the ball back into the court of people ought to know
these things. There will not be clear enough examples. If it applies 100
percent to codeine, it may apply 50 percent to another drug and it may
be irrelevant to a third one. But that\'s exactly the type of counseling
that one would need. Some people are more sensitive to drugs. There must
be a system behind this, and we\'re getting to the bottom of that
system. So I think that\'s possible to include in some fashion.

DR. McLEOD: I think in terms of the field of applied pharmacogenetics,
your comments are very true. I think in the context of the label, the
precedent is that just because there is a variable that affects one
drug, you don\'t have to mention everything else. So if you look at
renal function, you can clearly indicate that impaired renal function is
important for drug A, but you don\'t have to say anything about the
other 400 drugs that it also will influence. Now, behind that is the
more readily available knowledge that impaired renal function will
affect a lot of things. So I think that gets to what you\'re talking
about, that there\'s an education issue that is dependent of the agency
that needs to take place to try to sort some of this out.

If there\'s a clear drug-drug interaction or a clear basis whereby a
genetic variant for drug A will be important for a drug that is commonly
co-administered, then I think there\'s precedent to follow to try to
develop that into a label. But otherwise, I think it\'s going into a
very important clinical applied area but not necessarily an area that
needs to be in the label.

DR. RELLING: I\'d like to echo Dr. McLeod\'s comments. I completely
agree. We should be careful not to treat pharmacogenetic information as
completely different ancillary clinical laboratory information that we
have in deciding how to individualize medicines for patients, and the
renal function example is a really good one. It has broad implications,
but it\'s not part of the label and it doesn\'t prevent us from putting
that information in the label that all of the implications of having
renal dysfunction, having liver dysfunction, having diabetes, having
other comorbid conditions. The complexity and the far-reaching
consequences that having a genetic polymorphism might mean doesn\'t
preclude us from using that information, and it shouldn\'t be held to a
much different standard than any other laboratory information that goes
into the label is.

DR. VENITZ: Just to follow up on that, I think we have to separate what
the label for the drug of interest should say and what the label of the
test should say. A lot of things that you were talking about I think
should be in the label that goes along with the test because it tells me
how to use the test and what the limitations are. I think that\'s where
the information would go not only about false positives and false
negatives, but also things like what\'s the positive and negative
predictive value based on the prevalence of whatever you\'re testing
for. So the kind of information that as clinicians we expect of all of
our tests to be readily available.

Now, to go back then to your question, Larry, about what information
should be in the drug label, because I think that\'s what we are to
focus on, I\'m not sure whether you need that specific information.

What I\'d like to see is, number one, there is a polymorphic receptor
drug-metabolizing enzyme or transporter involved in the kinetics of the
drug, that there\'s evidence to suggest that.

Number two, that there\'s evidence to show that that has a consequence
in terms of the side effect profile or the lack of efficacy and what
those consequences are and that there is a way that you can test for the
genotype of that particular enzyme, transporter, or receptor.

I think it\'s those three pieces of information that should be there,
and I\'m not sure whether you need to list specifically the alleles even
if it has been studied as part of the clinical program or specifically
the pharmacokinetic consequences quantitatively because I think then
you\'re putting the burden of interpreting the results on combining that
information with the test because it\'s the interaction of the two that
leads one to change treatment if necessary.

DR. FLOCKHART: So you would go just with simply putting, as I was saying
at the beginning, the phenotype.

DR. VENITZ: Yes.

DR. McLEOD: I do think that the frequency information brings a lot to
it. It doesn\'t have to be the frequency of each individual genotype,
but for the TPMT example or for the 2D6 example, knowing that it\'s 10
percent makes someone at least pay attention. There are many examples
out there where if you look at the ultra-rapid metabolizer genotype for
2D6, it\'s 1 percent or so, and a lot of people might just say, oh,
well, if we ever come across one of those people, we\'ll do something
about it. But it\'s such a low frequency, they won\'t bother. Now, if
you\'re one of those people, it\'s a big deal. 10 percent. That\'s a
fairly large amount of your practice. If that number is robust, then I
think it would add something.

DR. VENITZ: I agree with that, but the reason why I would agree with you
is because it has significant consequences. Lots of times, even knowing
the prevalence, if the consequence is headache or whatever the side
effect profile looks like, it may not be relevant. And I\'m concerned
that we are already overfeeding information into the label that is very
difficult to interpret.

DR. DERENDORF: I think there should be two pieces of information,
frequency and magnitude, so that one can assess the situation. How often
does it happen, and if it happens, how bad is it?

DR. SADEE: If you bring frequency into play, then you might also have to
bring into play ethnic differences there. Clearly they are so large in
some cases between different ethnicities, that once you mention these
frequencies, it may necessary to do that too. One would like to possibly
avoid this. But it\'s an issue we need to consider.

DR. FLOCKHART: There is precedent for that in labels. Specifically in
the label that\'s on the screen right now, what level of genomic data
should be included in the label? I think if something is very common in
African Americans like the 3A5\*1 variant or is relatively rare in
African Americans like the 2D6 variants, that\'s worth putting in. If
that data is robust and there is a clinical consequence, it is worth
putting in.

DR. McLEOD: I think having the range of frequency that is found in, in
this case, the United States population, because this is the FDA for the
U.S., is useful. Putting the specific ethnic groups I do not think is
useful for two reasons. First of all, it gives someone an excuse to
forget about it or try to put it out of their mind in certain groups.
Oh, it\'s only 2 percent in African Americans; therefore, I won\'t even
think about it.

Also, there are so few components of the U.S. population that have been
evaluated that we could focus on the European American and African
American groups, Chinese American or Asian American in general, which is
a very heterogenous population often not evaluated, Hispanic Americans
are usually not evaluated, and then the huge numbers of others. So if
you have a range, if there is a robust range, then that\'s fine, but if
you start actually pinpointing the ethnic groups, then you might as well
list the ones you haven\'t tested as well. Often the range that is seen
with the more common ethnic groups in the U.S. does reflect the range
that is there in general.

I guess my worry is people now are trying to figure out whether
ethnicity should or should not be a component of medical decision
making, and I think we all have our opinion. I don\'t know that
including specific ethnic groups would be in a patient\'s best interest.

DR. SADEE: But that addresses also the cost-benefit issue. So there is a
limit as where you say beyond a certain frequency, that\'s where it
actually becomes cost effective through genotyping. So if you can define
a range of frequencies very precisely that you can assign to an
ethnicity, then yes, it could well be that in this case, let\'s say, for
Mexican Americans, it may not be worthwhile to do it, but for Asian
Americans, it may as a whole because it\'s cost effective. I think that
needs to be considered too. So the cost effectiveness is one that will
play a major role. You will only implement something that you get more
out of, you get a real benefit compared to the cost you have to put in
because the overall energies you can put into health care is limited,
and you take away from something else.

DR. McLEOD: That\'s a test issue not a drug issue. PSA is only ordered
for half of the population in the U.S. Females don\'t get PSA testing.
It turns out there\'s no reason to. So choices are being made on other
endpoints. Currently only breast cancer has HER-2 evaluation because
it\'s known to be more frequently amplified in breast cancer and
therefore of more utility. So what you mentioned about having a distinct
group, in that case a tumor type or a gender, is currently used in terms
of decision making.

Even though you could test HER-2 for every tumor type and see if you
find somebody that\'s amplified in lung cancer or whatever else, you
don\'t because of the limited utility, like you mentioned. But that\'s a
device issue rather than a drug issue. I mean, herceptin labeling
doesn\'t indicate much about that, as far as I know. It\'s more the
actual HER-2 test that reflects it.

DR. RELLING: Yes. I was just going to say I didn\'t hear it said that
the FDA needs to consider cost effectiveness of testing in its decision
of whether to mention the availability of pharmacogenetic testing for
individual drugs. I can\'t see how that would really be appropriate for
the drug label because those costs are constantly changing and the costs
of the test may change a lot depending on how its used. So I agree that
that might be part of a clinician\'s decision making, but I don\'t think
that that\'s really relevant to the labeling.

The other thing I was just going to mention because I\'ve heard
HER-2/neu testing being used as an example of how patients are tested
before it\'s decided whether to give them the specific drug, and that\'s
analogous to what would be done, for example, for TPMT testing and the
decision of whether to do that before giving 6-mercaptopurine. But there
is a difference, and some of that genetic testing like HER-2/neu testing
has implications as to whether the medication will work at all depending
on the results of that genetic test. So you might save the patient
inappropriate use of a medicine that wouldn\'t work by having
information on negative expression of HER-2/neu.

Whereas, at least as far as we know, for TPMT testing and for lots of
other pharmacogenetic testing, it wouldn\'t be a decision as to whether
the drug has any utility at all with the exception of your example you
gave of some narcotics and 2D6, but just a matter of how to dose the
medicines. So I think that\'s why there can be a little gray area as to
whether pharmacogenetic testing would have to be recommended prior to
prescription of the drug at all versus a posteriori after seeing how the
patient responds to the medicine.

DR. FLOCKHART: I think you have to think about what the label is for.
The label is to guide prescribers and to help patients. The label is
about a drug. So I think that information about the incidence, as we
said many times, is important. It makes a huge difference whether
something is .1 percent frequent or something is 20 percent frequent.

Personally I think there are situations where the ethnic difference is
so extreme, Howard, that I would disagree with you. There is such a
marked difference that you can\'t just throw out race. You can\'t say it
doesn\'t matter because in both the patient\'s and the physician\'s
decision about that drug ‑‑ not about the test specifically, but about
that drug ‑‑ it makes a difference whether they\'re African American or
they\'re Asian or they\'re caucasian if the difference is sufficient. We
need to talk about what sufficient is. It\'s not 1 percent. It would
have to be a very notable difference I think. There are situations where
ethnicity might be included in the label, and I think it\'s not useful
to say, Howard, that we haven\'t studied every sub-ethnic population
within the United States because what you would include would be
information about where there is a large difference where it really
would be useful in clinical practice. So if I\'m looking at an African
American, that\'s something ‑‑ let me make an extreme example. Something
that was 30 percent incidence in African Americans and 1 percent in
caucasians, that\'s a different decision for a patient and a different
decision for a prescriber.

DR. McLEOD: I agree with you, but what about other common groups that
aren\'t evaluated? That\'s where it starts falling down. For example,
2D6, the ultra metabolizer genotype is much more common in populations
from an East African heritage compared to a lot of the other
populations. But maybe Indian and Pakistani populations also have that
high frequency but just haven\'t been evaluated carefully. Maybe other
groups.

So it\'s positive information, but I think guess what it\'s missing is
there as well. Taking it and saying I\'m only going to test African
American subjects because they\'re the only ones that have the higher
frequency is not useful. That\'s what I\'m afraid of. If it\'s dictated
too carefully, people will say, oh, that\'s the only time I need to
look.

DR. FLOCKHART: That\'s a language question. You can put it in language
that says other populations have not been carefully studied, but
there\'s a positive here.

