AHDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
>
> CIRCULATORY SYSTEM DEVICES PANEL
>
> Tuesday, October 22, 2001
>
> 8:08 a.m.
>
> Walker/Whetstone Room
>
> Gaithersburg Holiday Inn
>
> 2 Montgomery Avenue
>
> Gaithersburg, Maryland
>
> [C O N T E N T S]{.underline}
>
> [AGENDA ITEM: PAGE]{.underline}
>
> Call to Order
>
> Dr. Warren K. Laskey, Acting Chairperson 3
>
> Open Public Session - \[No speakers\]
>
> Conflict of Interest Statement 3
>
> Introductions 6
>
> Sponsor Presentation: Cordis Corporation
>
> P020026, CYPHER Sirolimus-Eluting
>
> Coronary Stent System 9
>
> Dr. Dennis Donohoe, Vice President,
>
> Therapeutics and Clinical Research 9
>
> Dr. Richard Kuntz, Associate Professor of
>
> Medicine, Harvard Medical School; Chief,
>
> Division of Clinical Biometrics, Brigham
>
> and Women\'s Hospital; Chief Scientific
>
> Officer, Harvard Clinical Research
>
> Institute 51
>
> FDA Presentation
>
> Joni Foy, Lead Reviewer and Biomedical Engineer, Interventional
> Cardiology Devices Branch,
>
> Office of Device Evaluation, CDRH 97
>
> Dr. John Hyde, Lead Medical Officer 115
>
> Dr. Murty Ponnapalli, Lead Statistician 141
>
> Open Committee Discussion 157
>
> Questions and Answers 267
>
> Sponsor Comments 334
>
> FDA Comments 336
>
> Recommendations and Vote 344
>
> Adjourn 363
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> **Call to Order**
>
> DR. LASKEY: Well, good morning. My name is Warren Laskey. I\'d like to
> welcome you all to today\'s Circulatory System Panel Meeting
> discussing the premarket application for the Cypher Sirolimus-Eluting
> Coronary Stent System, P020026. And before we begin, I\'d like to
> thank everyone for their indulgence this morning. Due to some horrific
> events in our area, a number of us were delayed getting here, so we\'d
> like to thank everyone for their forbearance.
>
> I\'d like to ask the Executive Secretary to now read the conflict of
> interest statement.
>
> **Conflict of Interest Statement**
>
> MS. WOOD: Before I read the conflict of interest statement, I just
> have a couple of general announcements.
>
> First of all, Dr. Warren Laskey will be our acting Chair for the
> meeting today. And I\'d like to remind everyone to please make sure
> that you sign in at the registration desk and also please turn your
> cell phones off when you\'re in the meeting.
>
> The microphones that we\'re using today require that you keep the
> button depressed while speaking, so I\'d like to mention that for the
> panel and the speakers\' benefit.
>
> The following announcement addresses conflict of interest issue
> associated with this meeting and is made part of the record to
> preclude even the appearance of an impropriety. To determine if any
> conflict existed, the agency reviewed the submitted agenda for this
> meeting and all financial interests reported by the committee
> participants. The conflict of interest statutes prohibit special
> government employees from participating in matters that could affect
> their or their employer\'s financial interests. The agency has
> determined, however, that the participation of certain members and
> consultants the need for whose services outweighs the potential
> conflict of interest involved is in the best interest of the
> government. Therefore, waivers have been granted for Drs. Thomas
> Ferguson, L. Henry Edmunds, and Mitchell Krucoff for their interests
> in a firm that could be affected by the panel\'s recommendations. The
> waivers involved grants to their institutions for the sponsor\'s
> product study in which they had no involvement and for which funding
> was less than \$100,000 per year.
>
> Additionally, Dr. Edmunds\' waiver involved stock in a firm with an
> interest in the sponsor\'s product. The stock value is between
> \$25,001 and \$50,000. Copies of these waivers may be obtained from
> the agency\'s Freedom of Information Office, Room 12A-15 of the
> Parklawn Building.
>
> We would like to note for the record that the agency took into
> consideration other matters regarding Drs. Ferguson, Cantilena, and
> Krucoff. Each of these panelists reported interests in firms at issue
> but in matters that are not related to today\'s agenda. The agency has
> determined, therefore, that they may participate fully in all
> discussions.
>
> The agency also would like to note that, due to the regulations
> governing covered relationships, the panel Chair, Dr. Cynthia Tracy,
> will not participate in today\'s deliberations.
>
> In the event that the discussions involve any other products or firms
> not already on the agenda for which an FDA participant has a financial
> interest, the participant should excuse him- or herself from such
> involvement, and the exclusion will be noted for the record.
>
> With respect to all other participants, we ask in the interest of
> fairness that all persons making statements or presentations disclose
> any current or previous financial involvement with any firm whose
> products they may wish to comment upon.
>
> DR. LASKEY: Thank you. I\'d like to now ask the panel members to
> introduce themselves, starting to my right.
>
> DR. ZUCKERMAN: Bram Zuckerman, Director, Division of Cardiovascular
> Devices, Food and Drug Administration.
>
> DR. EDMUNDS: I\'m Hank Edmunds, University of Pennsylvania, surgeon.
>
> DR. WHITE: Chris White, Ochsner Clinic in New Orleans, Interventional
> Cardiology.
>
> DR. CANTILENA: Yes, I\'m Lou Cantilena, head of Clinical Pharmacology
> at the Uniformed Services University.
>
> DR. FERGUSON: Tom Ferguson, Washington University St. Louis, cardiac
> surgery.
>
> DR. KRUCOFF: Mitch Krucoff, Duke University, interventional
> cardiology.
>
> DR. LASKEY: Warren Laskey. I\'m an interventional cardiologist at the
> National Naval Medical Center in Bethesda.
>
> MS. WOOD: Geretta Wood, Executive Secretary, Division of
> Cardiovascular Devices.
>
> DR. AZIZ: Salim Aziz, adult cardiac surgeon and clinical associate
> professor, University of Colorado, Denver.
>
> DR. PINA: Ileana Pina, Heart Failure Transplant, Case Western Reserve
> University in Cleveland.
>
> DR. BAILEY: Kent Bailey. I\'m a biostatistician at Mayo Clinic.
>
> MR. MORTON: Michael Morton. I\'m the industry representative. I\'m
> with Soren Cove (ph) Cardiovascular.
>
> MR. DACEY: Robert Dacey, consumer representative from Boulder County,
> Colorado.
>
> DR. LASKEY: Geretta, could you now please read the voting status
> statement?
>
> MS. WOOD: Pursuant to the authority granted under the Medical Devices
> Advisory Committee Charter dated October 27, 1990, and as amended
> August 18, 1999, I appoint the following individuals as voting members
> of the Circulatory System Devices Panel for this meeting on October
> 22, 2002: Christopher J. White, M.D., Kent R. Bailey, Ph.D., L. Henry
> Edmunds, Jr., M.D., Mitchell W. Krucoff, M.D.; Thomas B. Ferguson,
> M.D.
>
> For the record, these people are special government employees and are
> consultants to this panel under the Medical Devices Advisory
> Committee. They have undergone the customary conflict of interest
> review and have reviewed the material to be considered at this
> meeting.
>
> This was signed by David W. Feigal, Jr., M.D., M.P.H., Director,
> Center for Devices and Radiological Health, on October 10, 2002.
>
> Pursuant to the authority granted under the Medical Devices Advisory
> Committee Charter of the Center for Devices and Radiological Health,
> dated October 27, 1990, and as amended August 18, 1999, I appoint the
> following individuals as voting members of the Circulatory System
> Devices Panel for the meeting on October 22, 2002: Ileana L. Pina,
> M.D., Louis R. Cantilena, Jr., M.D. Ph.D.
>
> For the record, Dr. Pina is a consultant to the Cardiovascular and
> Renal Drugs Advisory Committee, and Dr. Cantilena is chairman of the
> Non-Prescription Drugs Advisory Committee of the Center for Drug
> Evaluation and Research. They are special government employees who
> have undergone the customary conflict of interest review and have
> reviewed the material to be considered at this meeting.
>
> Signed by William K. Hubbard, Senior Associate Commissioner for
> Policy, Planning, and Legislation, dated October 18, 2002.
>
> DR. LASKEY: Thank you.
>
> **Introductions**
>
> The next segment of our panel meeting this morning is the open public
> hearing, and I\'d like to solicit comments from members of the
> audience who wish to address the panel. Are there any?
>
> \[No response.\]
>
> DR. LASKEY: If not, we\'ll close the open public hearing and begin
> with the sponsor\'s presentation.

x \[Pause.\]

> **Sponser Presentation: Cordis Corporation**
>
> DR. LASKEY: I\'m just glad you didn\'t bring a Macintosh with you this
> morning.
>
> \[Laughter.\]
>
> DR. DONOHOE: I\'ll get started while we\'re looking for the overhead
> light. Good morning, Mr. Chairman, panel members, FDA representatives,
> and panel consultants. My name is Dennis Donohoe. I\'m the Vice
> President of Therapeutics and Clinical Research at Cordis, and I\'d
> like to on behalf of Cordis thank the FDA and the panel for the
> opportunity to present to you today an overview of the clinical data
> submitted in support of the Cypher Sirolimus-Eluting Stent PMA.
>
> During the hour-and-15-minute presentation we have, I would like to
> review some of the background information on this project as well as
> describe the device, and then spend most of the presentation focusing
> on the clinical data submitted, particularly the two double-blind,
> randomized trials, the RAVEL and SIRIUS studies, which provide the
> primary clinical safety and efficacy data.
>
> The remaining half an hour, Dr. Kuntz will present a variety of
> subanalyses conducted on the SIRIUS study, then more directly address
> items that the FDA will be presenting to the panel.
>
> In terms of the background of this project, the FDA granted expedited
> review of this device given that it offered potentially significant
> therapeutic advance in the interventional treatment of patients with
> coronary artery disease. While it is a drug-device combination, the
> FDA is regulating this as a device given that its primary mode of
> action is that of a device, that is, the stent, and Sirolimus is
> simply augmenting the performance of the stent. The PMA was submitted
> June 28th of this year, and I\'d like to take this opportunity to
> acknowledge and thank the FDA for their rapid responses and clearly
> expedited review that allows us to come before this panel just four
> months after the PMA submission.
>
> We believe the clinical data submitted in the PMA and that we\'re
> about to review does show the comparability of the safety profile of
> the Sirolimus-eluting stent to that of the bare stent, that the
> superiority in terms of all angiographic and clinical endpoints is
> clearly demonstrated in the data, and that the one- and two-year
> clinical and angiographic data submitted also demonstrate the
> durability of treatment over that period of time.
>
> So what is the significance or impact of restenosis following coronary
> intervention? While restenosis has been long identified as the major
> limitation for percutaneous coronary intervention, there are
> approximately one million patients treated in the U.S. per year
> through some type of intervention of which about 80 percent have at
> least one stent placed. While both angioplasty and stenting have
> offered a benefit to these patients, both still carry a restenosis
> rate. For angioplasty, this rate is variably reported between 30 and
> 50 percent. Stents have improved this, on average, by about 40 percent
> but still report a rate between 15 and 35 percent, depending on the
> complexity of the patient population and the lesion being treated.
>
> This means that on a yearly basis approximately 250,000 patients are
> returning with restenosis, which means that patients are coming back
> with recurring symptoms requiring further treatment, either by repeat
> intervention, repeat angioplasty, stent placement, or brachytherapy,
> or potentially for surgical intervention.
>
> In understanding the concept of using a drug-eluting stent to try and
> reduce the restenosis rate, it would help to understand the mechanisms
> involved in producing the restenosis. This first picture here depicts
> an artery immediately after balloon expansion, after angioplasty. And
> as you can see, the plaque has been fully compressed against the
> internal wall of the vessel. The lumen is fully patent with maximum
> flow.
>
> Shortly after the procedure is completed, two mechanisms start to take
> effect that start to contribute to restenosis, the first of which is
> elastic recoil, and within a matter of minutes to hours after the
> procedure, the natural tendency of the tissue in the vessel wall
> causes the vessel to contract down in size. While it is not producing
> tissue that limits flow within the lumen of the vessel, there is a
> decrease in the overall lumen side, again, limiting flow.
>
> The second mechanism that contributes to restenosis is that of
> negative arterial remodeling. This occurs over weeks to several
> months, and this is basically the healing process following
> angioplasty in which there is contraction of the vessel over time,
> again, causing a decrease in the lumen and decreased flow.
>
> These two mechanisms account for the majority of the restenosis that
> occurs with balloon angioplasty. However, neither mechanism really
> contributes significantly when restenosis occurs following stent
> placement. This is because the stent is initially placed, it resists
> the elastic recoil of the vessel, and also resists the negative
> remodeling over time.
>
> However, there is a third component that primarily contributes to
> restenosis following stent placement and is estimated to account for
> about 30 percent of the restenosis following angioplasty. This is
> neointimal hyperplasia. This is the result of smooth muscle cell
> replication that occurs along the internal lining of the vessel wall,
> allowing cells to increase in volume and migrate into the lumen. As
> you see, this results in further lumen narrowing and restriction of
> flow. I think this demonstrates why the basic regulation of this
> drug-eluting stent is that of a device since the basic function is
> that of the stent, and that the role of a drug-eluting stent is
> specifically to target smooth muscle cell replication and prevent that
> form of restenosis.
>
> I\'d like to briefly review the components of a drug-eluting stent
> system. For the Sirolimus-eluting stent, there is a stent and delivery
> system, obviously. The stent, as we just discussed, addresses the
> initial negative remodeling and recoil. The polymer is coated over the
> metal stent and provides a reservoir for the drug and also provides a
> consistent release profile for the drug; and, finally, the drug
> component itself which, as we previously mentioned, is specifically
> there to inhibit smooth muscle cell replication and neointimal
> hyperplasia.
>
> The Cypher Sirolimus-eluting stent uses the Bx Velocity stent as the
> stent platform. This is a balloon-expandable, stainless steel stent.
> It has been approved in the U.S. for a threatened abrupt closure
> indication since May of 2000. Stent sizes that are 2.25 to 4.0
> millimeters in diameter and lengths 8 to 33 have been approved for
> this indication. An indication for elective stenting was received in
> February of 2001. Stent sizes approved for this indication were 3.0 to
> 5 millimeters in diameter and 8 to 33 millimeter lengths.
>
> There is a volume of data from multiple studies conducted involving
> this stent, and it is clear the data supports that this stent very
> adequately addresses the initial negative remodeling and recoil.
>
> The polymer on this stent is composed of two co-polymers that are
> nonerodable. While the details of this composition will not be
> presented in this public forum, details are provided in the panel
> packet.
>
> Each polymer component, in fact, is commercially available in other
> implantable devices, primarily in the orthopedic area. As I mentioned,
> the purpose of the polymer is to serve as a reservoir and a control
> release system for the Sirolimus drug release, and through a variety
> of in vitro and in vivo testing, the polymers have been shown to be
> biocompatible, non-thrombogenic, and non-cytotoxic.
>
> The polymer also has inherent elastomeric properties that allows it to
> accommodate for stent expansion while still serving its primary
> function of holding the drug and controlling the release profile.
>
> The drug itself, Sirolimus, is commercially available in the U.S. and
> several other countries on a worldwide basis under the trade name
> Rapamune, and it is produced and marketed by Wyeth. This drug was
> approved by the FDA in September of \'99 and by the European Community
> in March of 2001 for chronic systemic use as prophylaxis for renal
> transplant rejection. The safety and efficacy was established based on
> two randomized, multi-center studies involving just under 1,300
> patients, and it was clearly demonstrated that in order to obtain
> systemic immunosuppression, chronic administration of between 2 and 5
> milligrams per day with the intent of producing a mean whole blood
> trough level of between 7 and 14 nanograms per ml was required.
>
> Peak blood levels of greater than 200 nanograms per ml following a
> single intravenous administration have been found to be safe and well
> tolerated by patients. And Wyeth is supplying Sirolimus to Cordis and
> has also provided access to the NDA safety data.
>
> To understand the potential value of Sirolimus in inhibiting
> restenosis, we need to look at the mechanism of action of Sirolimus.
> Depicted here is representing a smooth muscle cell, and as you see,
> there are a variety of cytokines growth factors that impinge upon this
> cell after stent placement that trigger cell replication, and as I
> mentioned, the main contributor to restenosis is smooth muscle cell
> replication.
>
> Sirolimus has a specific mechanism of action that blocks smooth muscle
> cell replication, therefore, potentially decreasing the extent of
> neointimal hyperplasia. It additionally has some upstream effects and
> benefits and decreases restenosis by inhibiting some of the
> inflammation that occurs following stent placement, therefore,
> decreasing the number of stimulants that cause smooth muscle cell
> replication.
>
> It inhibits smooth muscle cell replication specifically by binding to
> a cytoplasmic protein kinase called TOR, or target of rapamycin, and
> this protein is the main signal that triggers cell replication. Once
> Sirolimus binds to this protein, it is not activated or able to
> trigger DNA synthesis, and the cell remains in late G-1. Once
> Sirolimus is gone, if the stimulants are still present, the cell will
> be triggered on to move through DNA synthesis and replication.
> However, if these factors are gone, the cell resets to G-0.
>
> This is a photomicrograph of a Sirolimus-eluting stent. As you can
> see, all aspects of the metal are fully covered by the polymer
> containing the drug. There is no exposed bare metal on the stent. In
> developing a drug-eluting stent, we understand there are two key
> issues that need to be addressed: the first is what is the effective
> dose, and the second is what is the period of time that the drug needs
> to be present to maximize the effect of neointimal hyperplasia.
>
> We conducted a variety of preclinical studies, two of which are
> presented here. On the left is a rabbit ileac arterial model and on
> the right is the porcine coronary artery model. In these studies, we
> used a bare stent and a pure polymer-coated stent with no drug as
> controls. As you see, there was no inhibition of intimal hyperplasia,
> but over a variety of doses that were tested, varying the amount of
> Sirolimus, what we have found through a variety of preclinical studies
> that consistently a dose of 180 micrograms per stent suppressed
> neointimal hyperplasia.
>
> Now, to clarify this, as you see at the bottom of the slide, the 180
> micrograms refers to the amount of Sirolimus on a 3.5 millimeter by 18
> millimeter stent. This equates into 140 micrograms per centimeter
> square surface area of the stent. So while smaller or larger stents
> will contain less or more total Sirolimus content, what remains
> constant is the 140 micrograms per centimeter square.
>
> As I mentioned, the second component we needed to evaluate was the
> duration of drug release, and we did this by developing two release
> profiles. Represented in this cartoon to the left is the stent itself,
> and the lavender area is the polymer-drug combination that is coated
> around the stent strut. This is a fixed amount of polymer and drug. In
> some of the stents, however, we put a pure polymer top coat. This
> served as a diffusion barrier to limit the diffusion of Sirolimus into
> the surrounding tissue. The result of this is presented in the graph
> to the right, and this is data from a porcine coronary model in which
> the fast release\--that is, the version that does not contain the top
> coat of polymer\--is represented in the lavender. As you can see,
> about 95 percent of the drug is released over 14 days. The green is
> the slow release, which does have the pure polymer top coat. And as
> you see, approximately 80 percent of the drug is released in 28 days.
>
> Having chosen the preferred dose from the preclinical testing and
> developed two release profiles, we then moved into Phase I clinical
> studies. The two Phase I studies that I\'ll review is the FIM, or
> First-in-Man, study involving a total of 45 patients enrolled at two
> centers, and as I mentioned, we tested both release formulations. The
> second Phase I study is a pharmacokinetic study specifically looking
> at the release profile for the slow release formulation.
>
> The First-in-Man study involved the enrollment of 45 patients in the
> treatment of single native coronary artery lesions. The stents used
> were 3 to 3.5 millimeters in diameter, and all lesions had to be
> treated with a single 18 millimeter stent. Patients were treated with
> two months of antiplatelet therapy plus indefinite use of aspirin.
>
> In this study there were two centers. The center in Brazil enrolled 15
> patients in the slow-release group and 15 in the fast, while the
> center in Rotterdam enrolled 15 patients in the slow release. As
> shown, we conducted angiographic IVUS and clinical assessments at all
> time points on these patients. In Brazil, the assessments were done at
> 4 months, 12, and 24, while in Rotterdam, the assessments were done at
> 6, 18 months, and 24 months.
>
> Before presenting the angiographic data, I wanted to specifically
> define two terms that were used not only in this study but all
> clinical data that I\'ll be presenting\--that is, the in-stent and
> in-segment analyses. As depicted in this representation here, the
> in-stent analysis includes all measurements that are within the bounds
> of the stent. The in-segment analysis includes measurements within the
> stent, but also includes 5 millimeters proximal and distal to the
> stent.
>
> With that, let\'s look at one of the angiographic parameters from the
> study. This is the in-segment minimal lumen diameter. What this
> represents is the area of smallest diameter over the total in-segment
> or lesion treated. The left axis is in millimeters and the Y\--and the
> X axis is time and Y is in millimeters. As you see, at baseline and
> post-procedure the groups are comparable. Green is representing the
> slow release and lavender is the fast release.
>
> This slide also demonstrates that over the 4- to 12-month period of
> follow-up there is some decrease in the minimal lumen diameter for
> both treatment groups, but then after 12 months you see that the
> follow-up is relatively flat for the period out to 24 months.
>
> This indicates several items: first, that the presence of the drug for
> the first 4 to 6 weeks does have a suppression of overall neointimal
> hyperplasia. For a bare stent, this decrease in this 4- to 12-month
> period would be expected to be in the range of 0.5 to 0.7 millimeters.
> It also shows that this effect is maintained out through a 24-hour
> period with only a minimal decrease from the post-procedure, a
> one-tenth of a millimeter decrease for the slow release, and
> three-tenths for the fast release compared to the post-procedure MLD.
>
> There were no significant differences in this parameter or any other
> angiographic parameters in this study between the slow and fast
> release.
>
> As I mentioned, there was IVUS assessment also done. Multiple methods
> were used to measure the extent of neointimal hyperplasia. What is
> represented here is one of those variables, percent volume
> obstruction. This is a measurement of the amount of luminal volume
> that is lost over time secondary to neointimal hyperplasia.
>
> As you see, at the 12-month time period there was an impressively
> small amount of luminal loss or volume loss, only 2 percent on
> average. At the 24-month time period, there was some additional loss,
> but really minor compared to the 12-month interval, moving from 2
> percent on average to 7 percent. These data again confirm what we saw
> on the angiographic parameters, that there is sustained benefit over a
> 24-month period, and, again, if you were to look at what would be
> expected for a bare stent, this luminal loss at 12 months should be
> around 25 to 30 percent.
>
> Now, looking at the clinical events in this study, I\'d like to again
> define some terms that will be applied to this study and all other
> clinical data that I\'ll be presenting. Target vessel failure was
> defined as target vessel revascularization with myocardial infarction
> or cardiac death that cannot be clearly attributed to the vessel other
> than the target vessel. Myocardial infarction was assessed, both
> Q-wave and non-Q-wave MIs using the WHO definition, and MACE events
> were also assessed, that is, major adverse cardiac events, consisting
> of death, MI, emergent bypass surgery, or repeat target lesion
> revascularization.
>
> I should indicate, too, that all clinical events in all these studies
> have been adjudicated by an independent clinical events committee.
>
> This slide summarizes the MACE events at the 24-month time period on
> all patients enrolled in the First-in-Man study. As you see, there was
> one death, which I will address in more detail shortly. There were two
> MIs, three TLRs, one patient accounting for one MI and TLR, with an
> overall MACE rate that\'s relatively low for a 2-year follow-up of
> 11.1 percent. Again, there were no significant differences in any of
> the clinical events between fast- and slow-release formulations.
>
> The one death that occurred involved a patient who had an initially
> successful procedure; however, the evening of the procedure they were
> noted to have change in neurologic status. A CT was performed
> indicating the presence of an intracerebral bleed, and the patient
> expired three days later. This event was considered unrelated to the
> use of the Sirolimus-eluting stent.
>
> The PK study is the second Phase I study. Based on the First-in-Man,
> which, as you saw, did not demonstrate any differences, angiographic,
> IVUS, or clinical, between fast and slow release, we chose to develop
> the slow-release formulation based on the concept that the longer
> residing time of the drug in the area to be treated potentially would
> provide more benefit as more complicated patient subgroups were
> tested.
>
> For this reason, we evaluated the pharmacokinetics of the slow-release
> stent. This involved two centers, a total of 19 patients, 10 of whom
> received a single 18 millimeter stent, and 9 received two 18
> millimeter stents. Diameters provided were 2.5, 3.0, and 3.5, and as
> you see here, the doses or total drug content on these stents are
> listed. The 2.5 and 3.0 diameters contained essentially the same total
> drug content, 150 micrograms. The 3.5 contains a dose closer to 180
> micrograms.
>
> Blood samples were collected starting 10 minutes post-stent
> implantation and through variable time periods out through seven days.
> This slide summarizes these data. On the Y axis is the whole blood
> concentration of Sirolimus in nanograms per ml; the X axis is total
> number of hours at each sampling time out through the seven-day
> period. The lavender curve represents the patients who received two 18
> millimeter stents, and the green a single 18 millimeter stent.
>
> As you see, the Cmax\'s are proportional, roughly 1.1 for two stents
> and about a little bit less than 0.6 nanograms per ml for a single
> stent. Tmax was the same for both, roughly 3.5 hours. You can see
> there is a rapid fall-off in the drug concentration over the following
> 72 hours, with a slower fall-off and a lower drug concentration being
> maintained because of the slower-release profile of the stent.
>
> To put this in perspective, with the Rapamune dosing these bottom
> curves represent the data I just presented to you. These two lines
> represent the therapeutic areas that I mentioned that are needed to
> obtain systemic immunosuppression.
>
> As you can see, even at Cmax, the total blood level of Sirolimus is
> ten-fold less than that that is achieved with oral dosing with
> Rapamune, and at seven days there\'s more than a 50-fold difference in
> drug dose.
>
> This indicates that there is a wide therapeutic window between the
> doses we are using and that needed for systemic therapy. And as I
> previously mentioned, doses up to 200 nanograms have been tested with
> no safety issues.
>
> I\'d like now to move into the Phase II and Phase III clinical
> studies. The Phase II study is a RAVEL trial. This was a double-blind,
> prospective, randomized study conducted across 19 centers in Europe
> and Latin America. A total of 238 patients were enrolled. And the U.S.
> pivotal study, the SIRIUS trial, this again was a double-blind,
> prospective, randomized study in which 53 centers participated,
> enrolling a total of 1,101 patients.
>
> Let\'s first look at the RAVEL data. This study involved the treatment
> of single de novo native coronary lesions. Stents provided were 2.5,
> 3.0, and 3.5 millimeter diameters, and all lesions had to be treated
> with a single 18 millimeter stent. There were 120 patients in the
> active group and 118 in the control. There was good angiographic
> follow-up at 6 months, 92 percent, and clinical follow-up out through
> 12 months was 92 percent.
>
> The primary endpoint for this study was angiographic late loss at 6
> months; secondary endpoints consisted of an IVUS assessment in a
> subgroup of patients at 6 months, as well as clinical assessments at
> 6, 12, and annually out through five years. Antiplatelet therapy for
> this study involved two months of antiplatelet therapy with indefinite
> use of aspirin.
>
> As you see here, looking at some of the key baseline patient
> demographics, these groups were comparable on all variables tested.
> There were no significant differences. On average, there were about 18
> percent of patients who were diabetic in this study.
>
> This slide summarizes some of the key baseline angiographic results.
> Again, the average RVD was comparable between these two groups,
> roughly 2.6 millimeters. All pre- and post-angiographic measurements
> were comparable, and the average lesion length for these two groups
> were identical at 9.6 millimeters.
>
> This slide summarizes the lesion, device, and procedural success.
> What\'s important in looking at this is to know that the ability to
> deliver the stent successfully, the Sirolimus-eluting stent, is equal
> to that of delivering a bare metal stent. And as you can see, the
> success rate in all three parameters was high for both stents and
> comparable. There were no significant differences at all between the
> delivery success of these two stents.
>
> We\'ll now look at the 6-month QCA evaluation. This slide is
> summarizing the late loss. Late loss, in fact, is calculated by
> looking at the post-MLD and subtracting the follow-up MLD. It\'s an
> indirect assessment again of the extent of neointimal hyperplasia. And
> I\'m presenting both the in-stent and in-segment results.
>
> As you can see, there was a highly statistically significant
> difference in favor of the Sirolimus treatment group for both
> parameters, with essentially zero late loss in the active group and
> 0.8 millimeters late loss in the control group for the in-stent
> assessment. And the in-segment, there was a 0.05 millimeter late loss
> in the in-segment compared to 0.75.
>
> While this term \"in-segment\" I previously defined, I wanted to
> highlight that the analysis for the RAVEL study, in fact, went beyond
> the 5 millimeter boundaries and included measurement of the vessel
> from side branch to side branch, proximal and distal to the stent.
>
> This is summarizing the binary restenosis rate. This is the percent of
> patients who have greater than 50 percent restenosis or stenosis at
> follow-up. Again, these results are similar to the late loss, both
> highly statistically significant in favor of the active group. There
> were on patients with binary restenosis in the Sirolimus group
> compared to 26.6 in the control. In the in-segment analysis, there was
> one patient for a rate of 0.8 percent compared to 27.5 percent in the
> control.
>
> As I mentioned, there was an IVUS subgroup analysis at 6 months. The
> sample sizes are listed here: 69 patients in the active and 70 in the
> control. You\'ll note that the external elastic membrane volume, which
> measures the overall size of the vessel, was comparable between the
> two treatment groups, as was the stent volume.
>
> All other parameters assessing the extent of the neointimal
> hyperplasia, again, was significantly in favor of the active treatment
> group. The neointimal volume was just 2 cubic millimeters compared to
> 34 in the control group. The lumen volume was larger in the active
> group at 130 cubic millimeters compared to 103 in the control. And
> most notably, the percent volume obstruction again was just 1.1
> percent compared to 26.1 in the control group\--all significantly
> different in favor of the active treatment group.
>
> We\'ll now look at the clinical events. This is summarizing the
> in-hospital MACE events. As you\'ll note, there were no deaths in
> either group. There was an equivalent number of myocardial
> infarctions, and the overall target vessel failure and MACE rates were
> identical at 2.5 percent for both groups.
>
> This slide summarizes the cumulative MACE events from the index
> procedure out through the full 365-day follow-up. You\'ll note there
> were two deaths in each treatment group. There were no differences,
> significant differences in the myocardial infarction rate, with 4 in
> the active and 6 in the control.
>
> There was a target lesion revascularization rate that was
> significantly improved for the active treatment group, with 0.8
> percent in the Sirolimus-eluting group compared to 36.6 in the
> control. Target vessel failure was also significantly improved in the
> active group at a rate of 4.2 percent compared to 19.5. And looking at
> all MACE, again, was significantly in favor of the active group, a
> rate of 5.8 compared to 18.6 in the control group.
>
> These data are represented here in a Kaplan-Meier estimate of
> event-free survival, that is, the percent of patients followed through
> this 360-day period that were free of any of these events. As you see,
> the 360-day period, there were 94.1 percent of the active group who
> were free of any of these events compared to 81.2 in the control. This
> again was significant at 0.002.
>
> I wanted to highlight the two deaths that occurred in the Sirolimus
> treatment group. They\'re listed here. First is a patient that expired
> 330 days post-procedure secondary to a gastrointestinal cancer, and
> the second patient expired approximately 333 days post-procedure
> secondary to rupture of a cerebral aneurysm. Neither event was
> considered related to the drug.
>
> Let\'s focus now on the pivotal study, the SIRIUS trial. This, as I
> mentioned, is a double-blind, randomized study. A total of 1,101
> patients were enrolled. Patients with single de novo coronary lesions
> were treated. Diameters for this study that were provided were 2.5,
> 3.0, and 3.5 millimeter stents. Lesion lengths were to be between 15
> and 33 millimeters.
>
> On randomization, you see there were 556 in the active and 545
> patients in the control. The primary endpoint of this study, which was
> agreed upon prior to the initiation of the study by the FDA, was
> target vessel failure as previously defined. Additionally, there was
> an angiographic subgroup analysis of 850 patients at an 8-month
> assessment point, and there was an IVUS subgroup involving 250
> patients, again, with an assessment at 8 months.
>
> Antiplatelet therapy was provided for 90 days in this study with
> indefinite use of aspirin. I should say also that angiographic and
> IVUS analyses were conducted by an independent core lab.
>
> Following the randomization, there were a total of 43 patients that
> were deregistered. The statistical section of the protocol identified
> the primary analysis as that of intent to treat. The intent-to-treat
> population was defined in the protocol at those patients who at least
> had an attempt to use the study device. In this study, there were 43
> patients who, in retrospect, were prematurely randomized, after
> randomization were found not to qualify for the study, and I\'ll give
> you some more detail on these. There were 23 in the active and 20 in
> the control group, leaving us with an analyzable group or an
> intent-to-treat group of 533 patients in the active, 525 in the
> control.
>
> As I mentioned, there was 8-month angiographic follow-up and 9-month
> clinical. There was a high angiographic follow-up rate of
> approximately 85 percent of the patients, and approximately 96 percent
> of the patients with clinical follow-up out to 9 months.
>
> This slide summarizes the reasons why these patients were
> deregistered. There were two patients in each group who, after
> randomization, were found not to have the stent size available needed
> to treat their lesions. The bulk of the deregistered patients were, in
> fact, patients who were randomized and then found not to actually
> qualify based on the inclusion/exclusion criteria of the protocol.
> There was one patient in the control group who withdrew consent
> following randomization, and that gives us the total of the 43
> patients.
>
> This slide summarizes the patient demographics at baseline. The intent
> of the SIRIUS trial was purposely to challenge this drug-eluting stent
> and to provide data from what was considered more of a real-world
> patient population. We think the study has done that, and
> approximately 30 percent of the patients had prior MIs, with about 24
> percent having prior revascularization and about 26 percent with
> diabetes. There were no significant differences in any of the patient
> demographic variables.
>
> This slide summarizes some of the key lesion characteristics. Again,
> you\'ll note the standard 44 percent with LEDs, and there were a total
> of about 55 percent of patients who had Type B-2 and C lesions. Again,
> these are lesions with more diffuse disease, more calcium and plaque
> buildup, and more tortuous type vessels.
>
> There was also a provision for allowing for overlapping stents, and as
> you see, there was an average of about 27 percent of patients between
> the two groups that did use overlapping stents in the study. There
> were no significant differences in any of these variables.
>
> This slide summarizes the baseline angiographic results. Again,
> you\'ll note the groups are comparable. There are no significant
> differences in any pre- or post-evaluations. The post\--or
> pre-procedure RVD was equivalent between the two groups with an
> average of 2.79 millimeters, and the average lesion length was
> identical at 14.4 millimeters.
>
> Again, we\'re summarizing the key success measurements from the index
> procedure, and, again, you\'ll note that there was equal performance
> with no significant difference between the Sirolimus-eluting stent and
> the bare metal stent.
>
> Let\'s again look at the late loss. This time in the SIRIUS trial, it
> was an 8-month QCA assessment, and, again, I\'m presenting in-stent
> and in-segment. Again, you\'ll see, as we did in RAVEL, a highly
> significant difference in favor of the active treatment group, with a
> late loss in-stent of just 0.17 millimeters compared to 1.0
> millimeters in the control. The in-segment analysis showed a late loss
> in the active group of 0.24 millimeters compared to 0.81 millimeters
> in the control group.
>
> And the restenosis rates, again, replicate what we see for the late
> loss, both assessments significantly in favor of the active group,
> with only 3.2 percent of the patients in the active group having
> in-stent binary restenosis compared to 35.4 in the control group. The
> in-segment analysis, we see 8.9 percent of the active patients with
> binary restenosis compared to 36.3 in the control group.
>
> The IVUS subanalysis presented here, as you see, there are 99 patients
> in the active and 76 in the control. There was no difference in the
> EEM volume or stent volume between these two treatment groups, and in
> all IVUS variables for neointimal hyperplasia, they were all highly
> significantly different in favor of the active treatment group.
>
> Just to highlight two of these, again, the neointimal volume was just
> 4.1 cubic millimeters at the 8-month follow-up for the active group
> compared to almost 57 cubic millimeters in the control group. The
> percent volume obstruction, as we\'ve seen in First-in-Man and RAVEL
> is relatively constant at about 2.6 percent compared to 34.2 in the
> control group.
>
> We\'ll now look at the clinical events, and this slide summarizes the
> in-hospital events. There was one death in the active group. There
> were no significant differences in the MI rate, nor were there any
> differences TLR, TVR. In fact, the MACE rates and TVF rates were
> comparable with 2.4 in the active group compared to 1.5 in the control
> group.
>
> Now, if anyone\--I believe somebody shut the power off to this plug
> here, if someone could turn that back on.
>
> We\'re going to look at the clinical events from out of hospital
> through the 9-month follow-up. As you see, there were four deaths in
> the active group compared to three in the control. There were no
> significant differences. The overall MI rate was marginally
> significantly different in favor of the active treatment group, and
> this was driven by the significant difference of non-Q MI rates with
> one patient, or 0.2 percent, in the active compared to 1.3 in the
> control. There was also a significant difference in TLR, MACE, and TVF
> in favor of the active treatment group. TVF, there were only 6.4
> percent of the patients with target vessel failure compared to 19.6 in
> the control group.
>
> This next slide summarizes all clinical events from the index
> procedure out through nine months, and in this slide we will present
> specifically the primary endpoint of the study, which included all
> MACE events, all events, target vessel events, from the index
> procedure through the full nine months. As you\'ll note, there were no
> differences between the death rates. There were five in the active and
> three in the control, and I\'ll provide more data on these five
> patients. There were no significant differences in MI rates. However,
> again, there was a highly significant difference in favor of the
> active treatment group for clinically driven target lesion
> revascularization with 4.1 percent compared to 16.6 in the control
> group. The target vessel revascularization not including target lesion
> was comparable between the two groups. The MACE events were
> significantly different, 7.1 compared to 18.9 percent, and the primary
> endpoint of the study was highly significantly different, again, 8.6
> in the active compared to 21 in the control group.
>
> This slide summarizes the five deaths that occurred in the
> Sirolimus-eluting treatment group. As you see, there was a patient who
> died of a cerebral hemorrhage following the index procedure. This was
> adjudicated by an independent committee as a cardiac event simply
> because it was related to the procedure and potentially to the use of
> 2b/3a inhibitors. The second patient had multiple organ failure,
> including pneumonia, liver dysfunction, renal failure, and congestive
> heart failure. The third patient expired secondary to renal cell
> carcinoma. The fourth patient had a subdural hematoma following head
> trauma. And the fifth patient had a stoke and died of acute
> intracerebral hemorrhage. None of these events were considered related
> to the use of the Sirolimus-eluting stent.
>
> This curve here, again, represents a Kaplan-Meier estimate of
> event-free survival for TVF. As you see, there was, again, a
> significant difference with 91.1 percent of the active group free of
> target vessel failure compared to 78.6 percent in the control group.
>
> Looking at the same event-free survival, but this time looking at
> target lesion revascularization specifically, again, we see a
> significant difference at the 9-month follow-up, with 95.7 percent of
> the active and 82.9 percent of the control group event-free survival.
>
> The angiographic core lab conducted very detailed angiographic
> evaluations on these patients. I wanted to specifically highlight for
> the panel this analysis which specifically looks at not only the
> in-stent late loss but also the margins, the proximal 5 millimeters
> and distal 5 millimeters.
>
> As you can see, the late loss in each segment analyzed is
> significantly decreased in the active treatment group. So this data
> indicate that there is no evidence for an edge effect or candy wrapper
> effect in using this stent.
>
> I\'d like now to quickly review a variety of safety assessments that
> were conducted through the RAVEL and SIRIUS trials. The first is the
> use of overlapping stents. As I indicated, there is on average about
> 26, 27 percent of patients who had overlapping stent use. The total
> stent length in this patient population was about 20 millimeters. The
> in-hospital MACE rates were equivalent. The stent thromboses rates
> were equivalent, with one SAT in each treatment group. There was one
> aneurysm in each treatment group, and, most notably, the MACE events
> and target lesion revascularization rates through 9 months were,
> again, significantly improved in the active treatment group, with the
> same relative improvement we saw in the overall patient population.
>
> This slide summarizes the stent thromboses across these two studies.
> In the RAVEL study, as I mentioned, there was only 60-day antiplatelet
> therapy provided. There was no thrombosis in either the active or the
> control group through the full 365-day follow-up.
>
> In the SIRIUS trial, which involved 90 days of antiplatelet therapy,
> there were two thromboses in the active and four in the control. One
> each had a subacute thrombosis, and there was one late in the active
> group and three late thromboses in the control group and, again, no
> significant difference.
>
> When we looked at aneurysms, there were no aneurysms reported at the
> six-month angiographic evaluation in RAVEL for either treatment group.
> There were two aneurysms in the active group found at 8 months in the
> SIRIUS study and four aneurysms found in the control group. This was
> not significantly different. You\'ll note that the rates for the
> control group was around 1 percent, which is in the range of expected
> background rate of 1 to 3 percent. No adverse events were associated
> with any of the aneurysms, and we used a fairly liberal definition for
> aneurysm of a ratio of 1.2 or greater.
>
> Now, I wanted to review incomplete apposition. I know this is not a
> new phenomenon. It has been identified before. However, I wanted to
> review some basic definitions with the panel.
>
> This term \"incomplete apposition\" also is sometimes referred to as
> malapposition, and by definition, you\'ll note at the bottom of the
> slide, this is defined as a separation of one or more struts from the
> vessel wall with evidence of blood behind the stent struts. So this is
> an IVUS evaluation or IVUS definition.
>
> At baseline, it is possible to have incomplete stent apposition if the
> stent is not fully deployed and fully apposed to the vessel well. This
> is represented here by the evidence of blood flowing behind the stent
> struts and the vessel wall separated from the stent.
>
> Over time, there are two options. This may progress to complete
> healing, that is, a neointimal hyperplasia takes place, this gap is
> filled in with tissue, and on follow-up the stent appears fully
> apposed. It may also be preserved or persist over the follow-up
> period. If no or minimal intimal hyperplasia takes place, the gap will
> still be present over time.
>
> The other variation on incomplete apposition is defined here. At
> baseline, you may have full stent apposition to the vessel wall, but
> on follow-up you find that there is a gap. This is referred to on this
> slide as late incomplete apposition. Again, there\'s a gap that
> appears. And in this model, you\'ll notice the total vessel area
> remains the same. It\'s also possible to have late incomplete
> apposition with positive remodeling, meaning that the gap, at least in
> part, is associated with expansion or increased area of the vessel
> size.
>
> So with those definitions, let\'s look at some of the data we have on
> late incomplete apposition. As I mentioned, this is not a new
> phenomenon. It has been defined with bare stents, and specifically
> there was an article just published last week in Circulation which
> specifically looked at bare stent placement and IVUS at baseline and
> follow-up at 6 months on 206 patients. They found a late incomplete
> apposition rate of 4.6 percent. They also found that all nine of the
> patients had some evidence of positive remodeling, and none of the
> patients had any clinical events through that follow-up time period.
>
> When we look at the RAVEL study, the RAVEL study did not have
> obviously the baseline. It was only conducted at the 6-month
> follow-up. So we were not able to differentiate preserve from late. We
> can only identify those patients who had incomplete apposition at the
> 6-month follow-up. This is summarized here. There were ten patients in
> the active group and two patients in the control, which was
> significantly different.
