SGDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DRUG EVALUATION AND RESEARCH
>
> NONCLINICAL STUDIES SUBCOMMITTEE OF THE
>
> ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE
>
> VOLUME II
>
> Tuesday, September 10, 2002
>
> 8:00 a.m.
>
> Committee Conference Room
>
> 5630 Fishers Lane
>
> Rockville, Maryland
>
> PARTICIPANTS
>
> [Chair]{.underline}
>
> John Doull, M.D., Ph.D.
>
> [Consumer Representative]{.underline}
>
> Gloria L. Anderson, Ph.D.
>
> [Guests]{.underline}
>
> Joy Cavagnaro, Ph.D.
>
> [Cardiotoxicity Expert Working Group (Chair)]{.underline}
>
> Kendall B. Wallace, Ph.D., DABT
>
> [Vascular Injury Expert Working Group (Chair)]{.underline}
>
> William D. Kerns, D.V.M., M.S.
>
> [Industry Participants]{.underline}
>
> Jack H. Dean, Ph.D., D.A.B.T.(Sanofi-Synthelabo, Inc.)
>
> Jack H. Reynolds, D.V.M (Pfizer, Inc.)
>
> James Green, Ph.D. (Biogen)
>
> [Government Participants]{.underline}
>
> David M. Essayan, M.D.
>
> James T. MacGregor, Ph.D.
>
> James Selkirk, Ph.D.
>
> Daniel A. Casciano, Ph.D.
>
> Helen N. Winkle, Ph.D.
>
> Frank Sistare, Ph.D.
>
> [Executive Secretary, Acting]{.underline}
>
> Kathleen Reedy, R.D.H., M.S.
>
> [C O N T E N T S]{.underline}
>
> [PAGE]{.underline}
>
> **Welcome and Introduction**s
>
> John Doull, M.D., Ph.D. 4
>
> **Meeting Statement**
>
> Kathleen Reedy, R.D.H., M.S. 5
>
> **Introductory Comments**
>
> John Doull, M.D., Ph.D. 7
>
> **Report of the Vascular Injury Expert Working Group** **and
> Subcommittee Discussion of the Report**
>
> William D. Kerns, D.V.M., M.S. 8
>
> **Open Public Hearing**
>
> **Subcommittee Discussion**
>
> John Doull, M.D., Ph.D. 91
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Welcome and Introduction**s
>
> DR. DOULL: Let me welcome you all again to the second day of the
> meeting of the Nonclinical Studies Subcommittee. We\'re a subcommittee
> of the Advisory Committee for Pharmaceutical Sciences.
>
> And yesterday we heard from Dr. Wallace. He presented the achievements
> of the working group---the Cardiovascular Working Group---and today
> we\'re going to hear from our other working group, and that\'s the
> Working Group on Vascular Injury.
>
> Okay. We\'ll do all these official things.
>
> I\'m John Doull. I\'m a Clinical Toxicologist from KU. Gloria?
>
> DR. ANDERSON: Gloria Anderson, Callaway Professor of Chemistry, Morris
> Brown College.
>
> DR. CAVAGNARO: Joy Cavagnaro. And I\'m on the committee as a
> representative from Bio.
>
> DR. WALLACE: Ken Wallace, University of Minnesota, Department of
> Biochemistry and Molecular Biology, and I chair the expert working
> group on drug induced cardiac toxicity.
>
> DR. KERNS: Good morning. Bill Kerns. I\'m from PhRMA Consulting in
> Boston, and I co-chair the vascular injury expert working group.
>
> DR. SISTARE: Frank Sistare, from the Center for Drug Evaluation and
> Research, FDA.
>
> DR. MacGREGOR: I\'m Jim MacGregor from the National Center for
> Toxicological Research, FDA.
>
> DR. GREEN: I\'m Jim Green. I\'m from Biogen, a toxicologist, and I
> represent Parma.
>
> DR. SELKIRK: I\'m Jim Selkirk. I\'m from the National Center for
> Toxicogenomics, part of the National Institute of Environmental Health
> Sciences.
>
> DR. CASCIANO: I\'m Dan Casciano, of the National Center for
> Toxicologic Research, FDA.
>
> MS. REEDY: I\'m Kathleen Reedy, Executive Secretary of the Advisory
> Committees and Subcommittees.
>
> **Meeting Statement**
>
> MS. REEDY: This is our meeting statement for today. If you notice any
> differences from yesterday, I\'ll be surprised.
>
> Acknowledgment related to general matters waivers for the Nonclinical
> Studies Subcommittee of the Advisory Committee for Pharmaceutical
> Science, September 10, 2002.
>
> 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 Food and Drug Administration has approved general matters waivers
> for the attending special government employees which permits them to
> participate in today\'s discussions. A copy of these waiver statements
> may be obtained by submitting a written request to the agency\'s
> Freedom of Information Office, Room 12A30 of the Parklawn Building.
>
> The topic of today\'s meeting is an issue of broad applicability.
> Unlike issues before a committee in which a particular product is
> discussed, issues of broader applicability involve many industrial
> sponsors and academic institutions. The committee members and invited
> guests have been screened for their financial interests as they may
> apply to the general topic at hand. Because the general topic impacts
> so many institutions, it is not prudent to recite all potential
> conflicts of interest as they apply to each participant.
>
> 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 addition, we would like to disclose that Drs. Jack Dean and James
> Green are the non-voting guest industry representatives. They are not
> government employees, and hence we do not screen them for conflicts of
> interest, and can may comments on their actual or perceived conflicts
> of interest.
>
> 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.
>
> **Introductory Comments**
>
> DR. DOULL: Thank you, Kathleen.
>
> Are there any comments on the disclosure?
>
> \[No response.\]
>
> I have two quick announcements.
>
> The topic that we\'re going to deal with today---the Vascular Working
> Group report, was available, I think---isn\'t that available to
> everybody?
>
> MS. REEDY: Yes, it\'s on the Web.
>
> DR. DOULL: And it\'s out on the table.
>
> MS. REEDY: And it\'s out on the table---yes.
>
> DR. DOULL: Okay. So if you don\'t have a copy of that report, it is
> available.
>
> I think the subcommittee got it a week or so ago. So they\'ve had a
> chance to review that.
>
> The other thing is I need to mention that after the break we will have
> an open public hearing, if there are any public comments. We don\'t
> have any formal requests for public comments. But we\'ll do that after
> the break.
>
> Do we have any other housekeeping?
>
> Okay. Then why don\'t we go ahead and proceed with out---Dr. Kerns can
> tell us about what\'s happening with the Vascular Working Group.
>
> Bill?
>
> **Report of the Vascular Injury Expert Working Group** **and
> Subcommittee Discussion of the Report**
>
> DR. KERNS: Thank you, John. And thank you to the NCSS for asking Ken
> and I to come today and yesterday to speak.
>
> I\'m here representing the Vascular Injury Expert Working Group, and
> our committee is composed of several members that represent industry,
> academia and government\--I think evenly balanced, and a skill set
> that has brought great value to the document that you see in front of
> you on the table.
>
> And I want to acknowledge everyone for having contributed to the
> document. Everyone did a very good job of having it come together.
>
> Importantly, along the way over the past 18 months to two years, we
> have\--several active contributors, as I\'m calling them, have joined
> the committee as ad hoc members, and have made substantial
> contributions, also, to the document in front of you. And I\'d like to
> recognize these members, as well, on this page, who represent,
> primarily, industry and I want to also acknowledge Jin Zhang from
> CDER, who was inadvertently left off of the membership list in the
> document in front of you.
>
> And to let you know that we\'ve been very busy---this isn\'t to read,
> but just to point out that we have been alive for 18 months---close to
> two years now. And we have met many times on the telephone,
> face-to-fact, to bring this document to fruition.
>
> Our next planned face-to-face meeting is at the ACT meeting in
> Hershey, Pennsylvania in early November.
>
> Today\'s objectives are to review with you once again our mandate, as
> we understand it. I want to spend some time describing to you why we
> think, and we agree, that this is an important issue that requires
> resolution. I want to review our progress that we\'ve made to date.
> And, finally, and importantly, a set of slides of discussion points
> for discussion and feedback from NCSS to the committee.
>
> Our mandate, as stated in the document on the table, as we understood
> it, was to evaluate and develop a thorough and current understanding
> of vascular injury issues, both pre-clinically and clinically. We have
> done this---and it has taken quite some time, to bring the whole
> committee up to the same level of experience and expertise. Keeping in
> mind that the committee is populated by many people who had no
> knowledge of this issue prior to getting together, and that took quite
> some time.
>
> We\'re charged also with identifying opportunities for new biomarkers,
> based on probable mechanisms of action. Important to note here---and I
> will show you in some slides, that we don\'t know mechanism of action,
> so we\'re really focused our biomarker search at this point on what we
> think to be most likely probable mechanisms.
>
> Ultimately, we will develop validation plans to bring the biomarkers
> to fruition so that they can be used preclinically and clinically. And
> that is the last two bullets or items that I don\'t think will
> actually come to fruition for a couple of years.
>
> So what is the issue? Drug-induced microscopic polyangitis in
> humans---also known as hypersensitivity angitis, or leukocytoclastic
> angitis, is not---or certainly rarely, observed in preclinical animal
> species. This is a fundamental problem. So, in summary, the most
> common even that occurs in humans with drug-induced vascular injury
> does not---we do not see in the nonclinical toxicology. It is,
> however, observed occasionally in clinical veterinary medicine in pet
> animals, as an adverse event to antibiotics, primarily.
>
> The current animal models are then poor predictors of drug-induced
> lesions in humans. Because the common drug-induced vascular lesions
> that we see in animals are \"not know\"---in quotes---to occur in
> humans, and they have unknown relevance. I say they\'re not known to
> occur in humans, because we have no way to really look, at this point
> in time. So we\'ve been moving forward for the past decade---many
> compounds are on the market, compounds that cause lesions in
> animals---and thus far there have been no serious related adverse
> events that we\'re aware of that occur in humans. But we don\'t know,
> because we don\'t know how to measure.
>
> Equally important, the lesions that we see in animals, induced by
> drugs, generally occur in vascular beds that are also prone to
> spontaneous disease. This is important, but I---and I don\'t think we
> as a committee---understand clearly what that means. But it must mean
> something, that these vascular beds, where we induce lesions with
> compounds, are also vascular beds that are prone to spontaneous
> disease, and we need to do something to understand why.
>
> To bring you up to speed with what we see to be the problem, I want to
> show you a few slides as to---so you can understand what the lesion
> looks like.
>
> \[Slide.\]
>
> This is a rat exposed to a dopamine agonist, a mesenteric artery.
> Dopamine---Fenoldopam, in this case---induces a segmental medial
> hemorrhage and necrosis in the rat mesenteric arteries. This artery is
> about 400 microns in diameter. It\'s one of the main---secondary
> branches of the splenic artery. Ultra-structurally, you can see
> the---if you\'re looking down at the surface of the endothelium, in
> this case, and the honeycombed appearance off to the sides are areas
> where smooth muscle cells have disappeared---undergone necrosis and
> disappeared---and the voids are filled with red blood cells. You saw
> the hemorrhage in the previous slide. You can see the red blood cells
> in this picture. And look at the endothelium, which normally---
>
> \[Pause.\]
>
> Now you\'ll all see my fine tremor.
>
> \[Pause.\]
>
> How do you work it, Jim? Which button. Ah. Okay.
>
> We talked about the red blood cells that have filled the voids in the
> smooth muscle that has disappeared. Also, look at the endothelium,
> which is important---and we\'ll come back to this later. But the
> endothelium is normally flat, pavemented, it\'s pushed against the
> internal elastic lamina, because it\'s this pressure on top of it, and
> shear stress and hoop stress.
>
> The endothelium in this animal is raised, it\'s swollen, it\'s
> separated one cell from another, and there are many white blood cells
> attached to the endothelium, and there are several endothelial cells
> that appear to be sloughing off into the circulation.
>
> \[Slide.\]
>
> This is another animal, also exposed to Fenoldopam. And you can see in
> this animal, the---this is an area where smooth muscle used to be, and
> it\'s now filled with almost 100 percent platelets, and a few red
> blood cells. I\'m showing you these slides to sort of see some ideas
> as to the kinds of biomarkers that we would look for, given this kind
> of scenario.
>
> The endothelium in this case, which is here, is---we
> haven\'t---there\'s not a lot of it in the picture, but it is necrotic
> and, essentially, not present.
>
> If you look at an animal that has been allowed to recover from this
> lesion for three days, again exposed to Fenoldopam, you can see that
> the smooth muscle is beginning to be replaced. There\'s still some
> hemorrhage cells that are sticking to the endothelium are neutrophils,
> primarily. They\'re migrating through, and there\'s adventitial
> inflammation, including mass cell degranulation---which was recently
> reported by Dr. Zhang at FDA.
>
> So, again, that should give you some more ideas as to the potential
> kinds of soluble factors that we might look for in plasma.
>
> I mentioned in my opening slides that these vascular beds are also
> beds where we see spontaneous disease. And if you look at 90 percent
> of retired SHR breeder rates, the vast majority of these animals will
> have a disease which is known as polyarteritis nodoza in the
> mesenteric bed.
>
> If you look at an animal exposed to Fenoldopam for two years, you see
> a dramatic increase in the same kind of lesion. So, again, we have a
> drug-induced lesion that occurs in an area where we have spontaneous
> disease.
>
> Many, but not all, of the compound-induced lesions in the rats occur
> in the mesenteric vasculature---not 100 percent, but a vast majority.
>
> I want to move on now to some slides on dogs---just a few more.
>
> \[Slide.\]
>
> This is a spontaneous disease in a dog in the coronary artery, known
> as idiopathic polyarteritis---also known as \"Beagle pain syndrome.\"
> But this is a spontaneous disease, the cause is unknown. But it is a
> florid, inflammatory response, with lots of neutrophils, fibronoid
> necrosis of the medial smooth wall. The media is totally absent in
> this case. And this is a spontaneous disease---the dogs spontaneously
> recover. And there are lots of biomarkers that we know to look for in
> this disease syndrome.
>
> Unfortunately, this occurs in the coronary arteries, and it
> occurs---yes, spontaneously, but it also occurs in toxicology studies.
> And, in many cases, more animals on a high dose will have this
> syndrome than in the low dose.
>
> On the other hand, we have a wide variety of therapeutic agents that
> cause, morphologically, a very different lesion in the coronary artery
> and right atrial appendage of dogs. But in many times it\'s difficult
> to distinguish the spontaneous disease from clear drug-induced
> coronary artery lesions in the dog.
>
> So, again, in the dog we have a vascular bed---namely, the extramural
> coronary arteries---that is frequently affected by a wide variety of
> pharmacological agents. And in the same vascular bed, we have a
> spontaneous disease.
>
> So, once again, I there are some links here that we need to more
> clearly understand, through new technologies.