DR. SADEE: What policy you will be setting is going to lead into the
future for a number of years. This is initiating a new trend.

I would like to bring up a consideration that actually technology will
outrun what we\'re discussing right now so that the prospect of having
your computer chip embedded where all the relevant SNPs are available is
not that far off. But in the area of drug metabolism or
pharmacogenetics, within 3 years you will not have a single test. If you
order a test, the cheapest way, this is only going to be one, two, or
three years away. The test will include 20, 30, or 40 or 50 SNPs
depending on how fast we do this, and that information will be
instantaneously available to all those who prescribe and to the patient
as well. It will be economically inefficient to do a single test because
the controls around the test are such that just doing the test is
extremely expensive, but adding 1 or 20 or 100 new SNPs will become
trivial.

That\'s why I brought in the implications of once we add this in,
there\'s a whole slew of new things that are coming our way. If we only
talk about the label, of course, we won\'t include this, but we must be
cognizant that this is coming very, very rapidly, and if we open
Pandora\'s box and seeing the single piece of genetic information there,
in three years this single piece will be a very complex piece of
information provided to all. That needs to be safeguarded. That needs to
be privatized in such a way it cannot be utilized elsewhere and so on.
So all these issues. It\'s an enormous issue and it starts right here
with setting the proper policy.

DR. RELLING: Well, this wouldn\'t be the initiation of genetic testing.
There are genetic tests that are being done all the time for factor V
Leiden, for MTHFR, for Gilbert\'s disease with UGT1A1, for G6PD
deficiency. So this has been out there for a while. I don\'t want people
to overreact to the idea that by just mentioning a few genetic
polymorphisms in relevant drug labels, it\'s opening a flood gate to
genetic information that hasn\'t been present for the last 10 or 20
years. There is precedence for having genetic information, using it in
specific ways and specific clinical information, and providing
clinicians with useful information for how they treat patients that\'s
not going to have overnight overwhelming sea change in patient care
related to genetic information if the FDA decides to have a more uniform
policy on how to incorporate genetic testing into drug labels.

DR. SADEE: Well, I think it is a sea change for drug therapy. There are
small pieces coming into play, but within the next few years, there will
be a sea change. That\'s how I see it coming.

DR. RELLING: I will be delighted if in one or two or three years we have
accurate genotyping information on tens or hundreds of SNPs. We\'re not
finding that it\'s all that easy.

DR. FLOCKHART: This is something where I heartily agree with Mary
actually. I\'m very concerned about how rapidly we move here, and I
think it has to be done very carefully. Again, I think Larry set out a
very nice rubric for doing it. But because we\'re doing it carefully ‑‑
and I think a lot of the conceptual issues with genetic testing have
been dealt with by things like G6PDH, even cholesterol. So it\'s not new
conceptual things, and I\'m nervous of calling it something big like a
sea change.

Really, these are genetic tests. They\'re not new. They\'re laboratory
tests. They\'re not new. They\'re tests that influence pharmacotherapy.
They\'re not new. These things have been done before. It\'s an evolution
to me rather than a sea change.

DR. LESKO: In the context of thinking about the broader paradigm that I
mentioned in my slides, there\'s another element to this. It gets to
perhaps prioritizing or thinking about the best clinical value for a
test. I can think of two different types of drugs that are based on how
they\'re used in therapeutics.

At one extreme we might have something like a thiopurine with a TPMT,
where there\'s a clear distinction between the activity of the drug in
the genotype.

Another example might be a drug like dilantin or phenytoin. I believe
it\'s a 2C19 substrate, but when you begin therapy with it, there\'s no
immediate response, either efficacy or safety. There\'s some time that
it takes to respond to that drug.

Contrast that maybe to a beta blocker, say, metoprolol where you\'re
using it for hypertension. So you see an immediate antihypertensive
response and can react to a dose adjustment based on an easily measured
phenotype. Warfarin with 2C9 substrate, polymorphic, but I can use an
INR.

So I guess my question sort of revolves around how to think about
priorities for a genetic test improving drug therapy in the face of
having or not having easily measured phenotypes that I can use as a
titrator of dose. It\'s sort of trial and error, but it\'s trial and
error in the context of being able to look at response readily.

This isn\'t a small question because I mentioned last week\'s New
England Journal of Medicine or JAMA, one of the two, with the new report
on adverse drug reactions. But again, like other reports similar at the
top of the list in terms of frequency were the antidepressants and the
beta blockers and drugs that are typically polymorphically metabolized.

So where do you think this vector of titrating a drug versus not
titrating a drug in a sense, a dilantin versus a beta blocker, come into
play in the thinking about a genetic test improving therapy?

DR. FLOCKHART: I always seem to have an opinion about these things.

First of all, I think that the availability of a phenotypic test does
not mean that a genetic test is useless. The phenotypic test often takes
considerable effort and is often not perfect. One nice thing about
pharmacogenetic tests is you do it once and hopefully if it\'s done
well, you don\'t have to do it again.

I could go through the specific examples that you mentioned, but
they\'re illustrative actually. In the case of phenytoin, the difficulty
with phenytoin prescribing is as one gets to the therapeutic
concentration, there\'s a risk that as you increase the dose, you
saturate metabolism and you go off the proverbial therapeutic roof. And
having seen this happen with a few patients, that is what it feels like.
So there\'s an issue there of although you\'re often measuring phenytoin
concentrations, you still get a big surprise when you change the dose,
and that\'s listed as an adverse drug reaction and that can cost a lot
of money.

I could make similar arguments with warfarin. You follow warfarin all
the time, but the way we normally do warfarin is we test INR a few days
after we make changes because we know it takes a while.

And in real clinical practice, I think we have to put this in the
environment of regular medical care in the United States. It\'s not easy
for people to see a physician. It just isn\'t. And it\'s not easy often
to just schedule an absolutely easily timed test for therapeutic drug
monitoring be it by phenotypic kind of changes like INRs or be it by
drug concentrations.

So I think more information available to physicians and prescribers in
general ‑‑ and that would include pharmacists and psychologists and so
on ‑‑ is only a positive thing in the prescribing process and an
addendum. An addition of a genetic test on top of an available
phenotypic test in general is not something I think contaminates the
prescriber\'s efforts. It enhances it.

DR. SADEE: I would just like to raise one general issue as a cautionary
note, and that is recently ‑‑ well, not just recently. There\'s a
recognition that gene expression, regulation and so on is not
necessarily related to a primary change in the DNA so that a SNP
analysis will tell you whether there\'s even a change in regulatory
agent. Most of those SNPs we don\'t even know. But there are many other
phenomena that are epigenetic, gene silencing, histone acetylation, et
cetera that could actually last over many cell generations or in an
individual. Now the first article has come out that this may actually
override many of the genetic changes.

So I just wanted to have this on protocol that we\'re cognizant of the
SNP analysis is just one of the many ways that one could assess
phenotypic variation and evolution across a population or within the
same individual as a function of environmental impact and so on.

DR. McLEOD: I think the framework that we\'re talking about will
encompass genotype, haplotype, gene expression profile, if there is a
profile A versus profile B, silencing, non-silencing, methylation,
non-methylation. If we do it right, whatever the means, it will be
useful.

I think it\'s already in place in a way. Going back to the renal
function example, below a threshold ‑‑ and it\'s different for different
drugs ‑‑ there are warnings about the implications for that. And it may
be the same thing. It may be that there\'s a reason in the future that
gene expression profile A patients are at higher risk of toxicity or
lack of efficacy, and if that data is as robust as we\'re talking about,
then it will be able to fit right into this framework because when it
comes down to it, the utility of these tools, regardless of whether
they\'re biochemical tests, a molecular test of any ilk, a protein-based
assay, we have to be able to stick a label on a person to then use it.
If they\'re in cluster A ‑‑ that cluster may have 33,000 genes in it ‑‑
they are cluster A patient, therefore their risk is X.

So I think the same framework will be useful because you\'re right.
We\'re talking about genotype today. We\'ll be talking about those other
things tomorrow or in the future, to be more precise. So I think getting
the framework right this time will then allow all the rest of it to just
slide right through.

DR. VENITZ: Just two points to follow up your comments. In the very
article that you mentioned, it is not apparent whether the genetic
testing would have made any difference because they didn\'t really
separate out drug-drug interactions, and the very drugs that you
mentioned are also prone to drug-drug interactions.

The second thing, more importantly for the discussion that we\'re
having, a lot of those studies that find an increased incidence of side
effects, let\'s say, usually find as the main reason for that is that
the information is available. It\'s not being translated in practice. So
it\'s not like we don\'t know it. It\'s not like we don\'t have the
genetic tests whether they\'re in the label or not. People don\'t know
how to use it or they don\'t use it. So there are systemic flaws.

I think maybe at a later point in time, we ought to discuss this. How do
we communicate that information in a way that it makes a difference, not
just in a way that it reflects the best science that we know of and all
the uncertainties involved, but in a way that it actually makes sense to
the prescribers that are not necessarily highly educated in those areas.

DR. LESKO: Those are both good points. We didn\'t talk much about it
today or even in our October meeting, but we are working on a guidance
that would encompass label language that at some point, when it\'s in a
suitable form, we might bring to the committee to talk about
representative language for including genetic tests in a label.

I did want to bring up another dimension because I think there are many
small bridges that we have to cross as we progress and move forward. I
don\'t think it would be appropriate to be thinking about cost
effectiveness in terms of a genetic test if it\'s important to public
health, although you can\'t ignore that and how it factors in the
thinking. We have to acknowledge that it does in some ways.

But probably more important in the context of a label with a
pharmacogenetic test is the test availability. It wouldn\'t make sense,
for example, to put a test in a label that physicians can\'t access if
they read the label and then choose to use it in applying it to their
patient. We are somewhat in a bit of transition in the sense that none
of the pharmacogenetic tests have been submitted or approved by the
agency. So we\'re dealing with a community of testing laboratories that
I\'m not quite sure what the availability of testing is, let\'s say, for
cytochrome 2D6, and if the sites are widely available for physicians to
access, what the quality of that report is from that laboratory. I
wondered if people had any thoughts on that aspect of what we\'re
talking about today.

DR. RELLING: I mean, you\'re right. It is an issue. I guess I don\'t
quite understand what is the percentage of specialized tests that are
done in health care or even non-specialized tests that are FDA-approved.
Is that something that is the vast, vast majority of laboratory tests
that are used? I don\'t think that it is. So the fact that there aren\'t
pharmacogenetic tests that are yet FDA-approved shouldn\'t be something
that would prevent clinicians from utilizing them.

I guess the Internet helps a lot because now it is relatively easy for
any of us to type in CYP2D6 genetic testing and probably come up with a
list of companies that are doing that. Maybe not as many clinicians as
need to know do know that they should look for things like CLIA approval
or CAP approval for the test that they\'re going to use as some sort of
external imprimatur that there\'s some basic quality control.