>
> When these events occurred, we did ask these 10 patients to return for
> an 18-month clinical angiographic and IVUS assessment. And as you\'ll
> note in the box below, nine of these ten patients have returned for
> evaluation. In all nine patients evaluated, the incomplete apposition
> has remained. None of the ten patients had any clinical events
> reported out through the 18-month period, and there are no other
> angiographic findings except for one patient who was noted to have an
> aneurysm on follow-up in the same area. This patient was asymptomatic
> for the aneurysm and was noted on earlier IVUS assessment to actually
> have evidence of a large hemorrhage within the vessel wall in the area
> of the aneurysm formation.
>
> In the SIRIUS trial, we did conduct an IVUS evaluation at baseline,
> post-stent deployment, as well as the 8-month follow-up. You\'ll see
> here post-stent deployment there was an equivalent number of
> incomplete appositions in both groups, 14.3 and 14.9 percent. At the
> 8-month assessment, there were 18.7 percent of the patients in the
> active group and 9.2 in the control with incomplete apposition, which
> was marginally significant, 0.08.
>
> Given that we had baseline and follow-up IVUS, we were able to
> differentiate and better define where these incomplete appositions
> came from. When we looked at this in a matched-pair group\--that means
> a group that has a baseline IVUS as well as a follow-up, with
> automated pull-back\--you see there was an equivalent number of
> patients who had resolved late incomplete apposition, an equivalent
> number had persistent incomplete apposition.
>
> However, there were nine patients, or seven patients in the active for
> 9.7 percent and no patients in the control group that had late
> incomplete apposition. This was significantly different.
>
> When we evaluated these patients in more detail, we found that none of
> the patients with overlapping stents had late incomplete apposition in
> the area of the stent overlap, which potentially is the area that
> would double the drug dose. Additionally, we found that none of these
> patients experienced any adverse events through this 9-month follow-up
> period, and three of these patients had evidence of positive
> remodeling.
>
> So what can we say in conclusion? Well, we know that with bare stents
> this is seen in the range of about 4 to 5 percent, and, most
> importantly, in terms of the clinical significance of this is the
> concern about increase in the stent thrombosis rate because of the
> exposed metal. As previously shown to you, there is no increased rate
> of stent thrombosis in the Sirolimus treatment group. In fact, the
> rates in both studies are less than 1 percent. And this is assessed a
> period of time after the patients have been off antiplatelet therapy
> from 6 to 16 months.
>
> As mentioned, the bare metal stents not only in the published reports
> but other data that\'s been released recently is reporting a late
> incomplete apposition rate of 4 to 5 percent. We also know that in the
> literature, brachytherapy has been associated with late incomplete
> apposition in the range of 5 to 10 percent. And, typically, these late
> incomplete appositions have not been linked with an adverse event. We
> recognize there is an increased rate of late thrombosis with
> brachytherapy, but this is more related to the issue of complete
> re-endothelialization.
>
> There is also a model that we can look at from a clinical standpoint
> on a daily basis. Patients have stents placed across side branches
> where technically are exposing metal to flow and not compressing
> tissue, and this in and of itself does not increase the risk of stent
> thrombosis.
>
> And, finally, as I mentioned, there was no evidence of late incomplete
> apposition in the area of increased dose, suggesting that it is not a
> direct drug effect causing this.
>
> The final topic I\'d like to review starts to specifically address one
> of the issues the FDA will present around the question of whether we
> have sufficient safety data for the full stent lengths and diameters
> requested. This slide summarizes data from the SIRIUS trial. As you
> see, on the Y axis this is number of patients, and the X axis is the
> reference vessel diameter. This study provided 2.5, 3.0, and 3.6
> millimeter stents. But as you can see, when you look at the RVDs, 146
> patients or roughly 27 percent of the patients involved in this study,
> in fact, were treated with vessel diameters less than 2.5. On the
> upper side, again, while the largest diameter stent was 3.5, you see
> that, in fact, there were 31 patients treated with vessel diameters
> greater than 3.5.
>
> This slide, again, summarizes the data in the SIRIUS trial, but this
> time looking at stent length. And while the predominant stent length
> was in the area of 10 to 20 millimeters, you\'ll note there were 173
> patients or roughly 31 percent of the patients in this study that, in
> fact, had stents used that were more than 20 millimeters in total
> length.
>
> To look at this another way and directly address the issue of the
> amount of safety data we have for drug and polymer, this is taking the
> same data I just presented to you. In this we\'re looking at number of
> patients on the Y. The first parameter on the X axis is the total
> amount of drug\--that is in micrograms\--that the patient is exposed
> to. The second line is representing the total amount of polymer.
>
> As you\'ll see, while the greatest number of patients were treated
> with between 150 and 250 micrograms of drug, in fact, there was a
> group, 20 percent of the patient population, that had drug and polymer
> exposure greater than 250 micrograms or greater than 700 micrograms.
>
> If we look at the group potentially at highest risk for the highest
> drug dose and polymer content, their adverse events are listed at the
> bottom. As you see, there were only two peri-procedural MIs; three
> TLRs, one of which was peri-procedural; no aneurysms, no thromboses,
> and one late incomplete apposition. So this does not suggest that
> there is an increase in adverse events and that there was a broad
> exposure in terms of the drug and polymer.
>
> Finally, this slide summarizes the drug content matrix. This is the
> list of stent lengths that Cordis is requesting for approval, and
> these are the stent diameters. If you look at this matrix in each box,
> it provides the total drug content by that combination of stent
> diameter and length. If you roughly triple that number, you\'ll have
> the polymer content.
>
> As you can see, based on the data I just showed you, we have a large
> majority of the data from these studies, including drug exposure up to
> 350 micrograms, with about 94 percent of the patients included in this
> shaded area.
>
> With that, I\'d like to now turn the presentation over to Dr. Kuntz,
> who present a variety of subanalyses on the SIRIUS trial.
>
> DR. KUNTZ: Good morning. My name is Rick Kuntz. I\'m an interventional
> cardiologist at the Brigham and Women\'s Hospital in Boston. I\'m also
> the chief of the Division of Clinical Biometrics there and the chief
> scientific officer for Harvard Clinical Research Institute, which ran
> this trial.
>
> This is my financial disclosure slide. I have no equity or consulting
> relationship with Johnson & Johnson or Cordis. The Harvard Clinical
> Research Institute is a nonprofit contract research organization in
> Harvard who ran this trial. Cordis does provide an educational grant
> to the Department of Medicine, the Brigham and Women\'s Hospital for
> fellowship training in clinical trials, and the travel expenses for
> today\'s trip were reimbursed by Cordis.
>
> I have two slides that I think are attached to the back of your
> section, and this is one of them. That may not be in the right order,
> and I\'ll tell you about the other one.
>
> In order to motivate why we do multivariable modeling, I can tell you
> academically we\'re interested in looking at mechanisms of how things
> work. And, in general, the fun part, I think, of analysis is the
> multivariable modeling after a study.
>
> In a study that\'s positive overall for the randomized portion,
> sometimes the subset analysis may disclose a lot of things that you
> don\'t want to look at. But, in general, subset analysis is helpful in
> determining patient subsets that may or may not benefit from a therapy
> shown to have an overall favorable effect as in this study. But this
> analysis is often risky since subsets are markedly diminished in their
> power to demonstrate an overall effect compared with the overall
> sample for which the trial was powered.
>
> This type of analysis, however, has demonstrated the anti-restenosis
> benefit of stenting. It\'s demonstrated the relationship
> mechanistically between the gain in an artery of a lesion for stenting
> compared to the loss, the so-called loss index. It\'s the technique
> that has been used to demonstrate the impact of diabetes on
> restenosis, and a lot of other mechanistic issues that we use in
> regular analysis for percutaneous trials over the last 15 years.
>
> All such analyses have generally been linear, that is, either we look
> at the linear regression or we look at a general linear model of the
> loge (?), for example, linear link, and this is typically used for
> biological systems. So these are conventional kind of boilerplate
> analyses that are performed.
>
> We know that if we\'re looking back at the last 15 years of
> angioplasty and stent trials from over 100 studies and probably over
> 30 or 40 well-designed clinical randomized trials that there are three
> major characteristics that affect the outcome of restenosis in
> studies, and they include reference vessel size, the length of the
> lesion or the stent that you use to treat that lesion, and the
> presence of diabetes.
>
> Now, it\'s important for us to evaluate these because some diseases
> don\'t have a lot of influence by case mix issues of the patient
> population. But restenosis does have a lot of influence due to issues
> due to the patient, that is, the size of their vessel, the length of
> the lesion, or the presence or absence of diabetes.
>
> We know that when we analyzed those factors in this study, we saw the
> same effect\--that is, we saw significant relationships of these
> factors, as we would expect, for the size of the vessel, that is,
> larger vessels have low restenosis rates; the length of the lesion,
> that is, longer lesions have higher restenosis rates; and the presence
> of diabetes, that is, patients with diabetes have higher restenosis
> rates overall.
>
> It\'s important that in order to make sure that the randomization
> worked, that when we adjust for these strong influential factors that
> we have a treatment assignment outcome which is still significant. So,
> therefore, what this models tells us is that the overall treatment
> assignment to Sirolimus was still independently significant in its
> ability to reduce restenosis, in this case angiographic restenosis
> measured by narrowing, after adjustment for these powerful predictors
> of the outcome.
>
> If we look at an orthogonal outcome, that is, clinical
> restenosis\--again, not measuring angiographic narrowing but the need
> for repeat of revascularization determined clinically\--we see the
> same predictors have the same influence overall, are highly
> significant, and an independent effect of the overall treatment
> assignment on the improvement in clinical restenosis, which is quite
> powerful.
>
> We know from previous studies on accumulated stent databases\--and
> this is from previous stent studies approved by the FDA\--that the
> influence of these three factors\--lesion length, the size of the
> vessel, and the presence or absence of diabetes\--have profound
> effects on the instance of angiographic or clinical restenosis. In
> this matrix, what I\'ve done is shown the incremental sizes of the
> vessel, the lengths of the lesions and bends, and the presence of
> diabetes to develop about 24 different cells here. And one can see
> that patients that have short lesions and are non-diabetic with small
> lesions, short lesions in large vessels, generally have low restenosis
> rates.
>
> On the other hand, the same patients with the same stents who have
> long lesions and small vessels and are diabetic could have almost a
> four- to six-fold increase in restenosis rate overall. So this is
> important to know because when looking at a new therapy that looks
> positive, like Sirolimus, we want to see that the effect has some kind
> of uniformity over this wide range of case mix. That is, if we see
> that there\'s a six-fold difference in the restenosis rate based on
> patient variables, we\'d like to see that this drug can hold up under
> those conditions.
>
> If we analyze, in fact, the control arm, the bare stent arm of this
> study, we see the same relationships exist here as we\'ve seen from
> previous stent trials. That is, we see the same low rates of
> restenosis in patients that have no diabetes, large vessels, and short
> lesions compared to patients with diabetes that have long lesions and
> small vessels. So we see the same gradient that we see from previous
> stent trials, and that, in fact, is pretty consistent in this study as
> well.
>
> If we look clinically at that\--that was an angiographic measure,
> again, a different way of measuring failure\--we see the same
> gradient, low rates of clinical restenosis for large vessels and small
> lesions in non-diabetics, and high rates of restenosis for long
> lesions, small vessels in diabetics.
>
> Now, if we look at the outcome of the active arm in this study, the
> Sirolimus arm, we see the same gradient exists there as well, that is,
> these main effects still affect those patients assigned to the drug,
> but the rates are substantially lower in these cells compared to the
> previous control arm and, hence, the overall mean average was
> different, as Dr. Donohoe showed earlier. And if we look at this
> predictor of angiographic restenosis, we have rates that go from as
> low as 3 to 4 percent in patients with big vessels and short lesions
> and non-diabetics to as high as 24, 25 percent of patients with
> diabetes and long lesions, suggesting that we still have issues with
> patients with diabetes, but hopefully we\'ve substantially lowered
> this to a good degree as the first start.
>
> Clinically, if we measured that, we can see the numbers. They still
> have the same gradient but are substantially lower. That is, this is
> the clinical impact on patients who require repeat revascularization,
> and one can see that it ranges from about 2 to 3 percent to about 10
> percent.
>
> Now, one way to be able to evaluate the impact of the therapy in this
> randomized trial on those different patient subsets is to subtract out
> the rates of restenosis from the two matrices, and you can get an
> absolute reduction estimate. Here we look at an angiographic
> restenosis outcome, and this is the difference between the control arm
> and the Sirolimus arm and shows the amount of restenosis episodes that
> are saved by the Sirolimus arm. And we can see that it\'s important to
> evaluate patients at risk.
>
> Patients at the highest risk here, the smallest vessels and longest
> lesions, had the biggest reduction in restenosis overall, suggestive
> of the fact that this did work well across low-risk and high-risk
> patients; and, in fact, patients that benefited the most were the ones
> with the highest risk.
>
> Another way to evaluate that is to calculate the treatment effect, and
> that is to basically look at the baseline risk minus the active risk,
> that is, the control versus active. And this is the relative
> difference in treatment, and one can see here that the relative
> difference or treatment effect is relatively uniform over all of these
> different cells. So this is, I think, quite profound because of a few
> reasons: number one, we have 18 cells here, different ways of cutting
> patients up, and we have diabetics, non-diabetics, long and short
> lesions, small or short vessels, and we have a very uniform treatment
> effect that goes from 64 to 81 percent across all of these cells.
>
> The other striking thing here is that the treatment effect here\--and
> in this case, angiographic restenosis\--is in the 60 to 80 percent
> range, much higher than what we normally see in contemporary therapies
> that leads to changes in standard of care, which is on the order of 25
> to 35 percent. So not only is there a profound treatment effect in
> reducing angiographic restenosis here, but it\'s very consistently
> demonstrated over a wide variety of characteristics that have
> tremendous impact on the risk of restenosis.
>
> If we look at the clinical reduction\--again, the other way to measure
> failure is to look at clinical need for repeat revascularization\--we
> see the same distribution of uniform high rates of reduction over a
> wide range of different risk factors.
>
> Now, there are other ways to demonstrate these subset analyses, and
> one common way is to illustrate the odds ratios using an odds ratios
> table. In this slide, it looks a little bit complex. Let me orient you
> here.
>
> Here we have the odds ratios of 1.0, which is the unity line\--that
> is, those therapies when compared between control and active\--if they
> fall in this line, there\'s no benefit. If they fall to the right of
> the line, there would be benefit for the control arm. If they fall to
> the left of the line, there would be benefit for the active arm.
>
> The overall odds ratio here is approximately 0.2 with a rate of 4.1
> percent versus 16.6 percent in the analysis of in-segment restenosis.
>
> If we look at the individual groups broken down by those of interest,
> like gender, for example, and those that we have predicted previously
> to be problematic, like diabetics and so on, we see that when we cut
> the patients into various different groups\--male, female, diabetics,
> non-diabetics, LAD location, non-LAD, small vessel, large vessel,
> short lesion, long lesion, patients with overlap or no overlap of
> their stents\--there\'s a very consistent relationship of the estimate
> of the odds ratio in strong favor of the treatment assignment to
> Sirolimus with the 95 percent confidence intervals, they\'re very far
> from the unit line, suggesting a significant difference, and the
> significant values are illustrated here by the p values (?) .
>
> Now, if we look at the odds ratios per se in clinical restenosis, we
> see the same relationship, very powerful odds ratios to the left of
> the unity line, suggesting a variety of different odds ratio benefits
> for all the different patient subsets that I illustrated earlier.
>
> Another important metric that you can use looking at odds ratios is
> the number of events that can be prevented per thousand patients, and
> one can see here that the number of events preventing clinical
> restenosis is in the 200 to 300 range in most of these variables. And
> if you take a thousand divided by that number, that\'s the next number
> needed to treat in order to prevent an outcome, and that number
> average between 4 and 5, which is very low for contemporary therapies.
> So all these analyses here do suggest that over a wide range of
> different patient subsets, there\'s a profound and consistent
> difference overall.
>
> Now, one thing that\'s important to also illustrate is that you can
> actually look for differences in subsets by testing for interactions.
> That is, we want to know, for example, whether there\'s interaction
> between the treatment effect and a patient subset. Did diabetics have
> the same benefit from the active arm as non-diabetics per se? And you
> can test that with interactions. We found that there were no
> interactions except for one, and that existed here in the large and
> small vessel.
>
> But this is a very interesting interaction. What we see here is that
> there was a significant difference in the benefit for patients
> assigned to Sirolimus for large vessels compared to small vessels, but
> the differences were all significantly better than control. So what we
> see is that we see two significant benefits, one super-high benefit
> and one moderately high benefit. So the only interaction we could
> define here was in the zone of positivity to show significant
> differences at this level, but still both sides better than unity.
>
> Now, this analysis can be very helpful because when we get to the
> prescriptive side of understanding why we do multivariable modeling,
> it\'s for us to understand how to use stents. For years we have always
> known that as you put stents in with longer and longer lengths,
> you\'re going to have higher and higher restenosis rates per se. And
> the admonition has always been to try to use as short a stent as
> possible in order to minimize restenosis. And if we look at the
> regression between stent length and the restenosis outcome from
> in-segment restenosis or angiographic outcome, in the control arm we
> do see this increment in restenosis risk as you add each millimeter of
> stent per se.
>
> But, as expected, if we applied this to the Sirolimus arm, we see that
> the same slope exists, but it\'s a lower slope. That is, we do see a
> significant increase in increment associated with stents, but the
> price paid for each increment in millimeters is very tiny compared to
> the price paid for the bare stent per se. And this is very helpful
> because often the interventional cardiologist has to wrestle with
> using a stent that may cover the lesion from the normal part of the
> artery to the normal part in order to prevent dissections versus
> trying to stent the obstructive portion of a lesion where they may
> want to minimize restenosis but trade off the possibility for
> dissection.
>
> This would suggest that the incremental price paid for using the
> longer stent is very minimal compared to what we\'re used to with bare
> stents.
>
> If we look at that same analysis using clinical restenosis, we see the
> same slope relationships, that is, an improvement that classical
> expected outcome of incremental risk associated with clinical
> restenosis with longer stents and the very shallow relationship seen
> in offset for those patients assigned to Sirolimus.
>
> So in our conventional subset analysis, the analysis that has been
> done for many studies in the past and has led to a lot of
> understanding of mechanistic outcomes, our analysis has demonstrated a
> consistent and strong treatment effect of Sirolimus across a variety
> of important subset categories. And there was no treatment interaction
> demonstrated of a patient subset that did not benefit from Sirolimus
> from, I think, a rather comprehensive analysis.
>
> Now, there are a lot of ways to do subset analyses, and we\'ve shown
> you one way, which I think is a rather conventional way. The FDA has
> performed a variety of subset analyses, too, and I\'d like to address
> those issues now.
>
> The reason to address those issues is because the FDA performed a
> lesion length and vessel size analysis on the results, which we\'ve
> shown here, which actually demonstrated a reduced efficacy for
> Sirolimus.
>
> The FDA analysis relied on a comparison of multiple subsets to
> demonstrate individually statistical significance. For example, in one
> of the analyses, each 5 millimeter increment of lesion length was
> tested for statistical significance.
>
> The FDA applied nonlinear models to the data to demonstrate limited
> efficacy of Sirolimus. The FDA also suggested that TVF, or target
> vessel failure, our primary endpoint, should be measured at 7.5 months
> rather than 9 months as pre-specified. And the FDA suggested that the
> trial may have been unblinded, and this may have led to higher rates
> of clinical restenosis in the control arm.
>
> Now, if we look at the notion of measuring lesion length and vessel
> size to demonstrate reduced efficacy for Sirolimus, our subset
> analysis was positive. So we weren\'t able to reproduce the overall
> effect per se, and I\'ve shown you those cases already. We demonstrate
> that when we look at lesion length and vessel size, using our
> conventional methods, we actually demonstrate it has a profound effect
> that\'s consistent over all those different subsets that I showed you
> earlier. So we couldn\'t reproduce the overall analysis to demonstrate
> any vessel size reduction in restenosis.
>
> The FDA analysis relied on a comparison of multiple subsets to
> demonstrate individual statistical significance, and I think there\'s
> some bar graphs that demonstrate the overlaps of the confidence
> intervals. Well, for each 5 millimeter increment of lesion length, you
> actually reduce power, and so each 5 millimeter subset is actually
> necessarily underpowered for a comparison in general.
>
> Usually when you compare subsets broken down into bends, the
> comparison of subsets is done to demonstrate a consistency of the
> estimates of the results, but not held accountable for each bend to
> demonstrate statistical significance.
>
> Here\'s the demonstration of the actual raw data. This is not modeled.
> This is just the unadjusted outcomes of restenosis, in this case the
> primary endpoint target vessel failure by lesion length. We can see
> here that the open circles, if you can see them, are generally all
> above the black circles here. The open circles are the control arm.
> The black circles are the Sirolimus arm. And what we can see is that
> over the range of restenosis rates per se, we opted to use linear
> modeling because there was a general trend of increasing restenosis
> with longer lesions, as we\'d expect, and a lot flatter slope with the
> black line dots here, and even at the play of chance, by and large
> most of these dots are lower in general. So we saw that over the
> course of the different bends we saw consistent effect overall of
> reduction in restenosis.
>
> If we look at the categories based on reference vessel size, which was
> also evaluated by the FDA, we also see a consistent relationship of
> reduction of restenosis as you get bigger, but the offset was
> higher\--higher event rates for the control arm compared to the
> assignment to Sirolimus. Again, this would be something we would
> generally model as linear because of the overall kind of scattergram
> here, although it looks rather linear per se. So we opted to use
> linear modeling because it just made more sense, and all the estimates
> here do, in fact, show, I think, a consistent outcome.
>
> If we look back at the lesion length categories per se, we also saw
> that in an area that the FDA had tested, we did see a significant
> effect that was greater for lesions over 20 millimeters. So even when
> we bend the patients over here alone and necessarily look at this
> underpowered subset, we still saw significant improvement in
> restenosis with that subset of greater than 20 millimeters for the
> primary endpoint, which was 9-month target vessel failure overall. So
> we didn\'t see the reduction in effectiveness even when we looked at
> the subset greater than 20 millimeters per se.
>
> We did look at their analysis on 16 millimeters or greater where we
> did see a significant reduction, but this was, I think, an issue of
> play of chance, because if you look at the breakdown of each
> millimeter, this is often seen in random data sets; that if you break
> it down, the valuation of greater than this number was highly
> significant for the Sirolimus arm compared to the one for 16, and the
> one for 16 was pointed out by the FDA as being the one not
> significant. But I think that the other ones are all consistent with
> being a positive result.
>
> The FDA applied nonlinear models to the data to demonstrate limited
> efficacy for Sirolimus. We could not reproduce the nonlinear quadratic
> or cubic models, nor could we justify its use by measurements of
> discrimination or calibration, which are the statistical terms that
> statisticians use for goodness of fit. Essentially we did a lot of
> analysis using nonlinear terms, and by our analysis the linear
> modeling was still the appropriate technique to fit the data.
>
> The FDA suggested that TVF should be compared at 7.5 months in a few
> of their analyses rather than the conventional 9 months as
> prespecified. And I\'d like to just talk to you about that because
> it\'s a very complex issue.
>
> The 9-month TVF endpoint is generally the standard endpoint used for
> measuring clinical restenosis, and there\'s a reason why. The
> prespecified 9-month endpoint requires carefully orchestrated and
> coordinated timing for the angiographic follow-up cohort. Analysis of
> these data, which is designed to measure the outcome at 9 months is
> not intended for analysis prior to 9 months because the orchestration
> of how you bring patients back for angiography.
>
> This is because previous studies have demonstrated that clinical
> restenosis is best measured by going out as far as possible. That is,
> in this study of 2,000 patients in the starter study, we know that if
> you measure restenosis even up to a year, you still get a better
> estimate of the restenosis rates than compared to 6 months per se. So,
> in general, working with the FDA over the years, it\'s been a standard
> to adopt the 9-month endpoint because it\'s a common middle ground
> between the 6-month angiographic narrowing that we know about and the
> 1-year clinical. So we picked the 9 months per se. So there\'s a
> rationale as to why you use 9 months overall.
>
> And one might think, well, haven\'t there been studies that
> demonstrate that narrowing happens at 6 months by all the angiographic
> studies done in Holland and Japan, and the answer is yes. But the
> clinical events that we measure are actually the actual
> revascularization event that occurs. And this is actually
> frame-shifted to the right by a few months, because after the
> biological narrowing occurs, the patient develops clinical signs and
> symptoms. The provider has to become aware. They have to be scheduled
> for repeat revascularization, which may take in some cases, especially
> outside the United States, up to several months. And then the patient
> actually has a revascularization event.
>
> Because of this frame shift from the biological thing, we\'ve also
> adopted an endpoint which is around 9 months for the outcome.
>
> Now, the FDA has suggested that the trial may have been unblinded and
> that this may have led to a higher rate of clinical restenosis for the
> control arm. Let me explain what happened here.
>
> Each site had a stack of A and B blinded stents that were used in the
> study, one of which was active and one of which was not active. And
> the notion might be that the potential for investigators could have
> systematically correlated the blinded Group A versus Group B when they
> started to see the follow-up that, say, Class A didn\'t have as much
> restenosis as Class B, and they would get the notion that Class A
> might have been the study drug. And that\'s something that\'s
> definitely a potential, and it\'s true with any study where you try to
> do blinding under such a classification.
>
> We had basically felt that this might be a problem because that
> tendency occurs in cases where you actually have positive results,
> because if you do see that one arm is not coming back with a lot of
> restenosis, you are vulnerable to being able to have the investigators
> correlate that, and that happens in a lot of randomized trials.
>
> So by anticipating that, we had set up a blinded CEC, which is
> typically for studies, that would be the final arbitrator for all the
> outcomes and would require demonstration of narrowing and clinical
> investigations to call an event an event. And, of course, this CEC was
> blinded to the\--Clinical Events Committee was blinded to the
> assignment.
>
> So if we look here, we see that there might be, in fact, some
> clustering of events that occurred here towards the end.
>
> Now, this is important to point out because if you\'ve seen studies
> like this before, you\'ll see that there are events occurring here
> around 8 months. We asked people to come back for their angiograms at
> about 8 months, and, in fact, we see this typically in most trials
> that require angiography because there\'s an opportunity to dilate
> patients that have come back for re-narrowing at this point.
>
> Now, what really happens is that patients generally develop symptoms
> in this range and that they have tight stenoses if they come back
> early. If they have stenoses around the time when their biological
> narrowing occurs and they have a scheduled angiographic follow-up,
> they ultimately wait until the patients come back for their scheduled
> angiographic follow-up to have their appropriate intervention.
>
> How much of these lines might be due to appropriate intervention with
> the scheduled angiography versus something that might have been an
> unblinded influence by the operators who actually treat over is
> something that is difficult to tell. But we can make some inferences
> about that.
>
> So the mechanism of clustering of those events around the 8-month
> period is due to the opportunity to treat patients with moderate
> symptoms and moderate restenosis. That is, generally people have 40 to
> 70 percent lesions come back with some symptoms, and they generally
> wait until their scheduled angiogram to come back and get treated.
>
> So they often defer their catheterization from symptoms to the point
> where they\'re going to have their planned effect. But the likely
> reason for higher rates in the control arm at that period compared to
> the active arm is the fact that the patients who are assigned to the
> control arm had more frequent 40 to 70 percent narrowings, so we
> evaluated that per se. And if we look at what we saw from the
> angiographic narrowing, here are the continuous distribution function
> curves of diameter stenosis at follow-up. And if you look at the
> control arm, approximately one-third of the cases had narrowings
> between 40 and 70 percent, which would be those cases that would be
> vulnerable to being treated by repeat intervention, most of the time
> very appropriate.
>
> If we look at the arm for Sirolimus, only about 4 or 5 percent of the
> cases actually have narrowings in the 40 to 70 percent range, so it\'s
> not surprising, if we look back at the zone of angiographic influence,
> that there were more events occurring in the control arm because there
> were more narrowings per se, especially at follow-up, compared to the
> active arm.
>
> The other problem is that if you do look at restenosis at this point
> here, we think that we are necessarily underestimating the outcomes of
> both arms and probably diminishing or underestimating the treatment
> effect, because we\'re not seeing the true incidence of restenosis
> that has been deferred or delayed until it occurs right here. So if a
> study is defined and designed to be measured at 9 months with an
> 8-month angiographic follow-up just before the 9-month time period,
> you actually don\'t get the opportunity to see what really happens in
> the study by looking back on that curve at 7 months. If we wanted to
> look at 7 months, we should try to end the trial there, and then we
> would have the angiographic at 6 months and have a better estimate of
> the 7-month outcome.
>
> So, in conclusion, the subset analysis, the conventional subset
> analysis demonstrated a consistent and strong treatment effect for
> Sirolimus across a variety of important subset categories that have
> been used in previous stent studies. There was no treatment
> interaction that demonstrated a patient subset that did not benefit
> from Sirolimus, and the use of the non-prespecified endpoints, such as
> the 7.5 clinical restenosis endpoint, especially in this complex
> study, or nonlinear modelings were not optimal in our analysis to
> evaluate the outcomes of this randomized trial.
>
> DR. DONOHOE: Mr. Chairman, I just want to present the final three
> conclusion slides.
>
> Just to summarize the overall safety data from the RAVAL and SIRIUS
> trials, as we noted, the death and MI rates for the Sirolimus-eluting
> stent group was comparable to that of the control group. And as we
> also saw in more detail, there were no deaths in the Sirolimus-eluting
> group that were considered related to treatment with that stent.
>
> The incidence of stent thrombosis was comparable to that of the bare
> metal and was, in fact, less than 1 percent, whether 2 months of
> antiplatelet therapy was used or 3 months was used.
>
> The overall incidence of aneurysms was also discussed. As you saw,
> there were two aneurysms found at the 8-month follow-up in SIRIUS and
> one found at the 18-month follow-up in RAVEL, compared to a total of
> four aneurysms found in the control group. That is, the overall
> incidence, again, for aneurysms in the active treatment group was less
> than 1 percent, and there were no adverse events associated with those
> aneurysms.
>
> We saw that the MACE events for the overlapping of Sirolimus stents
> was actually lower, significantly lower than at the control group. The
> data have been generated across a Sirolimus dose range that supports
> safety of stents up to 33 millimeters in length and over 4.0
> millimeters in diameter.
>
> The issue of late incomplete apposition has been observed more
> frequently in the Sirolimus-eluting stent group. However, it does not
> appear that it\'s related to any adverse clinical outcomes, and our
> plan is to follow these patients over the longer-term 5-year period.
>
> In terms of overall efficacy conclusions, we believe that both
> randomized studies clearly should support the superiority of the
> Sirolimus-eluting stent compared to that of the control group on all
> angiographic IVUS and clinical endpoints. The detailed angiographic
> analyses do not demonstrate any evidence of an edge effect. The
> efficacy is maintained across all lesion lengths and vessel diameters
> tested, as Dr. Kuntz has just presented. We acknowledge there is
> limited data for vessel diameters above 4.0 millimeters. However,
> since efficacy has been maintained across all other diameters, it is
> anticipated that it will still be maintained for diameters greater
> than 4.0.
>
> The 2-year angiographic and clinical data from the First-in-Man as
> well as the 1-year clinical follow-up from the RAVEL shows sustained
> benefit with no evidence of a catch-up effect.
>
> And, finally, in terms of the overall conclusions, we believe the data
> clearly demonstrate the significant therapeutic benefit of the
> Sirolimus-eluting stent in the interventional treatment of patients.
> The clinical benefit we believe does outweigh the potential risks, and
> the data, we believe, that we presented does support the intended or
> requested indication, that is, the Cypher Sirolimus-eluting stent is
> intended for improving coronary luminal diameter in patients with
> symptomatic ischemic disease due to discrete de novo lesions of
> lengths less than or equal to 30 millimeters in native coronary
> arteries with reference vessel diameters of 2.25 to 5.0 millimeters.
>
> Thank you.
>
> DR. LASKEY: Thank you, gentlemen, for really a lovely presentation.
>
> I think before we\--we should probably try to have lunch around 12:30,
> which would leave \-- \[tape ends\].
>
> \-- the sponsor based on this morning\'s presentation. Dr. Edmunds?
>
> DR. EDMUNDS: Do you have any autopsy data on the eight patients that
> died?
>
> DR. DONOHOE: The question was: Do we have any autopsy data on any of
> the patients that have died? There was an autopsy on one patient who
> expired in the RAVEL study at approximately 16 months, and this
> analysis was actually histologic\--pathologic analysis was conducted
> by Dr. Ramani\'s (ph) lab. This patient happened to have had a bare
> metal stent placed in a different vessel two years before their death
> and the Cypher stent placed 16 months before their death. The
> histologic evaluation included a comparison of the histology in both
> areas, the bare metal and the Sirolimus-eluting stent.
>
> The findings indicated that actually in terms of local inflammatory
> response\--and the reports of this autopsy have been submitted to the
> FDA\--that there was actually less inflammatory reaction to the
> Sirolimus-eluting stent and the polymer than there was to the bare
> metal stent.
>
> There was evidence of re-endothelialization by visual assessment of
> somewhere greater than 80 percent for the Sirolimus-eluting stent and
> by visual assessment greater than 90 percent for the bare metal stent.
> There were no other significant findings in terms of the issues of
> incomplete apposition or any other significant abnormal histologic
> findings.
>
> \[Inaudible comment.\]
>
> DR. DONOHOE: Sixteen months.
>
> DR. LASKEY: Ileana?
>
> DR. PINA: Yes, I have several questions. We\'ve been dealing with
> coronary disease primarily with our usual revascularization plus
> drugs. I have seen nothing about what these patients were on. We\'ve
> been using statins. We\'ve been believing in statins. Now we\'re using
> ACE inhibitors to remodel vessel walls. What kind of background
> therapy were these patients on, number one? Some were on Ticlid, some
> were on Plavix. Have you analyzed both? In other words, should you get
> approval, what do we tell the physicians to concomitantly add to the
> patients and for how long?
>
> DR. DONOHOE: In terms of general medication use, we did collect that
> information, and we can provide the details of that information. I
> don\'t remember the specific distribution, but it\'s a standard list
> of antihypertensives, statins, and other cardiovascular type
> medications. There were no apparent differences between the two
> treatment groups and the type of medications used.
>
> In terms of antiplatelet therapy, specifically Ticlid and Plavix, I
> believe in the SIRIUS trial there were only four or six patients who
> used Ticlid; all others used Plavix. And as I mentioned, the duration
> was for a total of 90 days.
>
> DR. PINA: Could we see the statin data? Because I don\'t think that in
> some of the foreign countries the statin us is as good as it is
> perhaps in the States, even with as much of a gap as we have.
>
> DR. DONOHOE: Yes, we can provide that to the panel. I don\'t have it
> right now. We\'ll get that information for you.
>
> DR. PINA: All right. May I continue? I have some other questions.
>
> I also looked at your list of sites and the list of inability to
> deploy the stent in certain sites, and there seems to be a tremendous
> disparity among sites. I\'m assuming that a lot of that has to do with
> operator experience. But there are some sites that there\'s really a
> disparity between the ability to expand the non-coated stent and the
> coated stent.
>
> Should there be some operator difficulty in one versus the other in
> actually deploying the stent? I mean, some of the differences were
> pretty wide. Some have like 75 percent in the so-called control arm
> and maybe 25 percent in the Sirolimus-coated arm?
>
> DR. DONOHOE: Well, I know there\'s a variable number of patients
> entered across the 53 centers, and I assume that the difference in
> terms of ability to deploy is probably based in part on the technical
> ability of the operator, but also in terms of the types of lesions
> that they\'re treating. It may be somewhat related to types of patient
> populations, whether the lesions are more heavily calcified or more
> difficult to expand in general.
>
> We have tested on a number of variables for poolability of the data
> across these centers, and in terms of the main endpoints of this study
> and the secondary endpoints, we did not find any evidence that the
> data could not be pooled. So I would assume that the variation you\'re
> seeing is probably more related to the technical issues at those
> centers.
>
> DR. PINA: So there should be no difference in placing one stent or the
> other, one being more difficult than the other?
>
> DR. DONOHOE: No. In terms of benchtop testing, there was no difference
> in performance in terms of the ability to expand the stents or deploy
> them. And as you saw in terms of the device success number in
> particular I presented, it\'s specifically looking at the ability of
> the operator to deploy the stent, Sirolimus or the bare metal stent,
> attained less than 50 millimeter diameter stenosis at the end of the
> deployment procedure, using that treatment stent, that is, the
> Sirolimus or the bare stent. And as you saw, it was roughly 99 or 98
> percent in each group.
>
> So, overall, the success rates were high and comparable between the
> two treatment groups.
>
> DR. LASKEY: Dr. Aziz, then Dr. Bailey.
>
> DR. AZIZ: This question relates to the diabetic population. Did you
> break up the diabetic population into Type I and Type II diabetics?
> And was there more of a beneficial effect seen in one subset versus
> the other, or are the numbers too small?
>
> DR. DONOHOE: We did break out looking at if we defined Type II as oral
> diet-dependent type diabetics and Type I as insulin. We did break that
> out. I believe for the insulin-dependent diabetic group in the active
> group there were only about 37 to 39 patients, so we\'re getting down
> to small numbers. For the oral and insulin-dependent diabetic group,
> in fact, all the angiographic and clinical endpoints were still
> significantly improved over the control group. For the
> insulin-dependent, there was a decrease in the\--particularly in
> segment restenosis rates, and in some of the variables, I believe, in
> the angiographic there was still some marginal significance, and I
> think primarily because of the sample size, we lost significance in
> some of the clinical endpoints.
>
> However, overall, I believe there was still about a 35 percent
> relative improvement in the insulin-treated diabetics.
>
> DR. BAILEY: Just a clarification. Referring to the blinding, were the
> angiographers and physicians taking care of the patients aware for
> each patient whether they had an A or a B stent?
>
> DR. DONOHOE: The investigators taking care of the physicians were
> aware whether they re opening an A or a B package. I think I mentioned
> the packaging, the stents are identical. Holding the stents, looking
> at them, you can\'t tell which one has a coating or does not have a
> coating on it. The angiographic and IVUS core labs, of course, were
> blinded, as well as the clinical events committee.
>
> DR. BAILEY: So the revascularization decision, the person making that
> decision wasn\'t aware of whether it was an A or a B stent?
>
> DR. DONOHOE: On the 9-month follow-up, they would only be aware if
> they took the time to go look through the charts to see which one the
> stent\--which stent the patient had been assigned to originally.
>
> DR. BAILEY: It seems\--it may be a small point, but it would have
> been, I would have thought, feasible to avoid labeling the stents in
> that way.
>
> DR. LASKEY: Of course, we\'ll have additional opportunity to query the
> sponsor this afternoon, but if there are no other\--sir?
>
> MR. : Yes. Slide 23 that you showed with the blood concentrations, are
> those average concentrations in the study of 19 subjects? Because\--
>
> DR. DONOHOE: They\'re the two curves you\'re talking about?
>
> MR. : Excuse me?
>
> DR. DONOHOE: You\'re talking about the two curves in the PK study?
>
> MR. : Yes, the pharmacokinetic. I think it was your Slide 23.
>
> DR. DONOHOE: Those curves were based on means, and I think there were
> bars at each time point. Let me just check.
>
> MR. : It was hard to see here. On Slide 22 there were bars, but on the
> next slide, where you also show the trough, concentrations for the
> five and the two doses of Rapamune. I\'m just asking because those
> curves were sort of\--you know, the Y axis was relatively large for
> the data that you\'re showing.
>
> And the reason I\'m asking is, you know, do you have any information
> on drug-drug interactions from your study population in terms of a
> change in concentration of your drug on individuals who are possibly
> on inhibitors of, you know, CIP 3a, for example?
>
> DR. DONOHOE: Is this the slide you\'re referring to?
>
> MR. : Yes.
>
> DR. DONOHOE: Okay. I wonder if I could actually ask someone from Wyeth
> to come up and address the question about what these levels represent
> and drug interaction.
>
> DR. ZIMMERMAN: Hello, I\'m Jim Zimmerman. I\'m the clinical
> pharmacokineticist in the Clinical Pharmacology Group at Wyeth. Wyeth
> manufactures and supplies Sirolimus, and we have a business agreement
> with Cordis.
>
> Now, your question\--do you still have a question on this slide, or
> you want to move on to drug interaction?
>
> MR. : Sort of the first question, you know, has to do with the\--in
> that study population of, I believe, 19 subjects, what was, you know,
> the variability in the pharmacokinetics, because I think those are
> just averages that are shown there, but it\'s hard to see. Because
> it\'s a CIP 3a, as you know, there\'s usually a fairly large
> individual variability in pharmacokinetics, so the question was: What
> was the, you know, variability? And then the second question was: Do
> you have information in terms of the effect of inhibitors of CIP 3a on
> the whole blood concentration from this product?
>
> DR. ZIMMERMAN: Okay. I understand the second question. I\'m still not
> clear about the first question. You\'re questioning why those
> are\--we\'re comparing averages with the single dose\--
>
> MR. : The question was: In that Slide 23, are you showing averages and
> what was the variability? If you\'re just showing the mean
> concentration, how, you know, variable were the concentrations that
> you actually saw in each of the 19 subjects in the pharmacokinetic
> study?
>
> DR. ZIMMERMAN: Okay. I don\'t have that information. Actually, the
> variability\--well, I can tell you that the variability in the Tmax\'s
> range from about, let\'s say, one\--hold on just a second. I do have
> that summarized here for you.
>
> Okay. You can\'t see this on the slide, but the bar at the 1 nanogram
> per ml goes up to 1.4, and I believe that is a standard\--error of the
> mean?
>
> MR. : I think that is\--yes.
>
> DR. ZIMMERMAN: Or a standard deviation. Standard error of the mean, I
> believe.
>
> MR. : Okay. And then sort of the second question?
>
> DR. ZIMMERMAN: Drug interactions. I\'m quite certain (?) does not have
> the information on the drug interactions in these studies.
>
> Now, in the development of Sirolimus, we did not conduct intravenous
> studies\--intravenous drug interaction studies. The only information
> we have is with oral administration. Since you\'re aware of CIP 3a-4
> and p-glycoprotein, the effect of those interactions\--those proteins
> on interactions, you might be aware of Dr. Wesley Bennett\'s work in
> which he indicates that the effect of the extraction of Sirolimus in
> the gut is about twice as great as it is in the liver. Also, the
> effect of ketoconazole, an inhibitor, and rifampin, an inducer, is
> also about twice as great as it is in the liver.
>
> So although I could show you the large magnitudes of the interaction,
> for example, with ketoconazole and Sirolimus is about\--almost a
> thousand-fold increase in concentrations; however, that does not
> translate\--you can\'t translate that to the IV situation. It\'s
> probably about 50 percent of that after an IV.
>
> Now, what about the clinical significance of drug interactions? I
> don\'t think the clinical significance is great, even for a drug like
> ketoconazole, because the concentrations are so low. You\'re looking
> at a concentration at peak of either 0.5 to 1 nanogram per ml, and
> even increasing that five-fold still has you in a very safe region for
> systemic exposure of Sirolimus.