>
> \[Slide.\]
>
> Lastly, one slide from a human case of hypersensitivity angitis---and
> I hope, by now, you can see that what occurs in humans is
> morphologically very different than what we see in animals. And I
> think, if you look carefully, you can see some eosinophils in this
> lesion---which is the hallmark of hypersensitivity angitis in humans.
>
> And this is a case---this is a skin biopsy from a patient who was
> taking an experimental drug, and the patient developed a rash, and
> this is what you see histologically. It\'s not that uncommon, but it
> doesn\'t happen in toxicology studies---in my experience.
>
> So I want to talk, then, through a few cartoons about what the problem
> is.
>
> Normally, we have blood flowing through blood vessels---neutrophils
> very happily swimming along. And the neutrophils---the blood is under
> a variety of different biomechanical stresses. One is called \"shear
> stress.\" Shear stress is a function of flow, divided by the
> cross-sectional area of the vessel. Shear stress is the force that
> tends to strip the endothelium off the internal elastic lamina as the
> blood flows by. And you can appreciate, based on the formula, that in
> order to control shear, the only one way the vessel can reduce shear,
> and that\'s by dilating or thoroughly relaxing. Because you can see
> that the diameter is indirectly proportional to flow---I\'m sorry,
> shear.
>
> However, if the vessel thoroughly relaxes, the vessel wall becomes
> very thin, and that does a very good job at controlling shear, but it
> does a very poor job of controlling tension. Because tension, or the
> forces that tend to explode the blood vessel wall, is a function of
> pressure and radius, but also indirectly related to wall thickness.
>
> So if the vessel is controlling its shear by getting thinner, the hoop
> stress increases dramatically. And many of us believe that these
> biochemical events are very important in the induction of lesions, and
> endothelial compromise.
>
> So how does this work, then, in a cartoon? And I think if you remember
> the three-day recovery slide from Fenoldopam, you saw the neutrophils
> pavementing against the endothelium, there\'s endothelial compromise,
> red blood cells and platelets---and the platelets in this slide are
> the white oval things at the bottom---have migrated through the
> compromised endothelium, and that\'s all been influenced by a variety
> of potential biomarkers---the selectins, ICAMs, VCAMs, PECAMs and all
> the items I have listed at the bottom of the slide, then all become
> fair game for---as opportunity areas for biomarkers. And sufficient to
> say, if you are human, this similar kind of even would be happening,
> but resulting in a very different morphological picture---and,
> primarily, we would be looking at eosinophils in that case, which are
> depicted in this slide, and not neutrophils.
>
> So then, in summary, we have identified in our document that you\'ve
> studied, I\'m sure, three potential mechanistic areas where we might
> look for potential biomarkers. And one is injury as a result of
> biomechanical change within the vascular lumen.
>
> Second---which I have not discussed today in detail---direct
> pharmacological or chemical injury to the vascular endothelium---and
> we have many examples in this category as well.
>
> And, lastly, immune-mediated vascular injury, or vascular compromise,
> which is classically seen more frequently in humans---but it is seen
> in animals with some of the biological agents.
>
> So the Committee, then, intends to focus on identifying biomarkers
> that would be involved in these three major categories of drug-induced
> vascular injury.
>
> So, in summary, regardless of mechanism, endothelial compromise
> appears to be an early and important---and an important event in
> vascular injury in rats and dogs. Drug-induced lesions in the rat and
> the dog appear in sites of spontaneous disease frequently, and this
> complicates the interpretation as to what this exactly means, I think,
> from the regulatory and safety perspective.
>
> As stated early, in the beginning, common drug-induced injury in
> humans is not, or is rarely, observed in toxicology studies. Our
> animal models, then, you might conclude, are not that good at
> predicting these events in human.
>
> Common drug-induced vascular lesions in animals are not known to occur
> in humans, and have unknown relevance; not known to occur, once again,
> because we don\'t know how to measure. And that\'s the purpose of
> being here, is to figure out and identify potential biomarkers.
>
> \[Pause.\]
>
> I\'d like to stop here, just briefly, and ask if there are any
> questions about the issue that we\'re here to resolve?
>
> Lastly---and in the white paper---one of the Committee\'s charges was
> to confirm that this is an issue worth resolving. And let me say, in
> this slide, that I think it\'s from the EWG\'s perspective, I think
> this clearly is an issue that requires resolution, and we\'re prepared
> to move forward and to do that.
>
> But let\'s just ask a few questions about the issue, so that we
> clearly understand it.
>
> Joy?
>
> DR. CAVAGNARO: Okay. Can you comment on other species---I guess, most,
> notably, non-human primates. But the information that you have from
> other species?
>
> DR. KERNS: That\'s a good question. I haven\'t really focused on
> primates or mice in this presentation, because there isn\'t a lot
> known. But I can tell you that many of the compounds we deal with do
> cause lesions in primates and mice.
>
> DR. CAVAGNARO: More similar to the dog and the rat, versus the humans.
>
> DR. KERNS: That\'s correct.
>
> DR. CAVAGNARO: So even when you suggest that there\'s no predictive
> model, that includes non-human primates.
>
> DR. KERNS: That\'s correct. So that lesions in the species that we
> usually use---primates, dogs, rabbits, as well---what have I
> missed?---mice and rats\--
>
> DR. SISTARE: Pigs.
>
> DR. KERNS: \--pigs---yeah, right, pigs, Frank---the lesions that we
> see do not mimic what we see in humans.
>
> But, nevertheless, we have to deal with it from a safety perspective
> and a regulatory perspective. We\'re trying to learn how to do that.
>
> Any other questions about the nature of the issue?
>
> DR. GREEN: Two questions, Bill. I didn\'t see anywhere in the paper
> the stated clinical incidence of this lesion?
>
> DR. KERNS: That\'s a good question. The---well, the lesion we see in
> animals---keep in mind\--
>
> DR. GREEN: The human.
>
> DR. KERNS: The human lesion---yes. Hypersensitivity angitis, also
> known as leukocytoclastic angitis is a rare event. I don\'t have the
> actual numbers, Jim, but it is---can anybody help me?
>
> DR. SISTARE: One study just recently done was looking at drugs
> approved, like, up to 1996. It was a member of my staff, Jim Weaver,
> actually did the study, and looked at all adverse events reported---I
> forget how far back it went---since the original data base. We\'ve
> switched to a new data base in 1996. But up until that point, looked
> at all adverse events, and he was focusing on immune events. He
> counted things like rash, and he counted anaphylaxis, and he counted
> vasculitis. And when he looked at all those adverse events, and he
> tabulated---rash was the most common, the most common adverse event.
> But vasculitis actually counted for 6 percent of the immune-related
> adverse events---the term \"vasculitis\" appeared.
>
> Okay? Now, that\'s a very broad term, and it would cover all these
> other things---angitis and these kinds of things. But that is the
> immune-related---to be clear. I mean, what Bill is saying is that
> oftentimes the animal is not a good indicator of immune-related human
> events. So, you know, our animal models to predict hypersensitivity
> reactions in humans, there\'s a blind spot there. WE need to do a
> better job at that. We have guinea pig tests and things like that,
> which some people question how good they are. But vasculitis, the
> immune-related---again, accounts---I don\'t know what the overall
> incidence, but of immune-related events, it accounts for 6 percent.
>
> But what Bill is talking about here now, in terms of the kinds of
> histopathological findings that are being seen in these preclinical
> studies, we don\'t know what the incidence of that might be in the
> clinic, if those same agents are given in a clinical setting, at
> certain doses. That\'s a---we can\'t answer that question, I think.
>
> DR. KERNS: I mean, I can provide some anecdotal information. My
> experience in talking with medical pathologists over the
> years---people have a lot of experience. You know, the kind of changes
> we see in animals, they don\'t recognize as being seen in humans in
> post mortem, from autopsy studies.
>
> So it is---this is the conundrum.
>
> So, Jim, I think the answer to the question is: it\'s not common,
> it\'s not rare, it\'s somewhere in the middle.
>
> DR. GREEN: One other question: I take it that, particularly in the
> nonclinical studies, attention was drawn to those lesions in the dog
> and rodent because gross observations were seen initially.
>
> DR. KERNS: Yes, these observations were initially recorded in dogs and
> rodents.
>
> DR. GREEN: So---I mean, thinking about the sampling strategy that is
> employed in all of the toxicology studies, where a vessel---a small
> segment of a vessel is identified and taken, in the absence of any
> kind of directive, gross lesions to draw your attention to that, is
> there---has there been any discussion about the fact that maybe these
> lesions have been missed in a more subtle form just because they were
> there but we didn\'t see them? I mean, we\'re always subject to
> sampling that\'s done, essentially, within these studies. And what is
> noted in the paper is some comment about different sensitivities in
> different anatomic regions.
>
> So if you weren\'t drawn there, there could perhaps be more subtle
> lesions that are occurring at a very low level, and we\'re just---our
> incomplete sampling strategy missed them.
>
> DR. KERNS: It\'s a very good point and, quite possibly, you\'re
> correct. I think one of the things that I think people in the PhRMA
> are tuned into now is that certain classes of drugs you would expect
> to see these kinds of events. And so there is focus on these vascular
> beds.
>
> We\'re going to talk a little bit later about our standard model that
> we\'ve put together in the rat, and we have addressed the sampling
> issue in the rat in that study.
>
> DR. SELKIRK: In that same regard I was wondering if you can\'t---based
> on what you\'ve seen in animals, and lack of what happens in humans
> and what the literature says, if you can differentiate that possibly
> in animals it\'s a more mechanical problem versus some sort of
> mediated hormonal or biochemical addition in human vasculitis?
>
> DR. KERNS: Let me just clarify that. In animals, one of three possible
> mechanisms of vascular injury is potentially biomechanical. You know,
> immune mediated is also a realistic probability and it happens. And
> direct drug-induced cytotoxicity does happen, as well.
>
> DR. SELKIRK: But does there seem to be a mechanical component in the
> human problem, then? At this point?
>
> DR. KERNS: In humans with hypersensitivity angitis it is probably a
> type-3 mediated response---immune mediated.
>
> Do you agree with that, Frank?
>
> DR. SISTARE: I think your answer that these are---there seem to be at
> least three mechanisms, and they\'re probably overlapping. Maybe some
> classes of compounds may dominate one mode of action versus another. I
> think it\'s really difficult to answer the question that if you have
> something which has a biomechanical effect, does that potentially
> contribute to---if you also activate immune components, so you
> activate cellular signaling which up-regulates adhesion molecules or
> something like that, and does some other things, would a biomechanical
> effect also contribute to that. It\'s possible. It\'s hard to answer
> that question.
>
> You know, there seems to be a growing attention to cardiovascular
> disease in humans, as long have been anchored in our diet, our
> cholesterol, our lipids, but there\'s growing attention to the fact
> that inflammatory mediators also seem to be growing---good prognostic
> indicators of vascular disease, and risk for heart attack, and stroke,
> and things like that.
>
> So, it seems to be, again---I don\'t want to over speculate, but it
> could be that there\'s an underlying vascular inflammatory component
> to a lot of human cardiovascular disease that has been ignored for a
> long period of time. And I don\'t want to say that, you know, 90
> percent of the drugs we\'re taking are causing problems. I don\'t
> think that\'s the case at all.
>
> But this---I think, you know, the kind of questions we\'re asking here
> will bring attention to an element of something that we may have
> ignoring for a long period of time. And I think Jim\'s point---you
> know, the fact that a lot of these lesions are seen
> microscopically---you know, once you know where to look, and you start
> using the microscope, you start seeing things that you may not have
> seen had you just looked at five or six different tissue sites, and a
> routine tox study, and not done---not been drawn there by some sort of
> macroscopic observation.
>
> So, you know, I think this is an interesting set of experiments that
> need to be done, and bio-markers that can be identified which could
> prove fruitful in a clinic.
>
> DR. CAVAGNARO: So, just to clarify---so the strategy is to try to
> be---to find more sensitive indicators of the current clinical
> situation, and not be more sensitive of the current lesions that
> you\'re observing in animals right now.
>
> DR. KERNS: Just the reverse. I think the charge, as I understand it,
> is to first identify biomarkers that are robust in preclinical
> species, and then try to transition them into the clinic. So we
> can---primary objective being to prove one way or the other, do the
> changes we see in animals occur in humans?
>
> DR. CAVAGNARO: Okay. So I\'m right, because\--
>
> \[Laughter.\]
>
> DR. KERNS: Okay. Maybe I didn\'t understand your question.
>
> DR. CAVAGNARO: We don\'t really---I mean, what I understood is it\'s
> not predictive of what we\'re seeing in the humans. And it seems to me
> that if you understand the human pathology, and can understand
> biomarkers, the goal would be to try to capture those biomarkers more
> sensitive in the animals.
>
> But to characterize---I guess I\'m a little bit confused---to
> characterize the lesion being more sensitive, and characterize a
> lesion that\'s occurring in animals that\'s not predictive of humans
> seems, to me, a little---I guess I don\'t understand the logic.
>
> DR. DOULL: I think, Joy, Frank is saying that the primary mechanism
> for the two things probably is the same. Therefore, one---the charge
> to the committee is to find preclinical biomarkers that are
> predictive. And the second charge is to find bridging
> markers---markers that work in preclinical situation that can also be
> used clinically.
>
> So, you know, you could, in fact, accomplish the first charge and not
> the second one, which would be less useful.
>
> DR. CAVAGNARO: But if your goal isn\'t to find \-\-- if your goal
> isn\'t to focus on the currently known human potential consistent with
> the human disease. I mean, you showed that cartoon there. That\'s
> where you\'re going to focus on---of that acute injury, those
> biomarkers---right?
>
> DR. KERNS: In animals first.
>
> DR. CAVAGNARO: No, no, I understand it\'s in animals. But the
> biomarkers are focusing on the human lesion versus the animal lesion.
>
> DR. MacGREGOR: But one of the things that\'s not clearly known is
> whether those---just because you do see a particular kind of
> immune-mediated lesion in the human, that doesn\'t necessarily mean
> that if the animal effect carried over that the---that may be largely
> spontaneous in the human. I doesn\'t mean that would necessarily carry
> into the human model.
>
> So one of the key questions we\'re hoping this group will address is
> the following.
>
> We know that in animals this type of lesion that\'s seen in animals
> occurs frequently. And the question is how confident can we be that
> that does not occur in humans. And do we have appropriate biomarkers
> to be able to address that question---and I think we\'re all in
> agreement that we do not have those currently. And then one of the
> questions for the group is there a potential for a biomarker that will
> allow us to address that question; that is, that what we see in
> animals in fact is not occurring in human.
>
> DR. DOULL: If we don\'t do that we\'re just predicting for rats and
> dogs is all.
>
> DR. KERNS: I mean, that\'s well stated, Jim, and that\'s my
> understanding of the charge.
>
> DR. CAVAGNARO: Oh, okay. Well, then I\'m---because I guess I was
> trying to see whether or not, as part of that, we were also going to
> try to---this incidence of 6 percent or whatever you\'re saying, try
> to---I guess that was---okay, so I\'m at the other part of the
> equation\--
>
> DR. DOULL: I think so.