But making that information available to both clinicians and to patients
is a challenge, and I don\'t know whether the FDA wants to take
responsibility for that or not. But those of us in this field deal with
it daily, that physicians and clinicians and patients want to know about
how they get genetic testing done and it\'s still at the point where
it\'s not easily ordered by any clinician anywhere they\'re practicing
and taken care of by the therapeutic drug monitoring lab or the
pathology lab that handles processing orders.

So although that is definitely a hurdle that needs to be overcome, in
the case of TPMT testing and CYP2D6 testing, at least for now, it looks
like those tests are probably here to stay and widely enough available
that they should be available to clinicians if they are mentioned in
package labeling.

DR. FLOCKHART: I do not have an opinion about this, what I\'m about to
say, one way or the other, but I just want to put it on the table. It\'s
whether it\'s appropriate for the agency to talk about actually
counseling in a label or not in the sense of we haven\'t don\'t this
with G6PDH, we haven\'t done it with other things. Is the smell of this
beast sufficiently different that we would want to do something like
that?

I have concerns about the availability of tests without counseling. I
know this has been carefully dealt with in the HIV area. So I would
welcome a little bit more discussion at some point about that.

DR. LESKO: I was thinking about another aspect of product labels, and I
recently searched the PDR for indications of therapeutic ranges for
drugs, how many labels indicate that and what we say about that.
There\'s actually a fair amount of drugs for which we recommend blood
level monitoring, and not much is said in the label itself about
interpreting blood levels other than this might be the therapeutic
range. There\'s no counseling component in labels with respect to that.

It sort of brings you around to the question about genotyping which
actually has some implications for third party reimbursement, and that
is, what do you call it? Therapeutic drug monitoring is looking at a
blood level and then adjusting dose and trying to get a patient in a
therapeutic range where the probability of good things happening is
higher and the probability of bad things happening is lower. It doesn\'t
strike me that it\'s necessarily screening to measure a blood level of
theophylline. It strikes me that\'s more monitoring. And if there\'s an
opinion on this I don\'t know, but how would you think about genotyping?
Is this therapeutic drug monitoring? Is it screening? What is the
appropriate terminology that would be applied to this activity?

DR. FLOCKHART: I think that\'s easy. It\'s case dependent. In the
majority of situations, I think it\'s like therapeutic drug monitoring.
You do it after you\'ve started on a specific drug. There are very few
situations possibly including 6-mercaptopurine ‑‑ I\'d welcome Howard\'s
and Mary\'s opinions about that ‑‑ where there might be a case for
screening before.

DR. SADEE: HIV therapy should maybe set an example because it\'s already
done. In 50 percent of the cases of high intensive therapy of HIV, you
have genotyping. In this case it\'s genotyping of the virus, but it\'s
the same idea. And that is being reimbursed. So I do not know who is
doing the tests and what are the quality controls and who\'s regulating
that, if at all, and how then the third parties decide to reimburse this
on the basis of what criteria. That may be a good example because it\'s
in practice.

DR. CAPPARELLI: At least in terms of the HIV genotyping situation, a lot
of it is actually done after therapy. In a sense the wild type is not
the issue or the sensitivity of the wild type. It\'s the sensitivity of
patients who\'ve already had therapy. So I think it gets maybe again
more towards the model of after therapy is initiated. In clinical
trials, that\'s a different issue, that there is some up front discovery
work being done, but I think for the great majority of this, it\'s
really again being applied after the initial exposure to the drug
classes.

DR. SADEE: There\'s continued therapy and so maybe initially you assume
that it\'s not cost effective to do it right away, but while you go
along, resistance is acquired, so it becomes necessary at one point.

DR. CAPPARELLI: No. It is a necessary component, but it also changes.
It\'s a bit of a different animal than genotyping the patient where
we\'re linking it to what we expect is an exposure pattern that we
expect to be relatively constant over time.

DR. RELLING: I don\'t know what difference it makes for third party
reimbursement, but it does seem that pharmacogenetic testing should be
more closely linked with therapeutic drug monitoring labs just because
the results are definitely interpreted by the people who are monitoring
and adjusting therapy and they may be very closely linked to a
posteriori tests of blood levels of the medications themselves.

And TPMT is a great example. We have a very detailed algorithm for how
we do genetic testing, activity phenotyping, and sometimes drug
metabolite level monitoring, and all three of those things are used in
conjunction with each other in really assessing what the patient\'s
status is. Certainly having all of those tests interpreted by the same
clinicians in a therapeutic drug monitoring laboratory makes sense I
think.

There may be some examples where there are genetic tests performed that
have implications not only for drug prescribing but for other health
risks or other interventions, and some of those prothrombotic genetic
risk factors are an example of that where it may be a bit of overlap
between how much is patient monitoring outside the context of drug
therapy and how much is patient monitoring within the context of drug
therapy. So some of those details are probably going to have to be
worked out over time.

DR. McLEOD: I think therapeutic drug monitoring is a good example of the
spectrum of what we\'re going to see because you have situations like
Mary described where you have very thoughtful linkage between the assay
and the interpretation, and then you have the other extremes whereby a
lab medicine department will measure something and put it onto the
results, and it stops there. Then it\'s up to the individual clinical
team to interpret what it means.

I think that\'s what\'s going to happen with pharmacogenetics. You\'re
going to have situations where you have the whole package where the
patient gets very thoughtful interpretation, and then you\'re going to
have just labs that measure stuff and report a result and then good luck
to you.

We see some of that now with direct-to-consumer marketing of
pharmacogenetics which thankfully isn\'t widespread but is occurring
whereby patients are encouraged to send a chunk of tissue in to the lab
where they can measure some stuff and send results back and then take it
to your physician for interpretation, which currently is not very
useful. We wouldn\'t want to encourage that as the industry standard by
any means, but I think it is and will continue to happen.

DR. SADEE: I think it\'s important that if there were a label on the
drug that says there is genetic variability, then the first important
piece there is not that one should go ahead and do genotyping, but it
alerts the prescriber and the patient to say there is a chance I will
have a very unusual reaction.

That was the same what happened to drug level monitoring initially. One
would want to measure as many drugs as possible and then one could see
the variation across the population. Then people like Lew Sheiner would
come in and say how can we, with that knowledge, apply it to a
population, minimize the risk by just looking at all the factors that we
do know and then suggest a dose which did mean that in many cases we
dropped measuring normal levels because it wasn\'t necessary. The
benefit was not sufficient. The error was so large that it was not
worthwhile doing it.

So just by having a genetic label doesn\'t mean that we\'re necessarily
locked into actually doing the genotyping, but rather that it alerts you
that there could be problems and here is one of the reasons for the
problem with that particular drug. That\'s step number one, and that\'s
all education. That\'s all in the counseling area.

Then somebody needs to decide whether genotyping is appropriate. In a
few cases, one may decide that a priori this drug should only be given
if there\'s genotyping, and this will be a small minority of cases at
the present time.

DR. VENITZ: Any final comments before we break?

(No response.)

DR. VENITZ: Then I suggest we take our scheduled break and reconvene at
10:30 for our last topic.

(Recess.)

DR. VENITZ: Let\'s get started, please.

Our last topic deals with transporters and drug metabolizing enzymes,
and Dr. Shiew-Mei Huang, the Deputy Director of the Office of Clinical
Pharmacology and Biopharmaceutics, will be giving us our final
presentation. Shiew-Mei.

DR. HUANG: Thanks, Jurgen.

What I\'d like to talk about right now, the last topic, is some of the
recent issues and challenges in the evaluation and labeling of drug
interaction potentials of new molecular entities. I\'d like to start to
review with you some of the recently withdrawn drugs from the U.S.
market due to safety reasons, and I also added two drugs that were not
approved in the respective year.

You can see that many of these drugs that were withdrawn had serious
drug-drug interactions. Terfenadine, mibefradil, astemizole, drug X,
cisapride, and more recently cervistatin, and drug Y. Many of these were
associated with serious effects. For example, we have seen cases of
torsade de pointes for drugs that were approved and were on the market
before the approval and also for drugs that are being reviewed. We have
seen QT prolongation. Some of the other drugs the toxicity involved
hepatotoxicity, acute liver failure, bromphenac and troglitazone, and
others such as alosetron, ischemic colitis, serious constipation,
rhabdomyolysis, bronchospasm, and other effects. Drug Y is an inducer
that\'s affecting the metabolism of other drugs. So you can see that
drug interaction is very involved in the drugs that were withdrawn
recently.

What about the drugs that are on the market? As we have discussed
earlier this morning, there\'s a tremendous number of adverse events
every year. There are about 2 million based on these reports, about
100,000 deaths that are adverse drug reaction related, and it ranks
about 4 to 6 of the cause of death in the U.S.. Not only is there harm
for the patients, there\'s economic and health issues related to this
ADR.

So why are there so many ADRs? In the recent study showing that one of
the reasons could be because there\'s a lot of use of drugs or patients
are given polypharmacy. Here this is the total use of individuals. This
use is any use that\'s prescription drugs, vitamins, herbs, dietary
supplements. And here is the breakdown between men and women.

If you look at the most susceptible group, elderly women over age 65,
you can see that more than 50 percent was taking more than five drugs at
one time, and about more than 10 percent were taking 10 drugs at one
time.

In a recent study in \'95, it shows that drug interactions represent 3
to 5 percent of preventable ADRs, and they are an important contributor
to emergency room visits and hospital admissions.

Earlier this month, a JAMA article has done a population-based
evaluation of three co-administration, and they found that ‑‑ this is a
study in Canada in an Ontario population. They showed that elderly
patients with digoxin toxicity, that they are 12 times more likely to be
given clarithromycin. In the paper this contributed to an interaction
that\'s based on P-gp. Earlier reports have shown that this could be
also because of a macrolide that\'s inhibiting bacteria lenton. That\'s
a microorganism that\'s contributed to the metabolism of digoxin to
dihydrometabolites.

In the same article, it has other combinations indicating, for example,
pharmacodynamic interactions, patients that are given ACE inhibitors
with hyperkalemia, and they are 20-fold more likely to have been given
potassium-sparing diuretics. And other one is related to a
pharmacokinetic interaction in patients with glyburide with the
hypoglycemic effect, 6-fold more likely to be given with an inhibitor of
2C9 such as cotrimoxazole.

There are some recent studies showing that this could be related also to
an interaction that\'s OATP based. That\'s organic anion transporting
polypeptide. So you can see there are a lot of interactions based on
cytochrome P450 enzymes or transporters.

What\'s interesting in this article is they also monitor these patients
and see their prescription. They\'re assuming if the doctors know there
is an interaction, then perhaps they would modify the regimen. However,
most of the patients discontinued. So perhaps the doctors do not know
about the interactions, even many of these were stated in the labeling.
For example, clarithromycin. This was stated in the labeling. Even it
didn\'t say P-gp, it mentioned microorganism interaction. So they have
postulated it\'s very likely because either the information was not
updated for some other cases or because there is so much information
overload. In the labeling there is so much trivial interactions that
will pop up in the computer systems that the hospital used, that the
operator just overrides anytime you see interaction.