>
> MR. : How about in terms of, you know, pharmacodynamic drug-drug
> interactions? When you look at the drug label for the compound,
> there\'s a black box warning for, you know, concurrent use with
> cyclosporin, for example. It\'s probably not pharmacokinetic, and
> it\'s probably a pharmacodynamic effect. Can you comment on the
> applicability of the drug label in terms of, you know, combinations of
> drugs in terms of this device?
>
> DR. ZIMMERMAN: I have not seen that labeling, but we know that the
> immunosuppressive effect of cyclosporin and Sirolimus is not strictly
> additive. There is an increased effect after administration. The two
> drugs together give you a greater immunosuppressive effect than
> Sirolimus alone or cyclosporin alone.
>
> MR. : If I can just ask one more question, Mr. Chairman. The question,
> I guess, for the company, for the sponsor, would be how much of the
> drug label do they plan on incorporating in the instructions for use
> and the device label, and specifically, just so that you can find it,
> in our packet it\'s in Tab 3.3.1, page 11, it has the black box
> warning in terms of a contraindication for hepatic artery thrombosis
> when those drugs are used together. So I guess the question is how
> much of the drug label are you planning on incorporating in the
> instructions for the device.
>
> DR. ZIMMERMAN: I think I\'ll let the sponsor answer this.
>
> DR. DONOHOE: I think actually the draft IFU that is in your packet
> is\--at this point we thought was probably sufficient in terms of some
> of the issues you\'re raising. We believe there is a very low
> concentration with minimal clinical significance of interaction, and I
> believe there\'s potentially a question that comes up later FDA will
> present to the panel, further discussion or input from the panel on
> that.
>
> MR. : So you\'re saying that\--I mean, as I see the instructions here,
> there really isn\'t anything in terms of drug information.
>
> DR. DONOHOE: Drug interaction data, yes.
>
> MR. : Okay.
>
> DR. LASKEY: And I think we\'ll return to that this afternoon as well.
>
> One final question.
>
> DR. PINA: Following on that same track and based on the question that
> I asked you before about the statins, Sirolimus is known to increase
> lipid levels, triglycerides quite substantially, and cholesterol kind
> of do track. And obviously the levels that I see here are much lower
> than what I would use in a transplant patient, but I think we need to
> see some data about what happens to triglycerides and what happens to
> lipids in general, and, therefore, the statin question comes back
> again as being, I think, rather important in your advice to physicians
> when they\'re going to employ this therapy.
>
> DR. DONOHOE: In the two studies I presented, RAVEL and SIRIUS, we
> actually didn\'t measure cholesterol or triglycerides following the
> index procedure or over a length of time following the procedure.
>
> I believe the data that\'s been generated on the effect of Sirolimus
> on lipid levels generally indicates that usually you start to see an
> increase between one and two months after starting therapy, and also
> that the relative increase of both triglycerides and cholesterol was
> proportional to the dose. At the 1 milligram oral dosing with
> Sirolimus, it was found that numerically there was an increase in
> triglyceride and cholesterol, but not a clinically significant
> increase. And that increase or relative delta kept increasing with the
> higher dose. So the reason we did not collect triglycerides and
> cholesterol over time is based on that information we would actually
> expect no impact on triglyceride or cholesterol levels, given the
> variables we\'re dealing with and given that it typically takes one to
> two months of constant daily administration to increase those levels.
>
> DR. PINA: But you may be dealing with a population that already has as
> one of its most significant risk factors hyperlipidemia, which we
> don\'t know. I mean, these are \[inaudible\] a little bit different
> than, you know, a dilated cardiomyopathy that comes to transplant and
> may have normal triglycerides to start with.
>
> DR. DONOHOE: Agree. Although I think generally\--and if anyone from
> Wyeth has any more details on this, my impression is that whether
> you\'re starting with low or elevated, patients were still at risk for
> continued elevation, and that these levels for short duration of
> exposure, I wouldn\'t expect to have any\--certainly any long-term
> elevated lipids, even with oral dosing. I believe once dosing stops,
> the lipids do decrease.
>
> DR. LASKEY: I just have one burning question, which is the flip side
> of this. Many of our patients are started on Hmg-CoA inhibitors at the
> time they leave the hospital following the intervention. Is there
> anything we should know about or speculate on in terms of the effects
> of rapamycin on hepatotoxicity or myositis, et cetera, et cetera, the
> side effects of Hmg-CoA inhibitors initiated simultaneously?
> Everything is thrown at these patients on their way out the door,
> oftentimes.
>
> DR. SCIROLA: I\'m Dr. Joseph Scirola (ph) from Wyeth. As you heard,
> Wyeth is the supplier and manufacturer of Sirolimus, and we have a
> business agreement with Cordis.
>
> The issue of interaction with Hmg-CoA is very, very relevant because
> of the fact that Sirolimus raises both cholesterol and triglyceride
> levels. And in our pivotal trials which were shown, approximately 60
> to 70 percent of the patients actually ended up on lipid-lowering
> agents, and for the most part they were Hmg-CoA reductase inhibitors.
>
> We\'ve looked, not only in these studies but other studies, at the
> potential interaction, not only pharmacokinetic but toxic
> interactions, and we have not found an increased incidence of
> rhabdomyolysis. In fact, of the few cases that have occurred, there
> have been other explanations.
>
> We also have an interaction study with aturostatin (ph), and there is
> no drug interaction between Sirolimus and aturostatin.
>
> DR. LASKEY: Thank you.
>
> I think the better part of discretion here would be to break for lunch
> at this point, and we\'ll come back in exactly one hour at 1:30 for
> the FDA presentation. Again, thank you very much.
>
> \[Luncheon recess.\]
>
> [A F T E R N O O N S E S S I O N]{.underline}
>
> DR. LASKEY: If we may, I\'d like to reconvene, please. Thank you very
> much.
>
> FDA, are you good to go?
>
> MS. FOY: Yes.
>
> DR. LASKEY: All right. We\'ll resume today\'s panel session with the
> FDA Presentation.
>
> **FDA Presentation**
>
> MS. FOY: Good afternoon. I would like to thank you all for reconvening
> with us this afternoon.
>
> My name is Joni Foy, and I am a biomedical engineer in the
> Interventional Cardiology Devices Branch in the Office of Device
> Evaluation, in the Center for Devices and Radiological Health. I am
> also the lead reviewer for the Cypher Sirolimus-Eluting Coronary Stent
> System, original PMA submission P020026..
>
> Today, myself, Dr. John Hyde, the lead medical officer, and Dr. Murty
> Ponnapalli, the lead statistician, will present the FDA\'s summary for
> this product, which is the Cypher Sirolimus-Eluting Coronary Stent
> System.
>
> I did want to mention that this product is the first coronary
> drug-eluting stent to come before the Panel for the treatment of de
> novo lesions in native coronary arteries. Additionally, the Cypher
> drug-eluting stent product is a combination product because it
> consists of a device and a drug component. As such, this PMA
> submission has been extensively reviewed in conjunction with the
> Center for Drug Evaluation and Research.
>
> As a Panel participant today, you are being asked to discuss and make
> recommendations on the applicant\'s PMA submission. Your points of
> discussion of the clinical study results and labeling recommendations
> will be taken into consideration by the FDA in the evaluation of the
> application.
>
> Finally, you will be asked to vote on the approvability of the product
> that was tested clinically.
>
> To give you a brief overview of our presentation, we will briefly
> discuss the following. I will identify the FDA Review Team members; I
> will provide a brief summary of the description of the product; I will
> also provide a brief summary of the nonclinical evaluation and
> summarize the major outstanding nonclinical issues to date. John and
> Murty will provide a summary of the clinical and statistical
> evaluation of the Cypher product; and then we will identify the FDA
> questions for the Panel to discuss.
>
> I would like to take this time to actually acknowledge the extensive
> review team that has been associated with this product. You can see
> that there are a number of individuals. Members from the Center for
> Devices and Radiological Health include myself. I am a biomedical
> engineer, and I am the lead engineer and reviewer, from the Office of
> Device Evaluation.
>
> Dr. John Hyde is a medical officer and the lead medical officer for
> this project. He is also a statistician, and he is from the Office of
> Device Evaluation.
>
> Dr. Nick Jensen is the lead animal reviewer from the Office of Device
> Evaluation.
>
> Dr. Neal Muni is a visiting medical officer to the Office of Device
> Evaluation, and he assisted with the review of the IVUS data and the
> death reports.
>
> Dr. Murty Ponnapalli is the lead statistician from the Office of
> Surveillance and Biometrics and served as the statistical reviewer.
>
> Mr. Doyle Gant is a biomedical engineer from the office of Device
> Evaluation who assisted with the ISO 10993 biocompatibility review.
>
> Dr. Scott McNamee is a materials engineer from the Office of Science
> and Technology and assisted with the polymer chemistry review.
>
> Mr. John Glass is the lead compliance/manufacturing review from the
> CDRH Office of Compliance, Division of Enforcement 3.
>
> Mr. Rodney Allnutt is from the Office of Compliance, Division of
> Bioresearch Monitoring.
>
> The lead scientific reviewers from the Center for Drug Evaluation and
> Research are the following:
>
> Dr. Xiao-Hong Chen is the lead chemist from the Office of
> Pharmaceutical Science, Division of New Drug Chemistry I, who actually
> reviewed the chemistry, manufacturing and controls of the drug
> substance and polymeric coating.
>
> Dr. Patrick Marroum is a pharmacologist from the office of Polymer
> Science, Division of Pharmaceutical Evaluation I, who reviewed the
> pharmacokinetics and dynamics and human PK study.
>
> And Dr. Belay Tesfamariam is a pharmacologist from the Office of New
> Drugs, Division of Cardio-Renal Drug Products, who assisted with the
> biocompatibility/toxicity review of the animal data.
>
> I would also like to take this time to acknowledge other members who
> are not listed on this, because this is the only opportunity to give
> them some public recognition.
>
> Dr. Albert Defelice is a pharmacology team leader from CDER; Dr.
> Kasturi Srinivasachar is the chemistry team leader from the Office of
> Pharmaceutical Science, Division of New Drug Chemistry I; and Dr. Doug
> Throckmorton, who is Director of the Division of Cardio-Renal Drug
> Products; Mr. Don Serra \[phonetic\], who is the Chief of
> Cardiovascular Products, Division of Enforcement III; and Dr. Gary
> Gray, who is the team leader, Cardiovascular and Ophthalmic Products.
>
> In addition, our administrative staff and our upper management,
> including Ms. Ashley Bellum, who is the Chief, ICDB; Dr. Donaby
> Tillman, who is Deputy Director for Cardiovascular Products; Dr. Bram
> Zuckerman, who is the Division Director; and Dr. Dan Schultz.
>
> \[Slide.\]
>
> That being said, let\'s get to the heart of the matter. I wanted to
> lay out a regulatory history that has been associated with the
> Pre-Market Approval application for this product.
>
> This application was actually reviewed under the PMA Modular
> Submission Program, and that actually means that sections or modules
> of the application can begin to undergo substantive review prior to
> submission of the last aspect of the formal PMA submission. In this
> case, the complete clinical cohort for the SIRIUS study was that last
> component.
>
> I wanted to also note that even though the Center for Devices and
> Radiological Health is officially designated as the lead center for
> this combination product as part of an official request for
> designation from the applicant, appropriate sections of this
> application have been and will continue to be reviewed in conjunction
> with the Center for Drugs and Evaluation Research.
>
> The Agency would also like to mention that the review of this product
> has been very interactive between the Agency to appropriately and
> timely identify issues, and the application to respond to these
> concerns.
>
> Module I was the Quality Systems and Manufacturing Controls module.
> Since CDRH has the lead for this combination product, CDRH compliance
> also has the lead.
>
> However, CDER also has the authority to inspect the manufacturer of
> the drug substance for compliance with current Good Manufacturing
> Practices. Inspections of the manufacturing facilities are currently
> underway.
>
> The Chemistry, Manufacturing and Controls model, or CMC as we will be
> referring to it, was subsequently reviewed by the Agency. This
> information was jointly reviewed by both CDRH and CDER.
>
> And lastly, Module 2 contained the bulk of the nonclinical testing
> that was submitted to support the application as well as an interim
> clinical summary of the SIRIUS study as well as studies of the RAVEL,
> First-in-Man, and PK studies.
>
> I also wanted to denote, as the sponsor has previously indicated, that
> the last component of the modular submission was submitted to the
> Agency on June 28, 2002 and was designated as the original PMA. This
> component contained the clinical report for the full cohort of
> patients enrolled in the SIRIUS study, the 12-month data from the
> RAVEL study, and the available 18- to 24-month data from the
> First-in-Man study, as well as the data from the PK study, and the
> applicant\'s versions of the updated labeling and the Summary of
> Safety and Effectiveness Data.
>
> Sine all of the modules were still under active review by the Agency
> and responses pending by the applicant at the time of the PMA
> submission, all of the modules were actually closed and rolled into
> the PMA application and subsequent issues addressed as part of the PMA
> review.
>
> Sine this application was granted expedited review status, the Agency
> completed their review of the PMA and all amendments submitted by the
> applicant by September 3. Based upon our review of the information
> provided, the Agency issued the applicant a Major Deficiency Letter on
> September 18, 2002. A Major Deficiency Letter is one of the letters
> that can be issued by the Agency to request additional information
> from the applicant, which is deemed necessary to complete the review
> of the submission.
>
> The applicant submitted their official response to the Agency\'s
> letter yesterday, on October 21, 2002. Obviously, the Agency has not
> had an opportunity to review this response for its completeness or
> adequacy in addressing the currently identified outstanding issues and
> information that may be been included in this amendment are not
> included within the Agency\'s presentation today.
>
> The Agency and the applicant will continue to work interactively to
> resolve the outstanding issues previously communicated to the
> applicant for this application.
>
> I want to briefly give you a product description as defined by Title
> 21 of the Code of Federal Regulations, Part 3, the Cypher
> Sirolimus-Eluting Coronary stent is a combination product, because it
> is comprised of two regulated components, in this situation, a device
> and a drug.
>
> The device component for the Cypher stent consists of the following:
> The Bx Velocity, balloon-expandable, 316L stainless steel stent. The
> Bx Velocity, as already articulated by the applicant, is currently
> approved for use in de novo or restenotic lesions, less than or equal
> to 30 mm in length, in native coronary arteries with reference vessel
> diameters from 3.0 to 5.0 millimeters.
>
> The Bx Velocity stent is also approved for the treatment of abrupt or
> threatened abrupt vessel closure in lesions less than or equal to 30
> mm in length, with reference vessel diameters from 2.25 to 4.0 mm.
>
> The Bx Velocity stent is approved on both of the delivery systems
> proposed\--the Raptor over-the-wire and the RaptorRail Rapid Exchange
> version.
>
> Only the Raptor Over-the-Wire delivery system was used during the
> SIRIUS study. Both the Over-the-Wire and Rapid Exchange systems are
> the subject of this PMA application.
>
> To make the Cypher product a combination product, the applicant has
> coated the Bx Velocity 316L stainless steel stent, both luminally and
> abluminally, with a drug/polymer coating.
>
> The proprietary coating process consists of a layered mixture of
> non-erodible polymers to which the drug substance is added.
>
> A drug-free topcoat is applied to the stent surface to influence\--in
> other words, slow\--the release kinetics of the drug from the surface.
>
> The drug substance used in this product is manufactured by Wyeth
> Pharmaceuticals.
>
> Sirolimus is the drug substance.
>
> Rapamune, which is Wyeth\'s trade name, is approved by the Agency in
> both tablet and oral solution formulations as an immunosuppressive.
>
> The applicant has leveraged the initial drug substance safety data
> provided in Wyeth\'s NDAs in support of this submission.
>
> Sirolimus has not been approved for the treatment of restenosis or for
> use in coronary arteries.
>
> The applicant refers to the product with the drug-free topcoat as the
> IXTC, or the slow-release formulation, whereas product without the
> topcoat is referred to as the IX or fast-release formulation. All
> patients in the treatment group of the SIRIUS and RAVEL studies
> received the IXTC or the slow-rate-release formulation, and the
> applicant is currently seeking marketing approval for the IXTC
> formulation.
>
> I wanted to expand a little bit on a previous slide that was presented
> by the sponsor. As you can see, for this PMA application, the
> applicant is actually requesting approval for the following stent
> sizes designated in this matrix\--diameters from 2.25 to 5.0 mm in
> lengths of 8 to 33 mm, with the exception of the 5.0 x 8 mm diameter
> stent size.
>
> Please note that the drug and polymer content vary as a function of
> stent size.
>
> Based upon the dose density of 140 micrograms per centimeter squared
> of metal surface area, the total nominal dosage of sirolimus ranges
> from a minimum of 71 micrograms to a maximum of 399 micrograms for the
> currently proposed matrix of stent sizes and is shown on this slide in
> white text.
>
> The total nominal dosage of polymer content ranges from a minimum of
> 208 to a maximum of 1,184 micrograms for the currently proposed matrix
> of stent sizes and is shown on the slide in red.
>
> As denoted in yellow on this slide\--it is kind of hard to see, and I
> don\'t have a pointer\--you will see that the SIRIUS and RAVEL studies
> were conducted using the 2.5, 3.0 and 3.5 mm stent diameters in
> lengths of 8 and 18 mm.
>
> The inclusion criteria for the RAVEL study included lesion lengths of
> less than or equal to 18 mm, whereas the SIRIUS study included lesion
> lengths between 15 and 30 mm inclusive in length.
>
> Consequently,a s part of the SIRIUS study, the applicant was able to
> implant two stents, which theoretically accounted for up to 350
> micrograms of drug and up to 1,040 micrograms of polymer in a small
> subset of patients. The Agency has concerns over the lack of chronic
> preclinical and/or clinical information to support the safety of the
> amounts of drug and polymer on the larger and longer sizes of the
> proposed stent matrix. The yellow right here denotes the stents that
> were actually implanted in the SIRIUS and the RAVEL studies.
>
> The last point that I wanted to mention was that the Agency does have
> concerns over the lack of chronic preclinical and/or clinical
> information to support the safety of the amounts of drug and polymer
> on the larger and longer sizes of the proposed stent matrix.
>
> I wanted to briefly touch on the nonclinical evaluation conducted by
> the sponsor. In vitro preclinical pharmacology studies and in vivo
> release studies, as outlined in Section 1.6 of the FDA summary, were
> performed by the applicant to assess the elution kinetics and toxicity
> of the Cypher product.
>
> Although effectiveness is demonstrated through human clinical trials,
> animal studies can actually provide important information such as
> detailed arterial histopathology and histomorphometrics, which are not
> obtainable through human clinical experience.
>
> \` In vivo animal testing, as outlined in Section 2 of the FDA
> Summary, were conducted on porcine coronary arteries, for the
> clinically-intended dosage and overdosage. The Agency will consider
> the animal study data when evaluating issues related to the long-term
> safety of the requested range of drug and polymer dosages.
>
> Biocompatibility testing in accordance wit ISO 10993 was conducted on
> polymer-coated stents or coupons, without the inclusion of the drug
> substance. Since the applicant did not actually conducted ISO 1-993
> testing on the finished product with drug substance, a chronic porcine
> implant study was utilized instead using finished product with drug to
> evaluate the biocompatibility.
>
> Bench testing as outlined in Section 1.4 of the FDA Summary was
> performed to evaluate the mechanical integrity and function of the
> Cypher product.
>
> As outlined in Section 1.8 of the FDA Summary, the applicant has only
> submitted limited data, which does not adequately support the
> requested shelf life at this time.
>
> To assess coating integrity, the applicant has performed drug content,
> elution, degradation impurity, residual solvent and particulate
> testing of the finished Cypher product. Although issues have been
> identified with coating durability on the bench and in animals, the
> potential implications on clinical outcomes are being assessed by the
> applicant.
>
> As outlined in Section 1.7 of the FDA Summary, the Agency is unable to
> ascertain whether there is an effect of sterilization method on the
> finished product at this time.
>
> To date, there are unresolved issues pertaining to the nonclinical
> testing submitted by the applicant in support of this submission.
>
> No data have been presented that indicate a clear safety concern in
> the clinical setting regarding mechanical device failure or
> malfunction., specifically talking about coating integrity issues.
>
> I also want to take this opportunity to identify some of the major
> outstanding concerns that we previously articulated to the sponsor in
> their Major Deficiency Letter.
>
> Several of these nonclinical issues are of note, and the reason why I
> have put these here is because they directly have an influence on the
> safety and effectiveness of the manufactured product. They are briefly
> summarized here.
>
> The first of these is an in vitro elution methodology. The development
> of an acceptable, discernable in vitro elution methodology and
> specifications are critical for adequate characterization of the
> product tested clinically as well as to evaluate consistency in a
> commercially-manufactured product. Ideally, the in vitro dissolution
> specifications should encompass the time frame over which at least 80
> percent of the drug is eluted or where the plateau of resolution is
> reached if incomplete leaching is occurring.
>
> The in vitro elution method is also important in establishing the
> stability data for the product. The ability of the in vitro assay to
> predict in vivo elution is valuable in evaluating the significance of
> future modifications to the product, such as a change to the coating
> process.
>
> The Agency is aware of the challenges faced by device manufacturers in
> the appropriate development of in vitro assays for drug elution given
> the nature of the drug, and the Agency is working interactively with
> the applicant in the development of an appropriate methodology via
> both a short-term and a long-term solution.
>
> The second data point here is the stability. Based upon the lack of
> supporting data which should include at a minimum drug elution and
> impurities, the Agency has not been able to assign an expiration date
> to this product at this time. The collection of stability data to
> support a shelf-life for the product is currently ongoing by the
> Applicant.
>
> Additionally, the Agency was recently notified of a modification to
> the coating process. The Agency is concerned that the changes to the
> coating process could influence multiple parameters of the
> manufactured product, such as elution, coating integrity, impurities,
> et cetera, and the applicant would need to be able to verify that the
> product tested clinically has the same characteristics as the
> commercially manufactured product. The Agency is currently reviewing
> this modification and assessing the need for additional testing.
>
> Once again, I would like to emphasize that the Agency is working
> interactively with the applicant to adequately address these issues in
> addition to the other issues previously identified. As previously
> indicated, the applicant did provide a written response yesterday to
> the Major Deficiency Letter which was issued on September 18. The
> Agency will review this supplemental information in a timely manner
> and work interactively with the applicant to resolve any additional
> outstanding nonclinical issues.
>
> This was previously articulated by the applicant. The applicant has
> proposed the following indications for use for the Cypher
> Sirolimus-Eluting Coronary Stent system:
>
> Improving coronary luminal diameter in patients with symptomatic
> ischemic disease due to discrete de novo lesions in length less than
> or equal to 30 mm in native coronary arteries with a reference vessel
> diameter of 2.25 mm to 5.0 mm.
>
> As previously indicated by the applicant, the First-in-Man study was
> conducted in de novo vessels where the inclusion criteria was
> reference vessel diameters of 3.0 to 3.55 mm inclusive and lengths
> less than or equal to 18 mm in length.
>
> The RAVEL study was conducted in de novo vessels where the inclusion
> criteria was reference vessel diameters of 2.5 to 3.5 mm inclusive and
> lengths less than or equal to 18 mm in length.
>
> The SIRIUS study was conducted in de novo vessels where the inclusion
> criteria was reference vessel diameters of 2.5 to 3.5 mm inclusive and
> lengths less than or equal to 30 mm in length.
>
> Now Dr. John Hyde will come to the podium and address some additional
> specifics about the clinical performance of the Cypher product that
> was tested clinically.
>
> DR. HYDE: Thank you, Joni.
>
> My name is John Hyde, and I was the medical reviewer on this product.
>
> First of all, I don\'t intend to go over the principal results of the
> clinical studies. I think Cordis did a good job of presenting those
> results. So the purpose of my talk today is really just to present
> some of the issues that the FDA identified in the course of the
> review. Some of these issues are not really problems per se, but
> represent aspects of the design or endpoint definitions that we feel
> you should keep in mind now during your deliberations. And many of
> these issues we have also raised to the sponsor, and in some of those
> responses, I see they have provided some serious and thoughtful
> responses to today that we have not had an opportunity to review in
> detail.
>
> Some of the other issues go to how broadly we can construe the
> indications, in other words, how well the data support extensions of
> the findings to the borders of what was studied clinically.
>
> In a sense, these are really second-order phenomena. We don\'t really
> have any dispute over the overall positivity of this study. I think
> the Sirolimus effect is fairly clearcut. And in fact, I think it
> speaks well to the study that we have already been in a position to
> raise some of these issues and have the potential to address them.
>
> \[Slide.\]
>
> This is just a recap of the supporting clinical data that were
> provided in this application. The SIRIUS study, in which 1,058
> patients were available for or provided evaluable data, was strongly
> positive if used as the primary endpoint, the clinical endpoint of
> target vessel failure at 9 months.
>
> The RAVEL study, with 238 patients, also was strongly positive. It
> used the primary angiography endpoint of late loss, but it also
> collected clinical date, and we have target vessel failure at a year
> as important clinical information from that.
>
> The PK study was really just a small study with short follow-up, but
> it did demonstrate that there is a fairly long elimination half-life
> in humans, more so than just the drug substance itself, which suggests
> it sticks around on the stent for a while, or any area of the stent
> for a while. But it doesn\'t really provide much more than just short
> clinical follow-up.
>
> And finally, the First-in-Man study, which had 45 patients, 15 of
> those were with the alternate formulation, so 30 patients actually had
> the clinically proposed formulation, and although it is a small study,
> it is the one that does afford us the longest followup to date, out to
> 2 years.
>
> In addition, there are other clinical studies that are ongoing and
> under way, but they were not provided in this application in any
> detail that we could review.
>
> The clinical data, then, really come primarily from the SIRIUS and
> RAVEL studies, and let me just contrast them.
>
> They were very similar in many of their design features, but there are
> a couple of differences to keep in mind. One is that the RAVEL really
> had shorter lesions. They all had to be covered by the 18 mm stent,
> whereas the SIRIUS allowed lesions as long as 30 mm. The RAVEL study
> also used much less IIbIIIa inhibitors during the procedure, only
> about 10 percent or so in contrast to the SIRIUS study, which used
> about 60 percent.
>
> And also, although they both had antiplatelet drugs following mostly
> plavics, the RAVEL study used it for 2 months, and in the SIRIUS, it
> was used for 3 months.
>
> \[Slide.\]
>
> I\'m just going to recap some of the efficacy issues. Some of these,
> there isn\'t really too much more to say other than to bring them to
> your attention, and some of the others, I\'ll have a little more to
> say on later in the talk.
>
> First of all, as was already mentioned, both of these used an A-B
> scheme; in other words, they were assigned Lot A, and they took the A
> package out of the closet, or the B\--although for logistics reasons,
> it is quite understandable why this was done, because you don\'t know
> exactly what size you\'re going to use, but it does, of course, have
> the risk that if even one patient is unblinded, the entire scheme has
> the potential for being unblinded.
>
> In the RAVEL study, randomization was accomplished by distributing
> envelopes to the centers, which of course has the risk that this
> assignment might be uncovered, or that concealment of assignment might
> be compromised with that particular situation.
>
> The SIRIUS study used a central randomization scheme.
>
> And finally, we don\'t meant to imply that we feel the study was not
> blinded properly, but we don\'t really have the information to address
> what the quality of the blinding was. There was no retrospective
> assessment of whether people knew the assignment or what they thought
> the assignment might be, so we just can\'t address that issue.
>
> And finally, in the SIRIUS study, as was mentioned earlier, there was
> a \"deregistration\" of some patients. About 5 percent of patients in
> each arm were deregistered, which means that after the randomization
> assignment, it was determined that they really shouldn\'t be in the
> study, and they did not receive a stent and then were not followed up,
> so we really don\'t have followup information on those patients.
>
> On review of most of them, it does appear that they objectively did
> not meet certain eligibility criteria, but on the other hand, there
> were many patients in the study who didn\'t quite meet the eligibility
> criteria, either, so that wasn\'t necessarily consistently applied.
>
> I guess as a worst case, you could say that the differences you see
> might be 4 percent less, but still, they are usually pretty strong.
>
> Okay, I don\'t really have much more to say to address that issue.
>
> \[Slide.\]
>
> These are three of the four issues that I will be talking about a
> little bit more subsequently. One of them is the influence of
> angiography on target vessel failure, TVF, and the Cordis presentation
> mentioned that, and I have some comments on that later; the effect of
> lesion length was addressed, and I will talk about that a little bit
> more, as well as the effect of vessel diameter.
>
> \[Slide.\]
>
> Another issue is the effectiveness for vessels of diameter less than 3
> mm. I know this is partly regulatory and partly science. Both of these
> studies compared the Cypher stent to the bare stent over the full
> range of vessel diameters, which was targeted to be 2.5 to 3.5 mm.
> However, the bare stent does not have FDA approval for de novo reasons
> in vessels of diameter less than 3.0, and therefore, superiority to a
> bare stent in those cases is not really prima facie evidence of
> effectiveness, so we need to supplement that finding with some
> additional information. In particular, a separate analysis was done
> for small vessels, and Dr. Ponnapalli is going to present that
> analysis subsequently and draw on historical angioplasty information
> using a Bayesian analysis.
>
> And also, just keep in mind that any of the other overall comparisons
> we are going to be looking at are including these small vessels and
> involve comparison to the not necessarily approved control in that
> range.
>
> \[Slide.\]
>
> A couple of safety issues to keep in mind\--one is late malapposition.
> Cordis presented some data on that, and I will be recapping that near
> the end of my talk. And some other issues\--these are just things to
> keep in mind; I don\'t know that we have anything specifically to be
> able to address these, and we have asked the sponsor to look at these
> in addition.
>
> One is that there are higher dosages with longer lengths and
> particular with the larger-diameter stents, as Dr. Foy pointed out.
> The sponsor is interested in a fairly broad range of lengths and
> sizes, some of which would use total doses that exceed what was
> studied in the clinical studies.
>
> Another question has to do with overlapped segments. In places where
> two stents are used, there is an area of overlap in which case the
> dose density would be higher. About a quarter of the patients I think
> fell into that group on analysis of clinical data, and that subject
> didn\'t identify anything, but we have asked the sponsor to see if
> there is anything on imaging targeting specifically that overlap
> segment that could be informative.
>
> Finally, we do not have any information on the interaction with
> brachytherapy, either, using a stent in a patient who has been treated
> with brachytherapy or using brachytherapy subsequent to treatment with
> stent.
>
> And finally, some issues\--and I think the panel has already raised
> some of these questions\--on what the potential for systemic toxicity
> is. Although the drug concentration is at a fairly low level, there is
> some sustained exposure to Sirolimus after the stent is placed, and
> one question is what should be our level of concern about that, and
> what have we learned about that.
>
> In the SIRIUS study, the sponsor did look at hematologic dysplasia, at
> least for the course of the hospitalization and did not notice any
> difference between the other groups, but as was mentioned, things like
> effect on lipids were not evaluated.
>
> \[Slide.\]
>
> Finally, a couple of other issues, and these are just things to make
> sure you are aware of. One has to do with the definition of MACE that
> was used in the studies. MACE did not include target vessel
> revascularizations that did not involve the target lead. Target vessel
> failure did include these, so there is a slight difference in the
> rates. MACE is about 1.5 to 2 percent lower than target vessel failure
> because of that definition.
>
> And secondly, Cordis changed the definition of MI from what was
> proposed in the protocol based on CKME to the WHO definition based on
> total CK. The practical impact of that is that it lowers the MI rates
> by about 4 or 5 percent. We don\'t view this as issues causing
> particular bias, because they are applied uniformly across both
> groups, but they do bear on how you might compare these to your
> historical experience, and in particular, there are some questions
> outstanding relating to the Bayesian analysis which was based on these
> rates.
>
> \[Slide.\]
>
> Now I\'d like to talk to talk a little more on four of these issues,
> one of them being the influence of angiography on target vessel
> failure as I think Cordis mentioned. That was one of the issues that
> we had raised.
>
> Here are some of the points points on that. First of all, the endpoint
> of target vessel failure was really mostly revascularization. There
> were some deaths and MIs, but the majority of events were
> revascularizations, and therefore, there is some discretionary
> component to that.
>
> Now, ideally, the FDA strongly prefers to have a clinical endpoint as
> opposed to a laboratory finding or an indigenous study to form the
> basis of a finding of effectiveness, and to the extent that the
> angiographic results may have influenced the clinical endpoint and
> there is some dilution of the clinical meaningfulness of TVF as an
> endpoint, as the sponsor mentioned, the events were adjudicated by a
> Blinded Events Committee, and that certainly is a helpful way to
> address that.
>
> So one other thing we proposed looking at with a sensitivity analysis
> was also to look at the TVF rates at a time point preceding
> angiography, which would be about 7-1/2 months before the
> \[inaudible\] angiography was scheduled. That does have the
> disadvantage, though, of fewer events at that point, and it isn\'t
> necessarily pure, either, in that the anticipation of an angiography
> may somehow affect the results. But it does give you another way of
> looking at the data as sort of a sensitivity analysis, and I think you
> have already seen these\--I am going to go over them quickly.
>
> \[Slide.\]
>
> This is the TVF-free survival in the SIRIUS study. You may not be able
> to see it too well. It covers the 9-month period of the study from
> left to right, and the dotted line is the control or Bx velocity stent
> \[inaudible\] Sirolimus, and you can see a progressive separation of
> the curves over time, but particularly one month before the end, there
> is a marked drop particularly affecting the control group, and this is
> at the same time point as the angiography was done, so that in
> particular this seems to affect the control group more than the other.
> So one thing we did was look at slightly before that time point to see
> if that really made any difference in our interpretations.
>
> \[Slide.\]
>
> There is a similar phenomenon seen in the RAVEL study. This covers one
> year of the study, and you notice that about halfway along there, the
> control group has a significant drop, and that coincides with the
> 6-month angiography endpoint. So there seems to be at least some
> temporal evidence that there is some bearing on the vascularization
> endpoint from the angiography findings.
>
> \[Slide.\]
>
> So what we did was an analysis that looks at the 7-1/2 months as well
> as the 9 months, and you can see from this, although you expect
> smaller rates at 7-1/2 months, there is still a preservation of the
> treatment effect. It isn\'t as large in absolute terms, but there is
> still at least a twofold difference in target vessel failure rates
> even looking at it at this point. So the study is pretty robust in
> this respect\--although as we stress the data a little more and look
> at some of the issues I\'ll talk about later, using 7-1/2 months may
> have more impact.
>
> \[Slide.\]
>
> Another thing to consider, as I mentioned\--because the control stent
> was only approved for 3 mm diameter and above, I also looked at the
> subset that had 3 mm and above as sort of a pure test of efficacy, and
> even in this situation, there is statistical evidence of a significant
> treatment effect of about the same relative odds\--at least a doubling
> of the rate on the control group compared to Sirolimus.
>
> \[Slide.\]
>
> I\'d like to take a couple of minutes to talk about the issue of
> lesion length. Cordis present some information on that previously. And
> basically, if there is any information that was provided in the
> clinical summary\--this is sort of the ageless problem of trying to
> get the most you can from the data, sort of stretching the data of
> what the clinical experience was\--so to some degree it is statistics,
> to some degree it is an art\--some might argue that it\'s a black art,
> and they may be right.
>
> So anyway, I am going to present some of the modeling I did at least
> on the data that was originally presented to us, and there is
> certainly a subjective element to this, so I am offering this as one
> end of the spectrum. I see that Cordis has done some additional
> analyses to address this, and they have done some other thoughtful
> things, but we did ask them to address this issue, but I\'m not going
> to speak directly to what they said today.
>
> \[Slide.\]
>
> Here is our take on lesion length, and again, I think additional
> analysis could be informative here. The initial thing that we looked
> at\--we did not take into account some of the multivariate modeling,
> and that could be enlightening.
>
> But just to recap what the issues are, the target range by the
> eligibility criteria in the SIRIUS study was that the lesion lengths
> should be 15 to 30 mm. It turned out that about 80 percent of cases
> actually fell lower than that, in the 8 to 22 mm range. This is using
> the quantitative coronary angiography assessment of lesion length
> rather than the visual estimate by the investigators. So there is some
> missing of the target incidence on that, and even by the visual
> estimate, there was certainly a strong clustering of the lesion
> lengths toward the low end of the target range.
>
> The second is the issues I mentioned before\--the incidence of TVF
> versus angiography\--and I think there is some discordance in the
> conclusions that might come through looking at the effective lesion
> length on those endpoints. The core issue, then, is what is the
> confidence we have in extending the findings of this study to the
> longer lesions.
>
> I should say that RAVEL doesn\'t really help us address this, because
> they only targeted lesions that could be covered by the 18 mm stent,
> so they don\'t really even have long lesions in that study at all; it
> really all pretty much comes from the SIRIUS study.
>
> \[Slide.\]
>
> This is a graph that shows the binary restenosis rate. This is the
> angiographic endpoint of assessment of whether or not there is greater
> than or equal to 50 percent stenosis in the angiographic subset, which
> was over three-quarters of the patients.
>
> The horizontal axis is lesion length as measured by quantitative
> angiography. And what is plotted here is the open circles are the
> control group, showing restenosis rates rising from 30 to 60 percent
> over the range that is plotted here; and the solid circles down below
> are the Cypher rates.
>
> Interestingly, the control rates tend to be higher than the target
> vessel failure rates, considerably, and the Cypher rates actually tend
> to be somewhat lower than the target vessel failure rates.
>
> I have plotted here error bars which represent 1.5 standard errors of
> the regression estimate, and here I have just used a simple linear
> logistic regression. So these are not subgroup analyses per se, these
> represent the model estimate.
>
> I used the 1.5 because there is an approximate correlation between
> overlapping of bars at that length and the finding of a statistically
> significant difference. But I think the message from here is that even
> for fairly long lesion lengths\--and there aren\'t a lot of patients
> out there above 30\--that using a binary restenosis endpoint, there
> seems to be a good separation between the groups.
>
> \[Slide.\]
>
> That is somewhat in contrast, though, to what you see if you look at
> the more clinical endpoint, the primary clinical endpoint of 9-month
> target vessel failure. This plot is similar in design, with the
> quantitative angiography lesion length along the horizontal axis, and
> the TVF rates for the vertical axis. Control again is the open circle,
> Cypher is closed. The error bar is 01.5, standard error is open model
> estimate.
>
> The model that was used here, though, is something a little more
> complicated than the linear model. In fact, I wound up using cubic
> regression models to fit these data. Now, certainly there is a
> subjective element to this, and there is not necessarily statistical
> significance of all the terms that were added into this model.
> However, as I said, I didn\'t consider the linear model necessarily to
> be my null hypothesis here, and this is partly a result of just some
> subjective modeling to try to see what really seemed to fit the data
> using some other things on top. So this is a subjective analysis, but
> I think it has fairly good fidelity to the data.
>
> And what this seems to indicate, anyway, is that certainly in a range
> of where most of the cases fell, to about 20 or so, there seems to be
> strong evidence of a treatment effect for Sirolimus, but that as you
> get to longer lesion lengths, there becomes some question of how
> well-separated they are. Although the estimates certainly show a
> persistent treatment effect of smaller magnitude, the uncertainty
> because of smaller numbers makes it less a clear separation as you
> saw, for example, with the angiographic endpoint.
>
> \[Slide.\]
>
> Further, if you choose to use the 7-1/2-month target vessel failure
> rate that we talked about earlier, not surprisingly, with lower rates
> and thus smaller difference, they even seem a little closer together
> here.
>
> \[Slide.\]
>
> The purpose of this slide is to underscore some of the problems you
> get to when you select subgroups and emphasizes why I really went more
> with a holistic modeling type of approach rather than subgroup
> analysis.
>
> If you look at the subgroup of lesion length greater than or equal to
> 25, there are only 51 patients total. That means about equal in both
> groups. And there is certainly a large treatment effect, but the
> confidence in that is somewhat muted.
>
> For lesion lengths greater than or equal to 20, there is a reasonable
> sample size, and there appears to be a strong treatment effect; but
> interestingly, if you pick your cutoff somewhere else, 18 or 16, for
> example, it is a little less clear. So again it goes back to the black
> art of trying to decide how to look at these subgroups properly. It is
> partly for this reason that I chose to try to fit a model of that and
> look at subgroups.
>
> \[Slide.\]
>
> Next, I would like to turn to the issue of vessel diameter. Again, the
> issues are pretty much similar as they were for lesion length, just
> with another variable. And again I offer what was presented in a
> clinical summary as one end of the spectrum, one way of looking at
> these data, and the sponsors presented some additional analysis as
> well.
>
> One thing to keep in mind is the proposed stent lengths run the gamut
> from 2.25 all the way up to 5.0, even though the eligibility criteria
> were a smaller range than that and certainly, the clinical data
> didn\'t quite encompass that range, although there are always
> individual patients that fall outside that, so the question is what
> can we learn from that.
>
> The issues with the reference vessel diameter are that the SIRIUS
> target range was 2.5 to 3.5 millimeters, and I think they came pretty
> close in that 80 percent of cases were in the 2.2 to 3.4 or a little
> lower. This is again using the quantitative coronary angiography
> assessment of vessel diameter which tends to be a little smaller than
> the visual estimate by about 10 percent or so. And again, the issue,
> then, is what is the confidence of extrapolating, in particular the
> issue would be to large vessels. Small vessels, as I mentioned before,
> because of the nonapproval of the control stent for small vessels, has
> some of its own special issues. And Dr. Ponnapalli I hope will talk
> about that next.
>
> \[Slide.\]
>
> This chart, similar to what was seem for the lesion lengths, shows
> binary restenosis, the angiographic endpoint plotted against vessel
> diameter over the range of just 2 to 4; I didn\'t go all the way up to
> 5 here. Control is the open circles at the top, and Cypher at the
> bottom. And again we see, at least with this particular endpoint, good
> separation between the control and Cypher stent, a strong treatment
> effect\--at least, we believe the extrapolation still looks pretty
> good even to the extremes of the vessel diameters studied.
>
> But again, if you look at the clinical endpoint target vessel failure,
> as we did before, this looks at target vessel failure plotted against
> vessel diameter over that same range, and here, I have plotted again
> the control, and one little feature is that the grade portion of the
> control indication, control graph, on the left side of the chart
> indicates the range in which that control stent is really not an
> approved device. So \[inaudible\] certainly that comparison is Cypher
> versus an approved stent.
>
> And we see over much of the range, anyway, there appears to be good
> separation both in terms of the estimated treatment effect and the
> confidence in that effect, although as we get up to the upper end,
> both a few patients and the fact that also the event rates are low,
> makes it harder, really, to discriminate differences there. These
> curves are fairly parallel. I did use a quadratic model, I think, and
> it improved a bit, slightly; linear doesn\'t really look too much
> different from this. I did not go all the way up to 5, however, which
> is one of the proposed stent diameters.
>
> One other feature\--there is that sort of dot-dash line right about in
> the middle of the chart\--and although the sponsor didn\'t make this
> argument, I\'ll make it for them\--one way of addressing the
> nonapproval of the control below 3 is to assume that things only get
> worse with smaller vessel diameters, so that the result at 3 for the
> control, the lower end of that confidence interval would be an
> acceptable \[inaudible\] even for smaller vessel diameters, and if you
> extrapolate that over, by that argument, you could say that down to
> 2.5 and even a little below, there is evidence that the Cypher stent
> is at least as good as the control would be at 3, and that might be
> viewed as also additional evidence for efficacy.