>
> DR. CAVAGNARO: ---and that is to try to be more predictive---to design
> the animals to be more predictive of what\'s actually happening in the
> clinic, which we\'re not doing that as well, either.
>
> DR. SISTARE: So that the human vasculitities---I mean, that\'s a good
> question, too. But you\'re right---I mean, that isn\'t the primary
> focus. The primary focus is we\'re seeing this huge---we\'re seeing a
> very---an---we\'re seeing a relatively common signal in a number of
> pharmacological classes of drugs which are coming to the agency for
> development, for approval for clinical trial capability, and there is
> consternation. We don\'t know what do to here. We can only go so high
> with a dose, then we start to see these lesions in animals. So you\'ve
> got to stay below that dose.
>
> But, it may be totally irrelevant, and we don\'t know. So we need a
> way forward. We need a scientifically grounded approach that will
> allow us to monitor what\'s happening here. Okay. So that\'s one
> approach.
>
> Now, you bring up a very good question. Now---but I think our thinking
> is that as we learn more about all the different components that are
> involved in the generation of these biomarkers in these animal models,
> I think our thinking is that there will be a collection of these
> biomarkers that would be applicable to the human scenario, and that
> some of these manifestations that we\'re seeing in the human, there
> may be some biomarkers that arise that would be overlapping, even
> though the mechanism may not be exactly the same, there\'s going to be
> some overlap. So that it may be helpful.
>
> So, that\'s a hope. The problem is that these types of injuries that
> we\'re seeing in humans are so unpredictive, it\'s so difficult to do
> those kinds of studies, to systematically look at that, so the light
> is brighter on the animal sides, and we can systematically control all
> that, and we can make a faster speed, I there for Frank, I
> guess---from the chemical---since it\'s a generalized chemical
> phenomenon, meaning large amounts of drugs seem to do this in humans,
> has there been any attempt at just a straightforward structural
> activity relationship, to see if certain chemical structures have a
> predilection for this effect?
>
> DR. SISTARE: In humans---again, it\'s different from animals. There is
> an SAR effort going on. I mentioned Jim Weaver---and Ed Matthews, and
> Joe Contreras\' group---are doing an SAR analysis for all
> immune-mediated type events, and trying to develop a model that may
> capture it categorically, whether there is some sort of alert that
> indicates that kind of a thing. That\'s ongoing. That is ongoing.
>
> But the other side of the coin, in terms of alerts that indicate what
> compounds are causing these things in animals, and we don\'t know
> what\'s happening in humans, we\'re not going there yet. No.
>
> DR. PAPOIAN: I\'m Tom Papoian, Sanford drugs.
>
> I just wanted to comment to the question Joy brought up about the
> bridging, or the commonality, or the differences between the lesions
> that we see in the animals and the predominant concern for humans,
> it\'s not necessarily the immune-mediated lesions, but atherosclerosis
> and ruptural plaques, which is attributed to an inflammatory reaction,
> which leads to heart attacks and stroke.
>
> Wether those two phenomena are similar or different; whether the
> animal lesions or the effect of inflammation on animals has the
> applicability to humans, I think, without quoting the---some results
> from our previous expert work in group meeting, I\'ll say one of the
> active contributors presented some preliminary data to show that the
> drugs---one of the drugs that was tested on animals produced increases
> in a marker that is commonly associated with inflammatory reactions in
> humans.
>
> So, there is a very good case correlation there that the lesions that
> we do see in animals may have applicability to the human clinical
> situation.
>
> I just wanted to make that comment.
>
> DR. KERNS: Okay, thank you. I\'d like to continue now.
>
> Progress, to date, over the past two years: we have, through the
> committee, as I mentioned earlier---the committee is a collection of
> disparate skills and interests, many of which have nothing to do with
> vascular injury. And we spent a lot of time over the first year, just
> bringing everyone on the committee up to speed with the issues that we
> were trying to solve.
>
> And that is behind us now, and we\'ve addressed a lot of issues along
> the way, dealing with that, including terminology and lots of details
> and mundane things. But I think the committee is now 100 percent on
> board, with a clear understanding, as you are, of the issue.
>
> We spend a considerable amount of time bringing together a standard
> protocol in the rat, that we have reviewed in its final form at SOT
> last year, and has now been agreed and published in our minutes.
>
> This is the protocol, Jim, that addresses the sampling bias, in
> addition to a number of other things, and it will be the protocol that
> we will use to generate tissues to pass around to different
> investigators around the country.
>
> We still require some more discussion, though, as to how to manage the
> data, and movement of samples around, and all these issues coming from
> these s, if you have a standard protocol, you must have standard
> compounds, so that we\'re all looking at disease induced by a standard
> set of compounds. Sounds simple, but to get the compounds we would
> really like to have, they\'re really not available to us, because
> they\'re proprietary and difficult---and you can always make somebody
> else\'s compound. But I think in this environment, that would not be
> the appropriate thing to do.
>
> So we\'ve identified three compounds that we think are available to
> us. One is Fenoldopam. One is a PD-IV inhibitor named CI-10-18, and
> one is dopamine. Why these three compounds? We had one agonist.
> CI-10-18 is a phosphodiasterase IV inhibitor. And dopamine, at high
> doses, is primarily aan alpha agonist.
>
> The lesions induced by dopamine versus Fenoldopam are morphologically
> different. I haven\'t gone into the detail today. And we---you might
> expect the biomarker profiles might be different---but we don\'t know.
>
> So, we\'ve chosen these three compounds because we believe they\'re
> accessible. Dopamine we can buy. And a lot of us at the committee
> level have a lot of experience already with these compounds. And
> certainly FDA does.
>
> We are in the process of crafting a letter to the suppliers of
> Fenoldopam and CI-10-18, and that letter---we\'re going to come to
> that later, is something that I need some input on from the NCSS.
>
> We have put together---and it\'s published in the White Paper---a list
> of\--large list of potential biomarkers in the table, with references
> to support them. And, also, we have come to---put together a short
> list of biomarkers that we think have high probability that we can
> deal with today. And I\'ll tell you about that.
>
> We\'ve identified soluble E-selectin as a high priority potential
> marker, and we have a proposal on the table that is currently being
> reviewed to develop the reagents required to pursue this.
>
> Another thing that you need to understand is that the---in the table
> in the report is a huge list of potential markers, but in order to do
> studies you need reagents. And rat reagents and dog reagents are not
> that readily available. So, to really do good work, we have to make
> the reagents, and that\'s the purpose of the E-selectin proposal. And
> it\'s just the beginning.
>
> Joy?
>
> DR. CAVAGNARO: So those three agents, there has been some incidence
> of---in humans, for all those three agents.
>
> DR. KERNS: No, these are compounds that cause lesions in animals---not
> humans.
>
> DR. CAVAGNARO: So there are no data---so, in your clinical data base
> that you\'re looking at, these agents don\'t show up.
>
> DR. SISTARE: Not the hypersensitivity angitis. These don\'t show up in
> that category. You know, we\'re talking about a different type of
> lesion, and we don\'t know, in humans, whether these might cause those
> types of lesions.
>
> But I will say, for example, though, that if you think about the
> dopamine category here---okay, so, phenylpropanolamine, I know that
> that\'s kind of mired in debate, but that was a drug that was taken
> off the market because of stroke and things like that---in women that
> were taking it for weight control. There is some old data showing
> that---in the rat---one could reproduce a cerebrovascular injury
> event.
>
> Is it the same thing? I don\'t know. You know, we don\'t have those
> kinds of markers to see if, you know, you could measure in the rat
> model. Would you see changes in biomarkers that you could then dose
> into women and start seeing biomarkers increase---some of which go on
> to develop strokes, most of which do not.
>
> Again, I know phenylpropamine is a little debatable, whether it should
> have been taken off the market, were the signals real and all this
> kind of stuff. But, you know, it is enough of a---you can\'t ignore
> it. You know, you can\'t ignore some of these things.
>
> The PD-IVs---I don\'t think there\'s a PD-IV on the market yet. Am
> I---there\'s not one on the market yet. There\'s a lot of them in
> development, a lot of them in clinical trials, and a lot of the dose
> escalation---the concern is that we\'re seeing vascular injury. And
> some of those PD-IVs, they happen in monkey studies, not human
> primates. So, you know, it adds to the concern.
>
> Fenoldopam is approved. It is approved for emergency use---short-term
> use. And that\'s a risk-benefit decision that went into the approval
> of that compound.
>
> And, I think, in addition, dopamine, given at high doses and as an
> alpha agonist, does cause peripheral vascular disease in humans, and
> that\'s been reported and published. But, once again, it\'s
> morphologically a little bit different lesion. But, nevertheless, it
> should be an area where we can induce change and look for biomarkers.
>
> DR. KERNS: Lastly, I\'ll try to allude to, as I go through the rest of
> the slides, the exciting things that are going on on the research side
> from member companies that are sitting around the table, and active
> contributors that are sitting around the table.
>
> So, I\'ve tried to summarize, in brief, the---some, but certainly not
> all, of the biomarkers listed in the White Paper. And into acute
> biomarkers, ones that might be more reflective of the inflammatory
> process that we talked about earlier. And lastly, how can we use the
> links to address this issue and bring a whole other new set of data to
> the table that we haven\'t seen yet.
>
> Acute markers---I alluded to the fact that there was some endothelial
> sloughing in the slides that I showed you. There is some published
> data now, I think, from FDA showing that apoptosis markers are
> increased. And so we intend to develop reagents to look at soluble
> fasligend and soluble CD-44.
>
> We\'re looking at circulating endothelial cells, as well.
> Surprisingly, we all have a low level of circulating endothelial
> cells. But when you perturb the endothelium via a variety of different
> mechanisms, both with catheters or natural disease in humans, your
> circulating endothelial count increases dramatically.
>
> The reports in the literature are a little bit confusing but,
> nevertheless, this is an area that we intend to pursue with vigor. And
> some of the companies around the table are already doing this and
> generating data, using our standard rat protocol.
>
> Colleagues at FDA have done a great job of pointing out the value of
> acute phase proteins in addressing---as a biomarker of inflammation.
> And certainly they are increased, particularly C-reactive protein that
> Tom was alluding to. They are increased in a variety of different
> vascular injury syndromes in the animal models. But we need more data,
> and we need to validate.
>
> And, lastly, figuring out how to capitalize on using tissue from our
> studies, doing GNRAs, doing proteomics, and metabonomics on urine or
> plasma, of which many of us around the table are already doing,
> there\'s a lot of data that we review when we get together, and it\'s
> always exciting, but it\'s difficult to interpret at this point. And I
> think that\'s the problem.
>
> So we need---I think the solution to that is a lot more data, and a
> lot more people participating in the program.
>
> We have a short list---at least I think it\'s a short list of markers
> that we\'re tending---but this isn\'t immutable---but tending to focus
> on at this point. And that\'s urinary metabonomics, an initiative
> being taken forward right now by Pfizer. Don Robertson si a member of
> our group, and he\'s supporting that effort.
>
> GSK is spending a lot of time---and others---looking at circulating
> endothelial cells.
>
> Frank\'s group at FDA, through CREDA, with Boeheringer-Ingelheim, and
> perhaps others I\'m not aware of, are looking at acute-phase proteins.
> And also other companies around the table are doing that as well.
>
> We have a proposal---many of us are interested in soluble E-selectin
> as a potential marker. And we have---the group has identified an
> investigator at DelHause University in Canada who actually has the rat
> E-selectin cell line---has a cell line that produces E-selectin
> antibodies---rat E-selectin antibodies. And we\'re working with this
> investigator right now to put together a proposal to allow---that will
> allow him to generate an assay system so that we can look at soluble
> E-selectin the rat.
>
> There\'s a proposal on the table, and we\'re right now looking for
> ways to fund it.
>
> So now I have four or five slides, in closing, which I\'ve entitled
> \"Discussion Points.\" And I think, Dr. Doull, I\'m looking for---the
> committee is looking for an exchange of information here, or exchange,
> comment---we\'re looking to hear what you folks think of what we\'re
> doing.
>
> \[Slide.\]
>
> The White Paper, you have a draft of. And please consider it as a
> working draft. It\'s by no means a polished document.
>
> However, it is our intention---and we\'re looking for your
> comment---to publish this as a review, somewhere---in the next six to
> nine months. The timeline of the committee is not really established.
> But the document needs polish.
>
> I\'m looking for your comment on this initiative, and also I---the
> committee would like to learn about the formal process to get NCSS
> ratification---and confirmation.
>
> I think---my opinion, that\'s just me speaking---I think it would be
> very important, as Ken said yesterday, to publish these papers, having
> agreement, or the blessing of the NCSS. But I don\'t know clearly how
> to do that, and I\'m looking for guidance.
>
> \[Pause.\]
>
> That can come from anyone.
>
> \[Pause.\]
>
> Any comments?
>
> \[No response.\]
>
> DR. DOULL: Well, as we mentioned yesterday, with the cardiovascular
> one, there are two issues. One is a scientific issue. And I think,
> clearly, the NCSS will give you feedback on our scientific
> interpretation of where you\'re going and so on.
>
> Then there is the other problem, and that is the one that meets the
> FDA requirements. And I\"m not sure we fully understand what those FDA
> requirements are, in order to publish it with the imprint of the NCSS
> on the publication.
>
> DR. KERNS: On behalf of the committee, would it be possible to action
> some one, or some small group to help Ken and I understand the process
> more clearly? Jim, is that something that you could take on?
>
> DR. MacGREGOR: Well, I mean, I think clearly the first step in the
> process is the discussion that\'s happening right now, and to get
> feedback form the subcommittee, and to determine if the subcommittee
> feels that the document that\'s been put forth is a valuable document,
> and is on the right track. And then, the next step would be, if
> that\'s the case, when this comes to a point that everybody\'s
> comfortable, that clear paths forward have been defined, then for the
> subcommittee to consider which of those might be followed. And if
> there---and to come out with a recommendation to FDA that certain
> paths should be followed, and that support for those paths should be
> sought.
>
> DR. DOULL: Let me back---follow-up on what Jim is saying.
>
> We have talked off and on about publication as a scientific review and
> a peer review journal, and so on. And we\'ve also talked about
> submitting that report simply to the subcommittee. I think it\'s going
> to be more valuable for what we want to accomplish if it\'s out there
> in the peer review literature. And so I think that\'s really what
> you\'re asking---is how do we go about putting a review paper out in
> the peer review literature which, in fact, has the cooperation, and
> collaboration and ratification, if you will, of the NCSS.
>
> DR. KERNS: That\'s correct.
>
> DR. DOULL: And that\'s what we\'ll explore.
>
> DR. KERNS: Okay.
>
> DR. DOULL: But before, actually, we do that, of course, we will need
> both from the cardiovascular paper---we\'ve had the outline, now
> we\'ll need the White Paper which spells out, as you have done, Bill,
> all of these different things for the committee to actually go through
> piece by piece and give you our comments on that.
>
> DR. KERNS: Okay.
