FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

ANTI-INFECTIVE DRUGS

ADVISORY COMMITTEE

October 16, 2001

 

 

 

Hilton Gaithersburg

620 Perry parkway

Gaithersburg, Maryland

 

 

 

 

Reported and Transcribed by:

CASET Associates, Ltd.

10201 Lee Highway, Fairfax, Virginia 22030

(703)352-0091

PARTICIPANTS

L. Barth Reller, MD

Barbara Murray, MD

Murray Wittner, Md, PhD

Ellen Wald

Thomas Perez, MPH

Steven Evert, PharmD

Julio Ramirez, MD

Thomas Fleming, MD

Michael O'Fallon, PhD

Robert Mumford, MD

Leo Rotello, MD

H. Shaw Warren, MD

Anthony Suffredini, MD

Craig Lilly, MD

Joseph Carcillo, MD

Peter Eichacker, MD

Celia Christie-Samuel

P. Joan Chesney, MD

Alan Cross, MD

Gordon Archer, MD

James Leggett, Jr. MD

Linda Forsyth, MD

Robert Lindblad, MD

Gibbes Johnson, PhD

Jay Siegel, MD

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

CONTENTS

PAGE

Call to Order, Introductions: Barth Reller, MD, Chair 1

Meeting Statement: Thomas H. Perez, MPH, Exec. Sec. 1

Opening Comments: Gibbes Johnson, PhD, Chair, FDA

Review Team 6

Eli Lilly and Company Presentation:

Introduction -

Holger Schilske, MD, PhD, Exec. Dir., Eli Lilly & Co. 8

Pathophysiology of Severe Sepsis - Rationale for Drotrecogin Alfa (Activated) Steven Opal, MD, Chief Infectious Disease Division, Brown University School of Medicine 13

Efficacy and Safety of Drotrecogin Alfa (Activated) in

the Treatment of Severe Sepsis

William Macias, MD, PhD - Medical Director, Eli Lilly 28

Benefit-Risk Assessment of Drotrecogin Alfa (Activated)

in the Treatment of Severe Sepsis

Jeffrey Helterbrand, PhD - Senior Statistical Scientist

Eli Lilly and Company 39

Clinical Experience in Pediatric Patients with Severe

Sepsis and Overall Conclusions

William Macias, MD, PhD - Medical Director, Eli Lilly 57

FDA Presentation:

Summary of Efficacy

Linda Forsyth, MD, Medical Officer, Center for Biologics

Evaluation and Research, FDA 108

Pediatric Data and Summary of Adult Safety

Robert Lindblad, MD, Medical Officer, CBER, FDA 126

Open Public Hearing 160

Charge to the Committee, Introduction to Questions 176

Discussion and Questions 212

P R O C E E D I N G S 8:35 AM

Agenda Item: Call to Order - Barth Reller, M.D., Chair

DR. RELLER: Good morning. I am Dr. Barth Reller, and I would like to welcome everyone to the meeting of the Anti-Infective Drugs Advisory Committee of the Food and Drug Administration for consideration of the drug drotrecogin alfa (activated) from Eli Lilly and Company.

We will open this morning's meeting with a statement by Tom Perez, our Executive Secretary.

Tom?

Agenda Item: Meeting Statement - Thomas H. Perez, M.P.H. Executive Secretary

MR. PEREZ: Good morning. The following announcement addresses the issue of conflict of interest with regard to this meeting, and it is made part of the record to preclude even the appearance of such at this meeting. Based on the submitted agenda for the meeting and all financial interests reported by the Committee participants it has been determined that all interest in firms regulated by the Center for Drug Evaluation and Research present no potential for an appearance of a conflict of interest at this meeting, with the following exceptions.

In accordance with 18 USC 208(b) full waivers have been granted to Dr. Thomas Fleming and Dr. Barbara Murray. A copy of the waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, Room 12830 of the Parklawn Building.

In addition, we would like to disclose for the record that Dr. Thomas Fleming and Dr. Barbara Murray and Dr. Ellen Wald have interests which do not constitute a financial interest within the meaning of 18 USC 208(a) but which could create the appearance of a conflict. The agency has determined notwithstanding these interests that the interests of the government in their participation outweigh the concern that the integrity of the agency's programs and operations may be questioned.

Therefore, Dr. Fleming, Dr.Murray and Dr.Wald may participate fully in today's discussions.

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 participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the record.

With respect to all other participants we ask in the interests of fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.

Thank you.

DR. RELLER: Today's application crosses many disciplines and consequently there are nine additional voting members and guests that will supplement the Anti-Infective Advisory Committee today.