>
> \[Slide.\]
>
> The next chart is similar, but I am using again a 7-1/2-month endpoint
> rather than the 9-month, and as expected, everything is a little bit
> lower; the event rate are lower. And although there is a statistical
> separation there, it is a little less clean, and one can\'t quite as
> easily make the extrapolation argument for the control below 3.
>
> Finally, let me just recap the safety issue of late malapposition. I
> think Cordis presented some important data, but let me just review it,
> because it is one thing we want particularly to get your input on.
>
> This late malapposition, probably better referred to as late-emerging
> or late-occurring malapposition\--we are talking about malapposition
> that was not necessarily present at baseline, or was not present at
> baseline, but appears later\--we did see malapposition at the
> angiographic followup in both the RAVEL and SIRIUS studies. In the
> SIRIUS studies, we know that some of those cases were late-occurring
> because we have baseline, and RAVEL did not require baseline data, and
> none was provided to us.
>
> So, there is no apparent clinical correlate with this, and our
> question would be what might be the implications of this, and has the
> followup been adequate to address potential implications of it.
>
> Just to recap the extent of the IVUS data and the SIRIUS study, about
> a quarter of patients were supposed to be getting IVUS\--these were
> done only at selected centers out of the impact study\--and followup
> was not complete to the point where, really, we have baseline and
> 8-month followup really on only about half of those that were assigned
> to get IVUS.
>
> \[Slide.\]
>
> Just to recap, baseline rates were the same between the control and
> the Cypher group at about 14-15 percent, but at the 8-month followup,
> the Cypher rate was 20 percent\--again, these aren\'t exactly the same
> patients\--but the Cypher rate was 20 percent, the control had fallen
> to 9 percent in the matched-pair analysis. It appeared that among
> those in the Cypher group, about half of them healed and half of them
> persisted, but there was an additional cohort that appeared late, so
> that of the 19 percent or so, about half of them are late-occurring
> malappositions.
>
> In the control group, again, about half of them healed, but at least
> in this particular study, there were not late-occurring
> malappositions.
>
> \[Slide.\]
>
> And RAVEL, there, everybody was supposed to get angiographic followup,
> and a subset of centers did the IVUS, and followup was very good
> there, so I don\'t have that table for this one. But again, the
> rate\--and this was at 6 months\--was around 20 percent for Cypher and
> 4 percent for control, so fairly similar for followup rates, a little
> different in the control.
>
> So we really don\'t have information on how much of it was
> late-occurring as opposed to persistent from the time of the target
> procedure.
>
> So, as I mentioned, there are no clinical sequelae, and this is just
> to recap what the extent of followup is so far, and I think more is
> available, and I guess that is on its way to us, or we have it now,
> but we have not had a chance to look at that.
>
> \[Slide.\]
>
> In the SIRIUS study, followup was at least 9 months, and at this time
> point, more should be available. The RAVEL study looked at patients
> for a year. The First-in-Man is an opportunity to look at 2-year
> followup, but again, the patient numbers there are small. But based on
> the clinical data, we have seen so far, there is nothing necessarily
> correlating with the finding of late malapposition.
>
> \[Slide.\]
>
> This is to recap our clinical conclusions. Overall, we feel there was
> evidence of safety and effectiveness, but extension to diameters
> outside of the 2.5 to 3.5 mm range is less definitive. The sponsor
> would like to use 2.25 up to 5.0.
>
> I should mention that although some patients in the study had
> diameters well below 2.5, they were all treated with a 2.5 mm stent in
> this study; nobody used the smaller sizes that are being proposed.
>
> Extension to longer lesions is also less definitive, and for both of
> these, we have asked the sponsor to analyze these issues, and they
> have provided some analysis to us.
>
> And finally, the IVUS suggests some abnormal remodeling, but we don\'t
> necessarily see any clinical impact at this point.
>
> DR. PONNAPALLI: May name is Murty Ponnapalli. I am a biostatistician
> in the Division of Biostatistics in CDRH.
>
> \[Slide.\]
>
> The first slide is on statistical evidence for effectiveness for
> vessel diameters larger than 3.0 mm. John Hyde already gave the
> statistical analysis. The control was bare stent. But for vessel
> diameter less than 3.0 mm, the bare stent is not approved by the FDA,
> so we ran into a problem, and the FDA agreed that the company, Cordis,
> could take historical controls instead of concurrent controls.
>
> Because we could not \[inaudible\] with historical controls, FDA
> agreed that the sponsor should make a Bayesian analysis, so my talk is
> going to be about this Bayesian analysis.
>
> \[Slide.\]
>
> Briefly to recap the design, the treatment is Sirolimus-eluting stent.
> What I call the substudy population is 370 patients with reference
> vessel diameter less than 3 mm. The control is balloon angioplasty in
> three historical studies.
>
> The primary effectiveness variable is major adverse cardio event rate,
> MACE, at 9 months post-procedure.
>
> I could not see that the definition of MACE is exactly the same in the
> historical controls also, and I would like to point this out to the
> sponsor.
>
> The statistical analysis we used is the so-called Bayesian
> hierarchical model with noninformative priors for the parameters.
>
> \[Slide.\]
>
> Pre-planned subgroup analysis\--sponsor and FDA agreed to the use of
> Bayesian methods with a historical control, as I already mentioned, in
> this subgroup.
>
> As I already mentioned, there is no FDA-approved bare stent for
> lesions less than 3 mm.
>
> The control is balloon angioplasty.
>
> And Bayesian methods were used to combine the three controls in an
> appropriate way, accounting for variability between studies, and then
> compare MACE rates using logistic regression.
>
> \[Slide.\]
>
> The next slide is on the details of the Bayesian statistics.
>
> This is a scientifically valid way of combining prior information and
> comparing it with current data. The procedure is to assign prior
> probabilities to parameter values\--for example, effects in logistic
> regression model; update to posterior probabilities after observing
> the data; then, base inference on the posterior probability
> distribution of the parameters.
>
> \[Slide.\]
>
> This slide is of the hierarchical model.
>
> Bayesian methods for comparing the MACE rate in the SIRIUS study with
> MACE rates in several historical studies; combines information from
> control studies, taking variability of studies into account; logistic
> regression of MACE rates using the covariates reference vessel
> diameter, lesion length, diabetes, left anterior artery disease,
> gender, minimal lumen diameter. These are the covarietes used in
> logistic regression.
>
> Assuming that prior studies are a sample from a larger population
> after covariate adjustment\--that is one of the basic assumptions we
> make using the Bayesian analysis\--just as we used randomness in the
> non-Bayesian method, we use this assumption in the Bayesian method. We
> used noninformative priors for the parameters.
>
> \[Slide.\]
>
> In the logistic regression model, we used the covariates: reference
> vessel diameter, lesion length, diabetes, left anterior artery
> disease, gender, minimal lumen diameter. That appears as the fourth
> bullet there.
>
> We assumed that the prior studies are a sample from a larger
> population. As I already said, we followed the assumptions necessary
> to make the Bayesian analysis\--which one could question, but all
> Bayesians use this.
>
> We used noninformative priors for the parameters. What this means is
> that the prior information that we used is not subjective; it is
> objective.
>
> \[Slide.\]
>
> So, using all this and using simulations to arrive at procedural
> probabilities, we get the following results.
>
> The probability of MACE with the treatment is 7.6 percent. The
> probably of MACE with the three historical studies combined is 24.4
> percent. And the next three rows are the probabilities of MACE for
> each of the historical studies\--for Benestent I, it is 33.6 percent;
> for Benestent II, 24.4 percent; for Stress, 23.2 percent.
>
> \[Slide.\]
>
> Summary from Bayesian Hierarchical Model.
>
> The probability of MACE with the Cypher product is considerably less
> than with balloon angioplasty in any one of the historical studies;
> and posterior probability is 98 percent that the MACE rate is less
> with Cypher product than with balloon angioplasty. This is the main
> criterion when we use the Bayesian analysis. This \[inaudible\]
> corresponds to P values in non-Bayesian.
>
> \[Slide.\]
>
> Then, the sponsor performed a sensitivity analysis. Since there is no
> randomization between the treatment arm and the historical arm, it may
> be the covariate, which is not balanced between the two, so a
> sensitivity analysis was performed to examine what the effect of an
> unmeasured covariate could be.
>
> The sponsor undertook an analysis of the sensitivity to an unmeasured
> covariate which has an effect on MACE.
>
> The general conclusion, based on simulations and so on, is that unless
> the confounding is excessive and the confounder has a larger effect on
> MACE, the probability that the Cypher MACE rate is better than balloon
> angioplasty remains greater than 92 percent. It no longer is exactly
> 98 percent, but it remains about 92 percent.
>
> Now, the summary:
>
> Preplanned subgroup analysis\--because there was no approved control
> agreed upon between the FDA and the company.
>
> Prespecified and appropriate Bayesian analysis plan.
>
> Posterior probability is 98 percent that Cypher product MACE rate is
> better than balloon angioplasty.
>
> Analysis is relatively insensitive to the effects of unmeasured
> covariates.
>
> Thank you.
>
> DR. LASKEY: Thank you.
>
> MS. FOY: Now, for the record, FDA would like to obtain panel input on
> the following questions:
>
> Question Number 1, for the evaluation of safety. The safety endpoints
> evaluated in the SIRIUS study included: MACE to 270 days; stent
> thrombosis to 30 days; and late thrombosis to 270 days. For the Cypher
> product, these were 7.1 percent, 0.2 percent, and 0.2 percent,
> respectively. For the Bare Bx Velocity stent, these same parameters
> were 8.9 percent, 0.2 percent, and 0.6 percent, respectively.
>
> Do the data submitted on the Cypher product provide adequate assurance
> of safety?
>
> Question Number 2. The applicant has requested approval for a range of
> stent diameters and lengths that corresponds to a nominal drug dosage
> as high as 399 micrograms. The animal studies conducted by the
> applicant on dosages higher than 180 micrograms were limited to 30-day
> followup. The SIRIUS study only evaluated 15 subjects who received
> stents, with a total nominal drug dosage greater than 350 micrograms.
>
> Question 2a. Given the limited preclinical and clinical information
> outlined previously, please comment on whether there is adequate
> evidence to support the use of stent diameters and lengths\--in other
> words, 4.5 mm and 5.0 mm diameter with a 33 mm length\--with a nominal
> drug dosage greater than 350 micrographs.
>
> Question 2b. If not, what additional studies or information would be
> necessary to support the safety of stents with a nominal drug dosage
> greater than 350 micrograms?
>
> Continuation of Question 2. Additionally, the nominal amount of total
> polymer ranges from 208 micrograms to 1,184 micrograms for the
> currently requested range of stent sizes. The animal studies conducted
> by the applicant on polymer dosages higher than 500 micrograms were
> limited to 28-day followup. The nominal total polymer amounts tested
> in the SIRIUS study ranged from 208 to 520 micrograms.
>
> Question 2c. Please comment on whether there is adequate evidence to
> support the use of stent diameters and lengths\--for example, 6-cell
> and 7-cell stents in lengths of 23, 28, and 33 mm and 9-cell stents in
> lengths of 18, 23, 28, and 33 mm\--with a nominal polymer dosage
> greater than 520 micrograms.
>
> Question 2d. If not, what additional studies or information would be
> necessary to support the safety of stents with a nominal polymer
> dosage greater than 520 micrograms?
>
> Question 3. In the SIRIUS study, the Cypher group had a 19 percent are
> of incomplete apposition at followup versus 9 percent for the control.
> This included a 10 percent rate of late incomplete apposition for the
> Cypher versus 0 percent for the control. In the RAVEL study, the rate
> of late incomplete apposition was 21 percent versus 4 percent for the
> control. There was no obvious clinical correlation between late
> appositions and adverse events.
>
> Question 3a. Please comment on whether additional information is
> necessary to evaluate the significance of the late stent malapposition
> found in the clinical studies.
>
> Question 3b. Is there any specific targeted followup, additional
> clinical investigation, animal studies, and/or bench-testing that
> should be requested to contribute information that would be important
> regarding the clinical findings?
>
> Question 4. In the RAVEL study, subjects received ASA for 6 months and
> clopidogrel or ticlopodine for 2 months. In the SIRIUS study, subjects
> received ASA for 9 months and clopidogrel or ticlopodine for 3 months.
> Please discuss your recommendations for the antiplatelet therapy for
> patients receiving the Cypher product.
>
> Question 5. The potential for interactions with several drugs has been
> evaluated as described in the Rapamune labeling. Interactions with
> other drugs might be expected based on known metabolism by Cytochrome
> P3A4. Please comment on whether the application adequately address
> drug interactions that are likely to be important or of interest. If
> not, what other information or studies should be requested?
>
> Question 5b. Has followup been adequate to address concerns about
> possible systemic adverse drug effects?
>
> Question 6\--we are going on to the evaluation of effectiveness now.
> The primary effectiveness endpoint for the SIRIUS study was target
> vessel failure at 9 months. Rates of TVF at 270 days were 8.6 percent
> for the Cypher group and 21 percent for the Bx Velocity control group.
> Does the evidence presented on the Cypher product provide reasonable
> assurance of effectiveness at 270 days?
>
> Question 7. Prolonged inflammation and notably increased restenosis
> were observed when polymer-coated but drug-free stents were implanted
> in swine. In swine implanted with Cypher product\--in other words,
> coated with both drug and polymer\--this effect was not observed at
> one month post-implant but was observed at both 3 and 6 months
> post-implant.
>
> Given the nonparallel time lines of healing between juvenile normal
> pigs and atherosclerotic older patients, do these findings raise
> significant concerns about the ability of the clinical followup to
> address the possibility of a similar delayed occurrence of neointimal
> hyperplasia?
>
> If so, please comment on whether additional testing or followup,
> either pre- or post-approval, is necessary to support the
> effectiveness of the Cypher product.
>
> Question 8. The temporal relationship between scheduled angiography
> and revascularization, and analysis of the subgroup that did not have
> angiography, suggest that angiographic outcomes may have influenced
> the clinical outcomes in a way that differentially affected the
> control group.
>
> Please comment on the adequacy of the primary endpoint, which is
> 9-month target vessel failure, for capturing the expected clinical
> benefit of the Cypher product in light of the possible influence of
> 8-month angiography results. Are there other ways the clinical impact
> should be assessed either for (a) evaluation of efficacy in
> determining the appropriate indication, or (b) for information to be
> conveyed in labeling?
>
> Question 9. Because the control stent is not approved for de novo
> stenosis in vessels of diameter less than 3.0 mm, the applicant
> provided additional analyses, including a Bayesian comparison, to
> historical angioplasty data.
>
> Please comment on whether adequate evidence has been presented to
> demonstrate effectiveness for stents with diameters less than 3.0 mm.
>
> Question 10. Univariate regression analysis of data collected in the
> SIRIUS study suggest that the treatment effect may be reduced in
> longer-length lesions. This could be due to either a true diminished
> treatment effect or a lack of power\--for example, too few
> subjects\--to detect a treatment difference in subjects with longer
> lesions.
>
> The applicant has performed logistic regression analyses, but these
> analyses only included main effects and did not specifically evaluate
> the possible interaction between each variable\--in this case, lesion
> length\--and the treatment effect\--for example, an analysis of
> treatment effect by covariate interaction.
>
> Question 10a. Does the data presented provide reasonable assurance of
> effectiveness for the treatment of the full requested range of lesion
> lengths\--less than or equal to 30 mm?
>
> Question 10b. The protocol for the SIRIUS study specified the
> inclusion of subjects with reference vessel diameters from 2.5 to 3.5
> mm. The proposed indications for use include reference vessel
> diameters of 2.25 mm as well. Does the data presented provide
> reasonable assurance of effectiveness for vessel diameters of 2.25 mm?
>
> Question 11, which relates to product labeling. One aspect of the
> pre-market evaluation of a new product is the review of its labeling.
> The labeling must indicate which patients are appropriate for
> treatment, identify potential adverse effects or events with the use
> of the product, and explain how the product should be used to maximize
> benefits and minimize adverse effects.
>
> Please address the following questions regarding the product labeling.
>
> Question 11a. Please comment on whether the Indications for Use
> Statement identifies the appropriate patient populations for treatment
> with this product. Specifically, subgroup question 1, has the
> application provided reasonable assurance of safety and efficacy for
> treating the full requested range of vessel diameters\--2.25 mm to 5.0
> mm. If not the full requested range, what range of vessel diameters
> should be included?
>
> Subgroup question 2. What length of lesions should be included in the
> Indications for Use?
>
> Question 11b. Please comment on the contraindications as to whether
> there are conditions under which the product should not be used
> because the risk of use clearly outweighs any possible benefit.
>
> Question 11c. Please comment on the Warnings/Precautions sections as
> to whether they adequately describe how the product should be used to
> maximize benefits and minimize adverse events.
>
> Specifically, please comment on whether a warning or precaution
> related to subsequent brachytherapy should be included in this
> section.
>
> Question 11d. Please comment on the Operator\'s Instructions as to
> whether it adequately describes how the product should be used to
> maximize benefits and minimize adverse events.
>
> Question 11e. Please comment on what aspects of drug pharmacology,
> mechanism of action, pharmacokinetics, drug interactions, or systemic
> effects should be added to the labeling to maximize benefits and
> minimize adverse events.
>
> Question 11f. Please comment on the remainder of the product labeling
> as to whether it adequately describes how the product should be used
> to maximize benefits and minimize adverse events.
>
> And lastly, post-market evaluation.
>
> Question 12. The Panel Package included the available 9-month data for
> the Cypher product in the SIRIUS study. In addition, the available
> 12-month data were provided from the RAVEL study, and the available
> 18- to 24-month data from the First-in-Man feasibility study were
> provided.
>
> The applicant has proposed continued followup, out to 5 years, on
> subjects from the SIRIUS, RAVEL, and the First-in-Man studies.
>
> The applicant has also proposed to collect data through one year on
> approximately 1,000 to 2,000 patients implanted with the marketed
> product using an electronic database.
>
> Question 12a. Please discuss long-term adverse effects that may be
> associated with implantation of the Cypher product including late
> thrombosis formation, aneurysm formation, myocardial infarction, and
> late stent malapposition.
>
> Question 12b. Based on the clinical data provided in the Panel
> Package, do you believe that additional followup as proposed by the
> applicant is appropriate to evaluate the chronic effects of the
> implantation of the Cypher product?
>
> If not, what additional followup information should be collected?
> Specifically, how long should patients be followed, and what endpoints
> and adverse events should be measured.
>
> That\'s the end.
>
> **Committee Discussion**
>
> DR. LASKEY: Thank you, FDA.
>
> I am going to arrogate my Chairman\'s prerogative here and move on
> beyond the panel asking questions of the FDA. I think we can do that a
> little later on. Let\'s get to the crux of the issue.
>
> I would like to open the committee discussion by asking Dr. Krucoff to
> provide us his review.
>
> Mitch?
>
> DR. KRUCOFF: I\'m going to have some questions along the way, so is it
> fair to just call people up as we need them?
>
> DR. LASKEY: Actually, at this point, it would be appropriate to ask
> the sponsor to please step forward; it may even be a shade cooler
> toward the front of the room.
>
> We are cognizant of this problem, and we have been working on it for
> the last 2 hours.
>
> Thank you.
>
> DR. KRUCOFF: I have to start with at least a couple of perspective
> comments, and if I am wrong in these perspectives, that will change a
> lot, so I\'ll just rely on somebody to jump in.
>
> As an interventionist and with so much awareness of the obvious
> effectiveness of what is a breakthrough and a major source of human
> misery for all of us in this technology arena, I think I can only say
> that I share a lot of the excitement that has brought this product
> clearly to an expedited review on an accelerated pace.
>
> It does, though, leave me with a sense of to be cautious about the
> mandate to today\'s review committee to review a clinical trial based
> on the data that we have at hand. Years ago, Bill Roberts taught me
> that a medical device is essentially the replacement of one disease
> with another\--hopefully, a less severe one. And I think we have to be
> cognizant of that.
>
> I want to thank the sponsor and their colleagues from the HCRI for
> putting together an enormous amount of data in a very clear, concise
> way, both what I got in the panel pack and in the presentation today.
>
> I also want to thank the FDA team, from across sectors of the agency,
> on a combined drug device for also putting together a panel pack that
> I felt was extremely helpful in synopsizing that.
>
> So what I am left with are a few assumptions. One assumption is that
> as the first panel pack I have ever received with an incomplete Letter
> of Major Deficiencies, that is not our business today; that
> follow-through on the manufacturing elements and essentially the
> completion of those deficiencies is going to happen through a separate
> interaction. So I am going to step away from that, other than the fact
> that, obviously, the ability to manufacture a stent that delivers in
> clinical practice what has been delivered in a pivotal trial is part
> of the assumption that I am going to move forward into the data with.
>
> The other part of this, though, that is clinical data-oriented is that
> I simply am not a believer that the practice of the black art of data
> manipulation constitutes a replacement for data, and that ultimately,
> if we are going to subject human beings to an intervention that we
> don\'t understand very well, the least we can do is start where we
> have data and then move conservatively as data has accrued rather than
> trying to use analyses that are so complex that even a statistician
> doing the analysis cannot honestly tell us whether it is a lack of
> numbers or a change in effectiveness that we are looking at when we
> look at charts and graphs.
>
> The last assumption that I\'m going to go through this with is the
> assumption of a clinician, that ultimately, the questions and answers
> here of where this device matters most is in how it is likely to be
> used.
>
> So my first question, actually, to the sponsor is: What is the total
> dose of drug delivered when 9-1/2, or let\'s say 10, stents on an
> average of 12 mm in length are all put into a single human being in a
> live course overseas in front of about 200 interventional
> cardiologists? What is the total dose of drug in that individual?
>
> I think the average we got on pencil and pad was about 15, or
> 10-15-ish.
>
> DR. DONOHOE: About 1,500 micrographs.
>
> DR. KRUCOFF: Okay. And I didn\'t hear anybody use that figure this
> morning. I just think we have to be realistic when we think about this
> as a breakthrough that clearly is going to help literally millions of
> people who suffer from coronary artery disease, that as it gets out
> into real clinical practice, if we have fuzzy edges here, they are
> going to get a lot more fuzzy in clinical practice, and that is the
> spirit that I\'m going to start with looking at the data, with where
> we really have data, and you clearly have data that is solid and real
> and to me provides a starting point.
>
> My ignorance\--can you help me\--in the device design, when you
> actually spray drug, does the drug only adhere to the outer surface,
> or is it also on the interluminal surface of the stent scaffolding.
>
> DR. DONOHOE: The polymer in the drug distribution is both in the
> outside and the inside of the stent, evenly distributed.
>
> DR. KRUCOFF: Okay. And is there any model\--because I couldn\'t find
> any\--as to if it is evenly distributed\--is 50/50 a fair
> assumption\--so about 50 percent of the total drug on a given length
> of stent would be opposed directly against the outer surface, whereas
> the other 50 percent would be what, actually, the bloodstream was
> seeing?
>
> DR. DONOHOE: Yes, I think that\'s correct.
>
> DR. KRUCOFF: Okay. The second question I have around the study itself
> was in the inclusion and exclusion criteria, and Rick, I\'m going to
> ask you or Dr. Potma maybe to help me with what, if any, analyses have
> been done on visual sight readings in the kinds of breakdowns we have
> looked at, as opposed to my assumption, which is everything that I
> could tell in the pack or in your slides today are from the core lab,
> which of course is understandable.
>
> The reason I ask, though, is that the inclusion criteria, length of
> lesion, in this study was from 15 to 30, whereas the average length of
> a lesion coming from the QCA lab was 14.4. So the average lesion
> length is actually below the inclusion criteria overall. And I am
> going to assume, but I would actually like to ask, is that just the
> difference between sight readings, visual readings, and estimates of
> lesion length and the QCA?
>
> DR. POTMA: My name is Jeff Potma. I was the director of the angiograph
> core laboratory for this trial.
>
> My disclosures are that I have no immediate stock equities in the
> company. I do serve on the advisory board, and the compensation of
> that is under the Harvard clinical research guidelines for
> compensation.
>
> That\'s a good question, because we noted from the first time we did
> quantitative analysis that our assessment in the core laboratory is
> quite different than the investigator\'s assessment who is standing at
> the table.
>
> To describe the discrepancy, it requires that we understand that the
> quantitative algorithms begin to call a lesion length when there is a
> 20 percent lumenal narrowing. It is just how both the CAS-2
> \[phonetic\] system and the CMS system that we use begin to do that.
> And it needs to be a consistent drop in the lumen diameter, and that
> continues until the vessel then becomes near 20 percent of what it
> normally is on the distal side.
>
> And specifically, then, we just call the single lesion when it is more
> than 20 percent narrowing.
>
> Now, there is a discrepancy, because in the catheterization
> laboratory, oftentimes, an investigator will choose a stent length
> based on where he or she sees lumenal irregularities within the
> vessel, and oftentimes those lumenal irregularities do not qualify for
> our greater-than-20 percent lumen \[inaudible\] by the angiographic
> core lab. So both with the RAVEL trial as well as with the SIRIUS
> trial, our lesion lengths were shorter.
>
> We used that 20 percent because that provides us the greatest
> reproducibility for repeated measurements. And that is very important
> for us in the core laboratory to make certain that our lesions are
> reproducible. The quantitative algorithms were set up to be
> reproducible, and that is the discrepancy.
>
> To specifically speak to the SIRIUS trial, I reviewed all the
> procedural angiographs myself throughout the beginning course of the
> trial, and whenever there was a clear discrepancy, when there was
> clearly a discrete lesion, I would write back to the investigator and
> say this lesion is too short for this study; please include a longer
> lesion length. And I do believe that that did have some influence on
> our lesion length throughout the course of the trial.
>
> So the answer to your question is there is a discrepancy. It is a
> discrepancy because our quantitative angiographic algorithms aim
> themselves at reproducibility, and the clinicians want to make certain
> they treat all areas of lumenal irregularity within the vessel, which
> is why they are visually seeing a longer lesion length that we are
> measuring in the quantitative core laboratory.
>
> DR. KRUCOFF: All right. And Dr. Potma, while you are there, let me
> just extrapolate, then\--what I think was mentioned during the
> presentations, the difference in diameter of the reference vessels
> between visual and a smaller diameter which came out of the QCA lab
> presumably is also a function of just a quantitative algorithm versus
> a visual estimate.
>
> DR. POTMA: That is correct, and we have looked at that quantitatively
> in a number of different studies, including the new approaches to
> \[inaudible\] ventral registry, which was subsequently published. I
> think that Dr. White\'s discrepancy is about 10 percent difference is
> what we see, about 0.3 millimeters.
>
> So we do feel that the majority of patients fit the inclusion criteria
> of the trial. Our QCA readings typically come out to be 0.3
> millimeters smaller than the visual estimates.
>
> DR. KRUCOFF: Thanks, Jeff.
>
> So, understanding that\--and I think we all understand the difference
> here, that in clinical practice, nobody is going to be sending their
> films to a QCA lab before they pull a stent off the shelf\--I would
> have loved to see some of the breakdowns, since lesion length and
> vessel diameter are clearly important issues of where this stent is
> going to optimally have its impact.
>
> But some of these analyses based on sight estimates, just to see
> whether that actually changes any of the conclusions around where its
> efficacy is or isn\'t in longer lesions/smaller vessels and larger
> vessels/shorter lesions would have been of interest to me just as a
> reflection of what is more likely to happen in clinical practice.
>
> You guys set an inclusion criterion of greater than 15 on the lower
> side. Was there a rationale for not wanting shorter lesions?
>
> DR. KUNTZ: Yes, there was. This study was aimed at showing a benefit
> clinically in restenosis. And as you know from the large amount of
> stent studies that were done in the 1990s, restenosis rates were
> anywhere between 9 or 10 percent\--it depends on the case mix\--to
> about 16 or 17 percent clinically.
>
> So in order to have adequate power with a reasonable sample size to
> demonstrate a benefit, and also to focus on patients who probably
> would benefit the most from a drug-eluting stent, those at highest
> risk, we aimed to try to enrich the population of patients at risk.
>
> The lesion length is everything, because once you start to enroll
> patients with a window to the right of larger lesion length, you also
> include a higher frequency of diabetic patients, and then the two are
> actually synergic in producing a restenosis rate.
>
> So when we do our calculations, we see modest increase in mean lesion
> length, from 10 to 11 mm in the stent studies to approximately 14.5 in
> this study, but that also increases the proportion of diabetics by 50
> to 60 percent. And as you can see, the control rates of restenosis
> went from this study, studies in simple lesions, the stent, the Bx
> velocity of approximately high teens, to 36 percent.
>
> So we actually did meet our goal, which was to get a population that
> was at risk for restenosis so we could have adequate power to
> demonstrate a clinical benefit, and that was the main reason for
> making the window 15 to 30.
>
> We also know that when you tell clinicians to give us 10 to 20 mm,
> they give us about 11; but when we said 15 to 30, we thought they
> would give us hopefully 15, and they gave us 14.5. That was the other
> reason.
>
> DR. KRUCOFF: So was there a rationale, then, in the pursuit of the
> labeling, the actual driver that will bring this to market and
> clinical use, for proposing a labeling that does not stop at a short
> length? I mean, if the rationale is that there is a lower incidence of
> vulnerability in short length\--say you want to design a trial where
> you will be able to demonstrate effectiveness, et cetera, et
> cetera\--why would you propose labeling that includes a shorter length
> where patients do relatively well with standard bare metal stent?
>
> DR. KUNTZ: That\'s an excellent question, and other than the fact that
> we do have a fairly decent subset of individuals who have lesions less
> than 14 mm that can be treated with shorter stents, and the benefit
> was still preserved\--I think I\'ll hand it over to Dennis to answer.
> That\'s a good question.
>
> DR. DONOHOE: I think, actually, the way we viewed it was the lesion
> length data generated in RAVEL combined with SIRIUS, which was
> providing data on a fuller spread of lesion lengths, from shorter to
> longer, and the request for shorter lengths, that is, less than an 18
> mm stent, or specifically, 13 to 18, we assumed that the data
> generated in RAVEL in combination with SIRIUS would be adequate to
> demonstrate that there was still additional therapeutic benefit in
> treating those shorter lesions compared to a bare stent application.
>
> DR. KUNTZ: I think one other thing to keep in mind is that\--and
> again, I\'m not speaking for the sponsor here, but just as a clinician
> looking at the data\--the 8 mm stent may not be intended primarily to
> be a stent to be placed for primary lesions, but it is often a lesion
> to be used to tack up a dissection and so on. So availability of a
> short lesion when using an appropriate long stent\--a short stent, I
> mean\--is actually quite beneficial if you don\'t want to add a lot of
> stent to the times when you need to have a second stent used.
>
> DR. KRUCOFF: I\'m not sure of the availability of a short stent and
> labeling for short lesion are necessarily one and the same, though.
>
> Okay. Again, my understanding of what I saw in the panel pack and what
> was presented today was that we saw essentially an actual treatment
> array of analyses rather than an intention to treat array of analyses,
> that the deregistered patients and the couple of patients who were
> treated with the wrong stent during the course of the trial were
> placed in there.
>
> Is that correct, or is that not correct?
>
> DR. KUNTZ: Let me clarify the deregistered patients, because it seems
> like it is a special case in this trial, but it actually happens in
> every trial.
>
> When you get a random assignment, we try to minimize the distance
> between the random assignment and the actual application of the random
> treatment. In some studies, like bypass surgery, where you have to
> actually set up the surgical treatment\--a bypass, if you are looking
> at a variety of bypass machines, for example\--the final arbitrator of
> the eligibility isn\'t available until the patient actually gets
> operated on, but they have to get the random assignment before to get
> consent and also to have the equipment set up. So oftentimes, you get
> situations where you can\'t actually apply the device because the last
> arbitrator of what you do to get into the trial isn\'t known.
>
> Many times in this study, although we tried to minimize as much as
> possible, there were a few operators who had outside films that
> demonstrated the lesion, and before they brought them into the lab,
> before the patient was dosed with a hypnotic or a sedative to get
> consent, they actually randomized them.
>
> We tried to caution against that in as many cases as we could, but
> often those patients were found not to have lesions and therefore were
> not treated at all.
>
> So most of these patients were not eligible because they didn\'t have
> lesions. That was the majority of them. This was a blinded study, and
> we know the blinding part we think worked very well up front. If there
> was any issue of blinding, it was in the followup part. So it wasn\'t
> surprising to us that this frequency of these registrations is equally
> distributed, because nobody knew, for example, that they were going to
> deregister a patient because they thought they were going to get the
> SIRIUS stent for the control; it was evenly distributed between the
> two arms.
>
> So it was a low frequency. They never got treated, anyway. There was
> no treatment for us to follow in those patients. So this isn\'t the
> classification of clinical trials called \"withdrawal\" where you
> actually shift \[inaudible\] patients who withdraw from the study; it
> is patients who never actually received the treatment at all.
>
> DR. KRUCOFF: Okay, I\'m with you there. I guess what I\'m trying to
> get at\--because there are at least two places in the panel pack where
> this is referred to\--is that we are really not looking at an
> intention-to-treat analysis. Is that wrong?
>
> DR. KUNTZ: We could do the intention-to-treat analysis. The problem is
> that they don\'t have restenosis; they are not eligible to have
> restenosis because they never got treated. Many of these patients
> never got therapy. Some did get treatments per se, but many of them
> didn\'t get treatment at all. They were on the table found not to have
> a lesion.
>
> So in order to understand freedom from repeat revascularization, they
> \[inaudible\] the first one to have the repeat from. If we were to add
> in there followup at some event, at 9 months, we would probably be
> looking at atherosclerosis progression in most of those cases, and
> they would be equal to our non-TVR rates, and we would be adding 4
> percent times 2 percent to both arms.
>
> It is certainly possible to do that, but unfortunately, we didn\'t
> engage the clinical followup in those patients because they never got
> the assigned therapy.
>
> DR. KRUCOFF: Okay. Rick, in the length and diameter and the 16-cell
> breakouts that you shared with us today, is that amongst the
> non-FDA-reviewed data\--whatever\--
>
> DR. KUNTZ: Yes, it is.
>
> DR. KRUCOFF: The paper by Dr. Ho\--and you were in the senior author,
> I think\--in the 1998 Circulation that you started with actually was
> 32 cells, not 16 cells.
>
> DR. KUNTZ: Right.
>
> DR. KRUCOFF: And you had broken them out in 5 mm increments and vessel
> sizes up to 4.0, discretely, presumably because you had the numbers in
> your dataset to make that a sensible thing to do.
>
> As I look at your presentations, though, here, the 16 cells
> essentially ought to have been collapsed as everything 3.0 and greater
> from a diameter point of view; so 3.0, 3.5, 4.0.
>
> DR. KUNTZ: Actually, we broke them into the actual terciles. It was
> actually 2.5 to 3.0, 3.0 to 3.5, and 3.5 and greater. We broke it into
> where the data was \[inaudible\]\--less than 2.5, 2.5 and 3.0, and
> greater than 3.0.
>
> DR. KRUCOFF: Greater than 3.0.
>
> DR. KUNTZ: And those were the actual terciles of the dataset. And we
> did that because in the article by Dr. Ho, we actually had 8,000
> patients to draw upon, and so this had 1,000, and so the 9 cells we
> have times 2\--because \[inaudible\] which is 18\--just made sense
> because we had fewer datapoints.
>
> DR. KRUCOFF: Yes, but\--and again, I think it is simply a factor of
> not having the numbers\--but the areas that clearly we would expect to
> be most illuminating from that kind of breakout would be the areas
> either where bare stents would do best, so you would see at least
> treatment effect just because you don\'t have much of a target to
> reduce, which would be in the larger/shorter lesions, the upper
> lefthand, and I guess in collapsing that into 16 cells as opposed to
> the 32, I am left, really, with a question mark, and I think the
> answer to the question mark is that you probably just don\'t have
> enough numbers.
>
> DR. KUNTZ: Actually, in the initial analysis that you referred to
> earlier, there were three columns and four rows, so we had 12 time 2
> is 24. The only thing we added was we had data of 3.5 to 4.0, and we
> don\'t have those cells in here because the study was intentionally
> 3.5, even though there were a fair amount above that. We actually
> divided them into the terciles. So we \[inaudible\] just one row.
> That\'s the major shift. So there was no collapsing of the lesion
> lengths part.
>
> So they are almost spot-on with respect to the same kinds of results
> in patients that\--and we do see in fact a lot of patients who have
> low risk and a lot of patients who have high risk.
>
> DR. KRUCOFF: So you feel from that breakout that you have enough
> information to feel comfortable that vessels of diameter larger than
> 3.5 mm\--4.0, 4.5, 5.0\--that there is data from this pivotal trial to
> support an indication here?
>
> DR. KUNTZ: I feel comfortable that the data supports the
> recommendation up to 4.0 mm. I think there is very little data above
> 4.0 to 5.0, other than the fact that one would expect this to continue
> above 5.0 is the logical extrapolation, but there is not data to
> support that. It is supported\--we looked at the reference vessel
> diameters in the datasets, and we do have data that goes up to 4.0 mm
> in the graph that I showed.
>
> DR. KRUCOFF: Okay. And again, that\'s all based on QCA measures?
>
> DR. KUNTZ: That\'s correct.
>
> DR. KRUCOFF: You didn\'t share any data with regard to IIbIIIa\'s
> other than from, what I saw, a significant proportion of this
> population was treated with IIbIIIa\'s. Have you looked at interactive
> effects or any sort of small vessel/large vessel, short lesion/long
> lesion\--
>
> DR. KUNTZ: We did extensive analysis of the IIbIIIa inhibitors with
> respect to interactions also to see if there was a main effect of
> restenosis, and so far, we couldn\'t find that there was any effect on
> restenosis with the IIbIIIa inhibitor on acute complications or any
> other interaction. But again, it\'s not really fair for us to make
> those inferences about IIbIIIa inhibitors because they were selected
> by the operators; they were not randomized.
>
> So inasmuch as we can observe based on the individuals, we can\'t see
> that we saw any synergistic effects. Often in studies like this,
> especially those at risk, the IIbIIIa inhibitor subsets come out with
> actually worse rates, but that\'s unfair to the IIbIIIa inhibitors,
> because physicians tend to use those inhibitors for patients they feel
> are at highest risk, so it tends to be highly confounded by the
> perceptions up front.
>
> So I think the most important analysis of a IIbIIIa inhibitor in a
> trial like this is to make sure we don\'t see anything funny happening
> or anything where there might be some negative synergism which we
> didn\'t observe. It is hard for us to make any inference about the
> effect of IIbIIIa inhibitors on the study design.
>
> DR. KRUCOFF: Okay. Thank you.
>
> Can you help me\--in a patient denominator of about 1,000
> patients\--and I am going to just pick out late incomplete apposition
> rate for a second\--so, say 10 percent have late incomplete
> apposition. And let\'s say one of those 10 actually turned into
> ultimately a clinical problem. At what level, from a safety analysis
> standpoint, is the Beta error in a 1,000-patient denominator? Where do
> we start to miss a one percent complication rate?
>
> DR. KUNTZ: Well, I may have somebody else talk about the late
> apposition issues per se, but statistically, I can offer some kind of
> off-the-cuff\--
>
> DR. KRUCOFF: Yes, that\'s really what I\'m asking.
>
> DR. KUNTZ: If we assume that when you manifest an outcome from late
> apposition such as spontaneous dissection, perforation, or symptoms
> leading to angiography discovery, discovery of aneurysm, certainly in
> our almost one year or more followup on these patients, we have not
> seen that yet in a patient, especially those identified in the small
> subset of IVUS or those who we did have an opportunity to do IVUS in.
>
> So, I don\'t have the calculator with me, but you would take PQ over
> N-squared and come up with 9.6, and that gives you the confidence
> analysis for that estimate, and my guess is\--
>
> DR. KRUCOFF: You can\'t do that in your head?
>
> \[Laughter.\]
>
> DR. KUNTZ: \[Inaudible\] but I think that we probably have fairly
> tight confidence that the incidence of this event occurring is
> probably less than half a percent if it is a problem from the
> \[inaudible\].
>
> DR. KRUCOFF: Do you know the average\--
>
> DR. BAILEY: Take 3 over the denominator\--that\'s roughly your upper
> confidence limit? You had no events out of how many malappositions?
>
> DR. KUNTZ: Well, we had 10 percent rate of malappositions, so you
> would take 10 percent times 500 randomized.
>
> DR. BAILEY: So how many malappositions were there\--30?
>
> DR. KUNTZ: It\'s 10 percent of the small subset; it will be
> extrapolated from the whole group\--
>
> DR. BAILEY: How many malappositions were there\--about 30?
>
> DR. DONOHOE: Seven patients with \[inaudible\] apposition.
>
> DR. BAILEY: Seven.
>
> DR. KUNTZ: Seven, but we had a small subset \[inaudible\] ultrasound.
>
> DR. BAILEY: Okay. So your upper confidence would be 3 over
> 7\--actually, it\'s less than that\--probably 2 over 7.
>
> DR. KUNTZ: We had a small sample of approximately 150 patients who had
> \[inaudible\] available. In that, there were 7 assigned to the
> \[inaudible\] for Sirolimus, and that calculated out to a 10 percent
> rate \[inaudible\]. So \[inaudible\] late apposition was 10 percent in
> the sample. Presumably \[inaudible\], then, that would be 10 percent
> of 500 patients. But we would expect that 50 patients would possibly
> have a late apposition, okay?
>
> DR. BAILEY: Okay. Maybe I missed the point, but I think the question
> was what evidence do you have that late apposition is benign.
>
> DR. KRUCOFF: Let me\--because I was actually asking the statistical
> question for a purpose, not to pick on late apposition in discussion
> at this point. What I\'m really thinking about is if these stents are
> placed in one million human beings per year, and we are making this
> decision on safety data based from a 1,000-patient study, which is
> normal at one level, on the other hand, this really is a breakthrough
> technology. So what I am really asking is if we missed a one percent
> or a one-in-1,000 complication of any sort, where is the cutoff? Where
> is the beta error level for a 1,000-patient denominator?
>
> DR. KUNTZ: And my answer to that is that if we assume that a clinical
> manifestation of that late apposition is something like an aneurysm or
> something that leads to discovery of a dissection, which we didn\'t
> observe, then, what we observed was zero out of potentially 50 cases
> that would have had that rate.
>
> So given a late apposition, the confidence interval will be 2 percent
> plus or minus some variable, and that would be PQ over N, whatever
> that is, probably plus or minus two or three percentage points, for
> patients who have late appositions.
>
> For any patient treated, it would be the estimate of zero over 500
> patients. So it all depends on whether we classify them as having the
> arbitrary finding at IVUS of late apposition versus any patient who
> gets treated.
>
> So in all cases, the lack of any significant consequence obviously is
> good, but if we want to be precise and say that we had confidence that
> there was less than a one percent rate of individuals who would be
> identified to have late apposition, we don\'t have that power.
>
> DR. KRUCOFF: Okay. Because obviously, one of the questions that we are
> going to address for the FDA questions is what is enough surveillance
> of the population who have already been implanted. So we\'ll have to
> come back to that at some level.
>
> Do you have the average number of stents placed per patient in the
> SIRIUS population.
>
> DR. DONOHOE: There were on average 1.4 stents placed per patient.
>
> DR. KRUCOFF: So, 1.4\--and that\'s just about what CSM averaged when
> they created a reimbursement code for this. So this should be a
> reasonable representation, ultimately going forward, if clinical
> practice and the reimbursement projections are anywhere close to one
> another\--which they probably won\'t be. Okay.