>
> DR. DOULL: We may have to have a little time to do that, because there
> are several members of our subcommittee who aren\'t here, and I think
> they all ought to have an opportunity to review the paper, and we\'ll
> send you our conglomerated comments.
>
> DR. KERNS: So, I\'d like to suggest, then, that---and please comment,
> Frank and Tom and what others are here---that, you know, what we have
> given to you is a working draft. We would like to finalize that, then,
> over the next\--month? That\'s a positive nod?
>
> \[Laughter.\]
>
> DR. KERNS: And send you a final---a penultimate draft for peer review,
> then, in October sometime.
>
> DR. DOULL: That\'s fair enough. We gave you a challenge, now you can
> give us a challenge---time challenge, at least.
>
> DR. KERNS: Okay. Good.
>
> Sorry---Jim?
>
> DR. GREEN: Just one comment first. I think that in my review of this
> paper, I think it would be an excellent contribution to the
> literature, and a review, not only for this particular issue, but it
> can serve as a template for other issues that we\'re looking for
> biomarkers of either activity, efficacy or toxicity.
>
> So, I think---I encourage the committee to proceed forthwith, and get
> something like this out into the literature.
>
> One comment that I will have, though---and it gets back to my question
> about, you know, how big a problem is this issue? And I don\'t think
> it\'s well reflected in here. And I think, in order to---and,
> obviously, you\'re getting a lot of interest and support from major
> pharmaceutical companies who are committing their resources. So they
> believe that this is an issue that somebody---or a group within the
> FDA thinks it\'s an issue. So perhaps this is why they\'re paying
> attention to it. But it\'s not clear to an independent reviewer as to
> why---you know, what is triggering this.
>
> Now, one of the things that I would also encourage you to think about,
> and perhaps reflect in here is---you know, why---what is the rationale
> for focusing essentially on the model that you\'re choosing---the
> rodent model. And is it just history of experience? It\'s practical?
>
> Well, you know, the situation that you\'re presented with right now is
> that there\'s a disconnect, essentially, between the presentation of
> the pathology in the human setting, and then what\'s reflected in both
> the dog and the rodent models.
>
> So, some would perhaps say that either of those models don\'t reflect
> a---quote-unquote---\"gold standard\" to reflect the human pathology.
> So unless you\'re making a case in here as to why the rat, why the
> dog---I mean, perhaps it\'s just simple anatomy.
>
> DR. KERNS: Right.
>
> DR. GREEN: I mean, I would think---is the blood vessel anatomy and
> biochemical structure of a rodent most similar, essentially, to that
> in a human, normal or pathologic setting? Is the dog that way? Or is a
> primate that way? Or some other model.
>
> It\'s not clear to me, essentially, what the rationale for that
> selection would be. And the context that I\'d bring this up in is we
> develop drugs all the time in animals, and we\'re looking for activity
> that is putatively thought to reflect activity in humans. So if we
> find a model that we believe---this, for example, clot-busting
> drug---essentially if it\'s active in dogs then it\'s likely to be
> active in humans. And why is that? Because the correlation has been
> set up, and then some would refer to perhaps that model as the gold
> standard.
>
> So whatever comes out of this with respect to biomarkers, we\'re going
> to be in a situation of trying to---or at least somebody\'s going to
> look: what\'s the clinical relevance of this observation? So if you
> haven\'t made a good case, essentially, for why you\'ve selected this
> model, there\'s somebody that\'s going to look at this and say,
> \"Well, it\'s a different lesion.\"
>
> That\'s the only comment I would offer.
>
> DR. KERNS: I think all very good comments, and we\'ll certainly take
> those on board, I think, in the next iteration of the document.
> Particularly, I think, reviewing the incidence data---clinically---I
> think is an important point that we need to cover.
>
> I think---let me just address your final comment, though, Jim---just
> to make it clear. And this is my understanding of the charge.
>
> And that is, we have a problem in animals. And I think what we\'re
> interested in doing is developing a set of biomarker profiling to
> demonstrate that these changes do not occur in humans. Okay? So I
> think, for me, that\'s the first objective.
>
> And so in that sense, then, we\'re not really dealing with the human
> disease---okay? Because of leukocytoclastic angitis, there are markers
> in clinical---human clinical medicine that are elevated in
> hypersensitivity angitis. They\'re not good markers, but they are
> used.
>
> We\'ve looked at those markers in our animal models and we don\'t see
> increases---okay? So, once again, what we\'re doing is developing a
> set of markers that we can use in a phase I, eventually, we hope to
> demonstrate that the changes we see in animals do not occur in humans.
>
> Sorry to keep reiterating that, but that\'s an important point.
>
> DR. CAVAGN-invasive or non-terminal. I mean---so we can\'t focus on
> histopathology.
>
> DR. KERNS: No. These are all non-invasive.
>
> DR. CAVAGNARO: Right.
>
> DR. DOULL: I agree. I think Joy and Jim have pointed out something
> that would enhance the document considerably. You know, there\'s the
> argument in tox that the rat gives us the wrong answer. In actual
> fact, when you look at most of those cases, the rat really isn\'t all
> that wrong. It\'s just that we don\'t understand while alpha-2
> globulin is different, you know, in one species and not in another.
> Once you really understand that, then you understand it\'s not really
> an exception it\'s just an aberration in most of those cases. And that
> really is what we need to understand here.
>
> That\'s why it\'s so research focused, rather than the presentation
> that we heard yesterday on the tropins.
>
> DR. KERNS: Good points, Jim, and we\'ll take those on board in the
> next iteration of the document.
>
> Joy?
>
> DR. CAVAGNARO: So, in the survey of the lesion in---presumably the
> studies were done in both dogs and rats, classically. Is it a hundred
> percent of the time that both species get it? Do rats get it more
> predominantly than dogs, and that\'s the rationale for the selection
> of the rat?
>
> DR. KERNS: In my experience, some drugs cause lesions in multiple
> species, and some drugs cause lesions only in rats or dogs or monkeys.
>
> DR. CAVAGNARO: Right. But this particular lesion.
>
> DR. KERNS: But the lesions that we\'re talking about here are seen, at
> the right dose, in rats at 100 percent. Okay?
>
> DR. DOULL: Those four biomarkers you were talking about---specific
> ones. The selectin and the\--
>
> DR. KERNS: Well, we don\'t have any data yet on the biomarkers, but
> the compounds, I think---Joy was alluding to the compounds, the model
> compounds we\'re going to use: Fenoldopam, dopamine and the PD-IV
> inhibitor cause lesions in 100 percent of rats at the right dose.
>
> And it just so happens, in this case, the PD-IV compound also causes
> changes in the dog, and dopamine also causes changes in the dog---and
> humans.
>
> Jim?
>
> DR. MacGREGOR: I might just get back to the reports and ask if
> everybody\'s clear about the possibilities for reporting. Because I
> think the group has really discussed how to publish this report in two
> different contexts. And I think it\'s important for the group to have
> some clear understanding how they\'re going to proceed.
>
> Clearly the group has done a tremendous job of pulling together a lot
> of useful scientific information that I think we all have agreed
> warrants publication as a scientific review document.
>
> But the reason the committee was formed was really to develop a
> background that could be the basis for recommendations of the
> subcommittee, with the concurrence of the parent advisory committee,
> might make to FDA as the paths that should be pursued.
>
> So that opens the possibility of a slightly different type of report,
> which would be a formal committee report that incorporates the
> scientific background into recommendations for courses of action that
> might be pursued.
>
> And I think either or both of those are possible, and they could be
> done in a variety of ways, depending on the desires of this group and
> the working group.
>
> I think clearly the scientific basis for the scientific review is
> there. The question is the degree to which the committee feels they
> want to use these conclusions as the basis of a formal report, and
> whether that should go public, or whether that should be an FDA
> document, with some recommendations about what\'s the most valuable
> path forward to address this problem.
>
> DR. DOULL: I would remind the committee that, you know, the name of
> our committee is the \"Nonclinical Studies Subcommittee.\" And that is
> the charge essentially. The bridging biomarkers is the second charge.
> We would hope that the biomarkers that are developed in nonclinical
> studies would, in fact, be could bridging markers. But that whole
> issue would have to be dealt with in the kind of paper you\'re talking
> about, Jim.
>
> DR. MacGREGOR: Well, maybe that\'s something that would warrant a
> little bit of discussion right now. I guess, in my mind, just
> expressing my personal opinion, for a non-clinical marker to be truly
> useful, it needs to be a bridging biomarker. And you really cannot
> completely separate the non-clinical from the clinical. You need to be
> thinking about those characteristics in both the animal models and the
> human that are going to make it useful in that way.
>
> In a way, this is an excellent model choice for an effort like this,
> because I think this is a clear need, where there are some
> morphological and mechanistic differences in things that are, at least
> normally, seen in the two species, with a very clear need for bridging
> biomarkers that can help bridge those pieces of information, and
> understand whether what\'s happening in animals does or doesn\'t
> happen in the human, and whether it\'s manifest in a different way, or
> just not happening---all those questions are still somewhat murky
> because we don\'t have appropriate mechanistic biomarkers to answer
> the questions.
>
> DR. DOULL: But if those three mechanisms that Bill talked about are,
> in fact, the primary mechanisms by which these effects occur in dogs
> and in rats, then those mechanisms are likely to be primary mechanisms
> for damage in people.
>
> So that, you know, that forms the basis for providing a set of
> biomarkers which have potential to be bridging biomarkers, if we
> understand them more full. I read that in your document.
>
> DR. KERNS: I mean---both very good parts. But I think, from the
> committee\'s perspective, yes, it\'s a nonclinical studies
> subcommittee, but we are incredibly influenced by the fact that these
> need to be bridging biomarkers. So we can\'t ignore that as we move
> forward.
>
> DR. DOULL: Well, when we circulate the document to the other members
> of the subcommittee, I think we need to talk about those issues, Jim,
> that, you know, we\'re thinking about a scientific review which
> includes all the information and so on, and also what we might present
> to, say the Advisory Committee on Pharmaceutical Science---as a
> recommendation.
>
> DR. CAVAGNARO: So---for the clinicians in the audience---no
> clinicians? So, I was just wondering, in terms of the data, with
> tconcerned about, so that when we bring them forward to the clinic, we
> won\'t be able to distinguish\--
>
> DR. KERNS: Right.
>
> DR. CAVAGNARO: ---because they\'re elevated in a basal\--
>
> DR. KERNS: Good question. There are many clinical diseases where
> circulating endothelial cells---E-selectin and acute-phase
> proteins\--clinical vascular diseases are elevated. And that\'s all
> been published. And that is---in part, that influences our decision to
> look at these markers in animals.
>
> But please keep in mind that our primary objective---if you remember
> the mandate on page two of your paper---it says, \"To look for
> biomarkers that we can transition into Phase I.\" It says \"Phase
> I/II,\" actually.
>
> So I would envision, you know, in the first instance, we\'re looking
> at normal volunteers with a baseline level of circulating endothelial
> cells, E-selectin, is non-detectible or at baseline---whatever it is.
> So in that clinical experiment, then, we\'re going to be looking---and
> we should be able to see, in theory---clear increases in their
> changes.
>
> So---as we get into patients with lots of diseases---vascular
> diseases, diabetes, atherosclerosis, smoking---I think it would be
> very difficult to find biomarkers that have specificity and
> sensitivity. And I think that\'s why we need to focus, at least
> initially, on phase I volunteers.
>
> Anybody else have an additional comment on that point?
>
> Was there another question here? Yes.
>
> DR. ANDERSON: Do you know what they\'re looking for in the urinary NMR
> and, two, do you know whether or not they compare the animal NMR---I
> think you said plasma---to human the NMR of the human plasma.
>
> DR. KERNS: Right. It\'s a good question.
>
> At this time, the urinary NMR has primarily been focused on rat urine
> from rats receiving the Pfizer PD-IV inhibitor, as well as a couple of
> other compounds---but only in the rat. And I can tell you that there
> are clear pattern differences in the NMR spectra from rat\'s urine
> receiving these compounds.
>
> To my knowledge, you know, this has not been transitioned into
> humans---to my knowledge. But that is something that we would plan to
> do eventually, you know, in the bridging stage.
>
> DR. ANDERSON: Well, their probably looking at metabolites, I would
> guess. So that\'s why they were different than\--
>
> DR. KERNS: Yeah.
>
> DR. ANDERSON: ---those that don\'t have it.
>
> DR. KERNS: I\'m not a metabonomics person, but I think---you know,
> the---yes, there are metabolites in urine, but also lots of fatty
> acids, many other compounds that are being looked at in the
> metabonomics profiling.
>
> You know, metabolites clearly differ across species, and that could
> be\--
>
> DR. ANDERSON: I\'m not a metabolite person, either. I\'m thinking
> about what NMR does, and looking at---well, it might be interesting to
> look at the human NMR, as well.
>
> DR. KERNS: The\--
>
> DR. ANDERSON: The human urinary NMR.
>
> DR. KERNS: Right. But we\'re not---we agree, eventually that will\--
>
> DR. ANDERSON: Differences or sameness could suggest a lot of thing.
>
> DR. KERNS: Right.
>
> Frank?
>
> DR. SISTARE: Some of the beauty of this effort is while there\'s some
> common protocols and sharing of data, many of the people that are
> working in this area are also doing things---you know, as Bill
> mentioned, we have CREDAs with other people, we have transfer
> agreements with other people, and there are other people that are
> doing---that are contributing to, like, the formation of the document
> that are doing some investigations on their own---maybe with
> proprietary compounds, these kinds of things.
>
> So, some of the investigators that are involved here, we\'ve been
> working with---we generate samples, and we would share them with a
> collaborator who would do urinary metabonomics, for example, on some
> animals that we have dosed. And we\'re looking at, say, protein
> biomarkers in the serum. We\'ll have the urine, we\'ll send it to
> them, and they will do some of these analyses.
>
> Now, I do know that some of the people that are involved here are
> looking at human urine as well; looking at cohorts of normals, and the
> human vasculitities---the clinical vasculitities, the Shirk Strauss,
> the Takiasu\'s, these kinds of diseases. And they are seeing
> differences. So it\'s encouraging.
>
> It is a challenge---I mean, to see---you know, do like a principal
> component analysis, and look at patterns of these---they\'re
> intermediary metabolites of carbohydrate metabolism and protein
> metabolism, and fat metabolism that they\'re seeing in the urine. And
> when---it is a challenge to identify which of these may be the
> critical ones that end up being the discriminatory biomarkers that you
> can hang your hat on. And there are certain controls. You have to
> watch diet---control diet, and make sure of these things.
>
> But some of these things are being done. There\'s a lot of success.
> Jeremy Nicholson\'s group, for example, has really lon of vasculitis
> at Pfizer. And at Pfizer they are looking at human applications, as
> well.
>
> DR. ANDERSON: I know that metabonomics has made a lot of progress in
> the last 30 years, but 30 years at Chicago they were tagging compounds
> with fluorine. And at that time I was the fluorine in spectroscopies,
> and I was running the samples for the people in the cancer research
> center. And then there\'s a big difference in what they do now. But
> that\'s why I was wondering about if there\'s a comparison between the
> animals and the humans, because that could perhaps tell a lot about
> what\'s going on.