Next we shall have introductions of all of voting members of the Committee that will hear and assess the material presented.

We will start on my far right with Dr. Eichacker. Please give your basic affiliation and name for the Committee.

Thanks.

DR. EICHACKER: My name is Peter Eichacker.

DR. RELLER: There is a little button at the bottom of the microphone. If we press that, the red light comes on. Then we are audible for all.

DR. EICHACKER: My name is Peter Eichacker. I am head of the Clinical Care Section at the Clinical Center at the NIH in Bethesda.

DR. CARCILLO: Good morning. My name is Dr. Joseph Anthony Carcillo, Jr., MD. I am Associate Director of the Pediatric Intensive Care Unit at Children's Hospital in Pittsburgh.

DR. LILLY: I am Craig Lilly. I am the Medical Director of the Intensive Care Unit at the Brugman(?) Woman's Hospital, Harvard Medical School.

DR. SUFFREDINI: My name is Anthony Suffredini. I am a Senior Investigator in the Critical Care Medicine Department at NIH, Bethesda, Maryland.

DR. RELLER: When you done with the mike, please turn it off. Thank you.

DR. WARREN: My name is Shaw Warren. I am a member of the Infectious Disease Unit at the Massachusetts General Hospital in the Adult and Pediatric Units.

DR. MUMFORD: Bob Mumford. I am in the Infectious Diseases Division of the Department of Medicine at the University of Texas, Southwestern Medical School in Dallas.

DR. O'FALLON: Mike O'Fallon, biostatistician, Mayo Clinic.

DR. FLEMING: I am Thomas Fleming, Chair, Department of Biostatistics, University of Washington.

DR. MURRAY: Barbara Murray, Infectious Diseases, University of Texas Medical School in Houston.

DR. WITTNER: Murray Wittner, Albert Einstein College of Medicine, Division of Tropical Medicine and Parasitology.

DR. WALD: Ellen Wald, Chief of the Division of Allergy, Immunology and Infectious Disease at the Children's Hospital, Pittsburgh.

DR. RELLER: Barth Reller, Division of Infectious Diseases and Director of Clinical Microbiology, Duke University Medical Center.

MR. PEREZ: Tom Perez, Executive Secretary for this Committee.

DR. EBERT: Steven Ebert, Infectious Disease Pharmacist, Meritor(?) Hospital and University of Wisconsin, Madison.

DR. RAMIREZ; Julio Ramirez, Chief, Division of Infectious Diseases at the University of Louisville, Kentucky.

DR. CHRISTIE-SAMUEL: I am Celia Christie, Professor and Chair in Pediatrics and consultant in infectious diseases, epidemiology and public health, University of the West Indies, Kingston, Jamaica.

DR. CHESNEY: Joan Chesney, Infectious Disease, Pediatric Infectious Disease, University of Tennessee Health Science Center in Memphis.

DR. CROSS: Alan Cross, Division of Infectious Disease, University of Maryland, Medical School, Baltimore, Maryland.

DR. ARCHER: Gordon Archer, Chair of the Division of Infectious Diseases of the Medical College of Virginia in Richmond, Virginia.

DR. LEGGETT: Jim Leggett, Infectious Diseases, Providence Portland Medical Center, and the Oregon Health and Sciences University, Portland, Oregon.

DR. FORSYTH: I am Linda Forsyth, Center for Biologics, FDA.

DR. LINDBLAD: Robert Lindblad, Center for Biologics, FDA.

DR. JOHNSON; Gibbes Johnson, CBER, FDA.

DR. SIEGEL: Jay Siegel. I direct the Office of Therapeutics at CBER, FDA.

DR. RELLER: Thank you very much. We will now have Dr. Gibbes Johnson, Chair of the FDA Review Team with opening comments.

Agenda Item: Opening Comments: Gibbes Johnson, Ph.D., Chair, FDA Review Team

DR. JOHNSON: Good morning. My name is Gibbes Johnson, and I would like to provide some brief introductory information on the drug product and the FDA review process for this biologics license application or BLA.

The sponsor of this BLA is Eli Lilly and Company and Xigris is the brand name for the drug product. The international non-proprietary and the United States approved name for the active pharmaceutical ingredient is drotrecogin alfa (activated). The common name for the active pharmaceutical ingredient is recombinant human activated protein C.

This biologics license application was assigned submission tracking number 125029, and this slide contains the action dates involved in the review of this BLA.

The application was received on January 26, and granted priority review status. The application was filed as acceptable on March 12. A major amendment to the BLA was received on May 23. This major amendment contained additional clinical data and extended the first action due date by 3 months.