>
> Let me just shift into the last array. I found myself at the end of
> all of this\--and if we need somebody from Wyeth, maybe we could ask
> them to come up to the table\--but one of the things that I was
> impressed by\--and whether it is because half of the drug is opposed
> directly to the outer component of the stent and really doesn\'t get
> into the bloodstream\--is the low blood levels that are associated
> with this entity. But I found myself wondering about allergy rather
> than other types of toxicities. And as I went through the Rapamune
> data, for instance, in what was reported in patients who are all on
> steroids and transplant scenarios was about a 5 percent incidence of
> skin rash determined to be allergic.
>
> So I have two questions. One is whether this is understood to be an
> idiosyncratic or a dose-related type of skin rash, or whether
> allergies to the drug in general have been appreciated to be
> idiosyncratic or dose-related. That\'s one question. And the second
> question is going to be did you observe any allergic reactions?
>
> DR. SCEROLA: Joe Scelora \[phonetic\] from Wyeth.
>
> We consistently observed a higher rate of a nonspecific rash in
> patients treated with Sirolimus, which generally disappears despite
> them continuing on the drug. So we don\'t think it is truly an
> allergic reaction; we think it is some other adverse effect.
>
> In our clinical trials, we actually saw a few clearly-documented cases
> of hypersensitivity reactions\--in part, as you noted, these patients
> are also on steroids, cyclosporin, for the approved indications.
>
> In our post-marketing reports from the field, which frequently come
> not well-documented, there have been some other cases of reported
> allergic events with the drug, but we don\'t have enough data to say
> that it is dose-related, and we don\'t really have enough data to say
> that there is truly an idiosyncratic reaction to it.
>
> DR. KRUCOFF: Okay. And the second question was in the SIRIUS cohort
> who received drug stent, and combining from First-in-Man through
> RAVEL, have you all encountered an allergic reaction?
>
> DR. DONOHOE: We have looked at that specifically, and actually\--there
> is a slide that we will put up shortly\--we have looked at the
> incidence of allergic reaction. That assessment was based on the
> investigators\' assessment that there was an allergic reaction.
>
> \[Slide.\]
>
> As you\'ll see in this slide, this is the total reported number of
> allergic reactions within the first 30-day period following the index
> procedure, and you\'ll see in terms of the absolute number of patients
> it is almost equal in both treatment groups. And we have also broken
> out or identified factors that seemed to be contributing to the
> allergy.
>
> The medication line, which accounts for most of them, was either
> medication given during the intervention procedure, and the bulk of
> those outside the procedure was actually the antiplatelet therapy.
>
> DR. KRUCOFF: Okay. In some of the animal reports and followup, there
> was a description of a possible delumenation local calcification. I
> have heard none of that observed either, or seen any of that observed
> in the IVUS population in humans at 9 months. Have you all come across
> any sort of calcification or other unusual observations?
>
> Peter?
>
> DR. FITZGERALD: My name is Peter Fitzgerald. I am an interventionalist
> at Stanford. I run the core cardiovascular analysis laboratory there.
> I have by way of disclosure no financial interest in Johnson and
> Johnson. I am a participant in the core lab facilities and am under
> the guidelines of Stanford\'s conflict of interest regulatory bylaws.
>
> With respect to the IVUS and being able to look at patients who have
> had these implants both in the bare metal population and the
> drug-eluting population, we have seen no change in placque
> composition. For example, that would be fibrous placque turning into
> calcific placque, either behind the stent struts, where potentially
> the highest dose can be delivered to the endovasculature, or at the
> edges, the proximal or distal reference segments.
>
> As far as the delumenation issue, that is a tricky one to be able to
> assess by intravascular ultrasound. The axial resolution of a typical
> 30- or 40-megahertz intravascular ultrasound catheter is on the order
> of 150 microns, which well exceeds the average thickness of the
> combination of the polymer and drug.
>
> DR. KRUCOFF: So, Peter, would it be fair to say that\--and
> understanding the animal models have different time frames\--but
> roughly in a time frame in the human that would probably at least
> incorporate the time frame of these observations in an animal, you
> haven\'t seen any unusual evidence of calcification or change in
> composition of the lesions?
>
> DR. FITZGERALD: Not at all, not only in this study but several other
> approaches both inside and outside the United States.
>
> DR. KRUCOFF: Okay, thanks.
>
> A question for one of your interventional experts, I guess\--it\'s
> speculation, but again, it\'s my interest, and I think we may touch
> back on part of this.
>
> For the small percentage of patients who get drug-coated stents who do
> have instant restenosis, what would the next line of treatment be?
>
> DR. MOSES: I am Jeffrey Moses, and I\'m an interventional cardiologist
> in New York. I do some consulting work for Cordis, and they did pay
> for my trip here, and I have some stock in my retirement fund.
>
> I think one thing to understanding is the nature of restenosis; even
> though we categorize them similarly, it is a totally different animal
> in the failure mode here. It is predominantly marginal, and it is
> almost exclusively focal. Diffuse stent restenosis is a very, very
> rare event with us.
>
> So if it is marginal, it will probably be treated with another stent,
> probably another drug-eluting stent. I think the diffuse, if we do
> encounter it, we\'ll treat conservatively with standard techniques.
>
> DR. KRUCOFF: Brachytherapy?
>
> DR. MOSES: At this point, I don\'t think we have any evidence to
> assume that brachytherapy has any either safety or efficacy given the
> fact that we have already manipulated the molecular environment in
> that vessel. And personally, I would not recommend it at this time,
> until we have further evidence.
>
> DR. KRUCOFF: Would you caution against it?
>
> DR. MOSES: Until we have evidence, I would not recommend it.
>
> DR. KRUCOFF: Okay. Well, that actually brings me to my last question,
> which is why, in Section 3.2 of this panel pack under \"Patient
> Labeling,\" you have a long discussion about the checkmate system.
>
> DR. DONOHOE: I think that\'s actually a packet to the patient, just
> explaining what the options are in general for treatment. It\'s
> consumer labeling.
>
> DR. KRUCOFF: Right after \"What Happens After Your Angioplasty or
> Stent.\"
>
> DR. DONOHOE: Yes. That\'s entitled, \"A Guide for Patients.\"
>
> DR. KRUCOFF: This is the patient guide; right?
>
> DR. DONOHOE: Right.
>
> DR. KRUCOFF: Where you start this whole thing about checkmate. So is
> this actually entitled just as a general, all-purpose\--
>
> DR. DONOHOE: That summary\--actually, I don\'t think it makes a
> statement about recommending brachytherapy after a Sirolimus-eluting
> stent takes place. I think it is purely reviewing all the potential
> options the patient could have for treating restenosis or treating
> stenosis.
>
> DR. KRUCOFF: Okay, thank you.
>
> DR. LASKEY: Dr. White, please.
>
> DR. WHITE: Thank you, Dr. Laskey.
>
> I will be brief only because I think Mitch did such a good job of
> covering the waterfront, and I have only a few specific things that
> are more information, I think, than criticism, because I also believe
> that this is, as an interventionalist, something that I think we have
> all been waiting for.
>
> One of the issues I have for you is that your recommendations again
> don\'t correlate so closely with the data that you provided, so I
> would like to just probe a little bit at the edges of the dosimetry.
>
> Rick, the table you showed this morning of the proposed
> Sirolimus-eluting matrix and drug content, where you had on the Y-axis
> the stent diameters going from small to big, and on the Y-axis, you
> have the length of the stents and the proposed dosages that would be
> administered\--it is on page 3 of the slides that you handed out at
> the bottom right-hand corner.
>
> DR. DONOHOE: Are you talking about the drug matrix slide?
>
> DR. WHITE: \"Proposed Sirolimus-Eluting Matrix and Drug Content.\"
>
> DR. DONOHOE: Yes.
>
> DR. WHITE: The only reason I want you to look at that is do you have
> evidence of efficacy for an 8 mm stent at\--obviously, you don\'t at
> 2.25\--but do you have any comfortability that if I put an 8 mm stent
> in somebody, a 2.25-by-8 mm stent, that that level of drug at 71
> micrograms would be an effective dose level? What supports that
> theory?
>
> DR. KUNTZ: If we\--a lot of\--let me just make a couple of opening
> statements, because there are a lot of issues raised about the
> modeling of this data.
>
> The parameters for this study were 15 to 30 millimeters in general,
> and we know \[inaudible\] go outside those boundaries typically in
> many trials; and also, 2.5 to 3.5, we know that they stretch out a bit
> a as well. That\'s typical. For any randomized trial, we define the
> reference population, and we do a randomized trial and see who wins.
>
> Then, our inference about the final overall results are made to the
> reference population that we aimed at \[inaudible\] criteria. That is
> typical for a randomized trial.
>
> In trying to figure out where in that sample zone we aimed at we may
> or may not have strengths or weaknesses, we probe, and the logical way
> to probe is to take dimensions that actually affect the outcome, like
> lesion length and vessel size and so on.
>
> So that is why we do this modeling. And if you actually take the raw
> data and look at them like we did, you have random chances to move
> around, so you try to fit a smooth relationship assuming that in
> biology, the effects are monotonic\--that is, they are usually
> first-order relationships. That is what most biological systems have;
> that is why fit main effect models.
>
> So the traditional main effect model that we fit here that produced
> these matrices is based on just conventional analysis of predictors,
> and when we do that, we see that that cell of the short lesion still
> has about a 70 percent treatment effect, but the risk of that group,
> that zone, is actually small to begin with.
>
> So our model suggests that the linearity of the relationship of the
> predictor and some patients we have in that zone, by looking at the
> actual raw estimates, are consistent with treatment effect extending
> to small and short lesions. But that is in a zone where the patients
> may not have that much risk to begin with\--but it is still a profound
> 60 or 70 percent treatment effect.
>
> DR. WHITE: I guess what I\'m asking is\--is there data that you have
> efficacy at that dose level?
>
> DR. KUNTZ: Well, the question is\--
>
> DR. WHITE: I understand the model and the\--that\'s good\--but could
> somebody get an 8 mm, 2.5 stent that\--
>
> DR. KUNTZ: The problem is that when you look at small subsets, what do
> you mean when you say is there data? Do you want significant
> difference, or do you want just the estimate to be consistent with
> what the overall main effect is\--because again, we are looking at
> endpoints. The overall study is the only one\--the overall sample size
> is used to power one single comparison. So when we get to the areas
> that have fewer patients representative, usually, what you want to do
> is show that the estimates are still consistent in the same zone, and
> we do have data for that. They are consistent. But to actually ask if
> that small sliver of data provides P values of 0.05 or less\--it\'s in
> a very unpowered zone.
>
> DR. WHITE: And then, you would make the same argument at the upper
> end, where you get above the sizes that were actually tested to 4.5
> and 5.0 mm stents?
>
> DR. KUNTZ: Yes, and I think the notion is that we know that in
> general\--and again, this gets to\--and I don\'t want to bore you with
> the modeling part\--but it gets to the point of understanding what it
> means to look at risk. And most risks in general for biological
> systems in clinical trials are linear, that is, when you look at the
> data that moves up and down, as our estimates did in the graphs that I
> showed you, usually, that\'s because that is an underlying linear
> effect. So when you fit the model to show that the slope is different
> at zero, you are suggesting that there is a relationship between this
> covariate and the outcome. When we look at those data, the separations
> tend to be very consistent across those zones.
>
> You can also use curvilinear models to fit them, but the curvilinear
> models have the problem that they might be more dependent on the
> formula that draws the curve rather than the data that fits it. So
> there are always controversies about which one to use, and we tend to
> try to use the linear models whenever we can, unless we can
> demonstrate that the fit or the quadratic and cubic terms have
> significance to actually displace a common sense linear model, and we
> didn\'t see that. So in our models, what we saw was that the
> relationships across these zones, especially from around 2.5 to 4.0,
> had the same level of separation in general if we look at consistent
> findings that have fit pretty well. And when we tested to see if that
> was something that was just a model relationship, we actually looked
> at the raw data, and we saw these points, from 2.5 up to 4.0 mm, for
> example, still showed relatively low separation as the actual
> individual estimates as well, which is consistent with the data being
> consistent with the overall treatment effect.
>
> That\'s the best way for us to actually make those statements. To get
> any more specific about saying is there really good evidence to show
> that we can expect a consistent statistical difference in a patient
> with really short lesions, we don\'t have the solid independent data,
> because the study would have to be focused on those per se. But is the
> data consistent with those groups of patients having benefit\--yes, it
> is.
>
> DR. WHITE: Do you have reason to suspect that endothelization of these
> stents is affected by this drug? Is it delayed over what you would
> expect for a bare metal stent?
>
> DR. DONOHOE: No. The preclinical data we have indicates that
> re-endothelization is already taking pace by the 14-day assessment and
> is near complete and is complete by a 30-day period of time. So the
> preclinical model suggests that there is no delay in
> re-endothelization, and on a clinical basis, just looking at the
> thrombosis rates that we see in both acute and late, there is no
> suggestion that we are affecting significantly delaying or altering
> the endothelial function.
>
> DR. WHITE: Why did you use a prolonged dose of Plivex or Tyflid
> \[phonetic\] in these patients?
>
> DR. DONOHOE: We actually conducted all studies outside the U.S. using
> 2 months of antiplatelet therapy, and the first studies were conducted
> in First-in-Man or RAVEL. We picked 2 months because the animal data,
> preclinical data, suggested that one month was a sufficient term for
> re-endothelization. Given that we had no clinical data, we opted to
> add an extra month just as a caution. When we\--
>
> DR. WHITE: Because you were fearful about endothelialization being
> delayed, or\--
>
> DR. DONOHOE: No, no. It was just given that we had no clinical data to
> that point, we had no data to say that 2 months was required, but we
> felt that providing an extra month was just an extra margin of safety
> for patients at that point.
>
> DR. WHITE: And SIRIUS went up to 3 months; right?
>
> DR. DONOHOE: SIRIUS was 3 months, yes.
>
> DR. WHITE: Why did you add the month when you didn\'t see any down
> side\--
>
> DR. DONOHOE: That was just\--in discussions with the FDA, there was
> interest in how much data we really had at that time point, and we
> started the SIRIUS trial not only addressing the acute thrombosis
> rates, or SAT rates, but also late thromboses, and we did have a good
> amount of clinical data from RAVEL indicating that they were not
> seeing a problem, but again, as a matter of just increasing the
> margin, we agreed with the FDA that we would add another month of
> antiplatelet therapy to a total of 3 in the SIRIUS trial.
>
> But we had no preclinical data to say that that was necessary. In
> fact, in the clinical data generated, there is almost an equal amount
> outside the U.S. that again suggests that 2 months also provides
> equivalent protection from thrombosis as is seen with bare stents.
>
> DR. WHITE: You are going to recommend 3 months in the U.S.; will that
> be the packet\--
>
> DR. DONOHOE: The packet right now purely summarizes the clinical data
> from the two studies, RAVEL and SIRIUS. I think one of the questions
> posed to the panel is what their feeling is about specifically
> recommending 2 or 3 months or a defined period.
>
> DR. WHITE: Is there any reason to think that this stent will behave
> any differently for MRI safety?
>
> DR. DONOHOE: No.
>
> DR. WHITE: I mean, it should be the same as any metal stent; is that
> right?
>
> DR. DONOHOE: Yes, that\'s right.
>
> DR. WHITE: I would like to ask again about brachytherapy, because I
> think it\'s going to be a big deal. Do you have any reason from the
> company standpoint to be concerned about the application of
> brachytherapy in stent restenosis?
>
> DR. DONOHOE: Well, within the SIRIUS trial, we have limited experience
> with brachytherapy of Sirolimus patients who have had restenosis. In
> fact, there were 7, and the average followup period has been 5 months,
> the longest has been 10, and none of the 7 patients have had any MACE
> events or adverse events over that followup period.
>
> We also know that the dose given during brachytherapy is far lower
> than the dose required to chemically alter the polymer if you were to
> deliver a dose of radiation to the stent. So it appears from a
> theoretical standpoint that the dose from brachytherapy is not nearly
> high enough to actually alter the polymer itself.
>
> So I don\'t specifically see from a company standpoint that we have
> any data that cautions the use of it. I would say that we don\'t have
> any data demonstrating the followup performance when there is failure
> following the Sirolimus-eluting stent, and we have very limited safety
> data at this point.
>
> DR. WHITE: How long is the Sirolimus detectable in the vessel? What is
> the longest\--I mean, is it all gone by 3 months? Is it all gone by 6
> months? Is it there for 3 years?
>
> DR. DONOHOE: For the slow-release, essentially 90, 95 percent of it is
> delivered over about a 6-week period of time.
>
> DR. WHITE: So there may not be very much drug at all at 6 months?
>
> DR. DONOHOE: No.
>
> DR. WHITE: And the matrix that it is in, the polymer, is that also\--
>
> DR. DONOHOE: The polymer itself is a nonavertable polymer, so the
> polymer stays on the stent over the full length of time that the stent
> is in place.
>
> DR. WHITE: The only last thing I would say\--and Jeff, maybe you can
> talk about this\--but is there any reason to think that physicians in
> clinical practice will be have any differently in their selection of
> lesions than your investigators did? I mean, you had 50 sites, so you
> had a pretty broad population of investigators.
>
> We all know that we eyeball lesions differently than the QCA labs
> measure them, so I am concerned about the labeling issue\--I want to
> label it the same way your investigators chose the lesions so that we
> get the same result. I don\'t want to label it according to the way
> the QCA lab measured the lesions.
>
> DR. POTMA: I absolutely agree with you that you want to make certain
> that there is concordance.
>
> I do think, to answer your first question about the lesion length,
> that between RAVEL and SIRIUS, we have indications for a full broad
> length of lesion lengths\--
>
> DR. WHITE: How far down did RAVEL go? They just had to be covered by
> 18, so\--
>
> DR. POTMA: By 18, so the average lesion length was 9, so the 50
> percent\--some of them were short. Now, I don\'t think that that
> necessarily in clinical practice means that you are going to treat a 5
> mm lesion with a 8 mm stent, because I think your minimal effective
> dose was very, very effective, and I personally would be looking upon
> the 8 mm stent in the armamentarium to be the added conduit that I
> need when I am just a little bit too short with an 18, rather than add
> in another 18 mm stent, to have a shorter lesion for that period.
>
> DR. WHITE: Would you be concerned that the 8 mm stent would do what
> you wanted it to do as a drug-eluting stent? Would you use a 12 or a
> 13 to make sure you got enough drug into\--
>
> DR. POTMA: For a short lesion, yes, I do think so, because we didn\'t
> go into much of the lessons learned from SIRIUS, but I do think, as
> Dr. Moses has indicated, that the restenosis when it did occur
> occurred at the edges, at an area where we don\'t think there was
> effective drug given to the vessel wall. And the one lesson that I
> think we might learn from the SIRIUS trial is we want to use a little
> bit longer stent-to-lesion-length ratio than we did in the SIRIUS
> trial, which was a 1.4 stent-to-lesion-length ratio,
> 1.6-stent-to-lesion-length ratio, compared to 2.2, which was the
> lesion length for RAVEL.
>
> So the practical thing for the clinician is that they are going to use
> a longer stent for a 5 mm lesion. They are not going to use an 8 mm
> stent; they are going to go a little bit longer than that. And as Dr.
> Kuntz demonstrated in his presentation earlier today, we don\'t lose
> as much by putting longer stents in when it elutes Sirolimus into the
> vessel wall.
>
> So the first question is, yes, we are going to be treating discrete
> lesions, but I do think there is a benefit\--there was in RAVEL; and
> secondly, we are going to be stenting a little bit longer
> stent-to-lesion-length ratio than we would in our clinical practice.
> And I personally would look at the 8 mm as the added armamentarium
> that I need to use an 18, and not because I\'m going to use the 8 to
> treat a 5 mm lesion, because I wouldn\'t do that.
>
> Now, with respect to vessel size, we also went down to very low vessel
> sizes in SIRIUS\--that was absolutely the case\--and I think those
> were 2.5 mm stents in most cases. I think that we will learn more
> about our comfort with small vessel stenting. I do personally believe
> that a 2.25 mm stent is the appropriate stent for a 2.25 mm
> vessel\--not a 2.5 mm stent\--and I think much of the relationships
> that we saw with a higher restenosis rate, particularly at the
> \[inaudible\] restenosis rates in smaller vessels, relates to the fact
> that we didn\'t stent enough for the vessel itself, and I think a
> longer stent is going to be very useful in that circumstance.
>
> DR. WHITE: But what do you think the QCA length is going to be for the
> 2.25 mm stents?
>
> DR. POTMA: Do you mean to vessel diameter?
>
> DR. WHITE: Yes.
>
> DR. POTMA: It will be sub-2. But most clinicians\--we get to follow
> every clinician in this country and how they do, and it turns out
> their balloon-to-artery ratios are pretty much 1.1-to-1.0, so what
> balloons they are selecting pretty much matches to what vessel size we
> are measuring. So they are not really doing such a bad job as the
> estimations go.
>
> But there will be a little bit of a frame shift. We will call smaller
> vessels in our clinical trials than clinicians will use, but
> nevertheless I still think we have to have smaller stents to match
> this in the smaller vessel sizes themselves.
>
> DR. WHITE: The question for us, though, is do we take modeling on sort
> of faith, without actually having experimental data to look at the
> results of that 2.25 stent. I mean, where do you come down on that?
>
> DR. POTMA: Yes. I think the issue is not the stent size itself. It is
> very important\--I think we all know the fundamental principle\--we
> want to match the stent size to the vessel size. Do we believe that
> this is useful in smaller vessels? Absolutely. We believe that this
> therapy of a drug-eluting stent works in smaller vessels.
>
> What we want to do as clinicians is to appropriately match the stent
> size that we take to the vessel size, so we don\'t get a margin
> dissection, so we don\'t get a perforation. So we don\'t want to leave
> us as clinicians to systematically oversize the stent to treat the
> smaller vessels.
>
> I think we have plenty of data in our clinical trials to say that this
> works in small vessels. What we want to do is pick the right stent for
> the vessel size. That\'s the way I look at it.
>
> DR. WHITE: That\'s it. Thank you very much.
>
> DR. LASKEY: Jeff, just a variation\--is there geographic miss in this
> study? Is that what I hear?
>
> DR. POTMA: The question is was there geographic miss in this study.
> And then, I would have to say: Define geographic miss. It is very
> difficult. This is a very subtle concept.
>
> We have looked very carefully at the pre- and post-dilatation
> balloons, and we have asked did we cause vessel injury at the margins
> themselves that were attributable to the pre- and post-dilatation
> balloon, and we have not been able to find a consistent relationship.
> That is some data that we will present at the HA.
>
> However, the real question that we have is even though there is
> efficacy at the edges, we have to ask why is the restenosis rate a
> little bit higher at the edges, and I think there are a couple of
> different reasons for that, potentially.
>
> One is that we are not truly stenting normal-to-normal. I have already
> mentioned the stent-to-lesion-length ratio that was different in RAVEL
> than it was in SIRIUS. I think that had we put longer stents in
> systematically, we would have gotten away from some of that edge
> phenomenon.
>
> The second thing is that we also did not conceptually protect against
> balloon injury at the margins both with the deployment initially of
> the stent and also some issues about going to very, very high
> pressure\--deploying at one pressure, pulling back a little bit, and
> then going to high pressure. And we didn\'t perhaps protect the
> margins as well as we should have.
>
> I think the lesson for all of that is that we want to make certain
> that everywhere that we injure an atherosclerotic vessel\--it may be
> different from a normal vessel\--but everywhere that we injure and
> atherosclerotic vessel, we want to make sure that we have adequate
> coverage with the drug-eluting stent. I think that\'s the lesson that
> we have learned about geographic miss.
>
> DR. LASKEY: Let me make a bold move here and try to get one more
> panelist in before the break.
>
> Dr. Edmunds?
>
> DR. EDMUNDS: I\'m a surgeon, so you\'ll have to forgive me for a
> rather simple approach. But I look at this as a topical agent
> administered to the inside of a coronary vessel where the
> concentration per unit area is constant, and I really don\'t see all
> of these issues when the safety factor as I read the data is 17. The
> 17 comes from the concentration in nanograms per ml from the 5 mg dose
> that you use for kidney immunosuppression and the peak 1 nanomotor
> lasting less than an hour that you have observed with this stent at
> the fast-release\--or, I guess that was the slow-release\--reaction.
>
> Is that a bad interpretation of what is going on here?
>
> DR. DONOHOE: I think that\'s exactly right, Dr. Edmunds. In this
> device, based on the questions asked about whether an 8 mm or an 18 mm
> stent still works, the main issue here is that we are keeping the dose
> per square centimeter\--that is, the dose-to-tissue we are seeing per
> square centimeter\--constant no matter what diameter or length stent
> is being used. And it is, as you indicated, compared to the systemic
> doses with Rapamune, significantly lower, and the tissue that is in
> direct contact with the drug or the drug-eluting stent is the tissue
> that is seeing the highest exposure to the drug.
>
> DR. EDMUNDS: Two more quick questions\--one is quick because they
> probably won\'t have the answer. Can you show me that restenosis curve
> beyond 270 days? Kaplan-Meyer curves don\'t have an end until the last
> of the oldest patient is accounted for. You have cut it off and would
> like to see the patients at risk. Do you have that data here?
>
> DR. DONOHOE: We do not, no.
>
> DR. EDMUNDS: Okay. That was quick.
>
> \[Laughter.\]
>
> DR. EDMUNDS: And you pushed out my last question.
>
> DR. ZUCKERMAN: Maybe I could make a comment, then.
>
> Dr. Foy, could you comment on why we don\'t have data past 9 months
> for the SIRIUS study?
>
> DR. FOY: Per our regulations, when we send a filing letter to a
> sponsor, we are supposed to receive a 3-month clinical summary. We
> requested this information, and I believe David Kornhauser
> \[phonetic\] said that they had to cut their study of in August, so we
> would not be receiving a clinical summary with the 3-month update,
> which would indicate SIRIUS trial patients.
>
> So we would actually like to see additional followup on those
> patients.
>
> DR. EDMUNDS: I have had a quick recovery. The malapposition problem
> which you have seen in the Sirolimus group, do you see that as a
> likelihood to produce a dissection down the line of that coronary
> artery, and if a dissection would occur, do you think the stent could
> keep it from compromising the lumen, the true lumen?
>
> DR. FITZGERALD: Peter Fitzgerald from Stanford again.
>
> I think you bring up an interesting issue given that we have observed
> the stent struts that over time have detached themselves from the
> vessel walls. This is no a new occurrence with respect to drug-eluting
> platforms. It is an occurrence that we have seen with stenting in
> general. And we don\'t have that observation followed up long enough
> to be able to indicate what its rate of, say, generating aneurysms is,
> what its rate of thrombosis is.
>
> One of the issues that I do feel comfortable with as an
> interventionalist is the ability for the stent to actually keep a
> dissection or some physical interruption in the vessel wall from
> migrating simply because the stent is encased in the vessel wall and
> providing some integrity and some strength to that vessel.
>
> So if you have this incomplete apposition that was described in just
> bare metal recently in circulation at about 4 to 5 percent, it is on
> the proximal portion of that stent, so it doesn\'t really have the
> opportunity if it does create a dissection long term to go anywhere,
> because you have essentially a stent that is keeping that vessel
> somewhat more rigid, if you will.
>
> So at least from a heuristic argument, I feel comfortable, although we
> don\'t have any support from data, but we certainly know in acute
> dissections when we stent them, we collapse the ability of that stent
> to migrate down the vessel.
>
> DR. LASKEY: Peter, are you implying that you actually physically
> locate these malappositions more proximally in the stent than more
> distally?
>
> DR. FITZGERALD: Right. In fact, the article that was presented just
> recently in Circulation, the vast majority are in the proximal area,
> and you have to wonder about why that may be. The vessels proximally
> are more tapered; they have an operated to not be quite opposed to the
> vessel well on baseline and then maybe have an opportunity long-term
> to have that small gap be observed, if we are looking for those.
>
> DR. EDMUNDS: Well, sine we are all speculating, my concern would be
> that at the junction of the distal stent with the native vessel that
> you would create a dissection of the distal native vessel because of
> the stent presence. But it\'s all conjecture.
>
> DR. FITZGERALD: Sure. But that may be different from this phenomenon
> that we are seeing over time of late incomplete apposition. I think
> you are absolutely right\--any time you intubate metal into maybe
> unrecognized distal reference segment, whether it be a drug-eluting
> platform or whether it be a metal platform, it is that transition
> between metal and plaque that may certainly generate an edge tear. You
> bet. We have seen that clinically.
>
> DR. LASKEY: Let\'s adjourn for 15 minutes, and let us please return at
> 4:15.
>
> \[Short break.\]
>
> DR. LASKEY: We have miles to go before we sleep. Thank you all very
> much. We are getting near that very special hour where everybody has
> to go somewhere, so let\'s adhere to the schedule.
>
> If we can pick up with panel inquiries, Dr. Cantilena, please.
>
> DR. CANTILENA: Thank you, Mr. Chairman.
>
> I was wondering if I could actually ask a question to Dr.
> Throckmorton. Is that allowed?
>
> DR. LASKEY: Anything is allowed at this hour. Go ahead.
>
> \[Laughter.\]
>
> DR. CANTILENA: Be careful what you say; you may get some unusual
> requests.
>
> Anyway, actually, Dr. Throckmorton, if you could help with some of the
> numbers we were running regarding possible concentrations in blood in
> terms of the question of systemic exposure. If you look at the number
> for the highest dose\--and I guess we have heard that that would be
> 1,500 micrograms, I believe\--and if you look at that in the setting
> of expected plasma concentrations over perhaps 4 to 6 weeks, and
> let\'s put it in the setting of inhibition of CYP3A4 so that you
> get\--and I guess the number for cuticonazole would be something like
> 10 or 11-fold increase in area under the curve\--the question is does
> that get you into the situation where you would have overlap between
> systemic exposure from the stent and that which you would expect from
> low-dose exposure to Rapamune?
>
> DR. THROCKMORTON: I am Throckmorton from CEDR.
>
> I\'m quite certain I would not be able to answer that question with
> any certainty. I imagine Wyeth-Ayerst could comment on that if they
> had that available. My sense is that you could probably find a
> situation where you might get close, at least in the initial
> placement. I don\'t know what the consequences of that would be; that
> is, I don\'t know what the dose response would be for some of the
> effects of Rapamune that people talked about this morning\--the
> hypertrachlus \[phonetic\] edema and things like that. You made that
> point. It seemed an excellent one. It seemed like something that we
> need to talk with the sponsor a bit more about.
>
> The doses do decline over time with this, and the sponsors presented
> some information about the in vivo release in humans, and again, that
> might or might not address your concern. The sponsor might be able to
> common on the upper dose limits and say the addition of cuticonazole
> or cuticonazole and a statin. But I know of no data exactly on that
> point from the available submission here.
>
> DR. CANTILENA: Okay, but I guess the point is that if you were to
> extrapolate directly from the oral exposure using the concentrations
> that are given to us in the pharmacokinetic study by the sponsor, and
> then, I guess if you assume that it is a linear system and throw in
> the inhibition, isn\'t there a whole subset of CYP3A inhibitors that
> could get you into a situation where you would have overlap with
> systemic exposure that you would see from the low-dose Rapamune?
>
> DR. ZIMMERMAN: Jim Zimmerman from Wyeth.
>
> The answer to that is no. But let me recap this now. With a 1,500
> microgram dose, we can project a peak of 6 nanograms per ml. But
> again, that peak is only one hour or two hours. And by 72 hours, that
> concentration decreases 40 percent.
>
> You have to remember\--I think we have to get a fix on this\--the
> target levels for Rapamune are steadystate levels; they don\'t change,
> other than inter-subject and for subject variability. However, the
> stent is a moving target. It constantly changes. Although it looks
> like it is at a steady state down a terminal lesion, it is not; it is
> constantly decreasing. And as we heard, it would take
> approximately\--well, it would take, I guess, about six or seven
> half-lives to get rid of the drug entirely. And if you make some
> estimates on that in terms of how much is measurable, for example, at
> 72 hours, you would be down to 3.6 nanograms per milliliter; another
> half-life, down to 1.8, down to .45. And if I count this, at about
> five half-lives, you can no longer measure the drug.
>
> DR. CANTILENA: Now, if I could actually refer you to Dr. Hyde\'s
> summary on page 19 of his summary\--and I guess it is Tab 4\--he gives
> the confidence intervals\--I believe they are confidence intervals;
> the percentile range with the lower limit for trough of 4.5 nanograms
> per ml on an oral dose of 2 mg per day. So my calculation was also 6
> nanograms per ml, but I thought that this would fall between the
> ranges that Dr. Hyde has given. And again, these are averages, and I
> would just caution the committee that any drug that is cleared by
> CYP3A4 has across the population, the healthy population, a
> variability of between 5- and 10-fold in terms of area under the curve
> just because of the expression of that enzyme.
>
> So if these are averages, then, can get to 6 just with inhibition, so
> if someone comes in for the procedure for the stent, and they happen
> to be on an inhibitor of CYP3A, I think you can probably see
> concentrations that at least overlap according to the calculations
> that Dr. Hyde has done. I was just asking for confirmation of that,
> but I can understand what you are saying, that the excursion into the
> overlap region would be transient is what you are saying, but the way
> my numbers and calculations work out, there does appear to be overlap.
>
> DR. ZIMMERMAN: Well, this momentary overlap is not a problem. I think
> it is more important to see what is the clinical significance of that
> peak.
>
> Could I see Transparency 17, and then we\'ll also look at 18.
>
> \[Slide.\]
>
> DR. ZIMMERMAN: This is 17. This was one of our first single-dose
> studies. We had doses up to approximately 68 mg if you look at a
> 2-meter individual, and the peaks are well over 100 into probably
> around 200 nanograms per ml. We did not observe any toxicity with
> peaks; in fact, we can give very large doses of Sirolimus without
> toxicity\--single doses. That is essentially what a stent is, a single
> dose.
>
> Can I see Number 18?
>
> \[Slide.\]
>
> DR. ZIMMERMAN: Here is another study. This is a multiple-dose study.
> And again, the peak concentration was up to 100 nanograms per ml.
>
> I don\'t think it is important to compare where the troughs are, the
> steadystate troughs and that peak, because that peak is so momentary.
> It is really important how significant is that peak to toxicity, and
> it really is not significant.
>
> DR. CANTILENA: I would just ask you\--you are showing the results of
> steadystate, and this is sort of analogous, I think, but that\'s in a
> relatively clean population. If you look at the drug label for the
> Rapamune, you see a whole host of drug-drug interactions, which to my
> knowledge for a lot of these interactions, you don\'t really have a
> concentration effect relationship established. So to say they don\'t
> have clinical significance, I\'m not sure that you can. I think that
> is an extrapolation. And that was my whole point of asking the
> question was that a lot of the adverse events, and a lot of the
> drug-drug interactions in essence don\'t have a concentration effect
> relationship for the Rapamune, and if you can achieve concentrations
> at least at the lower limit of what you observe at the low dose of the
> oral, then at least it is a possibility.
>
> And I guess I would just ask you to be rather direct\--are you
> excluding the possibility of a significant drug-drug interaction with
> the stent?
>
> DR. ZIMMERMAN: This is my personal opinion. I don\'t think there is a
> problem. Again, that\'s a momentary peak. You are down to 3.6\--even
> at the highest dose, like a 1.5 mg dose, you are down to 3.6 at 72
> hours. That short period of time is not a problem.
>
> The other thing is when was the interacting drug given. Was it given
> simultaneously with the insert of the stent, or was it given 72 hours,
> 3 weeks later? I think it makes a difference in time, because as I
> said, the stent concentrations are moving targets; they are changing
> all the time.
>
> DR. CANTILENA: Then, on the flip side, if you have someone who is on
> an inducer of CYP3A4 and has been on one chronically, what would the
> plasma concentrations from the stent look like, in your opinion?
>
> DR. ZIMMERMAN: Again, I don\'t think it is a problem. I think inducers
> are even less of a problem because inducers have no effect of release
> of drug from the stent, nor does the released drug have any effect, I
> believe, on the concentrations in the artery.
>
> DR. LASKEY: Thank you.
>
> Dr. Ferguson?
>
> DR. FERGUSON: Thank you.
>
> First, let me say that I want to congratulate the presenters on what
> has been a magnificent, clear presentation, recognizing that you are
> talking to a surgeon here, even, okay?
>
> I just have two questions. One gets to the point about the checkmate.
> When I read through the patient material at home, I was kind of struck
> by the fact that two pages-plus of the information for the patient had
> to do with the checkmate. And of course, now my concerns are even
> greater when I heard some of the comments that have been made today
> about that. I just wonder if you include this much material about
> checkmate, had you thought about the interaction situation prior to
> writing these?
>
> DR. DONOHOE: The patient guide that we submitted, as you see, actually
> covers a variety of different approaches that could be offered. They
> weren\'t meant to be linked, and obviously, the patient is reviewing
> this for general information. Ultimately, the decision about what
> treatment option is taken is the physician\'s, and this wasn\'t
> provide for the patient to be making decisions on what treatment
> options are best for them.
>
> DR. FERGUSON: Thank you.
>
> The next an last question would be again the issue of the shelf-life.
> I didn\'t hear that, and I would like to hear a comment about the data
> which has been collected on the shelf-life for the stents vis-a-vis
> the drugs and the coating.
>
> DR. DODINO: Good afternoon. My name is Ron Dodino, and I am vice
> president of Cordis.
>
> In terms of the data that we presented, again, Dr. Foy has mentioned
> that we have actually responded to the questions that were asked.
> Stability was one of them.
>
> We have offered data and have offered a proposed shelf-life to the
> Agency. What we would like to do is to discuss this with the Agency
> and propose a shelf-life together, moving forward.
>
> So we have presented data on stability indicating method data for the
> products.
>
> DR. FERGUSON: So it\'s not available for the panel?
>
> \[No response.\]
>
> DR. FERGUSON: I just asked a simple, straightforward question. If this
> is something that you want to work with the FDA on, that\'s fine, but
> I think the panel needs to know.
>
> DR. DODINO: The proposed shelf-life is 12 months. Actually, that is
> the shelf-life that we have been granted for commercial product for
> sale outside the United States\--12 months.
>
> DR. FERGUSON: Thank you.
>
> DR. LASKEY: I won\'t take much time. There are a number of more
> important questions.
>
> Rick, this was a unique opportunity to look at drugs and their effect.
> Why was not dose put into your many models? You could adjust away for
> everything\--how about a dose-effect relationship here?
>
> DR. KUNTZ: That\'s an excellent question, Warren. I think one way to
> look at dose is our lesion length analysis, because there is
> approximately, I guess, 8 micrograms per ml. Therefore, the effect of
> length on restenosis could be associated with a measure of dose, but
> we\'d have to disentangle the stent part from the lesion length
> contribution as well. So it would be hard to look at that.
>
> Looking at dose-response relationship in general, probably the best
> measure of dose response would be the changes in dose per unit of
> tissue that the tissue sees, and that was intended to be fixed across
> all the different vessel sizes and lesion lengths. So therefore, we
> had one dose to analyze.
>
> Other than looking at a whole artery dose per se, probably the best
> dose would be the dose that changes the concentration of tissue, and
> because there is only one dose available, we can\'t do a dose finding
> relationship in that respect.
>
> DR. LASKEY: It just seemed like a unique opportunity to look at
> something very fundamental, and with all due admiration, you are the
> master of teasing things apart, so I was looking for it in all your
> models, but I missed it. But clearly, absolutely dose irrespective of
> per-square-centimeter would have been an interesting way to look at
> either dose effect or dose toxicity.
>
> DR. KUNTZ: Yes, I think you\'re right. I think that outside of the
> notion that we\'re probably looking at fixed concentration per unit of
> tissue, the absolute dose would be interesting to look at, and we
> would probably have to integrate the length and the size and get that
> information, and it would be a good thing to do.
>
> We did it by looking at stent length, but I think you also get more
> dose on bigger stents as well. So we would have to do some kind of
> cross-reference of those two.
>
> DR. LASKEY: Dr. Aziz?
>
> DR. AZIZ: I too enjoyed the presentation, and I am a surgeon, so I
> think some of my questions may be directed that way.
>
> Let me ask if any patients in this study ended up going to surgery,
> emergently or needing surgery?
>
> DR. DONOHOE: I don\'t believe any in the active treatment group went
> to a surgeon on an emergent basis.
>
> DR. AZIZ: If there is a patient\--I\'m sure it will happen\--who does
> need to go to surgery, do you have any suggestions\--I\'m sure
> somebody must have thought about it\--for what would be done about the
> corporate vessel? I mean, can the stent be removed? Can you cut across
> that, or would you have to go beyond it?
>
> DR. DONOHOE: I think\--are you talking about bypassing into that
> vessel\--
>
> DR. AZIZ: Yes.
>
> DR. DONOHOE: \--the stent would be treated as you would a bare metal
> stent at this point, so if your option were to go into that stent and
> cut through it, you could potentially do that if you wanted to go
> distal. But the issue that would be relevant in terms of the
> difference between a bare stent and this Sirolimus-eluting stent is
> the fact that we have a polymer and a drug on board.
>
> Over the period of time that we have talked about in the 6-week period
> in which essentially 90 or 95 percent of the drug is released, beyond
> that point, there is essentially no drug effect in that tissue. So in
> terms of the tissue healing response, it should not be any different
> than the bare stent.
>
> In the shorter term, if bypass is done in that \[inaudible\] area, as
> we discuss, the rate of endotheliazation seems to be the same with or
> without Sirolimus present, so I would think that in terms of the
> endotheliazation that would occur an estomatic site would be
> uninterrupted also.
>
> DR. AZIZ: And just going back to the other problem that has been
> addressed earlier, the incomplete apposition problem, if you looked at
> the patients who did have that, let\'s say, diabetics who were the
> patients who had more calcification in the vessel, was there any
> particular common denominator or thread or similarity in those
> patients?
>
> DR. DONOHOE: No. It is a relatively small sample size to be looking
> for those factors, but we have looked at them, and we haven\'t seen
> anything in common. The only observation that we thought was a bit out
> of line with the general proportion of diabetics in the study is if
> you look at all the RAVEL patients, the 10 that had incomplete
> apposition, and the 7 SIRIUS that had late incomplete apposition,
> there was, I think, only one diabetic in that whole group. That was
> the only item that we found that \[inaudible\] the proportion of
> patients.
>
> DR. AZIZ: I think somebody else asked this question earlier, but I\'m
> going to ask it again. You mentioned that one patient had an autopsy,
> and you were able to look at the actual stent in place. Is that the
> only one patient in all the studies that was actually looked at at
> autopsy?
>
> DR. DONOHOE: Only one, yes.
>
> DR. AZIZ: Okay. Thanks.
>
> DR. LASKEY: Dr. Pina?
>
> DR. PINA: First of all, I want to thank you for your patience with all
> of our questions here.
>
> I am bothered by a bigger issue here. We are dealing with a drug that,
> as far as I know, has never been approved for atherosclerosis, placque
> reduction, injury, except for T-cells and perhaps even B-cells in
> transparent patients, and maybe, Dr. Throckmorton can explain to me if
> this gets approved, what happens to the labeling of the drug, because
> everything that is in here pertains to the renal transplant for which
> the drug is approved. We use it for heart transplants all the time,
> and true, there is some data in there about maybe less vascular injury
> in our transplant patients, but that has not been clearly documented,
> and I think vascular injury in transplant is very similar to
> post-angioplasty injury. It has endothelialization, it has media
> increase\--very, very similar.