So I think it\'s very important that we put the information properly in
the labeling. I think this is related to our discussion earlier this
morning. Also our discussion today about a classification system for
CYP3A inhibitors is related also to address the issue and proper
labeling.

In our Office of Clinical Pharmacology and Biopharmaceutics, our good
review practice and quality review, as far as drug interaction is
concerned, we ask several questions. We must evaluate drug interactions
well, especially in the cytochrome P450 area. So much is known and we
are expecting that this be evaluated.

And as discussed yesterday, many of the interactions were
pharmacokinetic based. So how do we interpret the clinical significance
of the drug interactions, such as 100 percent increase in AUC, a 2-fold
increase in Cmax? What\'s their clinical significance? I think we need
to evaluate the safety/efficacy database and explore the
exposure-response relationship, and many of the quantitative approaches
that were proposed yesterday were discussed with this committee.

The drugs that are withdrawn from the market that I showed you earlier.
We found that the Dr. Doctor letters that were sent out later may not be
as effective as we would like them to be.

We think that it\'s important that you use prominent labeling when the
drug is introduced to the market, and we also would like to project a
level of risk in drug interactions. And later on we\'ll address what
approach that we can take.

In addition, earlier on, the committee members already mentioned that
the labeling, even the information is accurate, it\'s important but it
may not be efficient. So I think we need to continue to develop better
means of communicating dosing information to practitioners and patients.
Larry mentioned yesterday about a labeling initiative that the agency is
taking where you highlight important interactions or information in
labeling or we give an additional medication guide to patients. There
are many other ways that we need to do. However, the starting point is
still the labeling. So I think today what we\'re going to talk about is
really focused on labeling.

So what is the optimal information for an NDA submission? Because so
much is known about cytochrome P450, we think it\'s very important, and
this is our guidance document that we have communicated to our sponsors.
We must elucidate metabolic pathways well, the contribution of key
cytochrome P450 enzymes, the fraction that\'s metabolized by those
particular pathways so that we will be able to properly evaluate the
effect of other drugs on the new molecular entities.

In addition, we need to evaluate enzyme modulating potential. The drugs
that were withdrawn from the market or not approved ‑‑ the one that I
mentioned. There are two drugs. Their main interactions is because of
this modulating effect. One is a strong inhibitor of cytochrome P450 and
P-gp. The other one is an inducer. So it is important to evaluate the
effect so that we will be able to understand the effect of this new
molecular entity on the other drugs.

We have several guidance documents that have been published over the
years. With \'97, we have an in vitro interaction guidance talking about
using in vitro metabolic methodology. In \'99 we published an in vivo
interaction guidance, and some of the committee members have been
involved in the evaluation of this guidance. And using the population PK
approach has been addressed by some speakers yesterday to address drug
interaction issues.

And this is important. We have a so-called MAPP. This is like a
reviewer\'s guidance. It\'s a Manual for Policy and Procedures where we
instruct the reviewers, when you have a new molecular entity that we\'re
going to contraindicate this drug with the other drug or that will
result in a dose change of the other drug, that the review team needs to
talk to each other if they\'re from different divisions so that
eventually the sponsor of the interacting drug will be informed, and if
there\'s a labeling change, they will be informed to submit supplements
to effect the change in the labeling.

We have the good review practice, which Dr. Lesko has discussed at the
FDA Science Board a week ago, which talks about what key questions that
we must ask in our NDA review, and that included drug interaction as an
important issue.

The CDER working group right now is working on an in vitro metabolism
because so much has evolved since \'97, and we are having recommendation
of a standardized approach to look at cytochrome P450 enzymes. We\'re
also developing a guidance to look at phase II of metabolizing enzymes
and other transporters such as P-gp. Part of this is being published in
our intranet for reviewers, and we are still developing other portions.

Again, in order to interpret the interaction outcome, the
exposure-response relationship is very important to explore, and this is
an guidance which Dr. Lesko mentioned yesterday.

I\'ll just briefly mention our office\'s good review practice. This is
one paradigm that we have recommended for our reviewers when we review
the interaction data. We say initially we could look at a new molecular
entity and use in vitro method using human tissues or expressed enzyme
for key cytochrome P450 such as 1A2, 2C9, 2C19, 2D6. For each of these
enzymes, we ask the question, is it a substrate or is it an inhibitor or
inducer?

This question is no different than what we asked in \'97 except at that
time we thought the method is only available for substrate and
inhibitor. Now I think we believe the in vitro technology has developed
so that we will be able to also evaluate using human hepatocytes, the in
vitro induction effect.

So if we ask this question based on the in vitro method, if the answer
is no, it\'s not an inhibitor or inducer, then we could stop and we do a
general labeling that that particular cytochrome P450 is not involved.
It\'s not being modulated by this new molecular entity. We would
supplement this with population PK to look at in the patient population
whether there is an interaction that we have missed. Are there other
transporters not screened by this particular method that we might detect
using that approach?

If the information is not available or we said it is an inhibitor or
inducer, then we recommend in our \'99 guidance that we use the most
sensitive substrates, for example, for CYP3A you could use midazolam or
some of the statins or buspirone, the one that\'s shown to be very
sensitive and very large-fold changes when you give an inhibitor. And if
the result is negative, then we could stop there and we can label it. If
the result is positive, then we can continue with less potent inhibitors
or use the drugs that are more commonly co-administered. And I\'ll
address how do we define most sensitive substrates.

So if the drug is found to be a substrate or not to be a substrate,
that\'s another determining factor. If based on in vitro information we
say it\'s not, then we could stop and give a general labeling again and
then use supplemental with the population PK information.

If it is a substrate or the information is not known, then we continue
this pathway and ask another question. Is this pathway major? If even
this drug is a 3A pathway, if it\'s metabolized by 3A but the renal
clearance is the major clearance pathway, then again we say you don\'t
need to evaluate. You can do a general labeling and again use population
PK to pick up unexpected findings.

However, with the event of pharmacogenetics, I think we need to be
careful or be mindful about this approach. For example, if you say this
drug is not a 3A substrate, it\'s a 2D6 substrate, however 3A may become
important in the poor metabolizer. I think recently we\'ve seen some
studies on tolterodine that it\'s a 2D6 substrate, but in poor
metabolizers we found ketoconazole has inhibited its metabolism and
increased the AUC by more than 2-fold.

So again, if the pathway is major or we don\'t know ‑‑ we don\'t have
the in vitro information ‑‑ then we recommended in our \'99 guidance
that we use the most potent inhibitor or inducer to study its effect.
Again, if the result is negative, because a lot of times we don\'t know
the percent contribution of the pathway, then we could stop there and
label. However, if the result is positive, then we continue the path and
use a less potent inhibitor or inducer.

We just show this as one of the paradigms. It\'s not the only way to do
it. However, we think with this approach, we can obviate certain in vivo
interaction studies and only focus on the cytochrome P450 that\'s more
important in the metabolism or in the modulating effect.

I want to talk about here, when we say most sensitive substrate and most
potent inhibitor and relate it to a document which PhRMA has just
published this month in the Journal of Clinical Pharmacology where PhRMA
has proposed a classification system for 3A. I just want to mention.
This is related to our approach as well, but it\'s an extension of that
approach.

In the PhRMA paper, actually PhRMA has ‑‑ we have started a discussion
when they had first prepared this early last year. They propose to use
midazolam as a probe substrate. This one has about 40 percent
bioavailability and it has both intestinal and liver high extraction. If
we use it as a probe substrate and we look at the AUC ratio with the
inhibitor versus without the inhibitor, given alone ‑‑ and these are the
various inhibitors ‑‑ you can see they have different degrees of
inhibition as manifested in the fold change in AUC of midazolam and the
use of boundaries of 200 percent and 500 percent.

So if a drug, an inhibitor, increased midazolam more than 500 percent or
the fold change was 5, then we call that a potent inhibitor or strong
inhibitor. If it\'s between 2- and 5-fold, then it\'s moderate. If it\'s
less than 2, it\'s mild. And with our \'99 guidance, we actually also
have one that says there\'s not an inhibitor if the ratio is between 80
and 125 percent.

So this classification and what is potential use ‑‑ what I want to say
is this has been used to guide in vivo studies. For example, if a drug
is found to be a substrate of 3A, we have been recommending using the
most potent one, and I think this has been commonly done. Again, it\'s
ketoconazole or itraconazole. Most of the time we see ketoconazole as an
inhibitor. However, if the result is positive and the extent of change
is so that you may wonder whether safety data would support that or not,
then you want to continue to study the less potent one to see what\'s
the extent of change. So this has been used. Even we don\'t have a
formal classification system in our review in our discussion with
industry, this approach has been used.

Initially PhRMA has recommended that this system also be used in the
labeling, although in the eventual published paper, it only recommends
that discussion with the regulatory agency on its use in the label.

But since the discussion, we have thought about this use in the labeling
for inhibitor and substrates, and I will show two examples later on how
this could be applied.

In our various discussions, there are concerns raised by individuals in
the working group, individuals in scientific rounds where we have
internal discussion and also with external experts like yourselves. Some
of the concerns that inhibitors may modulate a lot of other pathways,
other cytochrome P450 enzymes, other transporters. And if a compound was
labeled as a potent inhibitor, you\'re expecting a large change with
midazolam or some other substrates.

However, this potent inhibitor may affect other pathways and which may
have opposing effect, may end up with no interaction. One example could
be ritonavir which with alprazolam is a 3A substrate, but yet it may
also affect the glucuronidation induction such that eventually after
multiple doses, you don\'t see an effect. But most of the other
cytochrome 3A substrates, you\'re seeing a large-fold change even after
multiple dosing.

Similarly substrates are not just substrates of one enzyme. Midazolam is
a good example. It\'s a cytochrome P450 3A substrate. It\'s not a P-gp
substrate. But a lot of other 3A substrates are also substrates of P‑gp.
So it\'s depending on how this interaction ‑‑ the classification may not
precisely give us the output of what we would imagine based on the
classification system.

Again, there are multiple drugs being prescribed and we have shown that
elderly women, more than 50 percent, are taking 5 drugs at one time. If
we label a drug as a moderate inhibitor and if this person is taking
five moderate inhibitors, would that affect as potent inhibitors and we
may not catch this if we only look at the potent inhibitors.

In order for the system to work, we need to classify drugs according to
the system. With ketoconazole the data that I showed you, 16-fold change
is only from one of the studies, and there are many studies in the
literature, and the fold change ranges from 5 to 16. So depending on the
study design, the dose, the dosing regimen, so we have to be very
careful when we put the drugs ‑‑ to classify to the system. I think
there are a lot of other concerns. And there are also genetic concerns
on CYP3A, whether the same inhibition for CYP3A4 substrates versus the
3A5 substrates.