Three distinct facilities are involved in the manufacture of Xigris and pre-approval inspections of these facilities have been performed. Lonza Biologicals, Incorporated is the contract manufacturer for the bulk drug substance and was inspected from late May to early June.

DSM Catalytica Pharmaceuticals is the contract manufacturer for the final drug product and as inspected in August.

Eli Lilly Corporate Center performed certain release testing and all stability testing as well as having quality assurance oversight over the two contract manufacturers.

This facility was inspected in August. The agency will take action on this application on or prior to October 26.

The purpose of this slide is to recognize the FDA individuals responsible for the review of this BLA and to mention that the review process involves multiple disciplines. These disciplines include chemistry, manufacturing and controls or CMC, clinical biostatistics, pharmacology and toxicology. In addition, there are bioresearch monitoring facilities and inspections of these facilities.

Also, the regulatory project managers play an important role in coordinating the activities of the review committee.

Now, I would like to provide some general introductory information regarding the manufacturing of Xigris and recombinant human activated protein C.

It is produced by recombinant DNA technology in a human cell line, purified by a series of chromatographic and filtration procedures, analyzed for identity, potency and purity and the drug product is supplied as a sterile lyophilized powder containing recombinant human activated protein C, sucrose, sodium chloride and sodium citrate.

Now, recombinant human activated protein C is a glycosylated serine protease and activities include anti-coagulant via cleavage and inactivation of clotting factors 5A and 8A. APC, also, exhibits anti-inflammatory activities as well as pro-fibrinolytic activities.

At this time I will turn it over to the sponsor who will start their part of the presentation.

DR. RELLER: Thank you, Dr. Johnson.

I would like to call on Dr. Holger Schilske to introduce the presentation of Eli Lilly and Company.

Agenda Item: Eli Lilly and Company Presentations DR. SCHILSKE: Mr. Chairman, ladies and gentlemen, good morning. My name is Holger Schilske. I am the team leader for the product development team, the Xigris product development team at Eli Lilly and Company.

On behalf of Lilly, I would like to thank you for the opportunity to discuss drotrecogin alfa (activated) today.

The proposed trade name for drotrecogin alfa (activated) is Xigris.

The next slide, please?

The indication for which we are currently seeking approval is for the treatment of adult and pediatric patients with sepsis associated with acute organ dysfunction which is by definition severe sepsis. Treatment with drotrecogin alfa (activated) reduces mortality in patients with severe sepsis.

The efficacy and safety profile of this new life-saving therapy will be extensively highlighted in subsequent presentations today. The contents of this application meet all expectations contained in applicable FDA and ICH guidelines and it was designed and conducted consistent with agreement and advisement from the FDA.

We strongly believe the development of Xigris represents a revolutionary breakthrough in the treatment of severe sepsis, a devastating disease with an extremely high mortality.

Xigris is the first compound in a long row of failed ones that could clearly demonstrate that it significantly reduces mortality.

The next slide, please?

The next slide actually highlights the significant burden which the disease state of severe sepsis puts on patients and society. The annual incidence of severe sepsis in the United States is approximately 750,000 cases per year with a mortality rate of 28 to 50 percent despite the advances in modern medicine.

Also, the socioeconomic burden with regard to the costs of the treatment of severe sepsis is high, totaling almost $17 billion per year. The annual incidence rate, also, of severe sepsis is increasing due to our aging population and other various factors.

The next slide, please?

As presented on this slide, the incidence rate os severe sepsis even in comparison to other very significant diseases is very high, with the incidence rate of severe sepsis equality the incidence rate of congestive heart failure and breast cancer combined, and the number of patients dying from acute myocardial infarction and severe sepsis is roughly the same.

Next slide, please?

By breaking down the annual numbers on incidence rate and mortality, it is fair to say that in the United States on average 600 patients die every day with severe sepsis. Xigris has been shown to reduce the 28-day, all-cause relative risk of mortality by 19.4 percent. That means that one out of five patients who would have died will be saved.

The next slide, please?

This slide illustrates the structure of drotrecogin Alfa (Activated). Xigris, as you already heard this morning is a recombinant homologue of plasma human activated protein C.

The protein sequence of drotrecogin alfa (activated) is identical to that of human plasma activated protein C but differs in the carbohydrate portion of the molecule.

Human protein C was cloned by Lilly scientists in the early 1980s. The molecule shows a highly complex structure and requires four different types of post-translational modifications for its full biological activity.