>
> So here, we are dealing with actually putting a drug onto the vessel,
> and yet I hear very little about the chemistry of these patients, I
> hear very little about the side effects of the drug, and yet we are
> giving a drug for a purpose that we have never given before. And this
> is not a totally benign drug. It needs to be used appropriately. Now,
> I agree\--it is small doses, it is probably not doing anything, but I
> think you at least need clinical lab data, and I just haven\'t seen
> any.
>
> I don\'t know what to give these patients. I don\'t know whether to
> give them statins. I would hope they would be on statins. I would
> hope\--again, I made this point earlier\--I would hope that they would
> be on ACE inhibitors for vascular remodeling.
>
> So we are giving a drug directly onto the vessel wall, and this is the
> first time that I have ever seen this in a device. We are not just
> treating the lesion by opening it; we are treating the lesion by
> chemically giving a drug that I haven\'t seen any data yet in animal
> studies, for example, that this is really a drug that works. I know it
> is anti-inflammatory, but how much of the inflammation is involved in
> the vessel and in the changes that happen after angioplasty?
>
> So I am asking to go back, and I would even like to know why
> Sirolimus. There are other anti-inflammatory agents. What was it about
> this drug that was so specific and so unique that Cordis chose to go
> to this drug with Wyeth\--and it is a fine drug on transplant; we use
> it all the time; we use it in difficult patients; it is a terrific
> drug to use in transplants.
>
> So one of my questions again is regulatory. Here, we are approving a
> stent with a drug for a purpose that the drug as far as I know has not
> been approved for, and maybe Doug can help me clarify this.
>
> I have other questions, but I\'ll start off with this one.
>
> DR. THROCKMORTON: One question I think I can answer, and one question
> I am quite certain that the Agency has not yet come to a place where
> we can answer.
>
> \[Laughter.\]
>
> DR. THROCKMORTON: We are talking here just about the drug-device
> combination, so this will have no impact on the label for the approved
> drug product as it is administered as a drug for systemic use. That
> was the easy part.
>
> The hard part, and the thing that we have not yet finished grappling
> with, is the description of the drug component of the drug-device
> combination here. I share your concern about the need for adequate
> information to patients about the drug aspect of this combination in
> the same way that I know Dr. Zuckerman worries about the adequate
> description of the device part of this combination for patients. Both
> of those parts have to be adequately placed into labeling.
>
> For the drug, we are going to have to make decisions about what
> aspects about the consequences of known systemic administration as far
> as adverse events, drug-drug interactions, monitoring, a black box
> warning\--how many of those pieces would need to be in this label for
> safe and effective use. And without speaking for Dr. Zuckerman, I
> think we are a fair way away from finalizing that discussion.
>
> DR. PINA: The sponsor said that they actually had data available for
> lipid levels and statins and background medications on the patients.
> I\'m sure you must have collected that on your CRF forms, and I\'m
> sure you have CRF forms. This was a randomized, blinded trial. But we
> haven\'t seen any of that, so I am having a hard time even
> characterizing the patient population other than that they have a
> lesion, and I don\'t do angioplasty\--I am a noninvasive cardiologist,
> but I take care of patients with coronary disease\--I would like to
> know what this population looks like, if this is a population that I
> am going to send to my colleagues, and they may indeed have a stent
> placed.
>
> Do you have that data, or will you be supplying that data to the FDA?
>
> DR. POTMA: Jeff Potma. I actually had the unique opportunity of
> personally reviewing about 80 percent of these angiograms, and I can
> tell you that the patients have focal disease where they had their
> stent as influenced by the clinical trial design, but they had the
> disease of atherosclerosis in their other vessels.
>
> I would echo your comments about the importance of lipid-lowering
> therapy and secondary prevention measures, but not to treat the 15 to
> 25 mm segment of vessel where we are trying to prevent the intimal
> hyperplasia. The points that you are making about secondary prevention
> are points that need to be done in all patients who present to us with
> atherosclerotic disease. They all need to have their LDL cholesterols
> of 70 or 80. That is part of the normal clinical practice.
>
> The one piece of data that I would refer you to in the panel pack
> itself is the frequency of recurrent out-of-hospital myocardial
> infarction, which Dr. Donohoe mentioned earlier. Actually, if the
> hypothesis is that the patients who receive the Sirolimus-coated
> stents do worse because of pertubation to those levels, you would not
> expect to see a statistically significant lowering of the non-Q MI
> rate as you did in this trial.
>
> So I would argue that this is doing very important effects\--one, to
> emphasize what you are mentioning, that you have to lower lipids, and
> you have to take care of secondary prevention\--not for the 20 mm of
> segment that we stent, but for the other 200 mm of vessel that we
> leave behind with atherosclerosis. Specifically focusing on the area
> where the stent was placed, there were actually less out-of-hospital
> non-Q-wave MIs in those treatment groups because the disease of
> restenosis was prevented.
>
> So I don\'t think that there is evidence in the clinical data with
> respect to out-of-hospital recurrent MIs, but there is a higher
> incidence. In fact, you could argue that the incidence is lower
> because you prevented restenosis.
>
> So to echo your comments, yes, all patients, interventional
> cardiologists, noninterventional cardiologists, should know that
> lipids need to be lowered, ACE inhibitors need to be given,
> beta-blockers need to be given for all patients with atherosclerotic
> disease. And the patients in this trial were very similar to the
> patients that I treat in my clinical practice. But if we focus on that
> area that got the drug-eluting stent, the actual recurrent MI rate was
> lower, not higher, in those patients who received the drug-eluting
> stent for the out-of-hospital no-Q waves.
>
> DR. PINA: Thank you, and don\'t move for a minute, because this is
> probably also pertinent.
>
> There were also early myocardial infarctions\--there is a little bump
> in that curve early on the drug-eluting stent. They are small numbers,
> but can you talk about those?
>
> DR. POTMA: Actually, if it is okay with you, I would like to defer to
> Dr. Kuntz, because those would be in the confines of peri-procedural
> MIs. Some of the issues about the CKMD versus the \[inaudible\]
> criteria may come up.
>
> I think my comments were specifically out-of-hospital MIs, so maybe I
> could refer to Dr. Kuntz about the pari-procedural MIs.
>
> DR. PINA: You may want to tell me something about why triponines
> weren\'t measured, since the middle triponine leaks.
>
> DR. KUNTZ: We didn\'t measure triponines in this study systematically,
> because not everybody had triponines available to measure. This study
> was initiated 3 years ago, and there was a lot of \[inaudible\]
> deciding whether we would measure triponines. But not everybody had
> triponine available, and there wasn\'t a standard established at all
> the hospitals for the normalities like there is for CKMD.
>
> I think that if you are focusing on what is the impact of this
> drug-eluting stent, the concomitant medical therapy in the
> atherosclerosis portion of the patient disease, per se, just following
> up on Jeff\'s comments, we viewed the segment that is obstructive and
> easily treated as transforming into a scar needs to be prevented.
>
> With respect to disease that can occur at the nontreated segment,
> which was about 95 percent of the coronary we don\'t put a stent into,
> we do have two measures of atherosclerosis progression. One is the
> instance of MIs that Dr. Potma talked about, which was similar between
> the two groups, and the other is the incidence of nontarget lesion
> revascularizations which suggests new lesions that pop up and then you
> revascularize, which is usually around 2 to 3 percent, and they were
> also evenly distributed. Actually, the estimate was a little bit lower
> in the Sirolimus arm than it was for the control arm, but we would
> assume they were the same.
>
> So we had no evidence that the use of this stent caused any increases
> in classical atherosclerosis manifested events over the course of 9
> months in followup as new lesions that grew or MIs that occurred.
>
> Now, with respect to the peri-procedural MIs, it is a very interesting
> issue, because in our field, we are focused on measuring even small
> levels of cardiac enzyme elevations because of the legacy from the
> IIbIIIa inhibitor trials, as the IIbIIIa inhibitor trials have
> demonstrated definitively that they can reduce MIs, and the best
> signal of measurement is when we actually measure slow levels of MI
> using the CKMD rated at three times normal.
>
> This is traditionally a definition that you would use if you are
> trying to use a device or a drug to prevent peri-procedural
> complications. Classically, in the stent studies, we generally are
> interested in restenosis, so we have always used a less sensitive and
> more robust definition of MI, which has historically been the World
> Health Organization definition of MI, and that is a CK greater than
> two times normal, which happens to be very much less sensitive than
> CKMD at three times normal.
>
> So if you are doing a study of IIbIIIa inhibitor\'s impact on acute
> complications or embolic protection devices, you would want to use the
> one that is very sensitive, because that is how we can distinguish
> what is good. But if we are looking at a stent study where we are
> trying to evaluate impact of restenosis, you don\'t want to drown out
> the events of sensitive peri-procedural MIs, we want to make a more
> robust definition, and hence, our interest in using the WHO
> definition.
>
> We have the data broken down both ways. When we looked at the
> peri-procedural MI part, it was equally distributed between the two
> arms. There was no evidence to suggest, either using the robust
> definition or the sensitive one, that there is an increase in
> peri-procedural myocardial risk associated with the implantation of a
> stent.
>
> And the conventional wisdom about what causes those heart attacks is
> twofold. One is that there might be some distal emboli particulate
> that goes downstream, and the other is there might be pinching of some
> old side branches that may cause the small embolization. And they seem
> to be equally distributed between the two arms.
>
> DR. PINA: All right. Let me follow up on your point about the clinical
> events, either Q or non-Q or acute coronary syndrome.
>
> What about angina? Do you have any functional data, noninvasive data
> of ischemia, on these patients? I\'m sure a lot of the physicians
> actually got noninvasive studies, sine that\'s pretty common.
>
> DR. KUNTZ: Right. This is also an excellent question. It is something
> that we have been wrestling with for a long time in clinical trials in
> the studies that we have performed and I know that others have
> performed. We have not been able to completely classify angina in
> these kinds of studies unless we use instruments like the
> \[inaudible\] questionnaire or other quality of life instruments.
>
> So in studies where we are looking for devices or drugs that generate
> new vessels, like angiogenesis devices, angina becomes a very
> important issue, and it is a very comprehensive, frequent application
> of instruments by experts, like the quality of life questionnaire, the
> \[inaudible\] questionnaires, that give us some measure of angina.
>
> We didn\'t use that in this study because the typical failure mode
> clinically, whether right or wrong, has been the requirement of repeat
> revascularization determined by the physician and the patient in
> making the decision to come back into the hospital and getting repeat
> revascularization.
>
> The reason that we use that more robust endpoint is because there are
> 85 different ways of doing noninvasive testing, so it is very hard to
> standardize that unless you actually put into place a core laboratory
> and require people to do that. Having participated in studies where we
> tried to establish Bruce protocol or modified Bruce protocol for the
> exercise test, we still have huge problems in what people call
> \"modified Bruce,\" for example, so it is impossible for us to enforce
> a functional study at 4 to 6 months to go forward, and that has been
> very difficult to do in stent studies in general.
>
> Moreover, the reproduction of their initial symptomatology, which is
> probably the best measure of angina\--jaw pain, chest pain, or
> shortness of breath\--has also been quite difficult to do in these
> studies because many times, patients enter into a study without
> classifiable symptoms per se. They sometimes come in because they have
> heart failure, and they get diagnosed with a tight stenosis, or they
> have other measures of functional ischemia but no symptoms per se.
>
> And because of that heterogeneity, we have never really relied on
> measuring angina in having outcomes in stent studies, so we have
> always traditionally focused on two endpoints\--again, right or wrong,
> we don\'t know\--which is measurement of a narrowing portion with a
> sizable subset that has angiographic followup, and the clinical need
> for repeat revascularization that is externally adjudicated by a
> committee that would say that given the unique data of this patient on
> a patient-by-patient basis\--that is, return of their chest pain and a
> positive stress test, however it was done, and the findings of the
> cath lab, validated by a core lab\--the committee would agree that
> that was an appropriate revascularization, and that gets counted as an
> endpoint.
>
> That is why we have ended up with these extremely robust endpoints of
> repeat revascularization rather than common frequency of angina.
>
> Now, after all that explanation, we do have measures of angina that we
> can actually calculate, but I just think they will be noisy in
> general; but we can summarize those.
>
> DR. PINA: I agree with you that there are lots of different ways to
> look at ischemia\--some people like ECOs, some people like stress. Do
> you have any functional data, regardless of how the investigators did
> it? Every center may have their own way of doing it. I know we like
> dilbutamine \[phonetic\] ECOs.
>
> DR. KUNTZ: We do capture in the pre-revascularization categorization,
> CRF, we do actually document what functional study they had and what
> symptoms have they had. That is actually almost a narrative form,
> because the potential set of all possibilities is enormous, and it
> would just be a matter of classifying those, and trying to do that
> before, you have lots of bins with lots of different counts and so on,
> but this is a large enough study that we could actually try to do some
> collapsing of endpoints to get a measure of angina.
>
> DR. PINA: I think it would be an interesting piece of information to
> see how much ischemia\--you\'ve got a lot of diabetics, so you\'re
> going to have a lot of people who have no pain but in fact may have a
> positive study, a positive noninvasive study.
>
> DR. KUNTZ: Right.
>
> DR. PINA: I have no more questions, Mr. Chairman.
>
> DR. LASKEY: Dr. Bailey?
>
> DR. BAILEY: I want to also compliment the sponsor as well as the FDA.
> This is one of the more informative packets that I have seen. I will
> focus primarily on statistical issues.
>
> I think the data on face value form a pretty good overall picture of
> benefit with respect to the endpoint that was the primary endpoint.
> This primary endpoint is obviously not an angiographic endpoint, and
> it is really not exactly a clinical endpoint in the sense that out in
> the real world, people don\'t get angiograms 8 months after they have
> a procedure. So the blip that we have seen really is, you might say,
> an artifact, or at least at a very minimum, if you really wanted to
> estimate the impact of the therapy in the absence of routine
> angiography, you would probably want to extrapolate those lines out to
> wherever and hope that your extrapolation was correct.
>
> So I think we can appreciate the endpoint, and it is very dramatic,
> but keep in mind that it is not really a pure clinical
> endpoint\--\"pure\" isn\'t the right word to apply to a clinical
> endpoint, I guess\--but it is reasonably convincing.
>
> I wanted to ask one question on this issue of blinding, which I think
> you can belabor, but revascularization is an elective procedure. You
> were just talking about stress-testing. If you were to try to
> categorize the reason for revascularization, it would be interesting
> to see what percent of the time it was for symptoms or for ischemic
> response versus just 50 percent stenosis. And indeed it would be
> interesting to look at the rate of revascularization conditional on
> the percent stenosis compared between the two treatment groups.
>
> I don\'t really think that blinding is a serious issue here, but it is
> sort of a nagging concern whenever you have a somewhat behavioral
> endpoint. I wonder also if one wanted to create an endpoint that was
> perhaps less susceptible to the behavioral issue, what about taking
> all of the early revascularization as nonelective in the sense that
> the angiogram was early because it was motivated by something, but
> then, instead of taking revascularization at the routine angiogram,
> look at the percent stenosis and put that together. So in other words,
> it would be sort of a composite endpoint where you would take the
> early revascularization as a real clinical endpoint, but when you get
> to the sort of study angiogram, then just look at the percent stenosis
> and see whether there is a 50 percent restenosis or not.
>
> So that is my thinking on the endpoint, and I don\'t think it is a
> major concern, but I think it would be helpful to know how often the
> reason for revascularization was just the fact that you see the 50
> percent stenosis versus something prompted doing something to help the
> patient for some other reason.
>
> Now, having said that, as I said when I started, I think the overall
> results are fairly compelling, and I think the main issue is what
> patient population it can be extended to. And I think most of the
> comments that have been made around the table here, I would agree
> with, in particular the fact that you have got to apply the indication
> to the method that the people use out in the world to select the
> patients. So it has to be made very clear that if there really is a
> systematic bias with quantitative coronary angiography, one should
> make the indication correspond to the visual readings, or else one
> should reanalyze the data perhaps that way and see if that makes any
> difference.
>
> This is sort of a dilemma. In any clinical trial, you have an overall
> result, and then, how do you apply the results to\--what patient
> population do the results apply to?
>
> It is fortunate when they are as strong as they are here, because you
> feel more comfortable applying them at least to the patients within
> this study. But I really do have serious concerns about extrapolating
> the results beyond the borders of the patients who were recruited into
> this study, and that is where I think the different models that Dr.
> Hyde presented or that Dr. Kuntz presented\--we can disagree about
> what the most accurate model is, but the point is they are all
> plausible, and it is very important which model you use when you go to
> trying to extrapolate them beyond the boundaries of the patients
> recruited into the study.
>
> I would argue that even within the boundaries of the patients in the
> study, if you have a very small fraction of patients in a certain
> category, it is hard to know exactly how strong the evidence has to be
> with that specific subset.
>
> Clearly\--and again, it is the same dilemma we always have\--say your
> results apply to men and women, but you only had five women in the
> study. Obviously, that\'s not fair. Well, what is the right number?
> That\'s a hard question to answer. But I think we are most comfortable
> when you can use internal data without making any assumptions, and of
> course, usually, we don\'t have the power to have that luxury.
>
> So I think I would tend to come down that I am fairly comfortable
> applying it to the patients who were recruited into the study, but I
> am not very comfortable extrapolating beyond that because of a
> sensitivity to which is the right extrapolation model.
>
> And by the way, I think that, yes, it is true that\--I would refine
> the comment that Dr. Kuntz made that biology is linear by saying that
> most biological studies that we do don\'t have the power to detect
> nonlinearity.
>
> I think we are all in agreement that the exclusion of the patient who
> didn\'t meet the entry criteria even though they were already
> randomized is legitimate. I would just prefer to say that it is
> legitimate even though it is not an intent-to-treat analysis. Let\'s
> humor the statisticians, and let us keep the purity of that term, but
> go ahead and defend your right to do something else. I think that is
> reasonable.
>
> Okay. I guess I should make at least one comment about the historical
> controls. I think this is a reasonable thing to look at in terms of
> comparing the previous experience with the angioplasty patients.
> However, I guess one question I have regarding that is it is not the
> Bayesian analysis, it is a Bayesian analysis. I think it is
> commendable to incorporate the variability amongst those results in
> the different studies, but why are we then referring to the mean of
> those results rather than the best of the results for angioplasty? It
> is not really the most conservative analysis you could do, although I
> think I heard someone say that the results, if you just took the best
> angioplasty results, were still significant.
>
> But relevant to this same issue, I think I heard Dr. Hyde or someone
> else comment that the definition for the main endpoint was different,
> or the current definition of MACE was different than it had been in
> the previous angioplasty studies. If that is true, I think that that
> is a very important thing that would need to be addressed before
> relying on this comparison.
>
> Getting back to the endpoint, I wonder if, had the results been looked
> at by subsetting which group had angiography\--in other words, are the
> results similar in the group that had angiography versus the ones that
> did not\--that would be one way of looking at this sort of observation
> bias.
>
> I think those are my comments.
>
> DR. KUNTZ: I\'ll address those issues which are very valid, and thank
> you for those comments.
>
> With respect to understanding how to determine whether someone
> appropriately got treated or not when they came for angiographic
> followup, the Clinical Investigation Adjudication Committee, because
> it is blinded, has an algorithm that they follow. In general, they
> require\--and this is a committee of approximately 10 cardiologists
> who meet every Wednesday night to discuss these issues and have done
> over 8,000 cases in followup in the last 5 or 6 years, and it\'s the
> same crew\--they require anybody who has a narrowing between 50 and 70
> percent to demonstrate some level of either recurrent angina or
> functional study in a case-by-case unique basis. So when a patient
> comes back and gets treated, we should have the angiographic data.
>
> For narrowings less than 50 percent, and someone actually treated
> them, they require extreme data like a very early positive functional
> study, or else they would discount them. Then, they can\'t look at it
> as clinically-driven.
>
> If it is between 50 and 70 percent, they require at least recurrent
> angina on a narrative or a cap report \[phonetic\] demonstrating a
> functional study or the functional study itself.
>
> And we have extensive researchers who go out and find this stuff if it
> is not in \[inaudible\] form. And in general, if the stenosis by QCA
> is over 70 percent, most people would agree it is probably appropriate
> that the patient came back, because it is hard to explain how a 70
> percent lesion or tighter, especially using the current QC algorithms
> we have, would not be human anatomically important. So they do use
> that.
>
> And when they do find those approaches, on page 57 of the panel pack,
> in Section 531, you will see that there are those patients with
> clinically-driven and non-clinically-driven \[inaudible\] adjudication
> to demonstrate which ones actually get thrown out and which ones
> \[inaudible\].
>
> I\'ll just read the numbers for you. The clinically-driven TLRs is 4.2
> percent for the Sirolimus arm versus 16.9 percent in the control arm.
> And those cases actually received TLR, but the committee actually
> threw them out. It was 1.9 percent for the Sirolimus arm and 4.0
> percent for the control arm. So actually, there was almost 2-1/2 times
> more rejection of TLRs in the control arm that were inappropriate
> \[inaudible\] Sirolimus arm.
>
> So that just shows the mechanism of how the committee works and what
> they actually do to determine which ones\--
>
> DR. BAILEY: And they were rejected because\--what\--less than 50
> percent stenosis?
>
> DR. KUNTZ: They would have less than 50 percent stenosis without
> controlling systems, 50 to 70 without recent function study
> \[inaudible\] would be the main reason to throw them out. So they
> review each case on their own, and since they are blinded, they
> determine whether they were actually clinically-driven, taking all of
> the \[inaudible\]. So the data is internally consistent with them
> acting in a way to screen, to try to get appropriate\--
>
> DR. BAILEY: But the don\'t screen the non-revascularizations to see if
> that is appropriate.
>
> DR. KUNTZ: They also do screen the non-revascularizations.
>
> DR. BAILEY: Do they?
>
> DR. KUNTZ: Yes. So that we have another form for followup, that if
> patients have a positive angina or function study in their clinical
> followup, they actually investigate those individuals,and if they have
> a positive stress test and have not had an angiogram, or had an
> angiogram but were not treated, that\'s another signal that comes up.
>
> DR. BAILEY: So is your endpoint based on the appropriate treatment?
>
> DR. KUNTZ: Correct.
>
> DR. BAILEY: So it is sort of an intention to treat.
>
> DR. KUNTZ: You will find in an American interventional investigative
> group that not too many people squeak by without being treated. So
> that possibility\--
>
> DR. BAILEY: How many changes were made?
>
> DR. KUNTZ: I am not quite sure. There may have been just a half a
> percent or a percent that actually get upgraded, but we actually have
> those numbers, and we can give you those. But we do upgrade some who
> don\'t get treated, but it is not often that we see that with
> investigators, especially if they come back with angina or a study.
>
> So to your point that the angiogram does interfere with the clinical
> outcome, there is no question it does, and that\'s why we put all
> these mechanisms in place that try to minimize that effect.
>
> I think the point that we were trying to make was that the frequency
> of those patients who have those lesions that had to be adjudicated
> was four or five times higher in the control arm than it was in the
> active arm, and that\'s why you will see more events occurring there.
> Even if it were evenly distributed with no bias, you would expect to
> see more events occurring just because the opportunity is there; there
> were more narrowings in that group.
>
> The other important point is that one could ask why didn\'t we just
> view this study on a clinical basis\--and we would have all loved to
> have done this clinically as well, but we\--and I think the FDA would
> agree\--also know that it is important to get angiography followup on
> these patients as well. It is important to look at the angiogram,
> because we have discovered in some forms of radiation therapy, for
> example, and others, that there are patterns of restenosis that
> actually suggest harm or problems associated with that, and in looking
> at a new therapy, the angiogram actually is a very important way to
> measure the mechanism of narrowing. And there are certain patterns
> that we are familiar with that are good and bad patterns.
>
> So necessarily this was actually a pretty rich and large angiographic
> subset because we wanted to have power to detect any kind of endpoint
> that might be problematic, including the observation of late
> aneurysms, which we can detect by angiography, and patterns of
> \[inaudible\] stenosis and others that we have seen with other
> therapies, for example, de novo radiation therapy.
>
> So we were caught between a rock and hard place in trying to provide a
> study that was large, comprehensive and had elements of angiographic
> followup that would apply to those data and clinical followup. We
> tried to strike a balance by having about two-thirds of the patients
> required for angiography and one-third not and look at those cases
> overall with these mechanisms to try to minimize any of the
> interference that might happen from the requirement of a late
> angiogram.
>
> The second question you talked about was extrapolation, and again, as
> Dr. Hyde pointed out, this is the art of statistics and how to
> actually look at the data per se.
>
> I think there are a variety of different ways to evaluate the models,
> and I think that they are all kind of exciting, and from linear and
> nonlinear models, we learn a lot about how patients respond.
>
> I think that you are right that in the boundaries of what we have
> brought in as eligible\--and I think if we were to focus on the
> dimension of lesion length, 50 to 30, we have pretty good evidence
> that it worked in those ranges. That is, when we took patient who were
> 20 mm or greater\--although, as Dr. Hyde pointed out, it only
> represented about 20 percent of the cases\--there was still
> significant benefit even in that subset on \[inaudible\] analysis for
> Sirolimus compared to control. And our estimations might be
> different\--there might be a reason to use nonlinear versus linear,
> and we have certain preferences and so on\--but I think that in
> general, the data itself looked like it was relatively constant when
> we broke them into their bins over that range.
>
> So the fact that the boundaries of the patients\--we asked patients to
> come in who had 50 to 30 mm in relation to length by the
> investigators; we used a randomized trial that was positive in
> substantial portion, and when we looked at the S demands \[phonetic\]
> over that bridge, they still seemed to preserve the same distance of
> benefit overall, and the subsequent analysis of those greater than 20
> still showed statistical significance.
>
> I feel pretty confident that this thing works within 15 to 30 mm per
> se. Can we extrapolate beyond 30 mm? Well, we start to get to a point
> where we have less than 10 percent of beta above 30 mm, so it is going
> to be difficult to extrapolate at that level.
>
> If we look at the dimension of vessel size per se, we actually started
> with 2.5 to 3.5, but we did still work with smaller vessels and
> slightly higher vessels per se. If we look at those zones of
> extrapolation outside the boundaries, they do continue in their S
> demands, but they do fall off in their power to detect that.
>
> If you were to invoke that at 3.5 to 4.0 mm, the vessels would change
> in their physiology so that they wouldn\'t show the benefit\--or, for
> example, 2.25 or down\--then, you might be concerned that we don\'t
> have enough data to make that inference per se. But I think if we go
> from the values of 2.5 to 3.5 and look at the leaks that go over, I
> feel confident that we can show a benefit from 2.25, at least, and
> probably a little bit over 3.5, because the data are very strong. And
> as you know, when the vessel gets smaller, they have \[inaudible\]
> that is where we stand \[inaudible\] of those boundaries, but I think
> I agree with you that within the boundaries of the eligibility, I
> think it is pretty solid; extrapolating much beyond that is very
> tricky.
>
> DR. BAILEY: Not the eligibility, but what you actually get.
>
> DR. KUNTZ: Well, there is one thing \[inaudible\] your next point,
> which is if you tell an investigator to do 15 to 30, and then you
> actually get 10 to 40, we have to understand what it means to get a
> label for 15 to 30, because if they continue to get 10 to 40,
> obviously, you may end up with what you tell somebody \[inaudible\]
> what you actually get.
>
> So the most conservative approach, I think, would be to look at the
> boundaries of what the criteria were to get into the trial, because
> that is what we ask the investigators to do, and then we got back this
> sample which is slightly wider than that.
>
> So I think the decision to go either to the boundary itself or the
> eligibility or slightly beyond that just depends on how confident you
> are about the population group or the sample size and the zones.
>
> DR. LASKEY: Can I ask a question here? This is the best look at the
> data. When you apply these models to the population that was
> developed, it gets worse from there. So this is your best shot, and if
> it\'s tenuous at the end, it\'s going to be even more tenuous or maybe
> not even P equals NS when you get to not this population.
>
> So do you want to qualify these models as they apply to the fringes?
>
> DR. KUNTZ: Actually, I think this gets into some hairy statistical
> stuff, and I think the issue is that you lose power once you go to the
> edges of anything. If you look at any sample space for which we define
> the eligibility criteria, and the core of that was in the central part
> of the sample space, and we go to the edges, most of the time in
> randomized trials when you have a positive result, you actually make
> an inference about what the eligibility criteria were. That is
> classical in a randomized trial.
>
> In this situation where we observe areas, we have two ways of telling
> whether the treatment effect is effective. One is to look at the
> overall power for the individual small zones on the edges, and we lose
> power because the sample size falls off.
>
> The other is to look at the actual raw estimates themselves, and the
> raw estimates do maintain their distance out at the edges.
>
> So I would say that the data is consistent with working at the edges,
> it is just not proved that that small area is independent to show
> that.
>
> DR. BAILEY: I think Dr. Hyde presented the various cutoffs and found
> that when you lumped everybody over\--what was it\--3.5, I think, it
> was significant, which would tend to imply that at least the
> applicability goes somewhere into that range, but we don\'t know how
> far.
>
> DR. KUNTZ: Just to finish up the last few points that you made, the
> small vessel analysis, which was an analysis in which we pooled three
> previous trials using Bayesian techniques to add a component of
> variance for between-trial variance, projected an overall S demand of
> the outcome which was a central estimate and not a high estimate.
> That\'s how we ended up with the noninformative prior.
>
> This is a technique that we have used in estimating large sample size
> of the stents and trying to look at registries and seeing it there if
> a new registry matches up with an adjusted prior distribution from,
> say, a bunch of stent trials. That technique is helpful because in
> this special case, we will never see a study in the future of balloon
> angioplasty versus stenting for small vessels. Stents are so prevalent
> right now that we can never envision that we would ever be able to
> perform a \[inaudible\] study using balloon angioplasty in one group
> versus stents in another in America. I just don\'t think that is going
> to happen.
>
> However, there were four studies done in Europe and in Canada, and
> four randomized studies with sample sizes between 300 and 500 patients
> demonstrated in two studies no difference between balloon angioplasty
> and stenting and two studies demonstrating a significant benefit for
> stenting.
>
> So four studies with over 1,200 or 1,300 patients demonstrated that
> the stent in small vessels is at least as good as balloon angioplasty
> and possibly better.
>
> So with the combination of a Bayesian analysis and the fact that the
> patients with small vessels had benefit for Sirolimus compared to
> control, I think it would be safe to say that the Sirolimus is at
> least as good as or significantly better than angioplasty, because the
> stent arm in four randomized trials has demonstrated that stents are
> the same or better than balloon angioplasty. Hence, the system of
> Bayesian analysis where we actually used previous studies in the
> balloon angioplasty era to pull back in.
>
> So neither of those approaches is obviously direct randomized data,
> but I don\'t think it is possible to do a randomized trial anymore of
> standard stenting versus balloon angioplasty.
>
> But those pieces of information are actually pretty strong, I think,
> as indirect support to suggest that this has benefit.
>
> DR. BAILEY: Obviously, there is always the issue of historical
> controls. I guess my point was that you used the mean of the three,
> but the most conservative approach would be to take the best shot, the
> best result, for angioplasty. That was all.
>
> DR. KUNTZ: Right. I understand.
>
> You had a final comment about angiography per se\--I can\'t remember
> what the comment was, but maybe I addressed it in the previous
> comment.
>
> DR. BAILEY: Analyzing the data by the subgroup defined by who received
> routine angiography.
>
> DR. KUNTZ: Yes. That is performed, and we do have that analysis as
> well. We do have an analysis that separates out those patients who
> were prespecified to have compulsory angiography versus those with
> just clinical followup per se, and we see the same differences. We
> just see a lower rate, as expected, in patients with clinical followup
> without introduction of angiography. So as in every study we have ever
> seen\--
>
> DR. BAILEY: You have similar separation, but not the blip.
>
> DR. KUNTZ: Right\--similar separation in a distance, but the blip is
> in part due to actual deserved clinical difference in restenosis, and
> obviously, some component is driven by the angiogram that we will
> never be able to get out even with \[inaudible\].
>
> But the data is consistent in those cases that didn\'t require
> angiography, and we still have the same difference in clinical
> outcomes when angiography wasn\'t interfering with their evaluation of
> clinical \[inaudible\].
>
> DR. LASKEY: Before we get to the panel discussion of the questions to
> us, does anybody have a single, solitary question to ask of the group
> or the FDA?
>
> Yes?
>
> DR. KRUCOFF: Actually, I lied to you, Warren. I have two singles.
>
> I have one question for FDA, and I guess I\'m sitting here, just
> trying to sort out this whole small vessel business. As I look at it,
> and I look at the distribution here, what the original trial design
> that was approved as an IDE did, if I understand you all correctly,
> was approve the use of an unapproved bare metal stent in patients down
> to 2.5 mm vessels, randomized against an investigational combination
> of a stent with a drug-eluting polymer-coated surface in patients with
> 2.5 mm vessels.
>
> Is that right?
>
> DR. ZUCKERMAN: Yes. The original intent of the trial was to try to
> design a real-world trial, and that\'s why the inclusion criteria were
> 2.5 to 3.5, less than 30 mm.
>
> A frequent criticism of FDA previously has been that in the coronary
> stenting trials, we have evolved into a situation where our approved
> stents are in a range that only covers about half of the patients
> treated in the United States, which is not ideal. We can debate ad
> infinitum why that has happened, but here was a chance to try to get
> data in a more realistic range\--the 2.5 to 3.5 range.
>
> The tradeoff that FDA accepted was that in the 2.5 to 3.0, the control
> and the randomized trial would be a bare stent. That is why kind of as
> additional external data, we looked at the Bayesian methodology in
> which we were able to impute what would happen if we were actually
> able to include a balloon angioplasty three-arm trial.
>
> There was never any intent from FDA\'s perspective for this type of
> trial then to result in a request from the sponsor to result in a
> labeling basically where the whole world of coronary artery disease
> could be stented in one sense. Again, where one has a label from 2.25
> to 5.0, given that lesions are in the eye of the beholder, this kind
> of implies that significant lesions are amenable to treatment with a
> drug-coated stent.
>
> We would see the need for doing a\--usually, our advice is to do a
> trial in this median range, the 2.5 to 3.5, the small vessel range and
> the larger vessel range, which might include SVG graphs.
>
> DR. KRUCOFF: So, of the it looks like 268 if I\'m reading this
> right\--patients with 2.0 to 2.5 vessels who were randomized primarily
> in this trial, did the informed consent document actually tell
> patients that if you have a small vessel, you are going to be
> randomized between two investigational therapies?
>
> \[No response.\]
>
> DR. KRUCOFF: Okay. Then, my last question\--I happen to agree with
> Rick. I don\'t think there is a chance in the world that you could do
> a trial against plain balloon angioplasty in small vessels because it
> is simply not being done in the community. And you can acknowledge
> that, but I think that with acknowledging that, we ought to just
> analyze the data from a randomized trial where you have 124 patients
> in each.
>
> Now I go back to your tables, Rick, which were not in the panel pack,
> so I\'m going to apologize for missing this on the first pass. But
> what I don\'t see out of all your 16-cell tables is the primary
> endpoint. Am I missing that? Do you have these tables for target
> vessel failure?
>
> DR. KUNTZ: We do have the analysis, and we didn\'t bring that, because
> we were trying to use it to look at restenosis per se, because the
> risk of restenosis is worth focusing on.
>
> I don\'t think we have that data\--
>
> DR. KRUCOFF: All right. Just because I think ultimately, at least for
> me, the issues are going to be not what the inclusion criteria are for
> approval and for labeling of the product, but outside of the inclusion
> criteria, where do you go on assumption or on data, it would be
> helpful for me to see that.
>
> And just as a double footnote, your manuscript\--it is a four-by-four
> table, not three-by-three.
>
> But if you have these tables for target vessel failure, that would
> help me.
>
> DR. KUNTZ: Yes. My guess is that if we did it for target vessel
> failure, the treatment effects would be lower because target vessel
> failure adds to MI and death, so it would round out, and my guess is
> that the averages would be in the 40 to 50 percent range for treatment
> effect overall for the TVF part, so therefore, 60 to 80 percent for
> the clinical restenosis. That\'s the main difference in TVF and TVR.
>
> DR. KRUCOFF: In the big vessel/short lesions and the small vessel/long
> lesions?
>
> DR. KUNTZ: Well, we know that the main driver of TVF is the TVR
> component. It is about 90 to 95 percent of the components of TVF. So
> we would be looking at almost a map of the same thing. We would just
> be adding equally to both arms one or two percent of death and MI for
> the cells, and they would be extrapolated because there weren\'t that
> many deaths and MIs that have been followed. So it would be just like
> adding one or two percent per cell. And when you bring both up, the
> differences become relatively lower.
>
> DR. KRUCOFF: That\'s assuming that in fact it is not related to size
> or\--
>
> DR. KUNTZ: Well, I can tell you what that is right now, because we
> don\'t see that these things ever have influenced MI. We have actually
> looked at those, MI and death, which is a very low frequency, and we
> have never been able to find a significant predictor. So we would have
> to extrapolate out the average.
>
> **Questions and Answers for Panel**
>
> DR. LASKEY: At this point, I think the panel is hopefully prepared to
> address the questions put to us, so Drs. Donohoe and Kuntz, thank you,
> squared. You have been very helpful. Thank you so much. I\'ll ask you
> to step back.
>
> If we could put the questions up now and move on.
>
> Is anybody on the verge of leaving for the airport? Dr. Bailey, are
> you okay? Okay, everybody is staying.
>
> This is the part of the meeting I enjoy the most\--developing
> consensus.
>
> The first question? I am pro-MAC. This is addressed to Dr. Waxman and
> people at TCT who are MAC-hostile.
>
> DR. ZUCKERMAN: Dr. Laskey, since you have the questions, do you just
> want to read them?
>
> DR. LASKEY: That\'s fine with me.
>
> Okay, Panel. The first question is on evaluation of safety.
>
> \"The safety endpoints evaluated in the SIRIUS study included: MACE to
> 270 days; with the 7.1 percent versus 18.9 percent rate at 270 days;
> stent thrombosis to 30 days, 0.2 percent in Cypher, 0.2 percent in the
> bare stent; and late thrombosis to 270 days, 0.2 percent in Cypher
> versus 0.6 percent.\"
>
> \"Do the data submitted on the Cypher product provide adequate
> assurance of safety?\"
>
> \[Pause.\]
>
> DR. LASKEY: I sense there is consensus amongst the panel that it does
> provide assurance of safety.
>
> DR. WHITE: Can you better define that? Is that safety to 9 months? Is
> that long-term safety?
>
> DR. LASKEY: As they apply to the data provided to us, to 270 days; we
> have not seen safety data beyond 270 days, so I think our comments for
> acceptance of this data are limited to that. We would like to see
> additional data, and I think that will be forthcoming in additional
> comments.
>
> The second question, along the lines of evaluation of safety: \"The
> applicant has requested approval for a range of stent diameters and
> lengths and corresponds to a nominal drug dosage as high as 399
> micrograms. The animal studies conducted by the applicant on doses
> higher than 180 micrograms were limited to 30-day study. The SIRIUS
> study only evaluated 15 subjects who received stents with a total
> nominal drug dosage greater than 350 micrograms.\"
>
> \"Given the limited preclinical and clinical information outlined,
> please comment on whether there is adequate evidence to support the
> use of stent diameters and lengths\--that is, 4.5 mm and 5.0 mm
> diameter with a 33 mm length\--with a nominal drug dosage greater than
> 350 micrograms.\"
>
> DR. KRUCOFF: Can I propose that we actually address drug and polymer
> in this and the very next set of questions together, since I think the
> issues are largely around dimension and whether or not there is data
> to support it?
>
> DR. EDMUNDS: Let\'s answer the question; it just confuses me.
>
> DR. LASKEY: So we do not have adequate evidence in this range?
>
> DR. EDMUNDS: I disagree. We have shown no evidence that there is
> really any systemic toxicity to this drug. It is a topical agent, and
> it is proportional to the amount of release to the amount of area that
> it touches. I don\'t think we need to complicate it any more than
> that.
>
> DR. LASKEY: Do my colleagues concur?
>
> DR. KRUCOFF: I don\'t think we have any data in these areas, and I
> think the answer to the question has to be that there is no
> demonstration.
>
> DR. WHITE: I would concur with that, Mr. Chairman, on systemic
> exposure\--I have already spoken to that.
>
> DR. LASKEY: Along the lines of what\--and I think this is a good time
> to interject the carrier issue or\--however you want to call it\--the
> polymer issue, but when the drug is gone, all that is left is the
> polymer. We don\'t have any idea, other than extrapolating the
> experience with this polymer in joints and lenses, what the action of
> that, quote, \"inert\" polymer is on the vessel wall.
>
> We do know that there are many carriers of other substances which
> elute other substances which are highly toxic to the arterial wall by
> themselves. So I agree with you that we can\'t divorce the carrier
> from the drug, particularly when the drug is gone. So that remains an
> issue in my mind, and I think we should develop some verbal consensus
> on that issue.
>
> DR. WHITE: But Warren, I guess I\'m asking\--I would defer to our
> pharmacology colleagues here\--but what I heard presented\--and I
> guess we don\'t have evidence of this\--is that there are different
> doses with the stent, but it is evenly applied along the stent, and
> the way these devices will be used will induce, I think, a large
> variability in the total dose received.
>
> It would be nice to see what the gentleman, I think, from Wyeth said,
> which is that it doesn\'t matter\--I mean, that it is such a short
> peak that it doesn\'t matter. It would be nice to see some
> dose-response data that assured us that even at toxic levels, it
> wasn\'t.
>
> Maybe that just hasn\'t been presented plainly or clearly enough to
> us, because he seemed to be pretty comfortable that from the oral
> doses of this drug, it didn\'t seem to matter very much.
>
> DR. CANTILENA: I would just comment that in terms of systemic
> exposure, this is sort of an ongoing slow release for up to 6 weeks.
> In the calculations that I did with Dr. Throckmorton, we started with
> the slide that was shown by the sponsor as a total dose of 150
> micrograms, resulting in a peak concentration of 0.6, and then we
> heard that the highest dose would be exactly 10 times that, which,
> assuming linear, which I think you can, you are up to 6.0, and then,
> in the worst-case scenario, if you have an ongoing inhibition of
> CYP3A, you would increase that also by a factor of 10.
>
> So I think there is the possibility, which I think can be easily
> confirmed with a short study that can easily look at that.
>
> DR. LASKEY: That would be the answer to (b). I think it is fair to say
> that the panel does not certainly have consensus on whether there is
> adequate data here. Given that, there might be adequate data with, as
> you suggest, Dr. Cantilena, an additional study of drug dosage,
> systemic dose at doses greater than 350 micrograms.
>
> Good.
>
> DR. KRUCOFF: I just want to reemphasize the difference between\--we
> are talking about a topical application versus a systemic application,
> in an environment where I think we all would have a lot of questions
> about how important it is to cover\--to use a little longer stent as
> part of the topical application. That is where I just don\'t see that
> we could say that we have data, other than by doing what to me would
> be a pretty straightforward extended registry or subsequent study to
> get the data.
>
> DR. LASKEY: Are you happy with that, Dr. Zuckerman?