>
> DR. CASCIANO: I\'d just like to make a comment, to follow up on that.
>
> There are studies being proposed that would link metabonomics to the
> other omic technologies which would then help understand that the
> portobations that are occurring in discovering specific intermediary
> metabolites by also understanding pathway changes that might be linked
> to them.
>
> So those are beginning to occur in specific cases in rodents, so that
> hopefully that metabonomic data developed in the human would be more
> definable and credible.
>
> DR. CAVAGNARO: So, can I understand---so the protocol, the proposed
> protocol---the rat protocol, then for that protocol---do you have the
> list of the end points? Right.
>
> Okay, so for the protocol with the three---so each of the three drugs
> will have all of these markers? Or will they be selective? So for each
> of the three, will have urinary NMR, circulating---so that\'s the idea
> of the protocol.
>
> DR. KERNS: The answer\'s yes---but minimally. Because we have---as
> Frank pointed out, we have a standard protocol, but there is lots of
> independent work going on within companies around the table. So, in
> addition to these and others, there will be many biomarker data sets
> coming to the table.
>
> \[Comment off mic.\]
>
> DR. KERNS: Yes. There\'s some technical challenges. Doing the urinary
> NMR primarily has to be done at one site. It\'s difficult to do that
> and send the urine around. So this---I\'ve got some negotiating to do.
> If Don Robertson and Pfizer\'s going to do all this work, I think I\'m
> going to have to talk to Jack. So---but, in essence, yes.
>
> I mean, we would hope to have a robust set of data, of not just these
> four but many different biomarkers including these, from at least
> these three compounds in the rat. And then, hopefully, we\'d be in a
> position, as you\'ll see later on, in about a year, to make some
> decisions.
>
> Moving on with points for discussion, I was very happy yesterday with
> the discussion about potentially moving under the umbrella of NCTR.
> And opens a lot of opportunity for us within the committee to not only
> get work done, but to collaborate with other scientists in an
> independent but collaborative way.
>
> I think, with the---and I just learned yesterday about---and when I
> visited NCTR a month ago---about the new initiatives there in
> genomics, proteomics, metabonomics---Dan just mentioned.
>
> I think in addition to those---that resource, in addition to the
> resource we haveully, to expand our data base and knowledge.
>
> And we believe---many of us believe---that there\'s great opportunity.
> You know, we focused on the logical biomarkers. That\'s the table in
> the report. These are the logical biomarkers based on what we think we
> know about pathogenesis. But we have no idea what\'s going on at the
> gene level and the protein level. And there certainly is a lot of
> information there that we need to generate, bring to the table, and
> influence decision-making.
>
> And that remains to be done. Some of it---some member companies have
> already been moving in this direction, but the data are evolving.
>
> So I see this as an opportunity. I hope you do, as well. And, you
> know, I think what remains for me as a committee chair is to
> understand the process as to how we get in the queue, so to speak, to
> access resources at NCTR---not something we need to talk about today,
> but it\'s information I think, as committee chair, I\'d like to
> receive back from NCSS and NCTR.
>
> I mentioned earlier that we have a letter---it\'s just a one-page
> letter that\'s being crafted, to send to the key stakeholders at
> Abbot, who owns Fenoldopam, and Pfizer, who owns CI-10-18, two of the
> model compounds we intend to use.
>
> We would like to access, say, a half to one kilogram of each one of
> these compounds. I have already received informal agreement that this
> is possible, but we need to send a letter to the key
> stakeholders---Jack is one of them, Reid Patterson and his colleagues
> at Abbot are the others---a letter from the NCSS, FDA, requesting the
> compound. And I need your comment or discussion on that topic, and
> agreement to move forward.
>
> The second thing I need to know is that that is the easy part. Having
> receiving the compound---whatever we can get---how do we manage
> it---it\'s distribution to the customers on the outside? Is that
> something that we want to do through FDA? Or is it something we want
> to try to do through, in this case, Pfizer and Abbot?
>
> In an informal discussion I had with Jack yesterday, his suggestion
> was---give it to FDA. Probably simpler than having Pfizer receive a
> hundred requests for material transfer. And perhaps that\'s the smart
> thing to do, but I don\'t know if we have the infrastructure here to
> support that.
>
> So I\'m looking for some discussion around this topic.
>
> Joy?
>
> DR. CAVAGNARO: Let me understand. The Abbot Drug, and it\'s an
> approved drug, and is a marketed drug?
>
> DR. KERNS: That\'s correct.
>
> DR. CAVAGNARO: But the Pfizer drug is an investigational drug?
>
> DR. KERNS: That\'s correct.
>
> DR. CAVAGNARO: So that right there, that\'s a huge distinction, in
> terms of, I think, understanding---I mean, one\'s an approved drug and
> the investigational drug. And so now the investigational drug
> that---so I\'m understanding that the data from these studies will all
> be public, obviously, because of the relationship, in terms of\--
>
> DR. KERNS: We have agreed within our committee that everything we do
> will be published\--
>
> DR. CAVAGNARO: Right.
>
> DR. KERNS: ---and public.
>
> DR. CAVAGNARO: So now you\'re shipping investigational drug
> versus---well, I guess that doesn\'t make any difference in terms of
> animal studies.
>
> DR. KERNS: It\'s not an investigational drug. It is CI-10-18 is a drug
> that has been looked out at Pfizer and terminated.
>
> DR. CAVAGNARO: Oh, it\'s terminated.
>
> DR. KERNS: Okay. But they are developing, as are many other companies,
> other PD-IV inhibitors.
>
> DR. CAVAGNARO: Oh, okay. Okay. All right.
>
> DR. KERNS: So the PD-IV inhibitors are being developed. They\'re in
> Phase III. And I\'m sure, shortly, one or two of them will be
> submitted.
>
> DR. CAVAGNARO: So the drug that they\'ve discontinued, is that on
> stability? And is it being characterized? So, obviously, the approved
> drug will have its qualifications and, you know---so this drug, now
> that has been terminated, is it still being\--
>
> DR. KERNS: Tracked\--
>
> DR. CAVAGNARO: ---tracked, in terms of stability\--
>
> DR. KERNS: Yes. Sure.
>
> DR. CAVAGNARO: ---and etcetera?
>
> DR. KERNS: Yeah. That shouldn\'t be an issue.
>
> Dopamine, on the other hand, each investigator can buy from Sigma.
> That really is not an issue.
>
> So it\'s these two compounds that, to really kick off our experimental
> programs---you know, we need access to drug. And my---the committee\'s
> recommendation is to try to see if we can receive a gift from these
> two companies.
>
> DR. DOULL: The mandate of this subcommittee is to help our working
> groups in any way we can. So I think what we\'re saying is, we need to
> find out exactly how best we can facilitate what it is you want to do,
> Bill.
>
> DR. KERNS: Okay. Well, our request then is to agree with the strategy
> to pursue this, if you think it\'s a good idea, via this introductory
> letter, in this case, to Jack Reynolds and Reid Patterson.
>
> DR. MacGREGOR: I think this topic clearly moves to the mandate of the
> subcommittee, in terms of---as you said---recommending to FDA paths
> forward and mechanisms for taking these steps. So I think if a letter
> is to go out asking that materials be made available, I think in order
> to do that, the subcommittee needs to endorse the recommended, or the
> identified approach---approach that\'s been identified by the expert
> working group. And I think, in my mind, the letter should probably go
> from the subcommittee, asking that they endorse the concept that these
> materials be made available for study under a common protocol that
> would be useful to FDA and its collaborators.
>
> DR. DOULL: Yes, and I think we\'re at that point. The working group
> has made the request, and I think we need to explore our ability to,
> you know, facilitate that request. And we\'ll do that.
>
> DR. KERNS: So, with your permission, then, we will draft a letter for
> signature by at least yourself, Dr. Doull, and maybe me and Jim. I
> don\'t know who the others are. But I think, minimally, yourself, from
> ht. So, in that letter, are we going to try to work through the other
> pieces? Because, one, you need to know a mountain, and how are you
> going to manage that.
>
> DR. KERNS: Yes.
>
> DR. CAVAGNARO: So the expectation is that that should probably also be
> part of the letter, as well, and not just\--
>
> DR. KERNS: Yeah---the detail will be in the letter.
>
> DR. CAVAGNARO: Yes, I think we probably need to provide some detail.
>
> DR. KERNS: As to how it will be managed. Yeah.
>
> DR. CAVAGNARO: Right.
>
> DR. KERNS: I think, ideally, for the companies, it\'s one MTA coming
> to FDA. But I need to talk to Frank, and others here, as to how that
> could be managed. Maybe it could be managed at NCTR, as a distribution
> site\--also is a possible way to do it.
>
> Frank, do you have any thoughts?
>
> DR. SISTARE: Yeah. Traditionally, whenever we obtain a compound from
> the regulated industry, it is through a legal document; through a
> material transfer agreement. And the standard format indicates that we
> cannot give that to anyone else. It has to---you know, when we\'re
> done with the study, we have to give it back to them or destroy it.
>
> DR. KERNS: Really?
>
> DR. SISTARE: So, the way it\'s written right now, that\'s the
> standard. That doesn\'t mean that it can\'t be amended. So that\'s
> something that would need to be explored. And with the permission of
> the supplier, I\'m sure, you know, we could come to some agreement. It
> just has to---we just have to make sure that, you know, there\'s no
> perception of any impropriety and all that kind of stuff.
>
> DR. MacGREGOR: Yes, I think---I mean, I think clearly you\'d need a
> material transfer agreement to do this. But I believe those agreements
> certainly can be structured to make material available for research
> purposes. I think another question is if the material is to be made
> available and distributed by FDA, then how are priorities set for how
> that would be distributed? I mean, I think that\'s something that
> needs to be done through the oversight of the subcommittee, really
> working with the expert group. I mean, that\'s the mandate that we
> gave to the subcommittee, was to identify paths forward to solve
> certain problems to advance the science, and to provide oversight of
> collaborations that could be formed to pursue those objectives.
>
> DR. KERNS: That\'s a good point, Jim. So I think all that needs to
> come out in this \--
>
> DR. DOULL: Where we\'re at---we\'ve received your request, and we\'ll
> do our best to find out how we can help.
>
> DR. KERNS: Okay. Very good.
>
> Second, I think it\'s time for us to begin to think about planning for
> some sort of symposium in a year\'s time. It could be independent. It
> could be linked with cardio-tox group. It could be linked with ILSI,
> it could be linked with ACT, SOT---any one of a number of
> organizations.
>
> But I think between now and 12 months from now, the contributing
> scientists around the table will have generated a lot of data. And I
> think we need to begin to plan the presentation of those data, and get
> other people around the table---more ideas, and so on.
>
> So I think our recommendation is that---you know, I think Ken and I
> really haven\'t had time to talk about this, but how do we move
> forward along these lines, and, I guess, looking for discussion---what
> are your ideas. What are you thinking---with regard to the current
> state of the project? And how is it best organized? Is it independent,
> or is it aligned with some other meeting?
>
> DR. CAVAGNARO: So, is the expectation---if drug is available, that
> some of these studies---that there will be data to---so the October
> symposium of next year is to discuss the concept. Is it to \--
>
> DR. KERNS: There will be \--
>
> DR. CAVAGNARO: ---will there be data available from these \--
>
> DR. KERNS: \-- data.
>
> DR. CAVAGNARO: ---okay. So they\'ll be from this rat protocol \--
>
> DR. KERNS: Right.
>
> DR. CAVAGNARO: ---and now it will be an opportunity to present that at
> a more\--
>
> DR. KERNS: That\'s my whole---right.
>
> DR. CAVAGNARO: Oh, okay.
>
> DR. KERNS: Not just the rat protocol. Keep in mind there\'s lots of
> independent work going on around \--
>
> DR. CAVAGNARO: Right.
>
> DR. KERNS: ---the periphery, within companies, that is currently not
> available to our committee---formally. And I would hope that in the
> next 12 months a lot of that information could come to the table and
> be presented, as well.
>
> DR. CAVAGNARO: Is it my understanding that this initiative won\'t be
> picked up by ILSI or other organizations; that we\'re not duplicating
> anything---that this is given the go ahead that, you know, if we so
> bless this activity, that there won\'t be---or, if there are, it\'s
> more---not so much competition, but they\'ll look at another piece of
> it. So, in the end, we have really a collective data base?
>
> DR. KERNS: That\'s a fair question. I think---my understanding
> currently, this is an FDA project. And ILSI is not involved. But I
> know Jim is---sits on the biomarker group in ILSI. Maybe he might have
> a comment?
>
> DR. MacGREGOR: Well, I think, actually, this enters into yet another
> topic that we really haven\'t addressed, which is: having identified
> paths that should be pursued, you know, then where would the resources
> come from to do that.
>
> Now, we\'ve already heard that spontaneously, some of the people
> who\'ve been involved around the table have already begun to do some
> things along the lines of the discussion---and that\'s terrific. And I
> think once courses are defined, we need to think about---and in my
> mind, ILSI would be one of the organizations that I might think about,
> that might be interested in certain biomarker initiatives that would
> come out of here. And both at this group in its early stages, as well
> as some of the ILSI discussions, there\'s been discussion of trying to
> coordinate between FDA and ILSI priorities, to move forward in this
> way.
>
> So I would think that at some stage we would want to make initiatives
> that come out of this group known to groups like ILSI, and other
> groups, who may wish to participate or collaborate, or to bring it int
>
> I think we need to give some thought to what kind of a conference
> we\'re talking about; whether it will be a small conference, dealing
> with biomarkers for vascular injury, a broader conference dealing with
> biomarkers in general, or a big biomarker-type effort. And that would
> depend somewhat on whether it\'s ILSI, or SOT.
>
> The ACT thing that Ken did was very valuable to that committee, and it
> was very focused. And, you know, that has some merit in that it gets a
> lot of feed back to your working group.
>
> I guess what I\'m thinking is that we also need to explore that, Jim.
> That has to do with the future activities, really, of NCSS---you know,
> how we begin to put those together to publicize all that kind of
> activity, and how we begin to plan the future things that NCSS will
> do. We\'re not going to be limiting only to cardio and vascular-type
> biomarkers. Eventually we\'ll broaden that.
>
> DR. KERNS: Well, it sounds like there\'s reasonable consensus that
> this is something we should pursue in some format \-- and in 12
> months\' time. And I think the committees, and maybe Ken and I and
> Jim, need to take that on Board and come up with some plans and
> strategies to send back.
>
> DR. MacGREGOR: I think we need to not necessarily at this moment---but
> we need to set a time-line for the NCSS formal review of these
> proposals, and then to get some clear feedback from the subcommittee,
> their endorsement of these payouts. And then structure that into the
> next meeting of the subcommittee to determine where things should
> move.
>
> DR. KERNS: Just for information, when is the next meeting?