Biochemical characterization, pharmacology experiments and preclinical toxicology studies were conducted during the 1980s and early 1990s. The clinical evaluation of Xigris then began shortly after the initial IND was filed in 1995.

Next slide, please?

Today we will demonstrate that the data submitted in the biologics licensing application for Xigris meet or exceed the proof for efficacy and safety.

We will provide data to you that support Xigris's ability to save lives of patients suffering from severe sepsis. Our presentation will encompass a number of scientific and regulatory matters, and we will follow the outlined agenda.

First, Dr. Steven Opal, professor of medicine, Chief, Infectious Disease Division, Brown School of Medicine will discuss the scientific background of sepsis disease state.

Following him will be presentations by two Lilly scientists. Dr. William Macias, Medical Director of the Xigris Product Team will present the clinical trial results in adults and ongoing trials. He will be followed by Dr. Jeff Helterbrand, Senior Regulatory Scientist of the Xigris Product Team who will review the formal benefit risk assessment.

Dr. Macias will then conclude with an overview of the pediatric trial data and overall study conclusions.

We look forward to a full discussion of the issues raised. Dr. Macias will facilitate Lilly's response during the discussion period.

Also, we have a number of key scientific staff and external experts available here today to respond to your questions.

The next slide, please?

We, in particular wish to thank the following experts for working with us and for being here today to assist with your deliberations, Dr. Gordon Bernard, Professor of Medicine, Pulmonary Medicine Division, Vanderbilt University Medical Center, Dr. Brett Giroir, Chief Medical Officer, Children's Medical Center, Dallas, Associate Dean for Clinical Affairs, University of Texas, Southwestern Medical Center, Dr. Mitchell Levy, Associate Professor of Medicine, Brown University School of Medicine, Medical Director, Intensive Care Unit, Rhode Island Hospital, Dr. Steve Opal as already mentioned and Dr. Michael Seneff, Medical Director, George Washington University Medical Center, Intensive Care Unit.

We ask for your active consideration to recommend approval of drotrecogin alfa (activated) for the treatment of patients with severe sepsis. We strongly believe the documentation provided will support such action and we look forward to a mutually productive session.

We, also, would like to ask you to hold your questions, please until the end of our presentation.

I now have the pleasure of introducing Dr. Steve Opal for the scientific disease state overview.

DR. OPAL: Thanks, Dr. Schilske, and good morning.

Sepsis and severe sepsis is described as a clinical syndrome characterized by a host systemic and inflammatory as well as procoagulant response to microbial pathogens, and it goes by the acronym SIRS for systemic inflammatory response syndrome.

An intense host response may lead to organ dysfunction, and this is now designated as severe sepsis The mortality rate for severe sepsis remains high despite appropriate antimicrobials and supportive care and as such improved therapies for this disease are a major unmet medical need.

The current thinking as to the pathophysiology of sepsis is related on this slide, and it is now viewed that a network of integrated hostriden(?) inflammatory mediators actually induce severe sepsis, and these mediators are initially induced because of an infectious process resulting in the systemic release of a number of microbial products into the circulation, and these pathogen-associated pattern molecules such as endotoxin and lipoproteins and other elements are recognized by the innate immune response and both a cellular and humoral response is induced which includes such elements as the pro-inflammatory cytokine such as TNF, IL1 and IL6, bradykinin complement activation, phospholipid activation, oxidant stress is generated along with neutrophil proteases. There is activation and coagulation of the system and there is activation of platelets, and all these elements combine to induce a diffuse endovascular injury in the host and result in a coagulopathy of sepsis and these combine to induce organ dysfunction and if left unchecked may potentially lead to the death of the patient.