>
> DR. ZUCKERMAN: Yes.
>
> DR. LASKEY: Okay.
>
> \"Additionally, the nominal amount of total polymer ranges from 208 to
> 1,184 micrograms for the currently requested range of stent sizes. The
> animal studies conducted by the applicant on polymer dosages higher
> than 500 micrograms were limited to 28-day followup. The nominal total
> polymer amounts tested in the SIRIUS study ranged from 208 micrograms
> to 520 micrograms.\"
>
> \"Please comment on whether there is adequate evidence to support the
> use of stent diameters and lengths\--that is, 6-cell and 7-cell stents
> in lengths of 23, 28, and 33 mm and 9-cell stents in lengths of 18,
> 23, 28 and 33 mm\--with a nominal polymer dosage greater than 520
> micrograms.\"
>
> I think the answer is \"Not really; we don\'t know.\"
>
> \"If not, what additional studies or information would be necessary to
> support the safety of stents with a nominal polymer dosage greater
> than 520 micrograms?\"
>
> Well, the same answer, but I would probably ask for an additional
> length-of-time study. Again, if we are looking at the effect of
> polymer when the drug is gone, I would probably look at more than 28
> days.
>
> DR. EDMUNDS: Warren, I object. We don\'t have the data\--that\'s a
> given\--but I don\'t think the question is relevant when we haven\'t
> shown that there is any systemic toxicity at the doses that we\'re
> talking about.
>
> DR. LASKEY: I\'m not sure if this is about systemic toxicity, Hank.
> This is toxicity to the wall, perhaps.
>
> DR. KRUCOFF: Or the different between an intentional\--
>
> DR. EDMUNDS: You have no data to show that there is any injury to the
> wall.
>
> DR. KRUCOFF: But there is no data to say that if you line 60 mm of the
> wall with this stuff\--which the \"full metal jackets\" concept here
> is very much in the therapeutic potential of what would be the best
> result or what might open a whole new door of unanticipated results.
>
> DR. EDMUNDS: If you\'ve got a rash one inch square, and then you have
> a rash three inches square, you just add to the surface, and the dose
> and the surface go up together linearly. That\'s the way I see it.
>
> DR. CANTILENA: If I could just respond to that, you do have evidence
> of systemic exposure\--blood levels from the stent\--so you can
> extrapolate that if you increase the dose, you will probably increase
> the concentrations in whole blood. So that\'s your systemic exposure,
> and then the drug label talks about the relationship between systemic
> exposure and adverse events.
>
> So I think it\'s not that much of a jump, and I\'m just saying that
> you don\'t have the actual studies here, and there is a reasonable
> chance that the toxicity is probably going to be significantly lower
> from the stent. But if you get back to plasma levels or\--excuse
> me\--whole blood levels, you do have the possibility of comparable
> exposure at the higher dose. It is not something, I think, that is
> extremely far-fetched.
>
> DR. EDMUNDS: Can I respond?
>
> DR. LASKEY: Please.
>
> DR. EDMUNDS: In a transplant patient, you get 17 times the highest
> dosage, and you do it chronically, and there is no problem attributed
> to this drug.
>
> DR. AZIZ: I think in the transplant situation, you do get higher
> lipids as a result of that. Although these levels aren\'t as high as
> the transplant group, I think we should bear that into account, that
> there is an effect of higher levels in transplant patients.
>
> DR. LASKEY: And we\'re not talking about transplant patients here.
>
> Yes, Chris?
>
> DR. WHITE: And the other thing is to keep in mind the difference
> between the systemic drug issue and the local polymer issue, because
> the polymer issue is not systemic; the polymer issue is the artery.
> The sponsor described an inflammatory response. What happens in 2
> years?
>
> DR. LASKEY: That was my point, exactly.
>
> We don\'t have consensus, but we all agree that we need more data.
>
> The third question along the evaluation of safety: \"In SIRIUS, the
> Cypher group had 19 percent rate of incomplete apposition at followup
> versus 9 percent for the control.\" Obviously, this is incomplete
> apposition by IVUS. \"This included a 10 percent rate of late
> incomplete apposition for Cypher versus zero percent for the control.
> In RAVEL, the rate of late incomplete apposition was 21 percent versus
> 4 percent for the control.\"
>
> \"There was no obvious clinical correlation between late apposition
> and adverse events. Please comment on whether additional information
> is necessary to evaluate the significance of late stent malapposition
> found in the clinical studies.\"
>
> I think it is fair to summarize that the panel is saying we don\'t
> know what it means, whether it is just an IVUS curiosity or has
> potential clinical significance, and that followup beyond the data
> provided to us is certainly something that we would be interested in
> seeing, if not requiring.
>
> If I\'m not mistaken, does RAVEL not go out to 2 years? Don\'t we have
> 2-year followup on late stent malapposition in RAVEL\--18 months. So
> you have some of this, but again, it\'s an issue that needs to be put
> to rest in terms of whether it is a curiosity or a marker for adverse
> events.
>
> DR. ZUCKERMAN: I guess the question that I have, Dr. Laskey, is that
> during panel discussion, note was made about the small numbers in the
> IVUS cohort, and what we could conclude. While perhaps part (a) of
> your answer to please comment on whether additional information is
> necessary is to continue to follow those who have gone down the IVUS
> track, is there a need for larger numbers to be studied with IVUS to
> fully answer this question?
>
> DR. LASKEY: Well, here, we can play the statistical came, and maybe
> Kent Bailey can help us out. But we have a rate in this study called
> the \"biased subsample\" of IVUS, but there is information from the
> recent Gary Mintz \[phonetic\] paper on a baseline rate in a
> relatively unselected, non-study population for what this is. So there
> is information that to my mind would justify continuing to follow
> these people and not recruiting another whole cohort\--but I am
> willing to listen to my colleagues here for consensus or lack thereof.
>
> DR. KRUCOFF: I think that mandating additional IVUS procedures
> relative to the cohort reported in patients who are already enrolled
> would seem counterproductive to me. My understanding\--I guess we\'ll
> get to it later\--is that there is a plan for 5-year followup
> clinically in these patients, and out of a 1,000-patient cohort, if
> there were a significant problem, I would hope that that would surface
> as a clinical problem, that close attention to angiographic variables
> gathered in later clinical problems would make sense.
>
> The one thing that I might encourage would be if additional studies
> are done per the previous questions just answered, with longer stents
> or higher doses with greater drug and greater polymer exposure, I
> would certainly encourage both the sponsor and FDA to think about
> incorporating IVUS observations along the way, again, just to see if,
> relative to currently-tracked rates, it looks any different or behaves
> any differently.
>
> DR. LASKEY: Bearing in mind that it is not angiographically
> detectable, and the definition may vary from site to site as well.
> This is a technically dependent kind of finding, but you all need to
> standardize that.
>
> \"Is there any specific targeted followup\--additional testing, animal
> studies, bench-testing\--that could be requested to contribute
> important information regarding this clinical finding?\"
>
> I don\'t know if this is a clinical finding yet; it is a finding, an
> IVUS finding, perhaps of incidental significance, perhaps not, but I
> wouldn\'t call it a clinical finding yet, and I would just agree with
> Mitch that we need more information, certainly long-term followup.
>
> What do you think, Kent?
>
> DR. BAILEY: I think at a minimum just followup of the patients who
> already are known to have had late malapposition, or any
> malapposition, and if they are okay after a few more years, that\'s
> good news.
>
> DR. LASKEY: \"In the RAVEL study, subjects received aspirin for 6
> months and clopidogrel or ticlopodine for 2 months. In SIRIUS,
> subjects received aspirin for 9 months and clopidogrel or ticlopodine
> for 3 months. Please discuss your recommendations for antiplatelet
> therapy for patients receiving the Cypher product.\"
>
> I think the general rules have always been do what the study protocol
> mandated, and I don\'t think we would recommend anything different
> than that.
>
> Chris?
>
> DR. WHITE: I\'ll just stir that pot and say that it\'s a financial
> burden on the patients and that there is no evidence of any late
> healing problems or late thrombosis; there is no reason to be
> suspicious. And I would expect Marty Leone \[phonetic\] to quickly
> publish a paper that says that only 30 days is necessary for this, so
> it will change our clinical practice very quickly.
>
> But I would be happy to accept the RAVEL protocol as supporting
> information so that we can recommend maybe less than 3 months\' burden
> for our patients and still feel comfortable that we have met the
> safety.
>
> DR. PINA: Chris, what do you do now?
>
> DR. WHITE: I actually try very carefully to titrate or to select
> patients with more of a vascular burden to treat with chronic
> ticlopidine or Plavix, and I try to take patients who have less of a
> vascular burden and be sensitive to the cost of treating them. So I
> don\'t treat everybody the same.
>
> There is a minimum of one month of Plavix that I think we all agree,
> basically, that we use, but the people that I put on chronic therapy
> have more vascular disease than patients who have simple limited
> cardiac disease. I don\'t think everybody needs Plavix for life who
> has coronary disease.
>
> DR. PINA: I just think that we have a larger trial that has 3 months
> and 9 months of aspirin, and most of these cases are going to be left
> on aspirin anyway, because they will have vascular disease.
>
> DR. WHITE: No\--I agree with the aspirin part. But the question is do
> we want to set the standard in the labeling that really requires every
> physician to not deviate from that standard if we don\'t feel that it
> is really necessary.
>
> I think that\'s what it comes down to is RAVEL was only 2 months; it
> looks like there is no problem with late thrombosis. Why are we
> automatically picking 3 months without some reason?
>
> DR. ZUCKERMAN: I think there is a regulatory issue here to consider.
> Both clopidogrel and ticlid \[phonetic\] are not technically indicated
> in the PDR for this indication, so our general standard has been in
> stent labeling just to describe the way the unapproved drugs would
> use.
>
> We would certainly encourage the sponsor to do the sorts of more
> efficient studies that you recommended so that we could describe in
> the labeling just other conditions. But there is a certain line that
> we don\'t want to go further than in this application here.
>
> DR. LASKEY: Although lessons learned from brachytherapy would tell us
> otherwise
>
> DR. ZUCKERMAN: That\'s why we would encourage the sponsor to get the
> data. There is a precedent here with the STARS \[phonetic\] trial and
> the former development of stainless steel coronary stents.
>
> DR. LASKEY: Committee members
>
> DR. KRUCOFF: Morty, I think that gives you 32 days.
>
> DR. LASKEY: What are we recommending
>
> DR. KRUCOFF: I would be with Ileana just to start with the level of
> recommendation that is appropriate for a drug that is not approved,
> but to start with the protocol\--that\'s the data you\'ve got\--but
> recommended, not necessarily required\--the SIRIUS protocol.
>
> DR. LASKEY: I can\'t help but think about what Jeff Moses said when he
> finished here. He said we have altered the molecular milieu of the
> artery. We have done that, and I think we need to be safe.
>
> Question 5. \"The potential for interaction with several drugs has
> been evaluated as described in the Rapamune labeling. Interactions
> with other drugs might be expected based on known metabolism by
> CYP3A4.\"
>
> \"Please comment on whether the application adequately addresses drug
> interactions that are likely to be important or of interest.\"
>
> I think we can do that right now. No, it is really not.
>
> \"If not, what other information or studies should be requested?\"
>
> Mitch?
>
> DR. KRUCOFF: Just one question I didn\'t think to ask before, but is
> there any known cross-reactivity, allergically? Are there any other
> drugs that allergic reactions imply might cross over as an allergic
> reactivity to Sirolimus?
>
> MR. \_\_\_\_\_\_\_\_\_\_ \[Unidentified speaker\]: The class if drug
> is a macrocyclic lactone, which is actually different than some early
> confusion with macrolyte \[phonetic\] antibiotics, so there is
> actually no cross-reactivity with erythromycin or the other mycins,
> and it is a relatively distinct class.
>
> The only other related compound is tacrolimus \[phonetic\], which also
> doesn\'t show significant hypersensitivity reactions.
>
> DR. LASKEY: Lou, do you want to restate it
>
> DR. CANTILENA: Yes. I think that in terms of studies that should be
> done, it would be a very straightforward pharmacokinetic, drug-drug
> interaction study with inhibitors of cytochrome P4503A4, and all
> depending on the magnitude of the effects observed, and that would
> sort of impact on the labeling, which we will talk about later.
>
> DR. LASKEY: And those could be done in a handful of patients; is that
> right\--typical pharmacokinetic-
>
> DR. CANTILENA: Yes. It should be done probably, depending on the
> expected effect size, usually for CYP3A4 for polen \[phonetic\]
> inhibitors. In the oral situation, which this is not, you can usually
> easily get away with 6 to 12 subjects. But certainly it is unknown
> exactly what the effect size would be here because of the route of
> administration.
>
> DR. LASKEY: Again, I just want to reiterate something that I said
> earlier, which is the interaction with the HMG cholate reductase
> \[phonetic\] inhibitors, which may be started along with the stent
> implantation in patients who weren\'t on it preceding. So that\'s a
> very common drug, and we ought to look at that interaction for
> systemic toxicity.
>
> \"Has the followup been adequate to address concerns about possible
> systemic adverse drug effects?\"
>
> I think it has.
>
> Question 6. \"The primary effectiveness endpoint for the SIRIUS study
> was target vessel failure rate at 9 months, 270 days. Rates of TVF at
> 270 days were 8.6 percent for Cypher and 21.0 percent for the Bx
> Velocity control group.\"
>
> \"Does the evidence presented on the Cypher product provide reasonable
> assurance of effectiveness at 270 days?\"
>
> Actually, it is efficacy, isn\'t it? And I think it does. Can we all
> agree? Yes. Thank you. We\'ll see about the effectiveness soon.
>
> Question 7. \"Prolonged inflammation and notably increased restenosis
> were observed when polymer-coated, but drug-free, stents were
> implanted in swine. In swine implanted with Cypher product\--that is,
> coated with both drug and polymer\--this effect was not observed at
> one month post-implant, but was observed at both 3 and 6 months
> post-implant.\"
>
> \"Given the unparallel timeliness of healing between juvenile and
> normal pigs and atherosclerotic older adults, do these findings raise
> significant concerns about the ability of the clinical followup to
> address the possibility of a similar delayed occurrence of neointimal
> hyperplasia?\"
>
> I think I have heard that they do.
>
> Dr. White?
>
> DR. WHITE: I guess I\'m not sure that they do. The question is at what
> point\--how late. We have already said that 9 months is probably not
> enough to be completely sure. But I\'m not highly suspicious that
> there is a downturn in any of those curves. So I am pretty
> comfortable, but I would like to see that later data, I guess.
>
> DR. LASKEY: Okay. I think we all agree with Hank Edmunds\' comment
> about seeing more of the lines going beyond 270 days for event rates.
>
> \"If so, please comment on whether additional testing or
> followup\--pre- or post-approval\-- is necessary to support the
> effectiveness of the Cypher product.\"
>
> Again, I think that by observing the SIRIUS population out beyond 270
> days, we may have the answer. We probably will.
>
> Question 8. \"The temporal relationship between scheduled angiography
> and revascularization, and analysis of the subgroup that did not have
> angiography, suggests that angiographic outcomes may have influenced
> the clinical outcomes in a way that differentially affected the
> control group.\"
>
> \"Please comment on the adequacy of the primary 9-month TVF endpoint
> for capturing the expected clinical benefit of the Cypher product in
> light of the possible influence of 8-month angiography results.\"
>
> I think we have discussed this extensively here in the last hour, back
> and forth, and I think we are all satisfied with the explanation, and
> we understand the limitations of this approach, and we have known time
> and time again that rates in populations that don\'t undergo routine
> angiography are always less than those that do.
>
> \"Are there other ways the clinical impact should be assessed, either
> for a) evaluation of efficacy in determining the appropriate
> indication, or b) for information to be conveyed in labeling?\"
>
> Well, I think if we\'re sort of comfortable with the paragraph here,
> I\'m not sure we need to look for ultimate ways de novo.
>
> Mitch?
>
> DR. KRUCOFF: I do think that an analysis in the same structures as
> presented but using sight or visual reference vessel diameter and
> lesion length would be informative just to make sure it is not
> inconsistent with what the QCA results showed.
>
> DR. ZUCKERMAN: Well, Dr. Laskey, can we go back a moment on this
> question and go back to some of the points that Dr. Bailey raised as
> to how the angiography causes a blip in the Kaplan-Meyer curves which
> are perhaps artificial.
>
> Certainly these trials evolved from our initial stent experience in
> our intracoronary brachytherapy experience where it has been very
> important to look for edge effects and to use the angiogram as a
> mechanistic instrument. And certainly we know from some European
> drug-coated stent trials that the importance of angiography for
> picking up safety effects has been demonstrated again.
>
> On the other hand, to have three-quarters of the total patient
> population getting followup angiography perhaps is overkill,
> overpowered, and biases the interpretation of the true clinical
> effect.
>
> So I would like Dr. Bailey or Dr. Laskey to comment on how much
> angiography is necessary, but is there a better way a) to temper it
> and b) to perhaps indicate if it is worthwhile to perhaps indicate in
> a label the clinical restenosis rate in patients who do not undergo
> followup angiography\--i.e., is that a true representation of
> effectiveness in the real world
>
> DR. BAILEY: I think I agree with everything you said. I think we were
> reasonably convinced that given you are willing to accept appropriate
> revascularization, which I would say because all these people got
> angiography is not entirely a clinical definition, nevertheless I
> think the relative efficacy was shown, but certainly the clinical
> impact would be better estimated by the people who didn\'t get routine
> angiography.
>
> But one suspects that\--I mean, a good fraction of the
> revascularization events occurred prior to that time, so it is just
> sort of a little\--
>
> DR. WHITE: These patients were still blinded, so the decision to
> overutilize and overtreat should have been distributed equally so it
> doesn\'t affect the efficacy of the device\--I mean, the device is
> still powerfully effective; we just may have overutilized.
>
> DR. BAILEY: The question, though, is how many of those who were
> revascularized would have eventually come to attention and gotten it
> anyway.
>
> DR. WHITE: Is that important?
>
> DR. BAILEY: Well, some of those people may never have had any
> problems.
>
> DR. WHITE: That may be true, but I don\'t think that that impacts on
> the trough.
>
> DR. LASKEY: We\'re kind of torn here, and I thought that Rick Kuntz
> expressed it quite well, as usual. You need to decide whether you want
> to look at the biology here or the clinical efficacy, and your
> biology\--you needed to learn what is going on here, so you needed
> angiography, you needed pictures. If you just wanted to do a TOR
> study,it would have been your preference to do a TOR study. That\'s
> the clinical restenosis rate in the real world.
>
> I think that what we are grappling with here and the reason we are in
> this soup is because the study was designed to really look at both of
> these issues, and you have the biology and the angiography, and then
> you have the clinical relevance, but even that was strongly
> statistically significant albeit in the 15 or 20 percent of the group
> that didn\'t undergo routine angiography, so the effect is preserved
> in that small group, too, but it is a very telling lesson.
>
> You look puzzled.
>
> DR. EDMUNDS: But the donut is still the high line in the stent group
> of low restenosis. The hole is the loop in the control group.
>
> DR. LASKEY: And?
>
> DR. EDMUNDS: Well, the point is that the stent works. It gives you a
> much lower restenosis rate than we have seen clinically, and it was
> demonstrated angiographically in this study, and that\'s the point
>
> DR. KRUCOFF: I agree. I think no matter how you slice it, including at
> the 7-1/2 month point, the biology and the clinical are very
> consistent. I don\'t think it\'s \"soup\"; I think it\'s pretty
> consistent
>
> DR. ZUCKERMAN: The point, though, is I don\'t think anyone disagrees
> that within the context of this trial, the drug-coated stent is
> effective. It is more in the labeling. What is a better guesstimate of
> what the true clinical rate is, and it is perhaps in those\--the
> question is, is it in those patients who don\'t get followup
> angiography, and should that be indicated.
>
> DR. LASKEY: I think you can report both outcomes in the labeling and
> just leave it at that. If you wanted to do a TOR study, you should
> have done a TOR study. Certainly reporting both is nothing to be
> ashamed of. Both are very positive.
>
> DR. WHITE: Bram, are you concerned that you are going to magnify
> the\--I don\'t understand the concern, because stress and Benestent
> \[phonetic\], all of those trials are angiographically driven
> endpoints. When we quote restenosis rates to patients, we are quoting
> these angiographic rates. So that quoting the stenosis rate isn\'t the
> same as the number of people who are treated. It is still not going to
> change the people who had more than 50 percent restenosis rate.
>
> DR. ZUCKERMAN: The reason why I ask this question is that we are just
> concerned with truth-in-labeling and the labeling of the coronary
> stent. Table 17 that Drs. Bailey and Kuntz discussed is a very telling
> table because the evidence of the occulostenotic reflex, which was
> between 20 and 30 percent in both groups, i.e., revascularization with
> questionable clinical symptoms based on angiography, is a theme that
> we have seen for the last almost 10 years in stent versus stent
> trials, and reflects a certain rate that you will see in a clinical
> trial where angiography is necessary. But for the working clinician
> who wants to appreciate what the effectiveness of the device is, it is
> perhaps not the only number that one should consider.
>
> That\'s all.
>
> DR. LASKEY: Therefore, report both
>
> DR. PINA: Mr. Chairman, I think that, Bram, may be where the
> noninvasive testing would come in handy for information, because
> that\'s what is most commonly done. We don\'t ordinarily cath at 6
> months or at 8 months or at 9 months. I don\'t know\--Chris, do you?
> What do you do?
>
> DR. WHITE: No, we don\'t. But I think the interventional cardiology
> community is fairly comfortable with this data, and we understand the
> dichotomy of what is being discussed here. This is part of our daily
> life.
>
> The occulostenotic reflex is there. You get angiogram and\--look
> out\--you\'re going to get something done to you.
>
> The problem is that the noninvasive tests are not accurate enough. I
> mean, we all have stories of\--we don\'t want to divert to anecdote
> here\--I think reporting both is fine. Knowing what the restenosis
> rate is I think gives adequate information. Not everyone with
> restenosis needs to be revascularized for a clinical endpoint, and
> that is I think what Bram\'s point is. We ought to just report that.
>
> DR. LASKEY: \"Because the control stent is not approved for de novo
> stenosis in vessels of diameter less than 3 mm, the applicant provided
> additional analyses, including a Bayesian comparison to historical
> angioplasty data. Please comment on whether adequate evidence has been
> presented to demonstrate the effectiveness for stents with diameters
> less than 3.0 mm.\"
>
> We are intrigued by the Bayesian analysis\--Kent
>
> DR. BAILEY: I like the point that I think Dr. Kuntz made that looking
> at the historical data makes us comfortable using the bare stent as a
> control.
>
> So I think if we could resolve what subset of patients in the SIRIUS
> study benefitted and whether it can be extrapolated beyond that\--I
> think Bayes is nice, but it is the GI/GO thing. You can\'t really get
> more than you put in.
>
> So I think that is useful, but I think I like the idea of going back
> to the bare stent as a reference group.
>
> DR. LASKEY: I don\'t think the reservation we have is with 3.0 or
> perhaps even 2.5, but when you get down to 2.25, that\'s where we are
> not particularly happy no matter how much hand-waving that is.
>
> I think that summarizes our level of acceptance. Yes.
>
> \"Univariate regression analyses of data collected in the SIRIUS study
> suggests that the treatment effect may be reduced in longer-length
> lesions. This could be due to either a true diminished treatment
> effect or a lack of power\--too few subjects\--to detect a treatment
> difference in subjects with longer lesions.\"
>
> \"The applicant has performed logistic regression analyses, but these
> analyses only included main effects and did not specifically evaluate
> the possible interaction between each variable and the treatment
> effect.\"
>
> I thought you did; I thought you showed early on-
>
> DR. ZUCKERMAN: The question was written before the sponsor presented a
> very late analysis that has not been fully evaluated by FDA.
>
> DR. LASKEY: All right. But this business of post hoc power, that
> because you don\'t find something, you just don\'t have enough power,
> I thought that was a statistical no-no. You have power going into a
> study, but you have one power, and that\'s it. That\'s the power of
> the study, to find the difference. You can\'t really then backtrack
> after it\'s done and say, \"Here is our power; we were
> underpowered\"\--isn\'t that correct?
>
> DR. WHITE: I think he\'s talking about subsets
>
> DR. BAILEY: Right.
>
> DR. WHITE: It\'s underpowered for the subset of this whole thing.
>
> DR. LASKEY: Okay.
>
> DR. BAILEY: Right. The study wasn\'t powered to detect\--and most
> studies aren\'t powered to look at interactions, although this one
> comes pretty close because of the fact that the treatment effect is
> very large does suggest that there might be power to look at subsets.
>
> But the other point is what is the right null hypothesis\--and I think
> Dr. Hyde brought this up. Usually, we say with the null
> hypothesis\--we are trained to say the null hypothesis is no
> interaction, so we\'ve got to see data to prove that there is an
> interaction. But here, the conservative approach is to assume that
> there is a subset treatment interaction. So it should be a whole
> different way of looking at interactions, not demanding high levels of
> evidence that there is one, but showing that the data aren\'t
> consistent with enough of an interaction to make a difference.
>
> DR. LASKEY: So therefore, \"Do the data presented provide reasonable
> assurance of effectiveness for treatment of the full requested range
> of lesion lengths, including less than 30 mm?\"
>
> DR. KRUCOFF: I just want to mention again that there was an inclusion
> lower limits as well in this study that is not reflected in the
> request for approval, which is where we are talking about by going
> lower than 30, also going lower than 15. And I am as concerned about
> where data doesn\'t exist in shorter lesions, which we all know have
> lower restenosis rates when stented, and what has been provided as
> data supporting effectiveness.
>
> DR. LASKEY: I guess you\'re dealing us a hedge here. \"Reasonable
> assurance of effectiveness\"\--look at the curves, I think there is
> reasonable assurance\--it\'s not solid; it\'s not as though you did a
> head-to-head randomized trial in those regions of vessel lengths, but
> it is reasonable.
>
> Do we agree?
>
> DR. WHITE: I kind of like what Mitch said, and that is that I think
> we\--in clinical practice, we are not going to limit a practitioner\'s
> ability to treat a lesion that needs to be treated on an individual
> basis, but I think if we say that the data for the investigators were
> 15 to 30, and we found effectiveness for that data, then I think that
> that is where that stands. I see no desire to push that any lower
> than\--there is no reason to go any lower. And it doesn\'t limit how
> we treat patients, and it is a conservative approach for us to take
>
> DR. ZUCKERMAN: Okay, but the dataset under consideration by this panel
> today is the RAVEL data, the SIRIUS study, and the First-in-Man, with
> the RAVEL data being lesion lengths less than\--what is it; 15 or
> something like that\--
>
> DR. WHITE: And to be covered by an 18 mm stent; right?
>
> DR. ZUCKERMAN: Correct.
>
> DR. LASKEY: Those lengths on the order of 8 or 9 mm; right?
>
> DR. EDMUNDS: Can I just say something? In practice, if somebody has a
> 7 mm lesion, is he going to put in a bare wire stent, or is he going
> to put in a 15 mm coated stent? That\'s reality out there.
>
> DR. WHITE: But in reality, what we decide today doesn\'t really impact
> that very much in that I would like to be able to stand behind what we
> say today in the future, and I feel very comfortable about 15 to 30.
>
> It may be okay to treat 12\'s or 8\'s, but I feel very comfortable
> about 15 to 30
>
> DR. KRUCOFF: Yes, I think we have to remember the distribution curve.
> Even in the 15 to 30, in fact, the bulk of the distribution is in one
> section; it is not evenly distributed across 15 to 30. So at 15 and at
> 30, we are already tailing off, and I think that that is expectable, I
> think that is normal in a prospective design, but\--
>
> DR. WHITE: It goes back to Mitch asking for the site-specific data,
> and that is that my eyes see 15 mm, but Jeff Potma measures 11.2. I
> mean, I think we want to target our recommendations to what the
> investigators were trying to do.
>
> And I guess I have trouble with RAVEL because I didn\'t get a good
> feeling for the comparability of the short studies in RAVEL, whereas
> this trial seemed to be better.
>
> In fact, there is a graph that I looked at on page 112 that actually
> looks at terciles of lesions treated and compares them for the coated
> and uncoated stent, which is data that I was interested in, and it
> actually demonstrate across each tercile, small, medium, and large,
> the efficacy of the stent. That\'s the kind of data that I think makes
> sense. It doesn\'t deal with lesion lengths. Was there a lesion length
> table like that? What page? Help me, because that\'s really good for
> the diameter, because it tells you exactly what they got.
>
> DR. DONOHOE: \[Inaudible comment; no microphone.\]
>
> DR. LASKEY: Does that cover lengths and diameters satisfactorily?
> Okay.
>
> \"Does the data presented provide reasonable assurance of
> effectiveness for vessel diameters of 2.25 mm?\" This should be an
> easy one. No.
>
> Thank you.
>
> \"One aspect of the premarketing evaluation of a new product is the
> review of its labeling. The labeling must indicate which patients are
> appropriate for treatment, identify potential adverse events with the
> use of the device, and explain how the product should be used to
> maximize benefits and minimize adverse events. Please address the
> following questions regarding the product labeling.\"
>
> \"1. Comment on whether the Indications for Use statement identifies
> the appropriate patient populations for treatment with this product.\"
>
> \"Has the application provided reasonable assurance of safety and
> efficacy for treating the full requested range of vessel
> diameters\--2.5 mm through 5.0 mm.\"
>
> I think we just answered that for you, that at the extremes, it does
> not. And, panel members, where do we want to pare things down\--to the
> study inclusion\--
>
> DR. WHITE: Could I just draw the distinction in my mind as an
> interventionalist between the diameter range the length range is that
> the length range is at an individual operator\'s discretion, and that
> I can treat as long or as short a lesion as I like. But if we limit
> the diameter, that means that I will not have the ability to treat a
> 2.25-size vessel because it won\'t be made, it won\'t be sold.
>
> So the length business becomes\--we can be very conservative\--but I
> think the diameter, we ought to be more liberal.
>
> Does that make sense? No, it doesn\'t
>
> DR. KRUCOFF: Hell, no.
>
> \[Laughter.\]
>
> DR. KRUCOFF: I think it\'s called \"data,\" Doctor. I think the
> inclusion criteria are the center, the focus, of a trial that was
> prospectively statistically designed to answer and has clearly shown
> efficacy and safety in the boundaries of that trial, even though we
> know there are, again, tails out to the sides; those tails in diameter
> to are just as fuzzy, Chris, as\--
>
> DR. WHITE: But on page 112, if you look at the small size, the mean
> diameter that was treated in the small tercile was 2.32 mm. Now,
> that\'s QCA, and I think that\'s the rub here, but the range of those
> diameters was 1.48 to 2.56. So I think that you get pretty far down,
> and I don\'t think it would be a grave injustice not to accept this
> QCA data on the low end of the curve. I think it\'s all judgment,
> because there is some data to support 2.25. It is not just drawn out
> of thin air, and it\'s not a dotted line somewhere.
>
> DR. KRUCOFF: But the labeling is going to talk to clinicians who are
> using visual estimates, not QCA, and I am really concerned that we\'ll
> convey the wrong message.
>
> DR. WHITE: Are you so concerned that you\'re going to take the 2.25
> out of my hands?
>
> DR. LASKEY: I guess what we have learned here is that 2.25 is really
> 2.50, so your eyeball is overestimating the true\--so maybe we
> shouldn\'t be so concerned
>
> DR. ZUCKERMAN: What would be helpful to FDA and the sponsor is we are
> not taking the 2.25 out of your hands, Dr. White, but generally,
> labeling, as Dr. Krucoff indicated, reflects what was studied in the
> trial. So today, at both extremes, we have heard about lack of data,
> so if you have any suggestions for trial design for small-diameter
> drug-coated stents or large-diameter drug-coated stents that could
> move this process forward, we would always be interested in hearing
> it.
>
> DR. KRUCOFF: I think that probably would be pretty straightforward.
>
> DR. WHITE: I would think that a small vessel trial could be done at
> minimal expense. I don\'t know that it has to be a randomized blinded
> trial since we have this data already on board; we could maybe pick
> some objective performance criteria and collect data that might
> satisfy us on the smaller end of the scale.
>
> DR. LASKEY: This is a small vessel study here. This is the old story
> of QCA versus eyeball. It is actually smaller than we think it is, so
> in a way, these data answer it, that it is of use in small vessels.
> There is data here\--it is not robust, but there is data\--so I\'m not
> sure I want to do a whole randomized\--I wouldn\'t recommend another
> randomized trial to the FDA.
>
> Colleagues, where are we
>
> DR. BAILEY: I guess I\'m sort of lost. If the QCA and the visual are
> so different, what does the label mean, or what does the indication
> mean? And I guess I get nervous that the design of the trial is to
> recruit in a certain range, and then, in fact, a lot of the patients
> turn out to be outside that range.
>
> So, should the indication be what the eligibility criteria are, or
> what the patients actually were
>
> DR. KRUCOFF: I think you have to just recognize that the eligibility
> criteria go to investigators. The investigators at the sites use their
> eyeball to say that artery looks like it\'s eligible. And other than
> the 43 deregistered, that\'s where you get 1,000 patients.
>
> What is very clear is that when you do meticulous, highly
> reproducible, digital, quantitative angiography, we get different
> measures than what site investigators see with their eyes. That is
> well-described and well-known.
>
> But when you then label a product, that label is back to the
> investigators using their eyeballs out in the real world. I really
> think we either need to bridge the data or at least respect the gap,
> because this is ultimately for indications; this is for labeling
> that\'s going to go on a product and be used by clinicians in sites,
> not by core labs.
>
> DR. WHITE: But what we also know, as I think Dr. Potma mentioned, is
> that the optimal way to use these devices is to match the stent to the
> vessel size. So that if I really do use online measurement of my
> vessel, and I know that I have a vessel that is 2.3 mm, then I might
> well prefer to use a 2.25 stent than to try to underdeploy a 2.5 mm
> stent in that vessel; and I think that that\'s the clinical rub that
> we get into.
>
> And with the length issue, it\'s not such a problem, because I can
> always put an extra stent or leave one out; but with the small size,
> if we don\'t have an indication, we may not have a small size to use.
> The manufacturer can\'t build a size that\'s not indicated; is that
> right? They can\'t sell me or build a size that\'s not indicated?
>
> DR. ZUCKERMAN: Not without a clinical trial if the indications are 2.5
> to 3.5.
>
> DR. WHITE: So what we are deciding today is what the QCA means to us
> and what the eyeball means to us and how conservative and liberal we
> are willing to be with that data, because I think the conservative way
> to say we would like to have 100 patients, and maybe not randomized,
> and not even with angiographic controls\--there could be another way
> to collect this data, and we could make that recommendation as a
> compromise if you are not willing to accept the QCA data as the
> justification.
>
> MR. MORTON: Mr. Chairman, just one way of thinking of this\--and I
> think this is what we are saying\--is do we make it available along
> with the information on what came out of the study, so that each
> doctor can make an informed decision that the device is there when the
> patient need is there.
>
> DR. WHITE: Does anybody really believe that the 2.25 will not perform
> as the 2.5 did, I think? If you have significant doubts that it won\'t
> perform that way, then we ought to ask for more data. I think if the
> benefit of the data is that it probably will behave as the 2.5, and we
> have the QCA data that says the mean of 2.3 was effective, then I feel
> pretty comfortable about having that as a size
>
> DR. FERGUSON: As an Auslander \[phonetic\], but as I have listened to
> this today, it is apparent to me in my work at my place that matching
> the stent size to the vessel is much more important than some of these
> other factors. So I would come down on the side of being lenient about
> the size.
>
> DR. LASKEY: I think what you\'re hearing is that we\'re voting with
> our clinical\--you are getting a clinical gut reaction which the
> clinicians here all seem to buy into. The data may not be robust, but
> you are getting a clinical\--we are coming down on the side of being
> doctors here and not statisticians. So that we would opt to keep it
> available for the rare instance where it is needed.
>
> DR. WHITE: What about the high end, the 5.0 mm device?
>
> DR. LASKEY: What about it, Chris.
>
> DR. WHITE: I have shot my wad on the low end.
>
> \[Laughter.\]
>
> DR. LASKEY: Symmetry is all here.
>
> DR. PINA: Warren, I think if we\'re going to be lenient on that side,
> then we need to be lenient on the other side, but I do think that the
> product labeling, just like we said everything else needs to reflect
> the smaller number of patients and reflect the fact that the IVUS is
> clearly different than the eyeball. I think that as long as clinicians
> are aware of that\--
>
> DR. WHITE: The one difficult with the high end is that if you look at
> the QCA data and the range, there is no 5 mm vessel in the study,
> whereas there were 2.25 mm vessels in the study. So the range appears
> to be 2.98 to 4.34 for the drug-coated stent sizes.
>
> DR. LASKEY: Yes. I think the hooker here, if we are going to put on
> our clinical hats here\--a 5 mm vessel is probably not a native
> coronary; you know that those are single-digit restenosis rates with
> metal stents in the current year. I think what we\'re really talking
> about here really are vein grafts, and then that\'s a different best.
> So, then, how do you go off-label with these for vein grafts? But I
> don\'t know if we can jump that far ahead of ourselves here. But
> realistically speaking, that\'s what 5 mm speaks to me. It means a
> vein graft. I don\'t think you need a coated stent in a 5 mm-
>
> DR. WHITE: Bram, could you speak to us just a little bit about how it
> actually works if you ask for additional information to support that
> claim? What kind of delay, what kind of complexity would you be
> introducing into the process if you ask for that
>
> DR. ZUCKERMAN: I think what I have heard here\--and that\'s why next
> steps suggested by clinicians are important\--is that one does not
> need to repeat the SIRIUS trial to potentially approve
> smaller-diameter stents or larger-diameter stents.
>
> In fact, our general recommendation for a small vessel study below
> 2.5, due to the fact that you have more restenosis events without
> clinical symptomatic angina, is that we have accepted an angiographic
> endpoint for small vessel study. For SVG studies, we have also
> accepted angiographic endpoints.
>
> We would be looking for data that would complement the core dataset
> that used primarily a clinical endpoint. That is the paradigm that we
> have used in the past to make sure that this is an efficient process.
> We realize that there is a limited total product life-cycle with these
> devices and fast turnover; on the other hand the \"D\" in FDA does
> bespeak the need for data.
>
> DR. LASKEY: I have one question for Dr. Fitzgerald.
>
> Do you think it is more likely that one sees incomplete apposition
> with larger vessels, larger placque, more remodeling, et cetera, et
> cetera? Is that likely to be the case, or do you think you have seen
> that
>
> DR. FITZGERALD: I think the experience with observing late incomplete
> apposition in a drug-eluting arm is essentially nil. But in a bare
> metal arm, especially in the studies that have associated themselves
> with aggressive debulking, like the DCA studies, we have certainly
> seen that with bare metal, but it has only been at the edges. But
> there is just very little experience in the drug-eluting platform at
> 5. If you want me to speculate, I would be glad to, but there are no
> data in those size vessels.
>
> DR. LASKEY: My impression is that with larger stents, they tend to be
> underdeployed.
>
> DR. FITZGERALD: That\'s right
>
> DR. LASKEY: And an underdeployed stent is likely to have this beast?
>
> DR. FITZGERALD: But it is a preserved incomplete apposition, and we
> see this time and time and time again. That\'s a different beast than
> the acquired late incomplete appositions, but absolutely, on the
> periphery, we see this all the time\--preserved incomplete apposition.
>
> So I\'m not sure that it has much of a bearing here\--
>
> DR. WHITE: Have you looked at self-expanding stents versus
> balloon-expandable stents for this phenomenon, this epi-phenomenon, of
> incomplete apposition? I would bet that self-expanding stents have a
> lot of this. And we don\'t see clinical phenomena that co-correlate
> with that
>
> DR. FITZGERALD: No, not at all. And we only had one opportunity to do
> that in the coronaries, as you know, with the self-expanding stent
> some years ago, and we didn\'t see that.
>
> DR. LASKEY: So, based on our sense of fairness and symmetry, we would
> probably allow the 5 mm stent in for native coronaries.
>
> DR. WHITE: Yes. Personally, I was going to pull back a little bit and
> say that I really want that stent\--I really want to have it in my
> hands\--but I think that if I could do it in a quick and easy enough
> way with the data, I would be willing to delay that gratification for
> a few months in order to have the data to show that.
>
> DR. LASKEY: So you are suggesting the construct of an additional study
> for large coronaries.
>
> DR. WHITE: Yes, and small \[inaudible\].
>
> DR. AZIZ: Why don\'t you just vote on that amongst the panel?
>
> DR. LASKEY: I think there is enough dissension so that we\'ll take
> this up during the voting.
>
> \"What length of lesions should be included in the Indications for
> Use?\" Here we go. I think we should stick to the inclusion criteria.
> People will do what they\'re going to do\--we know that, and it comes
> up repeatedly\--but this is what we endorse.
>
> DR. BAILEY: And we hope that people continue to overestimate.
>
> DR. LASKEY: \"Please comment on the contraindications as to whether
> there are conditions under which the product should not be used
> because the risk of use clearly outweighs any possible benefit.\"
>
> I didn\'t hear that today\--did I?
>
> DR. WHITE: We didn\'t get a chance to actually ask about the use of
> the device in other therapies, did we? What about after failed
> brachytherapy? What about after failed\--any other treatment? Have you
> observed any particular pitfalls with this device? Should we warn
> people away from doing certain things?
>
> DR. DONOHOE: The only experience we have in treating patients who
> failed brachytherapy is in the compassionate use program right now,
> and that is ongoing; we don\'t have any systematic, clean data
> collection adjudicated to this point. But there is a group of patients
> in that group that is being tracked.
>
> DR. KRUCOFF: Dennis, how about thrombotic lesions or heavily-ulcerated
> lesions or just morphologically unique lesions? Are there any
> instances that you have come across that we should think about
> steering away from rather than toward?
>
> DR. DONOHOE: No. I think in terms of, as you saw in the exclusion
> criteria, heavy thrombus formation, the lesion was an exclusion, but
> there were a few patients in both this study and in RAVEL and in other
> studies, like the in-stent restenosis feasibility study, in which
> occlusions or heavier thrombus \[phonetic\] was present, and there
> didn\'t appear to be any safety issues in terms of using the Cypher
> stent in that patient group\--but it was a small number.
>
> DR. AZIZ: What about\--obviously, we don\'t have data for left veins
> \[phonetic\], things like multi-vessel disease. Right now, this data
> has really been targeting single-vessel, maybe two or three stents in
> the focal-type lesion. There is no other data that clearly addresses
> multi-vessel disease. Maybe I have opened up a Pandora\'s box there.
>
> DR. LASKEY: You have. I don\'t think that that is within our purview
> here.
>
> Is it worth commenting on the fact that the way the protocol was
> designed, you require pre-dilation; you are not forbidding primary
> stenting? Are you contraindicating primary stenting without
> pre-dilating?
>
> DR. DONOHOE: All the clinical data in both the RAVEL and SIRIUS trials
> were based on pre-dilatation. There was no direct stent data in that
> study.
>
> DR. WHITE: Do you know of any information that makes this stent
> perform any differently than the Bx Velocity, which has been used
> successfully for primary stenting? There is nothing about this stent
> that would make it less effectively as a primary\--
>
> DR. DONOHOE: No. The only clinical\--
>
> DR. WHITE: Do you scrape off the drug?