So with these concerns, we have several discussions since PhRMA has the
white paper. We have scientific rounds discussion within CDER. And we
have talked about this at professional meetings and open forum at the
American Association of Pharmaceutical Science meeting last year in
Toronto and more recently at the American Society of Clinical
Pharmacology and Therapeutics annual meeting. And Dr. Flockhart was on
the panel and Dr. Vega in attendance also participated in that
discussion.

I\'d like to bring it up again with this committee to see what other
factors we need to consider in implementing this. To facilitate our
discussion, I\'ll have two cases that came from our NDA data but the
data have been altered so that we can discuss publicly. Some of the
labeling recommendations have also been changed since our first
discussion based on the input from the scientific rounds discussion
internally.

So there are two cases I\'d like to talk about. First is the new
molecular entity as a substrate. As I mentioned earlier, based on our
good review practices, we need to ask three important questions. Are
drug interactions evaluated? What are the data? And what\'s the clinical
significance based on the exposure-response relationship? And how do we
label these interactions?

We look at this chart. This compound is a substrate; pathways, major.
And we will get an in vivo with the most potent inhibitor. So if you
look at CYP3A substrate ‑‑ and this is drug A. It\'s given with
ketoconazole. That\'s the most potent inhibitor based on the
classification system. AUCs increase 6-fold and Cmax 4-fold. And if you
look at the other two which has been classified as moderate inhibitors
based on the classification system, the AUC increased 4-fold and the
Cmax about 3-fold.

For this drug and the particular clinical response that we\'re looking
at, we thought Cmax was more appropriate. So we look at the Cmax. And
ketoconazole is a 4-fold increase and erythromycin and verapamil about
3-fold.

There is exposure-response data looking at one of the important clinical
responses, and there was some response relationship. We have not really
modeled it, but if you look at the clinical database, initially the
proposed clinical doses were 15, 30, and 60. And all of those three
doses, the data do support that they are safe and effective. We proposed
to approve 15 and 30 because of the drug interaction concern. The drug
is a linear kinetic, so you can see that there are 4-fold exposure that
we are comfortable with. When we approved 15 and 30, so you know if
people are given 30, there\'s a 2-fold possibility change and it\'s
still safe. If they\'re given 15, there\'s still a 4-fold increase in
exposure that would still have data to support its safety.

So how do we label those interactions? The potential labeling language
based on this data is not to take this drug with potent or strong 3A
inhibitors because you could increase 4-fold or more, and that\'s
outside our safety database.

What are the potent, strong inhibitors? And we have some list developed
up to this point. We\'re still debating what information supporting to
remain on the list or what other drugs that we need to include in this
list. But these are some of them in the PhRMA paper, some of them based
on our current labeling with ketoconazole and itraconazole, and so on.

We said we propose that we use lower doses with moderate inhibitors,
which means give 15. And we do have data with 60, so you can increase up
to 4-fold without any problem. And the moderate inhibitors so far
showing a 3-fold increase in exposure. So they\'re still within the
safety range.

What are the moderate 3A inhibitors? And based on some in the PhRMA
paper some of our internal information, they could be erythromycin,
verapamil, diltiazem, and so on.

The second case is new molecular entity as an inhibitor. Again, we ask
the three questions. The drug interaction is evaluated. What about the
clinical significance of the substrates? Since now we\'re talking about
the new molecular entity as a modulator, as an inhibitor of others ‑‑
the exposure-response information that we would like to have is for the
other drugs, other co-administered drugs ‑‑ how do we label this? This
is the case where it\'s an inhibitor. We want to study with more
sensitive substrates.

The sponsor did follow this approach. So this is drug Y. The study with
midazolam, the most sensitive 3A substrate. Here you show 6-fold
increase in AUC, 3-fold in Cmax. Here we\'re going to use AUC as a
parameter that we look at when we determine clinical significance.

For simvastatin, 8-fold, 5-fold increase in Cmax. Cisapride is 3-fold
increase, 2-fold in Cmax. The drug is not an inhibitor for 1A2 and the
other pathway, 2C9. The sponsor did the study and showed no interaction
with theophylline or warfarin.

So based on the information with midazolam, 6-fold increase in AUC. If
you look at this table, the drug appeared to be a potent or strong 3A
inhibitor. So based on our understanding of the other substrates, the
sensitive substrate or substrate with a narrow therapeutic index, which
are 3A substrates, we look at some of the labeling language in our
existing where the strong inhibitors are contraindicated.

So we look at two cases. One is sensitive substrates. The drug is
metabolized mainly by 3A, and the other one that was narrow therapeutic
range. They\'re softly defined because of their QTc prolongation effect.

So here those are not underlined. We consider they\'re sensitive
substrates: midazolam, triazolam, simvastatin, lovastatin, atorvastatin.
These are some of the drugs that are named in our \'99 guidance as
suitable for study as sensitive substrates because of contribution of
the 3A to the clearance.

And the ones that are underlined, some of them are not on the market
anymore. Some of them are still under IND use. We do have pimozide.
These are drugs that cause QTc prolongation and they\'re also major
contributors for drugs withdrawn from the market in the last five years.
So we\'re still compiling a list to see which are sensitive substrates,
which are substrates with narrow therapeutic index. And drug A, the case
one that I mentioned, may also make this list.

So how do we label this? Since this drug is a strong inhibitor, we think
in the labeling we do want to say that the use of this drug is a strong
3A inhibitor. We actually say in the labeling. Currently we have not
consistently done so. A lot of strong inhibitors in the labeling ‑‑ we
only said that it\'s an inhibitor. We do not mention anything about
strong or moderate. So we thought if we say the use of drug B is a
strong 3A inhibitor is contraindicated with some of the narrow
therapeutic index drugs or sensitive substrates or the co-administration
needs to be monitored such as midazolam or other drugs, sildenafil,
budesonide ‑‑ for those substrates that we currently have in
ketoconazole, itraconazole labeling, and we\'re still compiling the
list. And this is what the working group is looking at. So if we have a
strong inhibitor, what do we put in the labeling? This may facilitate
this information to be used in the computer system that\'s used in the
hospital.

I just want to mention some of the concerns that we discussed, these two
cases. I have discussed these two cases internally in our scientific
rounds and also in ASCPT meeting. In general, I think the feedback ‑‑
then you can comment later ‑‑ is this is an effective way to label an
interaction by indicating that the drug, if it\'s an inhibitor, whether
it\'s a strong inhibitor or moderate or mild or not an inhibitor. And
when we approve a drug which is a sensitive substrate, that we know what
drugs to put in the labeling to contraindicate or to put in precaution.

There are several concerns in that inhibitors may also affect other
enzymes or transporters such as UGT or P-gp transporter.

I just want to talk very briefly on P-gp ‑‑ especially we have seen the
report on clarithromycin and digoxin interaction in this April JAMA
article ‑‑ before we go back to questions for the committee.

The P-gp based interactions. How important it is and how that affects
our evaluation of drug interactions. We know this is an important
interaction based on the various reports.

If we are going to evaluate a drug, whether it\'s an inhibitor or
modulator of P-gp, knowing that there are a lot of inhibitors of 3A also
inhibit P-gp, such as ketoconazole, initially we take comfort that any
drug that\'s a 3A substrate, the sponsor will conduct a study with
ketoconazole. So if it\'s a P-gp substrate, you might see some effect.
So we may be covered in that area.

But what about as a inhibitor? This is the in vitro study showing that
there\'s still some differentiation of inhibitors that inhibit both 3A
and P-gp, but depending on the IC50 ratios, you can see the range from
less than 1 to more than 120 where you can see here\'s the 3A inhibition
effect much higher here compared to PSC833. This may help us to
determine what can we use for in vitro system in the evaluation of
whether this drug is a P-gp substrate.

If we look in the literature, most of the studies evaluating P-gp
substrate use fexofenadine and digoxin as a substrate. And some of the
literature data or the first two examples are based on PDR labeling that
ketoconazole and erythromycin ‑‑ its effect on fexofenadine which has
minimal metabolism and yet it increased the AUC and Cmax.

With itraconazole is shown a similar effect.

With verapamil, this is a recent study that was just presented at the
ASCPT meeting just a couple weeks ago, and this is Steve Hall\'s data
from Indiana, showing that verapamil perhaps inhibited and induced P-gp.
So depending on the time of administration, initially you might inhibit
the P-gp transport. So you have higher levels on day 1 and day 10, but
on day 38, the two interactions canceled out and you did not see a
change in day 38. I\'m interested in seeing more data coming out of
this, but this is something that\'s of interest showing the P-gp effect
on verapamil or other transporters.

On the other hand, we have seen also fexofenadine used to evaluate an
induction effect by rifampin, which you see AUC ratio decreased, or St.
John\'s wort. The data are a combination of various studies and they\'re
a comparison of multiple dose versus single dose, or this is with
different preparations, showing that St. John\'s wort, given acutely,
might have inhibited the P-gp, but given chronically as St. John\'s was
given to treat depression, that it actually induced the P-gp.

What\'s interesting again, this was some data published by George
Dresser and Richard Kim and presented again in the April meeting where
grapefruit juice is an inhibitor of 3A and P-gp here is actually showing
a decrease in fexofenadine levels. One of the possible mechanisms that
it\'s inhibiting OATP, the organic anion transporter polypeptide, which
is an intake transporter. So by inhibiting it, you reduce the absorption
and therefore a reduction in the level. So this put in a question of how
fexofenadine would be an effective P-gp substrate to study, if, as we
can see more and more drugs may affect OATP, whether this is a still a
suitable substrate to study.

The other one is digoxin that\'s often used by the sponsors in their
study. In some of the literature data, these go back 18-20 years on
quinidine and verapamil would increase some of the plasma levels. This
may not be at steady state, but at day 7 or various days after
treatment. I know this verapamil data is not 38-day treatment, so this
is still an increase in the plasma concentration.

And recently with ‑‑ this is a Merck publication with this drug as
shown, using digoxin to show that it has no effect on P-gp. Again, it\'s
the substrate that\'s been used to study induction, and rifampin has
shown a decrease in AUC and Cmax, St. John\'s wort also showing a
decrease in plasma levels, and a grapefruit juice study showing that
it\'s a small increase, a 9 percent increase.

I wanted to share with you some of our surveys. Right now we don\'t have
a guidance that said every new molecular entity must be evaluated to see
if they\'re a substrate or inhibitor, inducers of P-gp unlike the
cytochrome P450. However, we\'re seeing a lot of digoxin data. You can
see based on some of the surveys ‑‑ this was done in \'96 and up to \'97
‑‑ that cimetidine and digoxin are the two most often studied drugs in
drug interactions. Cimetidine was in the past because it was used as a
general, nonspecific inhibitor, and digoxin mostly because the
likelihood of co-administration as a narrow therapeutic drug. So the
sponsors tend to study it. So we do have a lot of digoxin data, except
our explanation of interactions may be different now. It may not be
change in tissue binding distribution. Instead it may be the P-gp
involvement.