There have been numerous attempts over the last 15 to 20 years to alter the outcome in sepsis by interventions which were designed to interfere with the pathophysiology of sepsis, and I will just show a few of these that I think are illustrative, the anti-endotoxin, monoclonal antibodies such as HA-1A and E5 and a variety of anti-TNF strategies and inhibitors of interleukin 1 have all been attempted in the past, and in each of these studies either large Phase II or Phase III trials designed to improve the survival of patients, the initial studies were unsuccessful, but in each case a subgroup was identified in each one of these studies often by post hoc analysis that suggested there might be a subpopulation within this septic population that may benefit from these agents and in each case a confirmatory trial was performed, and in each case the confirmatory study was unable to confirm the hypothesis that there was a subgroup of patients that might benefit from these agents, whether it was HA-1A going after gram-negative bacteremia or E5 and patients who had sepsis but did not have shock or the TNF inhibitor which tried to go after patients with severe sepsis without refractory shock or patients who had a predicted risk of mortality of greater than 24 percent using an APACHE II type system, and in each one of these circumstances the subgroup that was identified was not shown to be significantly benefitted in subsequent confirmatory trials, and I think these studies, as well as a number of other studies have taught us that there are some hazards in trying to do subgroup analysis in sepsis trials and, also, that we needed a new strategy to go after if we are going to improve the outcome of these patients, and within the last 5 to 10 years there has been a great deal of interest in the endogenous anticoagulants as a potential treatment strategy for sepsis, and the reason for this is that there is an increasing level of evidence, both experimentally and clinically using improved methods of detection of coagulation activation that shows us that activation of the coagulation system occurs very early in the septic process and is associated with a number of events including intravascular trauma generation and fibrin deposition and paired fibrinolysis, the depletion of key regulatory elements of the coagulation system, such as the protein C pathway in antithrombin, decreased capacity to activate protein C in the circulation and the evidence that the systemic inflammation has an interaction between the coagulation pathways and the inflammatory pathways involving neutrophils, other white cells and the endothelium.

Also, it has become apparent that activation of the coagulation system is largely independent of the type of infecting microorganism, and so, the data seen here which is from the Phase III trial have been shown in other studies as well and that is that if one looks at evidence of coagulation activation using very sensitive assays, such as a D-dimer which is a specific fibrin degradation product virtually 100 percent of patients who meet the criteria for severe sepsis will have evidence of coagulation activation, and this is true whether you have a gram-negative infection or a gram-positive infection or a fungal infection or sepsis without an identified microorganism. They virtually all have evidence of coagulation activation by D-dimer measurement.

It is, also, seen that a vast majority of patients had depletion in their protein C pathway and their protein C levels are inappropriately low in the majority of patients, and again, this is independent of the type of infecting microorganism as the cause of sepsis.

Prothrombin time is a very simple global assessment of coagulation, is abnormal in the vast majority of patients and the results are as compelling as is interleukin-6 as a global measure of pro-inflammatory cytokine generation that both coagulation and inflammation is activated simultaneously and in an interactive fashion in patients with sepsis and this is independent of the class of microbial pathogen.

Now, the mechanism of action of activated protein C is actually complex and multifactorial. It is certainly an endogenous anticoagulant but has other important properties, and I will just go through this figure to try to highlight these.

First, the coagulation system in sepsis is primarily activated via the tissue factor pathway through up regulation by pro-inflammatory cytokines of monocyte and endothelial cell tissue factor expression, and this results in activation of the coagulation system with the generation of thrombin within the circulation, and thrombin has many injurious effects within the microcirculation. It promotes fibrin deposition and platelet deposition resulting in an intravascular fibrin clot.

Thrombin has, also, been shown to react with specific receptors, thrombin receptors known as the PARs receptors or protease activated receptors and can directly activate cells such as platelets and white cells through the action of this receptor and through the presence in intravascular thrombin.

Thrombin has another property and that is that thrombin can not only act as a pro-coagulant but also, can potentially act as an anticoagulant when thrombin becomes bound to an integral cell membrane protein found in endothelium known as thrombomodulin and thrombomodulin and thrombin complex then has the capacity to convert circulating protein C into activated protein C, and this is a critical step in that protein C is zymogen and is an inactive precursor of the active moiety which is activated protein C, and this is actually mediated by thrombin itself in combination with thrombomodulin.

Activated protein C in combination with protein S will then feed back and inhibit the coagulation system by degrading factors 5 and 8A which are acceleration factors in the coagulation system.

So, there is a negative feedback loop here by which thrombin activation begets an inhibitor of thrombin activation and that is designed to regulate coagulation.

Unfortunately in septic patients this system is disrupted in that the protein C levels rapidly are consumed and this is due to decreased synthesis as well as increased utilization. Also, pro-inflammatory cytokines inhibit the synthesis of thrombomodulin by endothelial cells, and so the ability to peripherally convert activated protein C is abnormal.

Additionally neutrophil proteases, elastase and other proteases will cleave thrombomodulin as well as another receptor, the endothelial protein C receptor from the surface of endothelial cells further compromising the system and preventing the peripheral conversion of protein C to activated protein C where activated protein C can then go back and inhibit the coagulation system.

Now, it, also, turns out that activated protein C has at least two other properties of potential value in septic physiology, one of which is that activated protein C is a relatively important and significant inhibitor of PAI-1 or plasminogen activated inhibitor which is a molecule which inhibits the fibrolytic system, and so, activated protein C inhibits the inhibitor fibrinolysis, therefore, allows fibrinolysis to occur and allows plasmin to degrade intravascular fibrin clots which is a potentially desirable attribute in septic patients.