>
> DR. DONOHOE: The only clinical trial data we have involving direct
> stenting is coming out of a study similar in design to SIRIUS that is
> being conducted in Europe, and we have only recently looked at 30-day
> MACE rates and deliverability on this, and \[inaudible\] differences
> between the active and control group.
>
> DR. ZUCKERMAN: I think that for the purposes of this discussion, it is
> important to recognize what the FDA defines as a contraindication. An
> appreciation of that is in Section 3 of the proposed sponsor labeling
> where we are talking about a situation that you don\'t want to get
> into because as clinicians, you think it is extremely bad, verging on
> medical malpractice.
>
> The things that you have suggested go in the heading of \"Warnings and
> Precautions\" or just statements that in this patient population, we
> haven\'t studied the drug-coated stent\--are there any specific
> contraindications other than inability to use \[inaudible\]
> coagulation therapy or appropriate balloon inflation that people can
> think of?
>
> It is an order of statement that is much more serious.
>
> DR. AZIZ: But there, are you talking about contraindications?
>
> DR. ZUCKERMAN: Yes.
>
> DR. LASKEY: Are there any clinical scenarios where this might be
> inappropriate\--patients on Rapamune, patients on dialysis?
>
> DR. AZIZ: We don\'t have the data for that; right?
>
> DR. LASKEY: No, we don\'t, but we are just talking about setting up\--
>
> DR. AZIZ: That could come under \"Precautions\"\--
>
> DR. LASKEY: Okay.
>
> DR. AZIZ: \--because I think that\'s where the multi-vessel stuff and
> the left vein should really be mentioned, because the data that we
> have looked at is really looking at a single vessel and a focal
> lesion. So it is not a contraindication, but I think it is a
> precaution or a warning.
>
> DR. WHITE: That needs to be noted.
>
> DR. LASKEY: We would not suggest putting that into the product
> labeling. But we are in agreement with a verbal warning about the use
> in relationship to brachytherapy\--is that correct? We just have so
> much uncertainty about its safety in this setting that we would agree
> with leaving that in. Okay\--a warning.
>
> 11d. \"Please comment on the Operator\'s Instructions as to whether it
> adequately describes how the product should be used to maximize
> benefits and minimize adverse events.\"
>
> I am comfortable with the Operator\'s Instructions.
>
> DR. KRUCOFF: I think the one thing that I would be concerned about in
> language for both\--maybe some for Operator\'s Instructions and some
> for Warnings and Precautions\--would be to pretty overtly tell
> operators that this is not just another stent, and to make it clear
> that direct stenting might impact on the surface of this thing, that
> putting in multiple stent changes the dose applied\--just some sort of
> language, and again, whether it is more Warnings and Precautions or
> more Operator\'s Instructions to alert operators that using this the
> way it is intended to and telling them more about it may be more
> important than just another stent\--and just to be sure that that is
> clearly stated or bulleted somewhere in either Warnings and
> Precautions or Operator\'s Instructions.
>
> DR. EDMUNDS: What you bring up is limiting the number of stents per
> patient.
>
> DR. KRUCOFF: Well, I don\'t think you can pick a number so much as
> just to make operators aware that being cavalier about taking a
> breakthrough technology beyond where there is information about its
> safety and effectiveness is something they should think about.
>
> DR. EDMUNDS: Well, you have come full circle. You are worried about
> overdose and toxicity. You can put in yards and yards of stents, and
> you\'re going to get a pretty good dose.
>
> DR. PINA: Warren, Section 8.2 in the Instruction Manual does discuss
> where they have no data on brachytherapy, and we have left main in
> there, which, Salim, you had some concerns about, but that might be a
> good place to add multi-vessel disease as another area where we don\'t
> have data. That would be my only comment about the labeling there for
> the instructions for physicians.
>
> DR. LASKEY: Well, it is in the exclusion criteria which will be in the
> label so people can see that these folks were not in the study, and
> the data doesn\'t apply, technically.
>
> DR. ZUCKERMAN: That\'s right. The reason why patients with
> multi-vessel disease were excluded was because if you have three
> lesions in one patient, you get into cluster effects, nonindependence
> of the restenosis, so it makes for a cleaner trial. I don\'t think we
> have\--does the panel believe there is a special reason, though, why
> you couldn\'t stent two separate lesions if you have a patient with
> two-vessel disease?
>
> DR. AZIZ: I think the study doesn\'t address that issue. I mean, it\'s
> like putting two valves into somebody. I think this data, at least to
> me\--and certainly, I am not in a cath lab\--it really comes down to
> you are addressing focusing on one vessel, and your results, the good
> results, really reflect what you found in one-vessel disease.
>
> I think if you were looking at putting these stents in multi-vessels,
> you would need the data to look at that.
>
> DR. LASKEY: I think everyone in this room is aware that that is going
> to happen no matter what we say, and I guess there is a multi-vessel
> trial ongoing, so it is not as if it is being left unaddressed. But it
> is going to happen on day one. People will put a stent in the right
> and a stent in the LAD. I mean, we have to confront this, and we do
> all the time, and I guess we come down to is it safe to do it, but it
> will happen particularly for this product.
>
> \"What aspects of drug pharmacology, mechanism of action,
> pharmacokinetics, drug interactions, or systemic effects should be
> added to the labeling to maximize benefits and minimize adverse
> effects?\"
>
> I guess if you were to summarize your point of view\--
>
> DR. CANTILENA: Yes. I think if you do a pharmacokinetic interaction
> study, and you use a high dose of the stent drug, then that is the
> pharmacokinetic that you should show the whole blood levels that
> should show in the label, and if the drug interaction study that you
> do is positive, that should also be on the label\--actually, it should
> be in either way. But it is a drug and a device, so I think you should
> have information in there about mechanism of action and systemic
> exposure of a high dose.
>
> DR. LASKEY: Potentially.
>
> Yes?
>
> DR. PINA: Warren, I have been looking through here, and I really see
> very little about the drug itself, and I know that the additional
> Rapamune instructions are in there, but there is just very, very
> little about it, and I think they have to say more about the drug
> itself in this summary, because I think the docs are not going to
> necessarily read all the labeling, but they may read it just as a
> manual.
>
> DR. CANTILENA: I actually thought that the drug label from the
> Rapamune was not going to be included in the device.
>
> DR. PINA: Well, they have included it in here, but it is all about
> oral and acute use in transplant, so it is not going to be included.
> So there has to be more about the drug in the instructions to
> physicians.
>
> DR. LASKEY: Going back to Dr. Throckmorton\'s inability to answer Part
> 1 of the question, what is going on here? Are we just moving the
> labeling for Rapamune over, or what is happening?
>
> DR. ZUCKERMAN: Well, I think Dr. Pina hit the hammer on the nail here
> in that right now, the device labeling does not say much about the
> drug; that is inadequate per Dr. Pina et al. And now the challenge is
> to ask how much of the PDR-type labeling needs to go into a device
> label. And Dr. Cantilena, from what I heard you say, it sounds like
> most of it.
>
> DR. CANTILENA: Yes. Certainly you have evidence of systemic exposure,
> albeit extremely low at this point, but you haven\'t studied your
> high-dose stent, so after you do the studies as we have described, I
> think you should certainly have a description of the drug, the
> pharmacology, how it works, and the appropriate pharmacokinetics and
> interactions, if appropriate, all depending on how those studies come
> out.
>
> But it is systemic absorption of a drug\--it happens to be on a stent
> as opposed to in a tablet, but I think the operator should certainly
> have the information.
>
> DR. LASKEY: And I think it\'s obvious that this is a template for many
> other combination products, so we really need to be fairly rigorous
> about this one as the first out of the gate. So I would agree with
> you.
>
> DR. PINA: And let me stress the point that this is a drug that the
> average interventional cardiologist knows very little about, may not
> have even heard the name. So it becomes even more important to give
> information.
>
> DR. LASKEY: \"Please comment on the remainder of the product labeling
> as to whether it adequately descries how the product should be used to
> maximize benefits and minimize adverse events.\"
>
> I think that there is little additional information
> here\--pharmacology?
>
> DR. CANTILENA: No. I actually have just one question. The information
> that goes to the patient\--Bram, does your unit ask that there is a
> comprehension study that is actually done, or is that not standard?
>
> DR. ZUCKERMAN: It is standard. Have you found that this patient
> labeling is too complicated for someone with, let\'s say, a 6th or 7th
> grade education?
>
> DR. CANTILENA: I thought that was a possibility. So if there is
> results of a comprehension study that is appropriately done, I think
> that that would be something that you should check on, certainly,
> because I think that\'s important.
>
> DR. KRUCOFF: Is this the patient labeling in Section 3, too, that we
> are talking about, \"Patient Labeling for Cypher Sirolimus\--because I
> think that regardless of level of education, reading through this
> makes it very unclear how bare metal stent, a drug-coated stent, and a
> brachytherapy device relate to an individual\'s coronary artery
> disease. I think we had at least three comments to that effect.
>
> DR. LASKEY: Okay.
>
> \"The panel package includes the available 9-month data for the Cypher
> product in the SIRIUS study. In addition, the available 12-month data
> were provided from the RAVEL study and the available 18- to 24-month
> data from the First-in-Man feasibility study were provided. The
> applicant has proposed continued followup to 5 years on subjects from
> the SIRIUS, RAVEL, and First-in-Man studies. The applicant has also
> proposed to collect data through one year on approximately 1,000 to
> 2,000 patients implanted with the marketed product, using an
> electronic database.\"
>
> \"Please discuss long-term adverse effects\"\--and parenthetically,
> bravo, and we certainly applaud the suggestion that you follow all the
> patients in SIRIUS out to 5 years; I think we have said that
> repeatedly, and we commend you for being preemptive there\--\"Please
> discuss long-term adverse effects that may be associated with
> implantation of the Cypher product including late thrombosis
> formation, aneurysm formation, MI, and late stent malapposition.\"
>
> It is entirely possible all these things may happen. We don\'t have a
> handle on the rate at which they may happen. And certainly following
> the patients through 5 years should provide meaningful data to that
> effect.
>
> Okay, group?
>
> \"Based on the clinical data provided in the panel pack, do you
> believe that additional followup as proposed by the applicant is
> appropriate to evaluate the chronic effects of the implantation of the
> Cypher product?\"
>
> Yes, we do.
>
> DR. WHITE: Are we talking now about that electronic database, or are
> you talking about just the 5-year followup of the Cypher?
>
> DR. LASKEY: I guess this is twofold, yes. This is the SIRIUS study,
> which we certainly would agree with, and the electronic database I
> guess raises other questions in my mind\--
>
> DR. WHITE: Yes. Is there a model for that? What is the mechanism of
> that, and if it is for one year, why isn\'t that for 5 years? How does
> that work, and how do you follow people with an electronic database?
>
> DR. ZUCKERMAN: The prior precedents have been the followup of PMA
> cohorts in the stainless steel and brachytherapy trial\--PMA trials.
> And usually, that has just been followup of the patients enrolled in
> the original PMA cohorts.
>
> Here, the question is raised as to whether an additional patient
> population should be enrolled, because a) we are moving into a new
> arena where we have combination products with some questions about the
> local effect of the drug, whether the sample size studied in the
> original trial is adequate to pick up some of these late, rate events,
> et cetera, and so the sponsor has made some initial suggestions about
> enrolling an additional cohort. We would like some comments from the
> panel as to what the questions should be and what the utility would be
> of an additional cohort study.
>
> DR. LASKEY: Okay. So this is obviously an open-label registry. How you
> would ensure consecutive patients\--I think that\'s key, if that is
> possible. Certainly within institutions, it should be consecutive.
>
> And I guess this will determine any difference between effectiveness
> and efficacy, so it certainly will be useful to see in real life.
>
> However, I think the devil is in the details in terms of what the
> fields are going to be. I think that is absolutely key and how much
> work is required to get that data. We don\'t have a good idea about
> what is being proposed here for the electronic database for the new
> cohort, and if you want us to discuss that, I guess we should.
>
> DR. KRUCOFF: I have to agree that there would have to be details. But
> it would seem to me that if this commitment already exists from the
> sponsor that to dovetail that commitment into some of the comments
> that were made earlier about looking at higher dose that there would
> be an opportunity potentially to merge those agendas, so you could
> really be doing two things at one time and clarify, then, some of the
> size and length issues and drug and polymer exposure in conjunction
> with just gathering a broader real life experience.
>
> DR. WHITE: Could we just ask, is the sponsor talking about a
> post-market surveillance of bad things happening\--if somebody has a
> big problem, there is a website to go to and report it\--or are you
> talking about my data coordinators going through charts and every 6
> months meeting with somebody from Cordis and auditing charts and
> looking for events\--because that costs a lot of money.
>
> DR. DONOHOE: Actually, it is something in between those two. It is not
> pure post-market surveillance. The intent is to identify a group of
> centers across the country. That is the intent of enrolling
> consecutive patients in the treatment with the stent. And there is an
> electronic case report form collecting relevant baseline and followup
> information.
>
> There is no fixed monitoring process, and that is the issue related to
> how long can we maintain that in that kind of format in terms of
> extended followup. We are definitely targeting, and part of the
> commitment to signing up to participate in this is providing at least
> one-year followup data on these patients if the investigator is
> willing to participate.
>
> DR. PINA: Warren, I think it is a wonderful opportunity to look at
> some of the questions that have been raised here\--the smaller
> lesions, the larger lesions. We have been talking about multiple
> stents, which you didn\'t have in the original trial, but you know
> that that is reality, that that is what is going to be done in
> collecting two- and three-stent information.
>
> And then, I would add some of the other clinical data that should be
> pretty easy to collect because these patients are going to be in the
> hospital getting the stent, at least overnight or 23 hours. You are
> going to be able to get a lot of that clinical data that you don\'t
> have right now.
>
> DR. WHITE: I would just caution us that this kind of work, the kind of
> data that you are presenting today, is extremely expensive, lots of
> discipline. You guys put a ton of resources into collecting this kind
> of audited, reliable data. So if we are going to ask them to do this
> post-market, I think that that is something you need to make a
> commitment to up front, that it is not going to be easy; it is going
> to be very expensive. Your compliance with investigators\--you can
> offer your investigators now a chance to have a device when nobody
> else can have it; when it is approved, why am I going to fill out 18
> forms? It is something that needs to be thought about and talked
> about. If you want good-quality data, it is going to require a big
> effort. If it is not good-quality data, I\'m not sure what the value
> of it would be. So I think it\'s more than just a
> lightly-thought-out\--it\'s a nice thing to say, but are you willing
> to commit 5 percent of your budget to this? What are your plans?
>
> DR. DONOHOE: Well, there is a process\--actually, this electronic
> system is a system that we already have up and running. We have been
> employing it in a variety of countries on approval, including Europe
> and countries in Asia. So it is a system that we have already tested;
> we are testing the mechanisms in terms of maximizing investigative
> participation and entry of data. We continue to refine that as we find
> out what works best in this kind of format, and our intent is to roll
> it out in the U.S. following approval.
>
> DR. WHITE: Are you auditing\--I mean, are you sure the data is
> valuable?
>
> DR. DONOHOE: Roughly 10 percent of the data.
>
> DR. WHITE: I mean, there is some level\--maybe Rick can help you with
> understanding what the level of audit requires so you know you are
> getting reasonable reported data.
>
> DR. LASKEY: So we support that concept, but we are in the dark as to
> what really is being entered. But I think that a prospective
> consecutive registry with carefully planned out data fields is ideal,
> is just ideal, and will answer a lot of questions. But obviously, you
> and the sponsor have put your heads together about what is in these
> fields. We are just in support of the concept.
>
> Okay. Sponsor, do you all have any additional or final comments before
> the vote?
>
> Dr. Donohoe?
>
> **Sponsor Comments**
>
> DR. DONOHOE: Thank you, Mr. Chairman.
>
> I just have one comment for the panel, particularly to clarify, at
> least from my understanding, the issue around Questions 2c and 2d in
> this packet, and that was around the total exposure in terms of
> polymer content.
>
> I wanted to just in a way reiterate Dr. Edmunds\' comments. The total
> quantity of polymer is calculated here almost as if it is a drug. As
> he mentioned, when you place a coating or material on one square
> centimeter or three square centimeters, biocompatibility and changes
> if they do occur should occur where there is one centimeter contact or
> three square centimeters.
>
> And in the question about is additional preclinical data needed, just
> to highlight that in the First-in-Man trial in which we deployed 18 mm
> stents, we conducted angiography, clinical and IVUS assessment of
> these patients out to 2 years, and we do not see any evidence of
> vessel changes suggesting there is a longer-term biocompatibility
> issue. And I would suggest that that is relevant; whether you are
> talking about a single 18 mm stent or a 23 mm stent, the polymer is
> sitting right against the issue. It is not being eluted, and it is not
> a drug.
>
> DR. KRUCOFF: Dennis, just speaking from my point of view, recognizing
> that the polymer is distributed by square millimeters, my real concern
> is whether animal findings, for instance, with late inflammatory
> changes which have no apparent clinical equivalent in a human being,
> when we deliver 1.4 stents per patient, if you inflame 90 mm of an
> artery 3 or 4 months out, whether you cross some threshold where in
> fact it would be clinically relevant. To me, that is the context in
> which, since it is the same work relative to higher drug dose to
> collect data on larger polymer exposure, that the two are really one
> just by the nature of the device.
>
> DR. DONOHOE: I understand that concern, and the only thing I would say
> in response is, again in terms of clinical followup after 2 years,
> angiographic IVUS assessment and clinical, there does not appear to be
> even some suggestion of a significant inflammatory response in that 18
> mm stent, so it\'s unlikely that it would appear in a longer-length
> stent.
>
> DR. LASKEY: Thank you.
>
> FDA, any final comments?
>
> **FDA Comments**
>
> DR. FOY: Very succinctly to address this issue, as Dr. Zuckerman has
> already mentioned, the Agency has to go on data that has been provided
> to us, and based on the limited amount of preclinical data that we do
> have, we do have concerns about the polymer as well as the drug dosage
> issues. And specifically, since polymers are not erodible and stay
> resident, we would want to see more chronic information from
> preclinical, because you can assess different parameters from animals
> than you can from humans, although you want to have both datasets.
>
> So I think we would just like to reemphasize that we have actually
> asked the sponsor to provide us with information about looking at the
> dose response information\--in other words, whether or not there is an
> effect, whether you are talking about the area over the length. We may
> have received that information as of yesterday, but we haven\'t had a
> chance to review that information.
>
> I don\'t know if anybody else from the Agency would like to comment.
>
> DR. EDMUNDS: Is the issue polymer toxicity or drug toxicity or both?
> Drug toxicity I think we could lay aside. The question in b and c
> address drug toxicity, but you are raising polymer toxicity. That is
> something that is not on there.
>
> DR. LASKEY: Yes. I thought I tried repeatedly to make that point, that
> we are dealing with the polymer staying there forever, and we do not
> know the natural history of that or how irritative or nonirritative it
> will be to the coronary artery.
>
> DR. FOY: I think it is very hard to separate these two issues\--they
> are integrated within one another\--because the polymer is there as a
> carrier for the drug. And even though we have separated them out in
> this question to try to look at them as separate entities, they really
> are combined components, and you have to take both into consideration
> when you are looking at the data.
>
> What we actually do request of sponsors so we can try to assess the
> effect of the polymer only on the stent, without the drug, is just
> that. We want to see chronic preclinical information from the sponsor
> looking at the effect of the polymer only, without the drug, because
> we know that this is not going to be a clinically tested product, but
> once that drug is gone, this is a way to hopefully preempt the
> clinical ramification that there may be once that drug is gone from
> that product.
>
> DR. LASKEY: There is some back-and-forth here that deserves a
> rebuttal.
>
> Dr. Donohoe, do you want to address this final point?
>
> DR. CARTER: I am Andy Carter. I am an interventional cardiologist from
> Portland, Oregon, Providence Saint Vincent Medical Center, a part of
> the Providence Health System.
>
> I have been involved with this project since its inception as an
> experimentalist. For purpose of disclosure, I am a consultant to
> Cordis, and I have received research grants through Cordis. These are
> reported to the Providence Health System in compliance with our
> management on conflict of interest.
>
> DR. LASKEY: Andy, can I interrupt for a second? Are you speaking for
> Cordis, or as part of the open public hearing which we\--
>
> DR. CARTER: I am speaking for Cordis, Dr. Laskey. I\'m sorry if I
> didn\'t clarify that. And I am here to address issues relative to the
> preclinical data that is available on the polymer and the system in
> its entirety that I think is important and relevant.
>
> First, as a background, prior to embarking on studies to evaluate the
> efficacy of this system\--and by \"system,\" I mean drug and polymer
> at a fixed surface area on a given length of stent\--considerable
> testing was done to evaluate the various polymer systems including
> this one. And I point to data that we published in Circulation from my
> laboratory in September 2001 where we looked in two large animal
> models, porcine and canine models, at stents that were coated with
> this very same polymer system, with a polymer burden in a surface area
> that actually exceeds the clinically relevant polymer burden.
> Specifically, these were 600 and 1,800 microgram polymer loads without
> any drug. And as a point of reference, that would exceed, if we were
> to put the system together, the polymer and the drug, the total amount
> of polymer that the clinically relevant system would provide by about
> 20 percent even at the lowest polymer burden.
>
> These animals were followed for 60 days. In addition to that, there is
> preclinical data in a rabbit model. What we learned is, as stated in
> the published manuscript, that even at a threefold concentration of
> the clinically relevant quantity of polymer per surface area exposure
> to the volume of distribution in the target vessel, because that\'s
> what we are talking about, in the canine model, there is absolutely no
> difference in response on important histologic parameters\--neointimal
> area, percent in-stent stenosis, arterial inflammation, or injury\--in
> the rabbit model as well, but not evaluated at the higher dose.
>
> In the pig model, we did observe a difference in sensitivity to this
> system. At the lower load of polymer, it was very similar to bare
> metal stent; at the higher load, there was greater inflammation and
> more neointima. But that was at a load that was in excess of threefold
> the amount of polymer per unit surface area.
>
> Most importantly, the concern about this system long-term relates to
> the interaction of the leached polymer in the artery. This was very
> nicely addressed in the 180-day definitive GLP safety study, where 110
> stents were implanted in mini pigs with angiographic and histologic
> evaluation at 3, 30, 90, and 180 days.
>
> Now, our mandate in the preclinical laboratory is safety, and safety
> number one, so to address safety, there was no animal mortality, there
> were no thrombotic events, procedural, post-procedural, or long-term,
> and I think at a minimum\--and the implant technique here, important
> antiplatelet therapy similar 2 months to the RAVEL study with
> clopidogrel\--the bottom line is this documented safety.
>
> From a biocompatibility standpoint, there were differences over time,
> and what we observed when these stents were oversized 20 percent in a
> normal pig coronary artery is that at 30 days, we saw the persistence
> of a negative stenosis on angiography in the Cypher arm, approximately
> minus 20 percent, which is equivalent to the immediate post-procedural
> angiogram. We saw essentially a normal lumen in the control arm, with
> zero to 10 percent narrowing on average. There was, based on
> histology, at 30 days, a 50 percent reduction in intimal hyperplasia,
> as had been documented in several other preclinical studies at this
> dose.
>
> Importantly, we wanted to assess the effects over time, and we know
> that at 90 days, essentially, the drug is gone from the system and
> probably from the artery; by 90 days, these systems were biologically
> equivalent.
>
> What do I mean by that? On angiography, if we plot the data, there is
> no measurable stenosis in the Bx Velocity or the Cypher stent.
>
> If we look on histology, the parameters, neointimal area, percent
> in-stent stenosis, they are similar.
>
> There is a difference when we get into some of the more subtle
> appearance of the artery as it relates to injury and inflammation, and
> there tended to be in the Cypher arm over time a greater degree of
> observed inflammation and injury by the pathologist.
>
> But in the end at 180 days, when we are now 3 months past the time
> period that the drug has eluted from the stent and the artery, these
> vessels appeared identical as they did on the 90-day evaluation, and
> that is that the amount of intimal hyperplasia narrowing in the stent
> is identical for the 1XTC versus the bare metal stent. Again, we
> observed a slight increase in inflammation and injury, but it didn\'t
> correspond with a more traditional and harder measure of
> biocompatibility, and that is intimal hyperplasia.
>
> I do believe that these data sufficiently address biocompatibility in
> the porcine coronary model, and I don\'t believe that today, if we go
> back and try to connect the dots with some additional stent studies in
> the porcine coronary model, we will add substantially to our
> understanding of this system, particularly given the wealth of data
> that we have now based on the SIRIUS and the RAVEL studies.
>
> In the end, I spent a lot of time trying to understand why there is
> this disparate effect, and I would just leave you with the thought
> that I have challenged myself to try to understand why there would be
> a single physiologic reason for a pig or any other species to live
> with a 20 percent oversized stent, and we are learning as we look more
> carefully at these long-term specimens in the pig in particular that
> there are probably unique physiologic factors at play that really
> dictate the late intimal response and perhaps the inflammatory
> response to the prosthesis.
>
> So I hope that that lengthy discourse clarifies some of the
> preclinical data that may not have necessarily been brought to light
> in the presentation by Dr. Donohoe. It has been provided, and I am
> certain it is important.
>
> DR. LASKEY: Thank you very much.
>
> Finally, let me open the public hearing for the final time. Is there
> anybody who wishes to come forward and address the panel?
>
> \[No response.\]
>
> DR. LASKEY: If not, I would like to close the open public hearing
> portion and request voting directions.
>
> **Recommendations and Vote**
>
> MS. WOOD: The Medical Device Amendments to the Federal Food, Drug, and
> Cosmetic Act as amended by the Safe Medical Devices Act of 1990 allows
> the Food and Drug Administration to obtain a recommendation from an
> expert advisory panel on designated medical device premarket approval
> applications, PMAs, that are filed with the Agency.
>
> The PMA must stand on its own merits, and your recommendation must be
> supported by safety and effectiveness data in the application or by
> applicable publicly-available information.
>
> Safety is defined in the Act as \"reasonable assurance, based on valid
> scientific evidence, that the probable benefits to health under
> conditions on intended use outweigh any probable risks.\"
>
> Effectiveness is defined as \"reasonable assurance that in a
> significant portion of the population, the use of the device for its
> intended uses and conditions of use when labeled will provide
> clinically significant results.\"
>
> Your recommendation options for the vote are as follows:
>
> Approval, if there are no conditions attached;
>
> Approvable with conditions. The panel may recommend that the PMA be
> found approvable subject to specified conditions, such as physician or
> patient education, labeling changes, or a further analysis of existing
> data.
>
> Prior to voting, all of the conditions should be discussed by the
> panel.
>
> Not approvable. The panel may recommend that the PMA is not approvable
> if the data do not provide a reasonable assurance that the device is
> safe, or if a reasonable assurance has not been given that the device
> is effective under the conditions of use prescribed, recommended, or
> suggested in the proposed labeling.
>
> Following the voting, the chair will ask each panel member to present
> a brief statement outlining the reasons for their vote.
>
> DR. LASKEY: Thank you.
>
> I entertain a motion\--Mr. Morton, I\'m sorry.
>
> MR. MORTON: Very quickly, I would only echo what the panel has said
> about the excellent presentation by the sponsor and also note that the
> sponsor did proactively bring a plan for postmarket work which I think
> is admirable; and finally to thank the FDA, because this has been a
> very thorough and extremely timely review of this.
>
> DR. LASKEY: Do I have a motion?
>
> Dr. Krucoff?
>
> DR. KRUCOFF: I\'d like to move for approval with conditions.
>
> DR. EDMUNDS: I\'ll second that.
>
> DR. LASKEY: May we hear the conditions\--one at a time, so we can
> discuss them individually.
>
> DR. KRUCOFF: I\'m not sure of the appropriateness, but I think it\'s
> so involved that I think one of the conditions has got to be that FDA
> and the sponsor come to a satisfactory completion of resolution of the
> deficiencies in the Major Deficiencies Letter and get us all on the
> same page.
>
> I think the second condition should be that a condition of approval
> should be for lengths and diameters that are consistent with the
> inclusion criteria for the study, the SIRIUS study, the pivotal trial.
>
> DR. LASKEY: I think it\'s best, from past experience, if we take these
> one at a time.
>
> So, on the first condition that Dr. Krucoff is suggesting, is it an
> issue?
>
> DR. ZUCKERMAN: No, that\'s not an issue. You can assume that the
> sponsor and FDA will resolve the major deficiency issue questions.
> Otherwise, we can\'t go forward.
>
> DR. LASKEY: Thank you.
>
> So your first condition on approval, then, is that length and
> diameter\--
>
> DR. KRUCOFF: Are consistent with the inclusion criteria for the SIRIUS
> study.
>
> DR. LASKEY: And how are you suggesting that they be made consistent?
>
> DR. KRUCOFF: Lengths of 15 to 30 mm; diameters of 2.5 to 3.5.
>
> DR. LASKEY: Is there discussion on this point?
>
> DR. EDMUNDS: I thought we went higher, on the high side.
>
> DR. LASKEY: Yes, at one time we did.
>
> DR. EDMUNDS: And lower on the low side. Well, I have the amendment to
> 4.5.
>
> DR. LASKEY: 2.5 to 4.5.
>
> DR. EDMUNDS: Well, I don\'t know whether you\'ll accept the amendment.
>
> DR. LASKEY: We will obviously vote on that.
>
> What happened to 2.25?
>
> DR. KRUCOFF: I still think that we have been presented with data based
> on investigators\' visual analysis that were the inclusion criteria,
> and we have been presented with data from a QCA lab that is clearly a
> different set of numbers that unequivocally shows efficacy. But from a
> trial where the visual inclusion criteria were clearly stated were
> what every investigator was aware of and which I think are consistent
> with what then should be on the labeling and approval of the device.
> And I think whether to argue to go smaller or larger, smaller is to
> assume linear effects which in biological systems may be true, they
> may not be true. I don\'t think the burden of adding some registry
> data to actually answer that based on real information is a burden. In
> fact, I consider it a necessity.
>
> So I think that the visual estimate of lesion length and diameters
> that were used to enroll these patients is where the data is, and I
> think the data are terrific, but I think that we should have labeling
> and approval based on those data.
>
> DR. LASKEY: Further discussion?
>
> DR. WHITE: Given the postmarket efforts, and perhaps a more robust
> postmarket effort than we are used to, could we be more liberal in the
> approval of the device but ask for a review of those margins at the
> end of a period of time, 6 months or a year; could that be done?
>
> DR. ZUCKERMAN: Those plans generally have problems. What you are asked
> to vote on today is given what you have on the plate right now, is
> there a reasonable assurance of safety and effectiveness for a certain
> indication on the label. I wouldn\'t assume that you will get any
> other data.
>
> MR. MORTON: My only point would be that it would not be a few months,
> then, before the device is available; that given the difficult
> enrollment of a patient population that is going to be hard to find,
> it won\'t happen quickly.
>
> DR. KRUCOFF: No, I\'m certainly not suggesting to not approve the
> device.
>
> MR. MORTON: Then, I misunderstand and withdraw my comments.
>
> DR. KRUCOFF: This is a condition of approval, and all I\'m saying is
> that I think a condition of approval should be\--the labeling and the
> indications for approval should be the same as the inclusion criteria
> for the study that generated the data.
>
> DR. LASKEY: So modifications to the labeling; that\'s all.
>
> Do you have other conditions, Mitch?
>
> DR. KRUCOFF: Yes.
>
> DR. LASKEY: I will then rehash them at the end, and we will vote on
> each of them individually.
>
> DR. KRUCOFF: There are really not many. I think the instructions for
> use should contain stronger language than the current version,
> directed toward the operator to acknowledge the fact that this is a
> combination of a drug and a device and that issues like direct
> stenting or other off-label use considerations and techniques may have
> more ramifications with this device than with just variations on a
> bare metal stent; so just a cautionary but clearly stated.
>
> And my last condition is that the patient labeling section either make
> it clear or separate out different coronary option techniques relative
> to what is there, which I think currently reads like you can have a
> stent, and if your stent didn\'t work, that\'s why we made the
> checkmate\--just to make it clearer than the version that we have in
> the current panel pack.
>
> That\'s all that I would suggest for conditions.
>
> DR. PINA: Warren, may I modify that last condition about the patient
> labeling that it include more information about the drug, that
> patients at least be informed what the drug is and what the drug is
> used for and what we don\'t know.
>
> DR. LASKEY: This is the patient brochure.
>
> DR. PINA: The patient brochure, yes.
>
> DR. LASKEY: Okay.
>
> DR. CANTILENA: I would just suggest that we also apply as a condition
> the\--
>
> DR. LASKEY: Well, that\'s another\--hang on. We\'ll vote on these and
> then we\'ll entertain additional\--is that right?
>
> Sorry\--Lou, go ahead.
>
> DR. CANTILENA: Just the suggestion that we apply the additional
> condition for the high-exposure study with pharmacokinetic
> interactions, as previously described, and if positive and the
> concentrations are significant, that that be added to the labeling.
>
> DR. LASKEY: Are there other conditions that we want to add to the list
> at this point?
>
> DR. AZIZ: We have talked about precautions like patients with renal
> failure, left vain, multi-vessel. Do you think this is the point to
> address that, or\--
>
> DR. LASKEY: I personally think not. I think the latter two are
> political statements, and renal failure\--
>
> DR. EDMUNDS: The target is cleared by the intestinal tract. It is no
> threat to the kidney.
>
> DR. LASKEY: Yes.
>
> DR. FERGUSON: Are you entertaining others?
>
> DR. LASKEY: We will entertain as many as come forth.
>
> DR. FERGUSON: Okay. I asked the question originally that I don\'t
> think has been addressed, and that is about the use of brachytherapy
> with this device, and until more data is either given based on what we
> have heard today, I think that has to be a caveat.
>
> DR. LASKEY: Currently, it is a precaution in the IFU. If you want to
> strengthen the language, then, suggest that. But currently, it reads
> as a precaution, and I would agree with it just not being recommended,
> but that\'s up to the panel. We can craft the details. But it is
> currently\--have you seen how it is worded in the\--
>
> DR. FERGUSON: I have seen that, but I\'m thinking more about both the
> material for the patient and for the physician.
>
> DR. LASKEY: Okay, then, it should be in multiple places. Okay.
>
> Are there other conditions?
>
> \[Pause.\]
>
> DR. LASKEY: Well, then, we just might be ready to vote on each
> individual caveat.
>
> First, let\'s achieve consensus on\--I have five conditions to be
> appended to the motion for approval. Let me just recite them and make
> sure we have our house in order.
>
> The first is that the labeling pertain to vessels 2.5 to 4.5 mm in
> diameter.
>
> DR. WHITE: 2.5 to 3.5.
>
> DR. LASKEY: Someone said 4.5.
>
> DR. WHITE: The inclusion criteria.
>
> DR. LASKEY: Okay, so we\'re limiting these to the inclusion criteria.
> That\'s what I thought. Thank you.
>
> The second condition for approval is that the Instruction for Use
> emphasize the unique properties\--
>
> DR. KRUCOFF: Do you have length?
>
> DR. LASKEY: No. You didn\'t give me length.
>
> DR. KRUCOFF: Length of 15 to 30.
>
> DR. LASKEY: So we will maintain the study inclusion criteria\--
>
> DR. KRUCOFF: For length and diameter.
>
> DR. LASKEY: \--in the labeling for length and diameter.
>
> The second condition for approval will use language uniquely
> emphasizing the special aspects of handling of this new device.
>
> The third condition of approval requires buffing up of the patient
> brochure, both in terms of level of readability as well as the detail,
> including issues such as concomitant brachytherapy.
>
> DR. KRUCOFF: That includes information about the drug?
>
> DR. LASKEY: Yes, and Rapamune.
>
> The fourth condition relates to the requirement for a pharmacokinetic
> study looking at the risk-benefit ratio of high dose exposure.
>
> And the fifth condition for approval requires specific language to be
> added to patient brochure and physician instruction for use as to the
> potential hazard and warnings related to adjunctive brachytherapy.
>
> DR. ZUCKERMAN: Okay. And Dr. Laskey, what about the comments raised by
> the panel members regarding need for longer-term followup and IVUS
> followup?
>
> DR. LASKEY: I think the panel has been informed that there will be
> 5-year followup of the patients enrolled in SIRIUS and that there is
> ill-defined at this point postmarketing surveillance/registry of
> consecutive patients.
>
> Isn\'t that a done deal?
>
> DR. ZUCKERMAN: Okay, or it can be voted on as a condition of approval.
>
> DR. PINA: Bram, are you specifically talking about the RAVEL patients
> who are going to continued to be looked at? Is that the group that you
> are\--
>
> DR. ZUCKERMAN: \[Inaudible comment; no mike.\]
>
> DR. PINA: No, but the RAVEL patients also have had some continuous
> followup. Are we talking about all of them in conjunction, or just the
> SIRIUS, or just the RAVEL?
>
> DR. KRUCOFF: Mr. Chairman, can I just go ahead and state it, because
> obviously, I think we have been operating with an assumption, but
> maybe it needs to be stated as a condition of approval, that the
> stated intention for 5-year clinical followup of the SIRIUS patient
> population would need to be provided post-approval but as a condition
> of approval.
>
> DR. WHITE: Just SIRIUS, or First-in-Man?
>
> DR. LASKEY: All three? If we\'re going to go the route, then we need
> to specify, so all three studies?
>
> DR. KRUCOFF: My understanding was the commitment was to the SIRIUS
> population. Are you already set to go 5 years in all three of these
> studies?
>
> MR. DONOHOE: Yes.
>
> DR. KRUCOFF: All right. All three.
>
> DR. LASKEY: With respect to the late malapposition, I think we just
> wanted more long-term followup of the patients who are currently
> enrolled, and that is forthcoming from RAVEL at 18 to 24 months, as
> well as SIRIUS.
>
> So that\'s done; six conditions of approval. Shall we vote one at a
> time?
>
> So we have a motion, we have a second. We are going to vote on the
> conditions now by a show of hands, the first condition being that the
> labeling be applicable to the inclusion criteria for this study in
> terms of lesion length and vessel diameter, 15 mm to 30 mm, and 2.5 to
> 3.5, respectively.
>
> A show of hands in favor of this motion.
>
> \[A show of hands.\]
>
> DR. LASKEY: Thank you.
>
> DR. ZUCKERMAN: Okay. For the purposes of the transcription, can you
> indicate what the vote was, Dr. Laskey?
>
> DR. LASKEY: Six for and two against.
>
> I asked for a show of hands for all in favor. Let\'s do it again.
>
> All in favor of the first.
>
> \[A show of hands.\]
>
> DR. LASKEY: Six in favor.
>
> All against?
>
> \[A show of hands.\]
>
> DR. LASKEY: Thank you. So, for the transcriptionist, six in favor, two
> against.
>
> The second condition requires the crafting of language to meet the
> size of the unique and special precautionary handling properties of
> this novel new device, language to be crafted by the interaction of
> the FDA and the sponsor.
>
> All in favor, raise your hands.
>
> \[A show of hands.\]
>
> DR. LASKEY: That looks like it\'s unanimous, eight to zero. Thank you.
>
> The third condition\--the improvement of the patient brochure to
> address first of all readability, second of all to include information
> on Rapamune and its potential effects, and additional language also to
> be negotiated between the Agency and the sponsor.
>
> All in favor of buffing up the patient brochure.
>
> \[A show of hands.\]
>
> DR. LASKEY: Again unanimous, eight to zero.
>
> Tom, did I represent that pretty correctly?
>
> DR. FERGUSON: Yes.
>
> DR. LASKEY: Okay.
>
> The fourth condition is the requirement for a
> pharmacokinetic/pharmacodynamic study specifically designed to look at
> the higher-end exposure.
>
> All in favor?
>
> \[A show of hands.\]
>
> DR. LASKEY: Against?
>
> \[A show of hands.\]
>
> DR. LASKEY: Let the record show seven to one in favor.
>
> The fifth condition is to provide language to the physician brochure
> Instructions for Use that we have already covered in the patient
> brochure, the language pertaining to the use of brachytherapy or its
> relative contraindication in this setting.
>
> All in favor?
>
> \[A show of hands.\]
>
> DR. LASKEY: Eight-zip.
>
> And finally, the requirement to specifically include the 5-year
> followup, the clinical followup data, on the patients in SIRIUS,
> RAVEL, and First-in-Man.
>
> All in favor?
>
> \[A show of hands.\]
>
> DR. LASKEY: Eight-zip.
>
> That covers the conditions. We are now ready to vote on the final
> motion\--that is, the motion for approval with the conditions that we
> have just voted on.
>
> May I have a show of hands to accept the motion on the table, which is
> to recommend approval with all six conditions? All in favor, raise
> hands.
>
> \[A show of hands.\]
>
> DR. LASKEY: Great. Eight-zip.
>
> Congratulations.
>
> Quickly, can we go around the table and if you could summarize the
> reasons why you voted for approval.
>
> Hank?
>
> DR. EDMUNDS: I think that the trials in the aggregate have clearly
> demonstrated efficacy out to 9 months, and I am satisfied that the
> drug in the doses that humans have been exposed to is nontoxic out to
> 9 months. And I don\'t know how long it has been used as an
> immunosuppressive in transplant patients.
>
> DR. WHITE: I voted to accept the motion as well. I would have liked to
> see maybe a little more liberal sizing, but I understand the need for
> being conservative, and I am also comfortable with the reasonableness
> that the trial satisfied the requirements to be safe and effective.
>
> DR. CANTILENA: Yes, I would agree in general in terms of overall
> safety and efficacy, with the limitations that I have already
> discussed.
>
> DR. FERGUSON: I think they have done an outstanding job in presenting
> a very, very difficult situation with a new product which, as you say,
> is going to be a breakthrough in many, many areas, and I would
> consider the fact that we have been a little bit cautious is all to
> the good.
>
> DR. KRUCOFF: I definitely echo Dr. Ferguson and say thank you to the
> sponsors for making this a reality for patients and to the
> investigators and core labs and research organization for putting the
> data together that makes it unequivocal that for the patients included
> in this trial, this is going to revolutionize our profession. And I
> think to the FDA to be able to facilitate and expedite this so that
> people suffer less long a time period waiting is also something that I
> am very grateful for, and that\'s why I voted for approval.
>
> DR. LASKEY: Thank goodness I did not have to vote. I would have voted
> along with my colleagues. And I would like to commend first of all
> Cordis and second of all my colleagues for maintaining a sense of
> propriety and probity. There has been so much hype, obviously, over
> this, and this meeting has just been a pleasure to coordinate, even
> though it is 7:45; but it has been a pleasure having everybody chip
> in.
>
> DR. AZIZ: I voted in favor because I think the data is impressive, and
> I think it will have an impact in a very positive fashion.
>
> DR. PINA: I would like to commend both sponsors. I consider Wyeth a
> partner in this, and I would really encourage Wyeth to look at this
> drug closely and teach us about the mechanisms of what is going on in
> the vessel wall and perhaps extend some of this to our transplant
> patients which we end up losing because of coronary arteriopathy.
>
> DR. BAILEY: I voted in favor. I felt that this was a very well-done
> trial that showed significant efficacy for admittedly a hybrid
> clinical angiographic but nevertheless important endpoint in the group
> of patients who were recruited to the trial.
>
> DR. LASKEY: It is my pleasure to adjourn this meeting.
>
> Thank you all.
>
> \[Whereupon, at 7:45 p.m., the proceedings were concluded.\]
>
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