So digoxin has continued to be studied, especially if a sponsor is
developing cardio-renal products, antiviral products, but not necessary
in all therapeutic areas. So we have digoxin data even we don\'t have in
vitro data. So my question later on is with the interplay of cytochrome
P450 3A and P-gp, OATP, are we ready to recommend that P-gp as a
standard approach or is it sufficient that this still continue to be
studied because of the likelihood of co-administration. We do have a
MAPP for our reviewers to see if P-gp is going to evaluated, what are
the concerns that we need to look at when we evaluate in vitro data and
in vivo data.

So our next steps ‑‑ that\'s what we\'re doing right now ‑‑ is to revise
our guidance. This is the \'99 guidance looking at drug metabolism and
drug interaction. There are several issues that we would like to address
in our addendum or the revision.

One is to look at the classification system and to talk about it in our
guidance. The feedback we got from the PhRMA proposal, classification
system, has been positive, although in the Toronto meeting, there were
other suggestions of different systems, maybe just strong versus weak,
just two instead of three. And this is further being deliberated in our
working group.

We also need to generate the list of strong inhibitors and moderate
inhibitors and looking at literature data very carefully to see where
would they fit, understanding the concerns of the interplay of the other
metabolizing enzymes and P-gp.

We also want to say something about P-gp-based interaction. That\'s what
we\'re doing right now.

We do have a cross-labeling manual of policy and procedures. We\'d like
to finalize it. Again, we have worked on half of the components of this
manual where we look at CYP induction, inhibition, P-gp, and the phase
II metabolizing enzymes, and we\'d also like to finalize it.

So the questions for the panel based on my presentation. In addition to
the three questions that were in the agenda, what we discussed at our
internal meeting. What are the factors to consider in implementing the
classification system for CYP3A inhibitors in the labeling now that you
know what\'s our present thinking?

And do we need to define the sensitive substrates? Because we do need
the list of the substrates where we could properly put it in the
labeling so that when we\'re approving a strong inhibitor, we know what
to place, what drugs to be put into precaution or maybe
contraindication.

And if you agree with the classification system, should we now ‑‑
important to consider application of a classification system to
inhibitors of other CYP enzymes. We have heard that the adverse events
‑‑ a lot of them are related to antidepressants, calcium channel
blockers. These are 2D6 substrates. Do we want to consider that and
include that in the labeling so we can talk about strong inhibitors as
the substrates?

What about inducers? We have informally indicated that rifampin is a
strong inducer. Rifabutin, rifapentine are moderate based on our study
design. When we talked to the sponsor, if rifampin induced the
metabolism to such an extent that we have to contraindicate, then the
next step is to study rifabutin to see if the alternate
co-administration is proper. So we have done it informally. Is it
important to put the classification system in the labeling to facilitate
computer system in generating possible pairs or combinations of
interaction?

What about transporter-based interaction? Let me give you a limited
update on this. We probably can talk about, in subsequent meetings,
whether we should recommend routine evaluation at this point based on
what we know.

So I\'ll pause right here.

DR. VENITZ: Okay, thank you, Shiew-Mei.

Any questions about her presentation and/or comments in regards to those
three questions?

DR. DERENDORF: Yes. You mentioned several times, rightfully so, that all
interactions have to be seen in the light of the response, that the
exposure by itself really is not the clinical relevance, but it\'s what
it does to the patient later on. But yet, in your classification system,
you focus on exposure. You know, the weak, moderate, strong focuses on
the AUC, independent of what it really means clinically. And I think
there\'s an inconsistency.

Also, the language. A 4-fold increase in AUC ‑‑ to call that moderate,
it may be not relevant, but I don\'t think you would ever call a 4-fold
increase in dose a moderate dose increase. So this language I think
becomes very important, how this is seen by people who are not that
involved in the details.

DR. HUANG: Yes. On your first point, if I show you on our case 1, which
is a substrate, and we\'ve shown that there\'s a 4-fold increase with
ketoconazole and then a 3-fold increase with the moderate. So based on
that information, coupled with exposure response, where we feel that a
4-fold increase we\'re comfortable. I mean, more than 4-fold, we are not
comfortable and that determined our language. So if you have a different
data set where you say 2-fold increase I\'m not comfortable, then we
would have contraindicated the moderate inhibitors as well. Again, it
still comes back to what exposure-response data we have, and based on
the information we have, we\'re only comfortable to increase up to
4-fold. So we contraindicated in this case only the potent inhibitors,
but if the data are different, we could also contraindicate moderate
inhibitors as well.

DR. DERENDORF: I guess what I was trying to say is if you have an
inhibitor, it\'s not the inhibitor that decides if it\'s moderate or
strong, it\'s the other partner.

DR. HUANG: Exactly.

DR. DERENDORF: You can have the same effect that can be very relevant or
not relevant at all.

DR. HUANG: Right, and that\'s why we say we need to come up with a list
of sensitive substrates. So if it\'s a strong inhibitor ‑‑ there are a
lot of sensitive substrates out there, but we may not contraindicate all
of them. And you can see we have a differential ‑‑ we treat midazolam as
a very sensitive substrate, but yet we do not contraindicate it for the
second case because the drug can be titrated based on ‑‑ there are other
information you can use. But for those drugs that prolong QT, we put it
in the contraindication because we\'re sensitized with a lot of
experience from the withdrawn drugs.

And coming back to your question about 4-fold, whether it\'s moderate or
not, this is something we\'re discussing. In our open meeting, we
actually had a lot of questions. How do you determine that 4.4-fold is a
moderate, but yet 4.9-fold, which may be rounded to 5, is potent? How do
you differentiate this to the only .9-fold difference?

I\'ve been thinking about this, and I think this could ‑‑ maybe you can
equate to renal clearance where you said a patient was less than 30 or
20 mls per minute creatinine clearance is severely impaired. The
moderate is between 30 to 50, 30 to 60. And you always have this patient
at 32 versus 28, but they\'re in two different categories.

I think the purpose of putting them into different systems is there
would be precaution and we put it in the labeling. People will be aware
of it. It\'s not that they are going to just give 15 and then not
observe the patients at all. This is just to sensitize the prescribers,
health care providers, or patients that we know.

There is always this debate on the numbers. Should you put 4-fold? And
then we debate 3.5 versus 4.5, or do we put in 5 and debate what is
moderate?

DR. CAPPARELLI: Well, I think the key issue that you addressed earlier
is really the linkage to the substrate, at least in the first example.
It\'s helpful to have these working definitions, and whether or not
4-fold would be considered moderate in a controlled environment where
you\'re sort of maximizing the effects, I think that\'s something that
will evolve.

But I think your point as well in part is linking to the substrate that
you\'re looking at the interaction, and that\'s where the importance
comes. Taking it as a drug-by-drug basis, as you did there, I think is
critical to the process.

The one other question ‑‑ and it may be sort of a minor question ‑‑
relating to this is ‑‑ maybe two questions. One is that there may be
some differences between PO and IV administration, especially with drugs
like midazolam, for instance, where you\'re seeing a huge effect in one
area, and when it\'s given IV for short instances, the effect is not
nearly so great. At least in our working with the pediatric population
in HIV, having a very strong recommendation or a global one that
doesn\'t take that consideration into account really puts us in a bind
of what we can use safely or at least what information is given to the
practitioner and what can be used, where we don\'t see a problem with
having a large interaction as long as we recognize the route of
administration as well.

DR. HUANG: Yes. The classification system right now is based on the oral
midazolam to maximize the effect.

DR. JUSKO: Shiew-Mei, you\'ve done a very admirable job over the years
of managing a very confusing area of trying to make sense of drug
interactions. Sometimes they don\'t make complete sense. Like yesterday,
we saw an interaction where there was a 7-fold change with grapefruit
juice. I don\'t see that particular one mentioned or part of this
presentation. But my question is really something else.

Many pharmaceutical companies have implemented the in vitro screens for
drug interactions, being able to focus on particular cytochrome systems
as a way of anticipating whether to do in vivo studies or not. Have you
had an opportunity to do a retrospective on how well that whole approach
has been working?

And to follow up that, do you anticipate similar possible success in
being able to do in vitro screens of transporters to anticipate which in
vivo studies to do or not do?

DR. HUANG: Yes. As far as the in vitro system to predict in vivo, we did
some cases that we looked at where we have in vitro information and in
vivo. We did publish. This was early on in \'99. And we did find cases
where there are inconsistencies, and fexofenadine is one of the examples
where you show no interaction, and yet when you give it with
ketoconazole, you found a 2-fold increase. And later on we found this
possible involvement of P-gp. So there are a lot of exceptions. Many of
them are because of the P-gp involvement.

However, there are also other involvement as far as I over Ki ratio.
That\'s the one that we\'ve been using from in vitro data to project
whether there is an interaction or not. Right now we\'re just using the
ratio to say okay, based on this one, the number is so small we don\'t
think there will be an interaction. Or the sponsor would have done the I
over Ki. So you have a rank order of different isozymes.

What we often observe is that even all of this I over Ki are very small,
the sponsor still went ahead and did one study. And in that case
actually that\'s used as a reference point. Most often they pick the
most sensitive one, so the one with the highest I over Ki, and that one
shows no interaction. Then we\'re comfortable with the others. And we
have seen quite a few of those cases, though not all of them.

There are also other cases where I over Ki perhaps could not project the
extent of interaction, but that\'s in the area where there\'s a possible
interaction. Whether the in vitro system can accurately project, that\'s
really not our concern because in our guidance that we provided to the
sponsor, only when you don\'t see an interaction, then you can stop
right there.

But if you are projecting an interaction, then we recommend an in vivo
study to quantitate it. So even there are discrepancies in the in vitro
projection versus the in vivo observation, that is okay because the in
vivo study always follows when you see there\'s a possible interaction.

Whether there\'s not a precise correlation, partly could be because the
concentration in plasma may not represent a concentration in the liver.
So what we are recommending in our reviewer guide is to use the most
conservative approach. We use the total concentration in doing our
projection. We don\'t use the free concentration. So we are more
concerned if you use a much higher I in our calculation of I over Ki.

DR. FLOCKHART: I\'d like to, first of all, to take a 10,000-foot view of
this. I think that both you, Shiew-Mei, and the office in general and
PhRMA have done a sterling piece of work here in terms of coming up with
a classification scheme. In history I think we have this huge problem
with information overload about drug interactions, and a classification
scheme is going to help.

And I remember talking about this three or four years ago and everybody
just assumed this would be absolutely impossible. It is to PhRMA\'s
great credit that they managed to get together and put something
together that wasn\'t terribly different from what the FDA came up with.

Personally I think that three categories is appropriate because of the
contraindication issue, but I wouldn\'t go down burning on that. I think
some form of classification is important.