Additionally, as has been recently shown activated protein C, also, has anti-inflammatory properties and these properties include the actual binding and translocation and alteration of gene transcription frequencies of neutrophils as well as other white cells, monocytes and the effect has been shown to attenuate the pro-inflammatory cytokine generation, decrease surface adhesion expression and, also up regulate anti-apoptotic genes particularly in endothelial cells in such a way to protect the endothelium from injury and further injury found in systemic inflammatory states.

So, activated protein C as an anti-thrombotic is a profibrinolytic and is an anti-inflammatory molecule that, also, has anti-apoptotic effects.

If I could go to the next slide, please?

Okay, just briefly the preclinical evidence to support the use of activated protein C, I will just summarize this one slide. There is a wealth of literature in this topic and a number of different animal models, but I will just show you one of the original studies by Fletcher Taylor's group in 1987, where they showed using their lethal E. coli baboon model that the administration of activated protein C would reduce mortality in this system.

They, also, wanted to show if you use a sublethal dose of E. coli the administration of an antibody that inhibits the generation of activated protein C, the endogenous activated protein C converts a sublethal dose to a lethal infection, and if one then administers exogenous activated protein C in those animals in which the endogenous system has been turned off that can prevent this increase in lethality.

Just a comment about what is available in the literature with respect to the use of activated protein C as opposed to heparin as a treatment for DIC; this is a study performed in Japan and published last year in abstract form in Blood, and this group of investigators actually randomized patients who had DIC to either activated protein C, and I should point out this is plasma-derived activated protein C versus heparin at moderate doses of heparin and what was found was that the 30-day, all-cause mortality was 20.4 percent in those patients randomized to APC and 40 percent in those patients randomized to heparin. This is a small study. It was statistically significant, but it points out or at least indicates that it is possible that some of the other properties about activated protein C independent of its antithrombotic effects may be important in survival benefit in patients with sepsis.

So, in summary the therapeutic rationale for activated protein C in patients with severe sepsis is as follows: The basic pathophysiology of sepsis is now quite clear that the infection, the systemic inflammatory response and the procoagulant response is highly integrated in patients with severe sepsis, and via multiple mechanism of action activated protein C may disrupt this linkage between inflammation and coagulation and this may result in improved survival both experimentally and in clinical studies.

The baboon E. coli sepsis model indicates a critical role for activated protein C in survival activated protein C as opposed to protein C itself is the preferred treatment strategy because patients may be unable to adequately convert protein C to activated protein C in vivo in the face of severe sepsis.

So, thank you.

I will now turn the podium over to Dr. William Macias who will describe the clinical studies with drotrecogin alfa (activated).

DR. MACIAS: Thank you very much, Dr. Opal.

Mr. Chairman, members of the Advisory Panel, my colleagues at the FDA, my name is Bill Macias. I am a nephrologist and intensivist, and I am the Medical Director for the Xigris Product Development Team at Eli Lilly and Company, and I have the pleasure of presenting for you or reviewing for you the data supporting the efficacy and safest of drotrecogin alfa (activated) as therapy for patients with severe sepsis.

The objectives of my presentation are to provide the rationale for the proposed indication statement, to review the data supporting the recommended dose and dose duration for drotrecogin alfa (activated) and to review the primary efficacy and safety data from the pivotal Phase III study that demonstrates the favorable benefit/risk profile of the compound.

In addition, I would like to provide a very brief update on our ongoing clinical studies as well as review our experience in the pediatric patient population.

As Dr. Schilske reviewed for you the proposed indication statement for drotrecogin alfa (activated) would read as follows. Drotrecogin alfa (activated) is indicated for the treatment of adult and pediatric patients with sepsis associated with acute organ dysfunction with severe sepsis.

Treatment with drotrecogin alfa (activated) reduces mortality in patients with severe sepsis. Drotrecogin alfa (activated) would be recommended as adjunctive therapy to best standard of care.

The definitions of sepsis and severe sepsis contained in the indications statement are derived from the 1991, SCCM/ACCP consensus conference definitions for sepsis and severe sepsis.

Efficacy in adults with severe sepsis is based on data from a single pivotal Phase III study with supporting data from a single Phase II study.

Use in pediatric patients with severe sepsis is supported by data from open-label, safety and pharmacokinetic studies conducted in pediatric patients age 38 weeks' gestation to 18 years of age. However, efficacy must be extrapolated from well-controlled study in adults.