>
> DR. DOULL: We haven\'t actually decided. This meeting---you know,
> we\'re a little unstable, because we weren\'t sure exactly where NCSS
> really was---at home, or functioning and so on. I think now, then,
> although all the details of that have not been resolved, the intent is
> clear---Dan\'s intent and Helen\'s intent.
>
> So I think---the subcommittee now feels fairly comfortable about all
> that, and I think we are now in a better position to move ahead and
> make some plans for the future.
>
> DR. KERNS: Let\'s move on.
>
> The next item relates to the biomarkers. You know, we have provided to
> you in the table, in the report, a long list of potential markers,
> based on probable pathogenesis.
>
> My question, I think, from the committee is what do you think? Do you
> have some other ideas---other things that we should be thinking about
> at this point in time? We\'ve also tried to identify what we think is
> the low-handing fruit, so to speak, on this slide. And, you
> know---what are your thoughts, comments? Do you have other ideas, or
> should we be moving in other directions?
>
> That was a question to the committee?
>
> DR. DOULL: It\'s an overwhelming list.
>
> DR. KERNS: Any ideas?
>
> \[Pause.\]
>
> Ken? It\'s just a comment, and I\'m sure that your working group has
> already discussed this, and that is being able to distinguish between
> a primary and a secondary adverse vascular event. And that some of the
> markers that you have listed up there would probably change in
> response to a secondary toxicity, as well as a primary.
>
> I think it\'s just the nature of the beast that you\'re looking at
> that there\'s not real clear primary specificity.
>
> DR. KERNS: Very good point. And, I think, you know, specificity,
> sensitivity are issues that we will have to deal with down the road.
> And I think, at this---what you see is a shotgun listing at this point
> in time.
>
> I think the ones---the short list that I pointed out, are ones that
> perhaps have more specificity and sensitivity in normal animals and
> normal volunteers. But there\'s a lot more homework to be done
> there---but, ver good point.
>
> Joy?
>
> DR. CAVAGNARO: And is the protocol such that you will have multiple
> readings of those individual markers, or is it a single end-point?
>
> DR. KERNS: When you say \"multiple,\" what do you mean?
>
> DR. CAVAGNARO: I\'m sorry---over time.
>
> DR. KERNS: Over time---yes.
>
> DR. CAVAGNARO: Right. So the protocol is---and that\'s---what---can
> you describe just an outline \--
>
> DR. KERNS: Briefly, the protocol---these will be single---the model
> that we\'ve set up are single-dose studies, subcutaneous exposure,
> high doses; animals are sacrificed at various times. I forget the
> details now---number of times---but maybe seven or eight time points
> over a period of about 48 hours, roughly. I can\'t remember the
> details.
>
> And we\'d be looking at a variety of different endpoints at each one
> of those time points, varying from, you know, PK to potential
> biomarkers, a routine clin path, histology, addressing the sampling
> issue that Jim pointed out.
>
> So, a single-dose study. And so---so you have data to suggest that a
> single dose---you\'ve seen these lesions at a single dose, obviously.
>
> DR. KERNS: sure. These lesions occur within hours. The lesions I
> showed you this morning, early on---earliest events, endothelial
> compromise can be seen ultra-structurally within hours.
>
> DR. DOULL: okay. Your committee---working group has developed that
> protocol, and it\'s not in here, but we probably \--
>
> DR. KERNS: We should put that in there.
>
> DR. DOULL: Yeah.
>
> DR. KERNS: Actually, that was my intent \--
>
> DR. DOULL: ---you could \--
>
> DR. KERNS: ---actually, I forgot to do that, yeah.
>
> DR. DOULL: Yeah.
>
> DR. KERNS: It\'s a good point. We\'ll put that in the next draft.
>
> That\'s a very important point. I didn\'t---and I forgot to mention
> that. But, in terms of time course, these lesions occur---can be
> initiated very rapidly. And that\'s why I think biomechanical is a
> high probability mechanistic path, I think---for some of the
> compounds, but certainly not all of them.
>
> DR. DOULL: And I would add \--
>
> DR. KERNS: And, you know, regarding the model data, this---a lot of
> this has been published by people around our table. So we\'re all
> quite familiar with the details. And the single dose---the study
> paradigm is---should be no problem.
>
> DR. SISTARE: I\'m sure I would add that we\'re sort of starting there,
> because that would be one of the easier ones to tackle---to be able to
> develop some consensus, in terms of being able to pick a lesions that
> you can pick up within 24 hours, for example.
>
> There are other examples of compounds within the same class at lower
> doses that make take weeks or months to develop in some of the
> nonclinical studies.
>
> And that\'s probably going to be more like the clinical scenario,
> where we won\'t go with such high doses. We\'ll go with a lower dose,
> and then it\'s going to---it may surface at some late time. So we have
> to be cognizant to those kinds of things, and sampling times,
> and---you know, markers that may go up and down real quick. Other
> markers that may go up and stay up for a length of time.
>
> So, a lot of these markers have certain virtues, in terms of those
> kinds of kinetics. So that\'s why we had to take the shotgun approach
> to begin with.
>
> DR. KERNS: Just for clarity, although we\'ve talked about our standard
> rat mode, we\'ll put the protocol in the next iteration of the
> document. But there are several companies around the table who are
> still looking at other species, which is important, as well. I know
> Calvert, sitting behind you, they\'re looking at dogs still, and
> that\'s very important.
>
> But, on the practical side, Jim, we chose the rat for strictly
> practical reasons. And compound supply issues.
>
> DR. CAVAGNARO: So, when we look at the dog, will we also be looking at
> the same endpoints, at least? Those core---so, you\'re defining a core
> set, you know, of minimal endpoints that will track with most
> protocols. Because if---we\'re not going to be ab\--
>
> DR. KERNS: Yeah.
>
> DR. CAVAGNARO: ---you know, if we\'re looking at too many different
> things. And so, for the dog initiative, then, is it clear that we\'re
> going to look at the same endpoints?
>
> DR. KERNS: Right. At this point in time, the EWG does not have a dog
> initiative. There are companies that are going to continue to work in
> the dog, and as the reagents become available for the dog---yes,
> we\'ll try to look at E-selectin across species.
>
> The problem, once again, is reagent availability. So we\'re---and
> we\'re constantly looking and trying to address all those kinds of
> issues.
>
> DR. CAVAGNARO: But you can at least take samples \--
>
> DR. KERNS: Sure.
>
> DR. CAVAGNARO: ---when you can, and store them, and for future. It
> just seems a missed opportunity if somehow---I know it isn\'t our
> initiative, but if it\'s going to add to our initiative, presumably,
> at some point, that at least whoever else is doing it will be aware,
> and be able to \--
>
> DR. KERNS: Save tissue.
>
> DR. CAVAGNARO: Right.
>
> DR. KERNS: Yeah. That\'s a very good point. And I---although we
> haven\'t specifically addressed that with the dog folks, or the monkey
> folks, I\'m sure it\'s happening.
>
> Can assume that Calvert---?
>
> AUDIENCE: Yes.
>
> DR. KERNS: Thank you.
>
> Ken?
>
> DR. WALLACE: Just a comment on the design. You\'ve picked a few
> compounds where you expect to see an adverse event, and you\'ve done a
> very good job at formulating the path in which you should be able to
> detect those.
>
> But I\'m concerned about the possibility of seeing false positives.
> And have you considered including compounds that you could also assess
> the potential record of false positives, where you don\'t have a
> primary vascular injury?
>
> DR. KERNS: That\'s a very good point. And we\'ve talked about it
> within the group. And I think it\'s certainly something that we must
> do when we get to the validation stage---okay? But I think to keep the
> workload manageable at this point, we\'ve chosen not to go down that
> path right away. But it\'s certainly something that needs to be done
> before we close out this project---to look at specificity. We agree.
>
> DR. DOULL: One thing that our committee has talked
> about---subcommittee has talked about in previous things is
> this---what Joy mentioned, the data banking. You know, storage of
> samples and so on. There need to be facilities in order to do that
> sort of thing, and hopefully, that\'s some area---another area that we
> could perhaps facilitate in some way---as well as the agents that you
> use, the samples that are collected---or both programs, Ken.
>
> DR. KERNS: Additional comments on this slide---or questions?
>
> I\'d like to tell you a little bit---there\'s two last slides---our
> timelines, the EWG timelines, that were established in November of
> \'01, which was this committee had it\'s first meeting in May of \'01.
> November of \'01 we established this timeline. And I\'m only showing
> this to you to show you how hard the committee has worked to stick to
> the timeline.
>
> And I think if you look at the items that we would set---we would do
> and accomplish, according to the timeline, you\'ll see---and I\'m sure
> everybody will have copies of the slides later, that we\'re pretty
> much on target with meeting our objectives of coming to SOT in March
> of next year, having initiated ---past tense---a lot of standard
> studies, begun to generate lots of information and data that we can
> review at a face-to-face meeting in March of next year.
>
> The only thing that I think remains to be done is to develop a
> mechanism as to how we can begin to organize and manage all this
> information. And that\'s something the committee needs to take on
> board.
>
> We\'ve talked about the symposium today, and I think that\'s something
> that is---I don\'t know the exact timeline, but it\'s an important
> piece to this that needs to happen. And it\'s on target.
>
> And we\'re committed to working with the member companies, and the
> NCSS, to bring forward in November of next year some potential
> biomarkers for further investigation, supported by real data.
>
> DR. CAVAGNARO: Well, I\'ll have to echo with Jim. I mean, this is an
> amazing effort, to coordinate as many folks as you have, in terms
> of---and their contributions. I mean, again, it shows that the concept
> is actually---you know, hopefully, may work, and hopefully we\'ll be
> able to support, you know, the concerns that you have and so \-- to
> support, so that you\'ll meet those---the future, the future timelines
> as well.
>
> But, I guess I was a skeptic, in terms of this whole initiative, I\'ll
> have to admit, back, in terms of vasculitis as being a huge---huge
> area, of great unknown. And I think you all have done a great job in
> terms of at least putting it into some, I think, context that I think
> that we actually can design studies. So thanks.
>
> DR. KERNS: Well, thanks, Joy. And thanks from the committee. We
> appreciate it.
>
> DR. DOULL: I talked to Marion Erlich about the program for the SOT for
> the Utah---it is, of course, locked up, so that any kind of workshop
> or whatever would have to be ancillary to that meeting.
>
> That\'s not true for the ILSI meeting---for some of their meetings.
> But I think---that\'s one of the problems we\'ll have in our planning,
> is that those things do get pretty much locked up early on. So we need
> to think far enough ahead so we can really do that planning.
>
> DR. KERNS: Right. And that\'s why I\'m talking about October \'03
> today.
>
> DR. DOULL: Right.
>
> DR. KERNS: I think we\'re not ready in March for the SOT---we\'re not
> ready at that time.
>
> I believe that\'s the conclusion of my slides.
>
> DR. DOULL: Well, for the subcommittee, I\'d like to echo what Joy
> says. We are really impressed. You guys have done a fantastic job.
> Both of our working groups have just, I think, far surpassed anything
> that we would have anticipated. And it\'s---that\'s the important part
> of what\'s going on, is the momentum. Both committees now have
> developed a momentum which is crucial to the future success of the
> program. And we\'re committed to maintain that.
>
> Are there any questions for either of our working groups?
>
> \[No response.\]
>
> Well, I guess, then we\'ll go ahead and break.
>
> Let\'s see. We\'re scheduled to come back at 10:15? Why don\'t we go
> ahead and do that.
>
> \[
>
> Open Public Hearing
>
> DR. DOULL: Kathleen is out getting an agenda for the Advisory
> Pharmaceuticals meeting, which is October. And we will present a
> summary of where our working groups are in that October meeting---Dr.
> MacGregor and I.
>
> And so in order to do that we will need to get the couple committee
> members that aren\'t here, we\'ll need to get some feedback from them
> before we do that.
>
> At this point, I think, officially, we are asking if there is any
> public comment. We have no formal requests for public comment, but if
> there is any public comment we would welcome it.
>
> \[No response.\]
>
> Okay, I guess the minutes can show, Kathleen, that there was no public
> comment.
>
> MS. REEDY: All right.
>
> DR. DOULL: And we can move on.
>
> MS. REEDY: Yes.
>
> DR. DOULL: Okay.
>
> **Subcommittee Discussion**
>
> DR. DOULL: Well, at this point, we\'re scheduled to talk about
> subcommittee discussion, and the next steps. We\'ve done that
> partially in the meeting that we had yesterday, and partly in the
> meeting, again, that we\'ve had today.
>
> And as I indicated previously, one of the concerns that the
> subcommittee has had in dealing with our working groups is that we
> haven\'t exactly known where the NCSS subcommittee, in fact, is going
> to end up.
>
> As you heard from Helen Winkle yesterday, they are planning to do some
> reorganization within the Advisory Committee for Pharmaceutical
> Sciences. And at the present time it\'s not exactly clear what that
> reorganization---how that will look when it\'s done. But I think we
> heard from Helen yesterday, clearly, a commitment to preserve the
> ability of the NCSS to make recommendations to the Advisory Committee
> for Pharmaceutical Sciences that would come for from our working
> groups. And we certainly will intend to do that.
>
> And we also heard yesterday from Dan about the anticipated support
> from NCTR. So we\'re looking for that arrangement. We think it will
> really be exciting.
>
> Well, I think, then, the question is, in terms of the working groups.
> And I - Ken, when we did---yesterday, when we talked about things that
> your working group was bringing to the subcommittee, you really
> brought us three issues that you wanted us specifically to deal with.
> First, you have an outline for the paper which you\'re going to put
> together, and you want approval of the subcommittee for that outline.
> I think yesterday we said that we did approve that. We thought that
> was an excellent outline. And I guess the minutes should show that the
> subcommittee encourages the working group to go ahead and put together
> that---the final draft of that.
>
> Now the second issue that had to do with that outline was the next
> step. If you identify the data gaps in there, which we\'re assuming
> that is part of that outline, then the question is the plans to fill
> those data gaps, and whether that should be part of the outline.
>
> I think, as I recall from what we said yesterday, that was out
> intention---that you would, in fact, put together some kind of
> proposal which would fill the specific data gaps that you were talking
> about. And that the subcommittee, then, would look at those proposed
> plans and try to develop a procedure whereby we could help you achieve
> those plans to fill the data gaps.
>
> I think how the subcommittee responds specifically to those
> recommendations depends somewhat on the kind of recommendations that
> you bring us. But our intent, you know, was to be supportive, to
> accomplish the goals of the subcommittee.
>
> And the third thing we talked about is the cardiac group has focused,
> of course, on troponin, because that\'s a prime candidate. And the
> issue was: well, how about all the other biomarkers, you know. That
> certainly is a down-the-road agenda, and the question that you asked
> us was: how much of that should be in the present document? And, I
> guess, my own feeling is we would leave that somewhat to you all.
> Clearly, you\'re going to have to indicate in there that the
> committee, in their judgment, looked at all the potential biomarkers
> and decided that the troponins were, in fact, the ones that they
> wanted to focus on initially, and have done.