To deal with the specific question of transporters, if I could, again
looking from a fair height, the situation that we\'re in with cytochrome
P450s in vitro is that we have pretty much all the important ones mapped
and we have assays for them. We have specific substrates. We have
specific inhibitors. We have genetic tests. This is absolutely not the
case yet with transporters, and it\'s important because, as we\'re
seeing with the fexofenadine example, we have good assays for P-gp in
vitro. Nobody would debate that we can do that.

What we don\'t have is the full picture. So it\'s almost like we have 3A
but we don\'t have 2D6 and 2C19 and all the others. So it\'s hard at the
moment to recommend at the level of substrates a screening for
transporters for drugs in the same way as we screen for cytochrome
P450s. It\'s hard to recommend that at the moment because we ‑‑

DR. HUANG: Are you talking about in vitro?

DR. FLOCKHART: I\'m talking about in vitro.

DR. HUANG: Okay.

DR. FLOCKHART: On the other hand, at the level of inhibition ‑‑ and
Steve Hall and I reviewed this recently for a review article ‑‑ outside
digoxin it\'s very hard to find something that we believe is a
transporter-based interaction that matters to anything. Now, we have
digoxin. We have quinidine/digoxin is an important thing. We have
clarithromycin/digoxin is an important thing. We have verapamil/digoxin
is probably an important thing.

So if a drug comes along that is a potent inhibitor of P-gp, then if
it\'s likely to be co-prescribed with digoxin specifically at the
moment, I think it\'s a no-brainer to say that you ought to test in
vitro, test for the ability of a drug to inhibit P-gp. That\'s at a
minimum.

On the other hand, there may well be HIV-related drugs, because of P-gp
and lymphocytes, where this is important also.

So I think the importance of measuring inhibition of P-gp transport by
drugs during development is increasing. Screening for substrates of
transporters in general at the moment, I\'m not there yet.

DR. HUANG: And as far as in vitro screening, you don\'t think that
digoxin transport A2B/B2A with various cell systems will be able to tell
you whether it\'s a substrate?

DR. FLOCKHART: Oh, no, absolutely. I think you can tell whether
something is a P-gp substrate, but what you can\'t tell ‑‑ I\'m sorry. I
didn\'t elaborate the example of fexofenadine ‑‑ is what other
transporters it might also be a substrate for. So you don\'t have a full
picture. You might have a very narrow picture. In the case of
fexofenadine, it\'s probably very significantly transported by OATP as
well. So if you simply describe the P-gp story, you\'re going to get
confused, and we have got confused. The grapefruit juice effect on
fexofenadine comes from left field if you don\'t understand that
there\'s more than transporter involved.

DR. SADEE: Yes. I wanted to actually bring up the same point. We have
just completed a survey of many tissues and measured the transport home,
if you wish. So all genes that encode transporters ‑‑ and there are 48
ABC transporters, of which ABCB1 of P-gp is one. So we\'re looking at
one out of 48, and there are several hundred SLC transporters. So the
picture is relatively complex.

Nevertheless, it would appear that P-gp does play a dominant role in
many cases. The problem is that if one then relies on P-gp, sometimes it
fits and it may just be fortuitous. It\'s because there are five other
transporters that have similar substrate affinities and you get the
answer with just measuring P-gp and you wouldn\'t know the difference.
And that could be problematic because then you look at differences among
individuals and you cannot explain them anymore. So there is a bit of
caution.

On the other hand, I would agree that focusing on P-gp at the present
time is probably going to give you quite a bit of information in terms
of what we have seen that each drug correlates. We not only have just
looked at the expression of the transporters, but how does it relate to
drug potency across the tissues. That gives you an ability to say, well,
these and these and these transporters are relevant. Maybe I\'ll send
you that paper, so you can have a look at it. But P-gp does play a
prominent role.

DR. HUANG: Thank you.

DR. VENITZ: I\'d like to echo what Dave said. I think with the 3A4
inhibition, I think you are there.

The classification with three categories makes sense to me because of
the consequences that you would attach, either contraindication, dose
modification, or monitoring. And that\'s a gradation in consequences, so
it makes sense to grade your degree of inhibition by the same token,
provided that you have exposure-response information on the NME as you
had in your first example.

As far as the induction is concerned in your second question, I\'m not
sure whether we are there yet, whether the science is there to allow us
to compare different inducers. One of the reasons why, for inhibitors, I
think it works, because we have this nice midazolam ranking that allows
us to rank all of them on that scale. We don\'t have that for inducers,
as far as I know. So for inducers, I\'d be very reluctant at this stage
to categorize them, to rank them unless you have data to support for a
known, very specific substrate what the degree of induction is for a
whole bunch of different inducers.

As far as your last question is concerned, P‑gp, again other than
digoxin, I don\'t know of a clinical significant drug interaction. So
even if you did have that information in terms of inhibition is what
I\'m talking about right now, I\'m not sure what a clinician would do
with it. And the use of digoxin is going to go down, if anything at all.
So unless, as David was saying, it\'s likely that digoxin is going to be
co-administered with that NME, well, then you may want to do a clinical
study anyway, and the in vitro study would be irrelevant. But I don\'t
think the science is there yet to say from an in vitro P-gp substrate or
inhibition experiment, that we know what the consequences are
clinically.

DR. HUANG: As far as just the inducer, there\'s some data to show
rifampin is more potent than rifabutin or rifapentine as far as the data
with ritonavir, and there are several other ranking with ethinyl
estradiol. That is the only information I found and with St. John\'s
wort. Right now the labeling usually just says drugs that induce certain
enzymes, like rifampin, rifabutin, St. John\'s wort. That\'s how we put
it the labeling, \"may affect\" the drug disposition. But we also did
put in the contraindication for rifampin in one case and say rifabutin
can be used in that case. But we just don\'t have a system to say it\'s
a potent inducer right now.

DR. VENITZ: And that\'s basically what I\'m saying. You don\'t have a
study where midazolam is used as a prodrug to compare different
inducers, and until and unless you have something like that, I don\'t
think you can categorize them other than on a case-by-case.

DR. CAPPARELLI: One other point, at least on the transporter issues ‑‑
and I\'m in agreement with, I think, what\'s been said here in terms of
need for clinical information and the fact that we really have an
incomplete picture. The clinical information that we look at may be
qualitatively a bit different than what we have focused in on on
standard drug interaction studies because one of the issues is it\'s not
just systemic exposure that\'s going to change, but it\'s also going to
potentially be the change between systemic exposure and exposure in
various tissues. So one area where you may see a lot of exposure is the
fexofenadine, and one of the reasons we don\'t have sedation may have to
do with some of these transporters. So when you\'re dealing with
interactions at those levels, the studies really need to be designed not
only from the standard PK standpoint but really evaluating the dynamic
exposure-response relationship as well.

DR. HUANG: Yes. That\'s a good point because it\'s about the brain
penetration and for drugs that have CNS toxicity, I think that\'s a very
important issue.

DR. RELLING: In your case 1, the new molecular entity that ‑‑ you ended
up saying, do not take with potent CYP3A inhibitors. So was there
life-threatening toxicity from that new molecular entity, or was it
simply the potency of the inhibitors and the likelihood of a drug
interaction that made you say do not take instead of take with caution
or consider a dosage decrease?

DR. HUANG: There is severe but rare clinical consequences. For that
class of drug, we put it right in front of information for patients. So
there is significant consequences, although that clinical endpoint was
not studied in the exposure response.

DR. RELLING: Right, but that\'s your criteria for making a
contraindication, is the clinical consequence of overdose. Is that
correct? You never make it be that there is a contraindication or do not
take simply based on the potency of the interaction?

DR. HUANG: Well, for this one, we are particularly concerned with one
clinical endpoint, and that\'s why the sponsor was asked to conduct an
exposure response to see exactly how the concentration response will
affect where we actually study the drug\'s concentration when you gave
ketoconazole at that level. I was trying to tell you the endpoint
without telling you what the drug is. I probably cannot do that. But it
is severe enough that there\'s a concern.

DR. RELLING: I\'m just trying to understand is that your general
principle because I\'m a little bit worried about some labeling coming
out with very strong, what sound like contraindications. They\'re either
labeled as contraindications or they say do not take. And I\'m surprised
that that would be the case unless there were a very life-threatening
adverse event that would be possible like torsade de pointes or
something like that because ‑‑

DR. HUANG: Yes. We just say do not take.

DR. RELLING: I guess that was the only thing I was unclear about as you
were going through your slides. It does seem to me it is informative to
give prescribers an idea of the strength of the drug interaction, but I
would be careful about translating that wording into contraindication or
do not take. Treating childhood leukemia, there are only so many drugs
we can use, and vincristine is going to be affected by every P-gp
substrate and 3A substrate, but our alternative is not to say do not
take vincristine. It is to use with caution or dose adjust.

DR. HUANG: The decision was that the clinical outcome was such that we
want to say do not take. But in some instances, we actually also put a
time period there. We say do not take within this certain time.

DR. RELLING: Which also may not be helpful to the prescriber in some
situations. So I would be cautious about putting in such strongly worded
statements about not taking medications together when there may be few
alternatives for the prescriber. And you accomplish your task in many
cases just as well by just putting in the data. This is a very high
likelihood of a very potent drug interaction that could have as much as
a 6-fold or 8-fold or 10-fold effect on the exposure to the drug, and
that gives the clinician an idea of how serious the drug interaction is.

DR. HUANG: Yes. To go back to your question, we don\'t do it always this
case. Sometimes we put in precaution. For example, I think some of the
grapefruit juice interaction, we are not sure about the outcome. We just
say ‑‑ well, we did say do not take, but it\'s not in the
contraindication section. It\'s in the precaution section.

Actually I was going to ask health care providers, do you see a
difference when you say do not take or contraindicated? Do you see a
difference? We do have different labeling languages in our ‑‑

DR. RELLING: We have had this come up in recent submissions to our
protocol review committee. It\'s very confusing. No, there is not a
significant difference there. To the clinician, that means the same
thing. So it\'s confusing when something says there\'s no
contraindication, but another section says do not take. It doesn\'t make
sense.

DR. HUANG: To the sponsors, they make a difference.

DR. LESKO: Just a comment on the general question. I don\'t think we
have a link between the potency of the inhibition and what it says in
the label. I think that gets to what Hartmut asked earlier, and that is
there\'s a second step to making that decision, which is to evaluate the
potency or whether it\'s potent, moderate, or weak in the context of the
exposure-response relationship. And then that actually drives where it
goes in the label.

But in the specific example number 1, there\'s also another
consideration, and that is the area under curve increase in exposure
exceeded by far the exposure that we had seen with the approved doses.
So if people were exposed to this exposure, there\'s no clinical
experience with it in terms of it being safe. It just wasn\'t studied at
a high enough dose in the clinical trials to have safety information. I
think that was in her example. 30 milligrams was the upper dose, but the
exposure in the interaction may have been equivalent to 120 milligrams.
And I think that drives where the information goes in the label as well.