The inclusion of the mortality reduction statement in the indications statement is felt to be important as the benefit associated with drotrecogin alfa (activated) is the improvement in survival, and we would intend that drotrecogin alfa (activated) be used in patients who are assessed as being at risk of dying from severe sepsis by the treating physician.

The Phase II study EVAA was initiated in 1996. This study was a randomized double-blind placebo-controlled study of drotrecogin alfa (activated) in patients with severe sepsis. The primary objectives of the study were to assess the safety of drotrecogin alfa (activated) as a function of infusion rate and infusion duration, to assess the impact of drotrecogin alfa (activated) on coagulation abnormalities, primarily on the level of D-dimers and to assess the pharmacokinetics of drotrecogin alfa (activated).

In addition one of the intents of the Phase II study was to determine the dose for Phase III testing, and we had prospectively determined that that dose would be based upon the infusion rate an infusion duration that produced the maximum decline in D-dimer.

The study was conducted in two stages. Stage 1 explored an infusion duration of 48 hours, an infusion rate that ranged between 12 and 30 micrograms per kilogram per hour.

Stage 2 explored infusion durations of 96 hours and infusion rates of 12, 18 and 24 micrograms per kilogram per hour.

As mentioned the primary pharmacodynamic marker for this study was the effect of drotrecogin alfa (activated) on D-dimer levels.

This slide displays the median percent change in D-dimer from baseline to end of infusion with all patients grouped by the treatment infusion rate to which they were assigned.

A statistically significant monotonic dose response was present with the largest declines in D-dimer being most evident in patients receiving the 24 microgram and 30 microgram per kilogram per hour infusion rates.

Infusion rates of 12 and 18 micrograms per kilogram per hour were not associated with sizeable declines in D-dimer levels.

A similar observation was, also, seen when we looked at serial IL-6 levels. IL-6 was used as a surrogate measure for systemic inflammation. Again, a monotonic dose response was present with the largest decline in IL-6 being most evident in patients receiving the 30-microgram per kilogram per hour infusion rate.

There were no safety concerns noted in the Phase II study. In patients with severe sepsis drotrecogin alfa (activated) displayed linear pharmacokinetics, and there was no accumulation of the drug for infusion durations up to 96 hours.

The decline in D-dimer and IL-6 levels was most evident at infusion rates greater than 18 micrograms per kilogram per hour, and the maximum decline in D-dimer was most evident at the end of a 96-hour infusion. Therefore, the 24 micrograms per kilogram per hour infusion rate for 96 hours was recommended for Phase III testing.

The Phase III study was started in 1998. This study was a randomized double-blind placebo-controlled study conducted in adult patients with severe sepsis. There were 164 investigative sites in 11 countries. The dose investigated was the single dose identified in the Phase II study. Both drotrecogin alfa (activated) or placebo were administered for 96 hours. The primary objective was to determine the effect of drotrecogin alfa (activated) on 28-day all-cause mortality, and the secondary objectives included an assessment of the safety and analysis of the effect of drotrecogin alfa (activated) on organ function as well as an assessment of the pharmacokinetics and pharmacodynamics of the drug.

The population studied had severe sepsis defined as the presence of known or suspected infection, evidence of systemic response to that infection and one or more sepsis-induced organ dysfunctions.

This slide displays the study design. Patients had to meet all inclusion and no exclusion criteria within a 24-hour time period. From the moment all entry criteria were met an additional 24-hour period was allowed to obtain consent, randomly assign the patient and initiate the study drug infusion.

Study drug was administered for 96 hours. Routine patient care was not dictated by the protocol, and 28-day all-cause mortality was assessed for all patients exposed to study drug for any length of time.

The first patient was enrolled in the study in July 1998. The protocol was amended once very early in the course of the study. The first patient was enrolled under the amended protocol in June 1999.

The first interim analysis conducted by an independent data and safety monitoring board was conducted in October 1999. The efficacy stopping rules were based on the method of O'Brien and Fleming. The recommendation at that time by the DSMB was to continue the trial without modification of the protocol.

The second interim analysis was conducted in June 2000. At that time the recommendation from the DSMB was to stop the trial for highly statistically significant results.

The last patient enrolled in the study completed the study in July 2000. At study completion 1728 patients had been randomly assigned to either drotrecogin alfa (activated) treatment group or the placebo treatment group.

Of those patients randomized to drotrecogin alfa (activated) 21 patients did not receive treatment, and of those patients randomized to placebo 17 patients did not receive treatment. The most common reason for not receiving treatment is that the patient developed an exclusion criteria after informed consent was obtained or the patient died prior to the start of the study drug infusion.