>
> The question then is, you know, whether there should be any review of
> other potential biomarkers to indicate the basis for the decision to
> select troponin. And I think that\'s all that\'s really required in
> the document that you\'re putting together.
>
> The down-the-road document---you know, once you go through---we go
> through the troponin exercise, you\'re going to have to then do what
> Bill\'s committee has done, in a sense, and go back to the drawing
> board and decide, are there other ones there, and which ones would be
> the ones that would be most profitable? I like Bill\'s term, \"the
> low-hanging fruit\"---whether there are other low-hanging fruit that
> would be done.
>
> But I think if we suggested to the working group that they do that
> now, that\'s probably going to slow them down, don\'t you think? To
> add a big section on that to the present document?
>
> DR. WALLACE: Yeah. I would like to minimize how much effort we commit
> within the document to discussing the next generation, if you will, of
> cardiac biomarkers. That more---the last two points were more points
> for the future activities of the working group, and not necessary for
> inclusion in the document.
>
> The point---the information gaps, was does the NCSS want to engage the
> working group to take a lead role on identifying, devising paths
> forward---plans for filling those information gaps? Does the NCSS want
> to engage the working group in that activity.
>
> And then the third point is just to affirm the understanding that the
> NCSS does want the expert working group to continue on the theme of
> biomarkers once the troponin document is complete, and engage the
> working group in discussions, much like Bill\'s group has
> done---alternative biomarkers, including the emerging technologies.
>
> DR. DOULL: Right. And I think yesterday the comments from the members
> of the subcommittee were that we have a great team put together, and
> we want that team to continue to work---they already have done all the
> leg work, and therefore it would be most efficient and---to just
> continue that process, so that---yes, Gloria?
>
> DR. ANDERSON: I think it would be helpful, at least to me, if in your
> introduction you gave some background information on other---potential
> other biomarkers; no any in-depth discussion, but at least to put this
> in context.
>
> DR. DOULL: Joy?
>
> DR. CAVAGNARO: I\'m sorry, I had a conflict yesterday---but, so, if we
> understand initially we set out that these two initiatives were
> priorities within the---based upon current regulatory hurdles, if you
> will---but there were some significant impact, in terms of moving
> forward.
>
> And so would it be that once we identify these certain initiatives
> through this committee, that, in fact---and they\'ve addressed the
> issue, that they somehow move on and other---other issues may then be
> considered.
>
> I guess my concern is is that these becoming living groups, and then
> we then prevent---you know, resources, for example, would be
> key---that the issues that were brought up---you know, like PET
> imaging---some of the newer technologies that I thought we
> were---shelved before, because we can only prioritize two.
>
> I just want to make sure that, you know, we still, as a committee,
> have opportunity to introduce the newest and the key areas. And it
> would almost be like this would be their initiation, and then once
> they succeeded as a committee, perhaps they could somehow evolve into
> another---you know, graduate out of this committee, and somehow be
> supportive in some other initiative.
>
> I don\'t know if that\'s clear. But, I mean, I just want to make sure
> that we don\'t lose, as a committee, what I think our charge is, is to
> keep our pulse on those areas where---may be constantly---you know, it
> might be changing, and may need---you know, we may need to set up
> another working group, etcetera. So I don\'t know \--
>
> DR. DOULL: Yes, I think the limitation of the groups we set up is
> they\'re focused---the cardiac group and the vascular group. So that
> it\'s only biomarkers which are related to those two areas, which they
> would be considering as alternative biomarkers.
>
> There are other issues---you know, the omics issue as a biomarker, the
> imaging issues as biomarkers and so on, are issues that the
> subcommittee as a whole needs to return to to see---you know, we
> decided to delay imaging because we didn\'t feel it was mature enough,
> really, to move into that area. We need, of course, to reevaluate
> that. And if that\'s changed, then we would need to do something
> appropriate.
>
> I think we probably do need re-look at omics. I think we bypassed
> omics because we thought, gee, there\'s a lot of activity going on in
> that, and we\'ll be rediscovering the wheel to some extent. I\'m not
> sure that\'s---you know, in retrospect that was the best decision. And
> we certainly need to re-look at that again.
>
> Dan?
>
> DR. CASCIANO: Can I comment?
>
> DR. DOULL: Sure.
>
> DR. CASCIANO: Well, we have to keep in mind that omics are just
> technologies and techniques. And so what we really should be focusing
> on are the biological questions, and not on the technologies that are
> available to answer the biological questions. And omics can be applied
> too any biological question that comes to this committee. So I\'m not
> sure if we should just focus on omics itself.
>
> DR. DOULL: As a source of biomarkers.
>
> DR. CASCIANO: Well, to me, omics are sort of like a spectrophotometer.
> And I don\'t think we---yeah, and it\'s more expensive. It\'s a tool
> that will help us answer the basic question that we have, and, in my
> mind, it\'s just a tool.
>
> DR. SELKIRK: Just a couple of---to go a little further with the omics
> prospect. I think omics can do at least two things. One, it\'ll
> confirm biomarker placement in a pathway. In other words, it will tell
> you if you have a biomarker out in space, where that biomarker fits.
> Because things like micro-ray and proteomics will look at a lot of
> things at once, and then attempt to help you place that single
> biomarker in a pathway and sort of validate its---it will sort of
> validate its placement as a true biomarker.
>
> But it also will help tremendously in discovery of biomarkers, because
> it can look at so many things at once, and build pathways that will
> evolve biomarkers with time.
>
> So, yes, it\'s a tool, but the more data we build into it, the more
> knowledge we will have coming out of it at the other end.
>
> So we\'re in the early stages, but I think with time we\'ll see great
> acceleration, in terms of biomarker discovery and validation, using
> all the various omics that we are now beginning to have at our
> fingertips.
>
> DR. DOULL: Yes, and hopefully, this committee would have a mechanism
> to keep our finger on some of those exciting things so that we would
> know the right time to step in and say, \"Hey there\'s a tool that\'s
> potentially valuable in liver damage, for example, or whatever.
>
> Does anybody have any other comments on the cardiovascular one?
>
> Frank?
>
> DR. SISTARE: I think some of the comments have been excellent with
> respect to sort of next steps, and we don\'t want to create an Expert
> Working Group to live in perpetuity, just because \-- they\'ve done a
> great job, we\'ve got excellent people here, and it\'s a shame to
> disband them. But, clearly, the charge to this group was focus on
> biomarkers of tissue injury in the heart. And they\'ve done a great
> job. And there\'s still work to be done. So we\'re premature, in terms
> of talking about disbanding them. But, they are looking to the future.
> They can see an end to their work, and they\'re saying, \"When we\'re
> done with us, what do you want us to do?\" Okay.
>
> The charge really is on CDER, I think, to answer that question. CDER
> needs to answer that question, go through their committee, and
> say---\"We still have a problem\"---okay---and figure out what the
> best way to deal with it. \"We still have a problem with QT.\" We do,
> and we need to deal with that. Is this the best mechanism, or are
> there other mechanisms to do that? We have to figure that out.
>
> We have another problem that has been brought to our attention with
> respect to the mechanical injury aspect of what you\'re saying.
> There\'s clearly a class or two of compounds that have surfaced, and
> then clearly a problem in clinical trials---some post-marketing
> indications of problems. Clearly the animal is showing these issues.
> You see it on histology. The question is, is there a biomarker? We
> could clearly use the expertise of this group to help us with that. Is
> that the most important pressing problem? We\'ve got to go through a
> system to figure that out, you know.
>
> Maybe---you know, there may be a system where the committee doesn\'t
> meet quite as often. You know, there may be---you know, the frequency
> of this particular committee meeting may go down to once a year,
> whereas vasculitis there\'s still a lot of activity. That was a much
> more immature problem, much more---a lot more effort needed to go into
> that, whereas troponin was a pretty mature biomarker. So meeting
> frequency enters into the thing as well, in terms of budget
> considerations.
>
> So, these are important---very important things that need to be worked
> out.
>
> What I\'m hearing, you know, as Helen sets up this group, over on the
> CDER side, is that pharm tox community in CDER needs to communicate
> with them and say here are our needs, and make the case, you know, as
> you would in a court of law. We need to make our case and be really
> clear with it, and then let the chips fall where they may. It may say
> this committee in CDER may go to the NCSS and CTR and say, \"We really
> feel that there\'s a need from some research to be done here,\" you
> know. That may be what happens.
>
> But these are good questions. I don\'t think we\'re going to be able
> to answer them today.
>
> I think---what I\'m hearing, though---as a member on the CDER side of
> things---we need to be clear about getting some of these priorities
> addressed.
>
> DR. DOULL: Yes, we were fortunate when we created these working
> groups, that we---we were lucky enough to get really first-class
> people to serve on both of these working groups.
>
> And so---but, you know, as you change priorities, then that may
> require a different group of experts with different focus, and so on.
> So I think that\'s---that\'s what NCSS, in fact, has the ability to
> do, is to hopefully get the best experts to deal with a particular
> issue.
>
> Just because it worked twice doesn\'t necessarily mean it\'s going to
> work again, Frank. \[Laughs.\]
>
> DR. MacGREGOR: I think I would endorse what I think Joy and Frank are
> both saying, is that I think when both of these reports are final and
> come in to the subcommittee, that would be the time that the
> subcommittee should step back and take a look at the big picture, and
> the broad charge given to the subcommittee, which is where are the
> most fertile opportunities for collaborative science that can really
> move things forward?
>
> And I think it may be premature to decide where the cardiac tox group
> should go at this point, because we don\'t really have the assessment
> of the gaps and what really needs to be done. And I think probably you
> need to know where the committee really feels you should go, and the
> role that the committee should play in going there, to deal with those
> gaps on the very specific issue they were charged with, which was the
> biomarkers of cardiac injury.
>
> And I think it\'s been---Bill said it\'s been about 18 months since
> the groups were formed, and it\'s probably been about two years since
> the subcommittee set its initial priorities. And a lot of new things
> have happened in those two years---new programs have been established
> at FDA. One of the areas that was discussed and decided not to pursue
> was hepatotoxicity, partly because there was a focus in ILSI and in
> other places at that time. But now NCTR has a new hepatotoxicity
> program, and new capabilities to bring some of the newer technologies
> to bear.
>
> And so I think the committee really needs to reassess where the
> priorities should be reset when these two reports are in and final,
> and decisions are made on how to follow-up on those recommendations.
>
> Well, I think, Ken, in terms of our response to your---the working
> group, essentially those are the way would deal with those three
> issues pretty much. Is that adequate for---do you have other concerns
> to bring to us?
>
> DR. WALLACE: The only---I\'m sorry. The only other concern I have is
> one that was echoed by Bill, and that is, when we have this document
> that we want to publish in the peer review literature, is that we have
> to know what the policies are within the structure of the agency, as
> far as publishing them with some sort of approval by the NCSS, or if
> they should be done independently. We just need---are both looking for
> guidance back from the NCSS on that.
>
> DR. DOULL: Yes, and I think our response to that is that, you know, we
> strongly encourage the publishing of the scientific paper, because we
> think it has great merit for the clinical---for the scientific
> community.
>
> And we support the idea that the NCSS will, in fact, endorse that
> paper, and will be part of it in the sense that that adds to the
> credibility, somewhat, of the whole process.
>
> Now, the mechanics of that I guess we haven\'t fully explored yet. Jim
> tells us that there are certain hoops we have to go through in order
> to do that. And we\'ll explore that, to figure out how best we can do
> that in a way that helps you accomplish what you want to do, which is
> to put a paper out there that does, in fact, present the situation
> clearly.
>
> Whether or not we may eventually have to have two publications---one
> which we would take to the Advisory Committee, for example, with a
> recommendation, as opposed to that one that\'s in the peer review
> literature, I think we have to explore that and figure out which is
> the best way to help you folks get the job done. And we\'ll do that.
>
> DR. DOULL: Okay. The report that we heard this morning from Bill on
> the vascular side also raised another---other questions that the
> subcommittee needs to deutes so that our response is clear. And one of
> those had to do with the suppliers to the agents---or, the suppliers
> of those three compounds that you\'re concerned about.
>
> And you said that you would draft that letter, and that the question,
> then, is whether those compounds should come to the Food and Drug and
> be distributed by Food and Drug, or whether there\'s some other
> mechanism which would be more preferable.
>
> I gathered, from the discussion, that coming to Food and Drug seemed
> to be the method that would be most desirable. And I gather from Frank
> that there are some precedents for that, and some problems also with
> doing that. And so, clearly, we have to explore that, Bill, in order
> to be able to respond as to how best we can do that. And I think
> we\'ll do that. We\'ll find out what is the best way we can undertake
> that in a way that will help you all.
>
> DR. KERNS: I think, then, that along those lines, that I\'ll finish
> drafting the letter as much as I can, and send it to the NCSS, and
> then we can fill in the details once we more clearly understand the
> MTA requirements and what flexibility the FDA has.
>
> And I think we also mentioned that perhaps NCTR might be a home for
> distribution as well---something to consider.
>
> DR. DOULL: We probably ought to do that a little more broadly, in a
> sense, because we\'re down the road talking about storage of samples,
> and collection of blood and what have you and so on. And, you know, we
> may need a mechanism that is, in fact, broader than simply
> distributing the dopamine or those three compounds, so that---I guess
> if there\'s some regulations, Jim, that hamper that in some way, we
> probably ought to know about that early on, because they may be
> different at NCTR, in terms of data---that storage.
>
> DR. CASCIANO: There are some similarities, and there are some
> differences in here. I mean, we\'re a little bit more flexible than
> the product centers, because of the different mandates.
>
> But weearly we need to look into all those things, and we really
> shouldn\'t lose sight of what may be the simplest solution to the
> compound distribution. That is, we need to ask do we really need an
> MTA, or could the materials just be made available from the company
> that makes them. That might be the simplest to do, unless they have a
> problem with that.
>
> DR. DOULL: Well, I was thinking, you know since we have an opportunity
> at the end of October to talk to the Advisory Committee for
> Pharmaceutical Sciences, if there is some mechanism that would be
> facilitated by that opportunity we perhaps could ask the Advisory
> Committee to help us do whatever we\'re going to do.
>
> But, hopefully, we would have some indication as to what we ought to
> do---by then.
>
> Okay, the second thing, Bill---you talked about comments and responses
> to the White Paper, which you provided us with, and we gave you some
> this morning. I think, there again, we\'ll---these have gone out to
> the other members, to Jay Goodman and to Ray Tennant, and I\'ll get in
> touch with those---both of those members and add their comments to
> what we have from this morning\'s comments. And we\'ll then provide
> those to the working group, along with the thanks of the subcommittee
> for your---to both of you---your groups for the hard work that you\'ve
> done, and for the fact that you\'ve reflected glory on the intent of
> this whole effort.
>
> If it had been a disaster, we\'d have been in trouble. Instead, it\'s
> a superlative achievement, and we\'re delighted.
>
> DR. KERNS: Thank you, John, and I\'ll communicate that to the people
> who did the work.