DR. RELLING: But an alternative to saying do not take or
contraindication would be to suggest the possibility for dose reductions
in that situation. I\'m sure it depends on the overall utility of the
new drug entity to clinical care, but there are some drug entities that
are so critical that we use, it would not be helpful if the labeling
tied the hands of the prescriber to not allow them to use a critical
agent just because of a drug interaction that might not be avoidable.

DR. HUANG: One of the things that we really couldn\'t say because for
this particular case, there are only 15 and 30 available. If there\'s an
8 milligram or 7.5 milligram available, then we could say take the 7.5
milligram dose to start with. Sometimes we have the choices, but the
majority of the time we do not have that choice. So we either have to
make the dosing regimen change, like instead of b.i.d., give q.d. if
it\'s possible. Occasionally we have that kind of recommendation. A lot
of times we don\'t.

DR. RELLING: The idea that the dosage formulations available would be
what would tie your hands sounds a little silly for people who work in
pediatrics. We never get to use the formulations that are available. We
always have to cut things down. So there are alternatives.

DR. HUANG: That\'s a good point. These are for adult use and we don\'t
have the pediatric for that particular case. I think that\'s a very good
point.

DR. DERENDORF: I\'d like to follow up what Ed said earlier that we\'re
focusing in the whole session on systemic exposure really as the major
piece of information. But there\'s more to a drug interaction, and one
area that we\'re not talking about at all is pharmacodynamic
interactions. I know that the data situation is not very good, but I
think that\'s an area that needs to be explored in the future much more.

DR. HUANG: A lot more population pharmacokinetic study ‑‑ we have more
chances of seeing pharmacodynamic interaction that was evaluated in that
way from the sponsor. So we do have cases where pharmacodynamic
interaction was evaluated in that setting. And you are correct. 90
percent of the interactions are pharmacokinetic based.

DR. FLOCKHART: Just two things which are really just filling in gaps. I
think the cytochrome P450 interactions ‑‑ I think we largely have it
figured out. I think with P-gp or with transporters, we\'re slowly
getting there.

The reason we\'re not there with inducers I think relates to an
important thing, and that is that these are pleiotropic. Nearly all of
them have multiple effects. We don\'t have specific inducers. I happen
to believe we don\'t have a lot of specific inhibitors either.

Induction is really a big thing. So we published a paper a year or so
ago showing that RNA levels are changed by rifampin for a whole bunch of
transporters, 10 of the ABC transporters, a bunch of the SLC
transporters, glutathione-S-transferase, UGTs, sulfotransferases,
cytochrome P450s, a number of other enzymes, and also that you can\'t
actually go into to an individual enzyme system and say rifampin is
going to turn on all of these because it\'s specific within them.

So the inducers have very complex effects, and it follows that something
that is a potent inducer for 3A like rifampin would turn on midazolam
potently, but you can\'t translate that to a bunch of other drugs very
easily. So saying broadly that it\'s a potent inducer unfortunately is
not an accurate statement. It has to be tempered in a drug-specific way.
That\'s inducers. So really there\'s not a good system for inducers at
all.

I think one last point, and this is something that hasn\'t come up yet,
but it\'s something that I did bring up at the ASCPT meeting and have
said multiple times, and I know that a number of people disagree with me
about this. But I think in these studies, once we\'re beyond in vitro
and we\'re in the clinic doing drug interaction studies, we\'re in an
environment right now where the availability of surrogates is
blossoming, the availability of proteomic surrogate markers, the
availability of a large number of possible surrogates. And while people
are resistant to including them in these kinds of studies, I\'m a strong
advocate for including them absolutely whenever possible because that
makes the whole drug development process actually I think a lot more
efficient if you have good information about the markers you\'re going
to use in phase III and beyond early on. A relatively small investment
for a lot of payback.

DR. VENITZ: One more thing that I\'d like to add that we didn\'t discuss
either, and that\'s related to all the discussion focused on changes in
parent drug exposure. One thing that obviously has to be kept in mind is
that by the time that you inhibit, you\'re going to change the metabolic
profile. By the time that you induce, you\'re changing the metabolic
profile of circulating metabolites. That has to be considered when you
make those decisions because those metabolites may contribute to safety
and efficacy issues. Like in your first example, you mentioned, well, we
don\'t have any data at the 120 milligram dose. Well, giving a 120
milligram dose may not be the same as giving a 30 milligram dose and a
strong inhibitor because your metabolic profile may be different, which
could have safety consequences.

So part of whatever the considerations are in the review team has to
focus on do we know what those metabolites are, do we know what activity
they may or may not carry, and is it sufficient. Just to look at dose
limited toxicity from a phase I, is that the same as inhibiting or
inducing.

DR. DERENDORF: To follow up, the same is true about the quantification
of interaction with a simple 3-fold, 4-fold, 6-fold. I think that\'s
concentration- dependent frequently on either partner. So it\'s
dangerous to come up with a constant number for that.

DR. LESKO: That\'s going to be a complication because if you go to the
second step of the assessment of exposure response, we\'re really by
default talking about the parent compound exposure response being
realistic relationships between metabolite and response are going to be,
in most cases, not available.

DR. VENITZ: But as opposed to requiring the company to give 120
milligram dose, you could tell them give a 60 milligram dose and an
inhibitor because then you\'re mimicking what you\'re concerned about
which is inhibition, or the inhibition is going to push your systemic
exposure of the parent and change the metabolic pattern. But just giving
a higher dose, you\'re not going to change the metabolic pattern. Yes,
you\'re going to achieve higher systemic exposure of the parent, but you
don\'t know what happened to the metabolites that you\'re shutting off
and the metabolites that are going to be formed by ‑‑

DR. HUANG: Yes, that\'s a very good point. There\'s a concept paper on
QT evaluation, and we actually talk about the drug, if it\'s a substrate
of 3A, then it\'s expected that you want to study it with ketoconazole,
again as a standard approach so that we can evaluate the highest
exposure that you may see when you give it with other drugs and what
would affect the QT. We have discussed that, although we did discuss
whether this is a better approach than giving a higher dose. If we know
ketoconazole is 4-fold, is it better to study the 4-fold dose or just
study this drug with ketoconazole?

DR. VENITZ: In your first example, I would say that it\'s better to
study ketoconazole in a high dose because that mimics what you\'re
concerned about, not only in terms of mimicking your exposures that you
haven\'t seen the response related to, but you\'re also going to look at
any change of metabolites it may impact on.

DR. HUANG: Just to get back to Dr. Jusko\'s question. You mentioned
about grapefruit juice. I guess that\'s probably the only study that we
see the highest change, the one that was presented yesterday on drug A
where grapefruit juice increased AUC 7-fold. And you say why we didn\'t
include it in the potent inhibitors. Because a lot of times the fold
change, while we did see some fold change of 20-fold with some of the
statins, I think that\'s a fluid statement on grapefruit juice. It
depends on what brand you use, how many times you dose it, did you dose
it 2 hours before, at the same time, one-half hour, 2 hours. So the
results are going to be variable.

But I think we need to consider where to put grapefruit juice, but
understanding that it\'s very variable. I think once we put a precaution
in the labeling, I think the patients and health care providers
hopefully will get the message that with grapefruit juice, you could
expect anything that could happen.

DR. VENITZ: Any further questions or comments by the committee members?

DR. SADEE: I just have a general comment on this. I look at drug-drug
interaction as sort of a phenocopy of the genotype situation, so the two
are intricately linked, and the phenomena you observe can be interpreted
with knowledge that they\'re really that closely related. So I think
that helps to look at it that way.

DR. VENITZ: Thank you again, Shiew-Mei.

That gets us to our concluding remarks. Larry?

DR. LESKO: Thanks, Jurgen.

My concluding remarks are going to be very brief and represent an
expression of appreciation and gratitude to the committee. I think we
all feel from the agency that the last two days have demonstrated the
commitment and engagement of the committee members in the discussion of
clinical pharmacology issues. I think we\'re all looking to a common
goal and that is to advance clinical pharmacology not only into
regulatory decision making and policy but also into the drug development
process. I feel that this committee has succeeded in achieving that goal
of advancement.

So I can\'t really express my appreciation enough for the work of the
committee over the last day and a half. Besides, it was just a lot of
fun. There was a lot of intellectual discussion and I enjoyed it
immensely.

As you can see us writing very vigorously here, all of us on this side
of the table, we\'ve carefully recorded the opinions, recommendations,
and advice that this committee has provided us. I often felt that the
comments and advice were like putting a microscope and looking at a
slide of the issues and they slowly came into clear focus. As we go
forward with this committee, we\'d like to maybe spend time at our next
committee meeting reflecting on the advice given at this committee
meeting and talk about a little bit how we\'ve utilized the information
that came out of the committee to try to keep some continuum to our
discussions.

So with that, I think I just want to say again, thanks to the committee
and thanks to Dr. Venitz for his great job as chair. I hope we all made
it easy for him.

We look forward to the next meeting. I know we have talked about some
tentative dates that Dr. Venitz may discuss.

I also understand from a break that coincident with this discussion of
the committee meeting on pharmacogenetics, there was also a broadcast on
National Public Radio, which I wasn\'t aware of. So I hope I can get a
transcript. One of our own advisory committee members was involved in
that, as I understand it, Dr. Flockhart. Is that correct, David?

DR. FLOCKHART: Yes.

DR. LESKO: So there you go.

(Laughter.)

DR. LESKO: So our next step is a public broadcast production of
pharmacogenetics and drug development. I\'m just kidding about that.

Anyway, let me close with saying thanks very much and all of you have a
safe trip from Rockville back to your home, wherever you\'re going.

DR. VENITZ: Before we adjourn, just one thing for the record that I
forgot to mention. We didn\'t have anybody sign up for the open public
hearing. That\'s why we didn\'t have any problems in running over as far
as time is concerned.

As Larry indicated, we are looking right now tentatively at October 8th
and 9th, which is a Tuesday and a Wednesday, as the follow-up meeting
for this committee.

DR. DERENDORF: 7th and 8th.

DR. VENITZ: I\'m sorry. 7th and 8th, right. Tuesday, Wednesday, the
first week of October I guess. We\'ll get in touch with you to confirm
that and put an agenda together.

Then lastly, I agree with Larry about not only having a lot of fun over
the past day and a half, but also this being a very productive meeting,
and I hope we can continue next time we meet.

DR. FLOCKHART: And thanks to the chair, excellent chairing.

DR. VENITZ: I just found out that our Executive Secretary who\'s
responsible for the logistics and for the smooth running of this
operation, Kathleen, is going to retire.

MS. REEDY: No. I\'m going to another division.

DR. VENITZ: She is going to transfer out of the Advisors and Consultants
Staff, and I really want to officially appreciate what she\'s done.

MS. REEDY: Thank you.

DR. VENITZ: Thank you, Kathleen.

(Whereupon, at 11:52 a.m., the subcommittee was adjourned.)