>
> DR. DOULL: I guess I\'m like Joy, I held my breath for a little bit.
> You know, we didn\'t know this was going to work out---gangbusters.
>
> Okay. I have, in there, the justifications of the selection of the
> agents, and the selection of the four tests that you\'re going to do.
> And you said you would include something in there?
>
> D\--
>
> DR. KERNS: Yep.
>
> DR. DOULL: ---and some justification for the specific biomarkers. You
> had that huge table, which listed them all. And then that was
> distilled down to the four that you selected. And, I guess, the
> question was exactly how did that process work?
>
> DR. KERNS: Yes. Agreed. In addition, we will add the rat protocol. We
> will add some justification about how we chose the rat versus the
> monkey, etcetera.
>
> And we will add some discussion on the incidence of the drug-induced
> lesions in humans. No problem.
>
> DR. SISTARE: And I think, you know, Jim\'s suggestion is how big of a
> problem is this? Not just based on the human known angitis-type
> reaction, but in terms off what we\'re seeing in terms of the
> animal---try to put a perspective on how big of a problem that is, and
> why is this an important thing to draw our intention to.
>
> DR. KERNS: That\'s no problem.
>
> DR. DOULL: Is there---Frank, is there data on the---why compounds or
> new drugs are rejected? The most prevalent \--
>
> DR. SISTARE: The only data you get out of the FDA is why drugs are
> pulled off the market. We often don\'t know why drugs are
> stopped---why developed gets stopped by sponsors. And a lot of times
> that decision is made by them---they decide to not pursue a particular
> candidate, and that information isn\'t always shared. We can make
> guesses, but that information isn\'t always shared. And there\'s a lot
> of complex decisions. They go into that.
>
> So FDA could not provide that information. The only information we
> could provide is when a drug is pulled off the market, why. But why a
> drug is stopped in a Phase II, or Phase I or a Phase III trial, we
> don\'t always know why.
>
> DR. DOULL: And you hear that all the time---that 80 percent of the new
> drugs somehow go down the toilet.
>
> DR. SISTARE: Right. We know the numbers---we know the numbers. We
> don\'t know the reasons behind them, though, always. And that would be
> beautiful. We\'d love to have that information, you know. There\'s---I
> don\'t know---I just don\'t know of any definitive source for that
> information. We\'d love to have that information.
>
> DR. MacGREGOR: You know, PhRMA has published that kind of information,
> but in very broad categories, like things that have failed due to
> economic considerations versus drug toxicities and so on. But I\'m not
> sure it\'s been ever done in terms of specific causes of
> toxicity---failure due to specific toxicities.
>
> DR. DOULL: I\'m just thinking, as a front end for these papers---you
> know, that certainly would be a lead-in, because it would say Food and
> Drug---you know, we\'re wasting a lot of money. We\'re wasting a lot
> of effort. We\'re doing a lot of redundant studies and so on.
> Certainly, we ought to figure out a way to do it better if we could.
>
> You had mentioned, Bill, also the need for the NCSS to do some future
> planning. And we agreed, that\'s a charge that we\'ll take, and try
> and figure out, with---in conjunction with the working groups, how
> best to bring this information out.
>
> We have a lot of information which would be of great use and value to
> the scientific community out there, and the question is whether a
> workshop would do that---a small workshop focused on one of these
> problems, or a larger workshop focused on biomarkers---how best to do
> that.
>
> DR. KERNS: Well, that would be very helpful, I think---receiving that
> directive to Ken and myself. It would be very clear, then, what we
> needed to be doing. It would be very helpful.
>
> DR. DOULL: Yes, I would think the working groups could advise us as to
> where \--
>
> DR. KERNS: Sure.
>
> DR. DOULL: ---they think it would be most helpful \--
>
> DR. KERNS: Yep.
>
> DR. DOULL: ---you know---we\'re happy to do that, too.
>
> DR. CAVAGNARO: Can I just make a comment?
>
> Jim---since Jim is currently or outgoing chair of the PhRMA drug
> safety committee, can you discuss, you know, the---whether or not this
> initiative has been discussed in a broader forum, amongst all the
> member companies and, you know---and the support and enthusiasm,
> or---of the---group?
>
> DR. GREEN: Sure. Yeah.
>
> Well, I think both---there\'s a high degree of awareness
> amongst---let\'s see, there\'s 15 member companies that are on the
> Drug Safety Steering Committee of both of these initiatives, as well
> as the committee\'s activities.
>
> So, speaking on their behalf, and reflecting my own opinion, I think
> they would be remarkably impressed. I think what---the questions would
> remain, especially with the pending changes within the advisory
> committee structure in Pharmaceutical Sciences, and the creation of a
> tox path group in that, is an understanding of the logistics into
> how---and particularly these areas where new technology is producing
> potentially decision-making data sets, or may be viewed as
> decision-making data sets by those folks that are reviewing our
> applications. And if you have several hundred reviewers, in several
> divisions, it\'s very easy for there to be mixed impressions about the
> state of readiness of a particular new technology, a new approach, a
> new marker, etcetera.
>
> So I think, to the extent that this kind of committee, in addition to
> the new evolving advisory committee structure can have some kind of
> influence, and sponsors can see that, with respect to communication of
> points of science and interpretation that affect the day-to-day
> review, I think there would be remarkable support.
>
> Easier said that done, though.
>
> DR. SISTARE: Along that line, I will just mention one event---one
> thing happening in CDER. CDER has formed two committees, for example,
> focused on pharmacogenomics and toxicogenomics---a clinical and a
> nonclinical committee---to coalesce a consensus thinking, in terms of
> should a sponsor choose to submit such data, you know, how would we
> want that? You know, that kind of thing. And that\'s something that
> will allow us to generate internal thinking---internal consensus---but
> then having this mechanism allows us to externalize our thinking and
> get some feedback on that.
>
> So, I would just add that, in terms of the new technologies and how to
> get reviewers tuned into a consensus, in terms of how it should be
> approached across the different review divisions, it is important to
> have that internal committee, and then to have a place where we can
> interface with PhRMA on that.
>
> And one could potentially see, you know, that we have a problem with
> standards. And then we need to go to the NCSS, through NCTR, to help
> with standardization. That may be an issue. There may be some
> experiments that need to be done. I don\'t know.
>
> But I think having the matrix, having something in place really, I
> think, helps---helps the process. And I think we\'re going a long way
> toward that.
>
> DR. DOULL: I think, actually, when this subcommittee was created, that
> kind of was the hope that, you know, we would find---it seems logical,
> in a sense that, you know, having the group looking at biomarkers
> which would contribute nonclinical and bridging markers and so
> on---all that makes good sense.
>
> I think when the committee was formed---or subcommittee was formed, we
> had no real idea of the complexity of forming subcommittees,
> particularly one that\'s doing this kind of activity, because it\'s
> somewhat different than activities have been done before. So, you
> know, ienjoy some of the results of all that experience. And,
> hopefully, we\'re going to move in the direction you\'re talking
> about, Jim.
>
> Ah---let\'s see, the only thing I had written---else written down,
> Bill, was the timeline thing that Joy raised, and you also said that
> would be part of your report. For the timeline of those effects, and
> in animal studies?
>
> DR. CAVAGNARO: Right.
>
> DR. DOULL: She was asking about, you know, how long it takes in a rat?
>
> DR. KERNS: Time to injury.
>
> DR. CAVAGNARO: Right.
>
> DR. DOULL: Yeah. I guess the inter-species argument also would be
> something that should be mentioned there, because the dogs---as I
> recall what you were all saying---the dogs don\'t totally replicate
> the rat stuff. Well, at least you need to talk about that in the
> report.
>
> Have we got other issues, Bill, that the subcommittee needs to
> address?
>
> DR. KERNS: No. I\'m happy.
>
> DR. CAVAGNARO: So---one more question. So there will be this
> protocol---the rat protocol---with the various---you know, the four
> areas that have been discussed. And then you mentioned the fact that
> there are ongoing activities.
>
> Who is capturing. You know, it\'s not your charge, but who will be
> capturing the overall data base, if you will. So there\'s the NCSS
> initiative and then, clearly, companies---I mean, we heard
> that---Calvert---oh, Astra-Zeneca, is going to do some \--
>
> Now, I mean, when---I presume that those initiatives, when we have the
> October symposium or workshop, that would be a forum for others, you
> know, engaged in this area to present. Is that what you\'re
> envisioning?
>
> DR. KERNS: That\'s my hope.
>
> DR. CAVAGNARO: Yeah.
>
> DR. KERNS: Once again, it is their choice---to share or not to share.
> But my hope is to, over the next 12 months, to interact with, you
> know, the companies doing work independently. And, hopefully, we can
> share at the table. And I think---we\'ve already initiated that
> process, and it\'s worked quite well so far. So I would anticipate
> that will continue and culminate in a symposium sometime next
> year---next fall, where people will formally share these data.
>
> As far as capturing and organizing, collecting and collating, I think,
> for the people doing independent work, that will come from their
> publications, and we\'ll see it once it\'s published.
>
> DR. SISTARE: Actually, it raises a very good point. Maybe this might
> be an opportunity to try to capture a conference proceedings. You
> know, like, maybe get Tox Path interested in maybe publishing the
> proceedings. That might be a really nice way to capture everything and
> really encourage some of the individual investigations going on to
> bring it to a point of fruition, where it can be shared.
>
> Sometimes a stumbling block is you\'re working with a compound that
> you can\'t put the structure---you know, you can\'t cite it, you
> can\'t put the structure in. We always have to figure out how to do
> that. That\'s always a problem. But there\'s probably some way of
> doing it. We just have to figure it out.
>
> DR. DOULL: At our last meeting you raised the issue about
> confidentiality of results and how that was being handled amongst the
> various members of the group. And you didn\'t bring that up this time,
> and so I gather you\'re---the methodology that you developed for that
> is \--
>
> DR. KERNS: Well, we\'ve agreed amongst the members sitting around the
> table that everything we do will be in the public domain.
>
> DR. DOULL: Okay.
>
> DR. KERNS: And I think when we contact our---the suppliers of
> Fenoldopam and Abbot, the PD-IV inhibitor, I think we need to make the
> same agreement, or put the same words in that letter so that, you
> know, there\'s nothing proprietary will surface out of this.
>
> And we need to make it clear, as we distribute compound, that
> the---you know, the other customers understand the rules here. Because
> that\'s the way that we circumvented this issue, of creating
> intellectual \--
>
> DR. DOULL: I recall we had no easy answer to that problem.
> So---\[laughs\].
>
> DR. KERNS: Well, that\'s what we decided---that\'s what would be
> easiest. It won\'t happen---theoretically.
>
> DR. DOULL: That\'s an old adage. If you out wait the problems they go
> away---a dean\'s adage.
>
> Any other arguments, comments or suggestions?
>
> Yes---go ahead, Gloria.
>
> DR. ANDERSON: Mr. Chair, as we move to what I perceive to be a
> different level, having gotten these two reports, and having given
> some instructions as to how they should proceed, it might be a good
> time to look at the background paper that we received when the
> committee was formed, and review the objectives that were set forth
> and see where we are, and perhaps either get some guidance from the
> advisory committee, or give them some recommendations on how we might
> proceed, beyond these two papers.
>
> DR. DOULL: I agree. And since that---the next Advisory Committee on
> Pharmaceutical Sciences is scheduled for October 21^st^ and 22^nd^,
> and Jim and I will give some thought to that specific mandate for our
> subcommittee, and also to report on the progress of the two working
> groups.
>
> \[Pause.\]
>
> All right, we heard the recommendations by Helen on the reorganization
> of the advisory committee, and I think---you know, other than
> commenting on the fact that for the subcommittee we\'re delighted with
> the fact that she\'s going to maintain the link to the regulatory
> recommendation pathway. It\'s premature, really, to get into that too
> much because we don\'t know exactly, other than what she told us will
> happen.
>
> I think, Jim, we need to be sure that the members of the subcommittee
> are fully informed about what happens in the October meeting.
>
> DR. MacGREGOR: Mr. Chair, with regard to the October meeting, I might
> encourage the subcommittee to complete your review of these documents,
> if possible, and to be able to go to that committee with a---you know,
> a clearly formed view of the subcommittee that, hopefully, could be
> endorsed by the parent committee at that point, so that endorsement
> could go back to the working groups.
>
> DR. DOULL: Yes, we willo that we will be able to bring those to the
> advisory group if we have additional things.
>
> And Gloria and I---you\'re going to be at the October meeting.
> Yes---we\'ll be there. So, hopefully, if there are questions about the
> working groups or where we\'re going and so on, we\'ll be able to
> respond to those.
>
> DR. CAVAGNARO: \[Off mic.\]
>
> DR. MacGREGOR: You\'re aware of the date? October 21^st^ and 22^nd^ is
> the next ACPS meeting. And you indicated that you\'d like to do some
> further revisions. But could those be back to the group in time for
> them to comment, or, if not, I guess what I\'m asking is if the group
> could complete its review with the absent members on what we have now?
>
> But, in any event, we\'d need a clear indication, between you and the
> group as to whether you will or won\'t have a \--
>
> DR. KERNS: Understood. I wasn\'t aware of this meeting this morning.
>
> \[Laughter.\]
>
> DR. KERNS: So let me back up a little bit here.
>
> What is the timeline to---how far in advance of the ACPS do you want
> the document?
>
> MS. REEDY: September 25^th^. Actually, the briefing documents have to
> be to me on September 23^rd^, which is a Monday.
>
> DR. CAVAGNARO: So---I\'m happy just to get the---this working
> protocol. I\'d like an opportunity to look at that. But, as to the
> other more detailed, I think, you know, it\'s stated and you can do
> that.
>
> DR. KERNS: We can certainly send that as a attachment, I think. It\'s
> just a two-page outline. And Jim, Ron has that so you can send that, I
> think.
>
> So, regarding the next iteration of this document, then, it will not
> be circulated before your---in time for your next---the ACPS meeting.
> So please use this document to work from---
>
> MS. REEDY: Use this one? Okay.
>
> DR. KERNS: in addition to the attachment that Jim and Ron will send
> out.
>
> DR. DOULL: Yeah. My thought would be simply to e-mail the NCSS members
> and say, you know, that protocol is out, and if you have any comments
> send those back immediately and then call them to see if they had any
> additional comments. And to try and capture some of the comments that
> we had yesterday and today.
>
> \[Pause.\]
>
> Great. I\'ve run out of agenda.
>
> Anybody else have anything for our subcommittee?
>
> \[No response.\]
>
> Do you have anything, Jim, that we need to do?
>
> DR. MacGREGOR: Well, if we\'re closing, I guess I would like to
> formally go on record with my compliments to the two working groups. I
> think they\'ve made tremendous progress and I think the outline in the
> report really show the fruits of a lot of labor that went into those.
> So my thanks---my thanks to them for a job well done.
>
> DR. DOULL: We are adjourned.
>
> \[Whereupon, at 11:18 a.m., the meeting was adjourned.\]
>
> \- - -