In total 850 patients assigned to the drotrecogin alfa (activated) group completed the protocol and 840 patients assigned to the placebo group completed the protocol.

The site of infection as assessed by the investigator was similar between treatment groups. The majority of patients had the lung identified as the site of infection with approximately 20 percent of patients having the abdomen identified as the primary site of infection.

Urinary tract infections were identified in approximately 10 percent of the population. The types of infecting organisms were, also similar between treatment groups. Approximately 25 percent of patients had gram-positive infections; 22 to 23 percent had gram negative. Pure fungal infections were present in 2 to 3 percent of the population and approximately 30 percent of the population had no identifiable microorganism, a finding very consistent with prior sepsis studies.

Almost all patients had laboratory evidence of a coagulopathy. This slide shows on the ordinate above the percent of patients with abnormally high values and on the ordinate below the abscissa the percent of patients with abnormally low values. Almost all patients had elevated D-dimer and thrombin, anti-thrombin levels.

Approximately 70 percent, 75 percent of patients had elevation in the prothrombin fragment F1.2 indicating ongoing thrombin generation.

Approximately 80 percent of the patients had a reduced protein C, protein S and anti-thrombin level indicating the consumption of endogenous anticoagulants.

This slide shows a similar analysis for other measures of coagulation and systemic inflammation. Approximately 40 percent of the patients had elevated PAI-1 levels indicating impaired fibrinolysis.

As Dr. Opal mentioned all patients had elevated IL-6 levels indicating a state of global inflammation. Almost all patients had elevated prothrombin times. Approximately 60 percent of patients had elevated APTTs and only about 30 percent of patients had abnormally low platelet counts.

Taken together the inclusion criteria for the EVAD study defined a population with severe sepsis in which the majority of patients had documented infection. All patients had evidence of a systemic response to that infection that was characterized not only by an inflammatory response but a pro-coagulant response with evidence of thrombin generation, fibrin deposition and impaired fibrinolysis.

Again, as Dr. Opal showed you, the systemic response to infection is really independent of the infecting organism. The most common types of sepsis-induced organ dysfunction were respiratory and cardiovascular dysfunction, and this slide displays the 28-day all-cause mortality for both treatment groups.

The placebo mortality was 30.8 percent. The drotrecogin alfa (activated) mortality was 24.7 percent. Based on the primary analytical plan this resulted in a 19.4 percent relative reduction in the risk of death in favor of Xigris, a highly statistically significant finding with a two-side P value of 0.005.

The Kaplan-Myer(?) curve shows that drotrecogin alfa (activated) improves survival compared to placebo. An absolute difference in the survival curves is evident within days following the start of the infusion and continues to increase throughout the entire 28-day study period.

A 20 percent relative reduction in the risk of death is evident throughout the entire 28-day study period.

This slide provides a variety of sensitivity analyses that demonstrate that a highly statistically significant reduction in mortality is evident regardless of the way the clinical trial data are analyzed.

The first row shows the relative risk reduction and the P value for the primary analysis. The second row shows the results of a non-stratified analysis as performed. The third row shows the results of patients are analyzed as treated as opposed to as randomly assigned, and there were three patients that received all or part of the wrong therapy, and finally the fourth row shows the analysis for all randomized patients including the 38 patients who did not receive study drug.

In each instance a very consistent relative risk reduction was observed that was highly statistically significant.

As I mentioned there was one amendment to the protocol. The amendment occurred very early in the course of the study. To analyze the potential effect of that amendment on outcome we looked at the cumulative mortality rates for patients enrolled at sites that participated both under the original and the amended versions of the protocol.

This graphs shows the cumulative mortality rate for the placebo population and the cumulative mortality rate for the drotrecogin alfa (activated) population.

This is approximately 1460 of the 1690 patients. The first vertical line shows the point at which the first patient was enrolled under the amended version of the protocol and the second vertical line shows the point in time where the last patient was enrolled under the original version of the protocol.

A treatment benefit was clearly evident prior to the introduction of the amendment. The placebo mortality rate gradually drifted down over the course of the study as did the mortality rate for the drotrecogin alfa (activated) population.

Based on this analysis and other analyses we don't believe that the amendment had a substantial impact on the overall outcome of the study.

This graph displays the relative risk and the 95 percent confidence interval for a variety of subgroups defined by patient demographics.

On the left side is the subgroup of interest and on the right side is the number of patients within the subgroup and the mortality rates for either the drotrecogin alfa (activated) group or the placebo group.

For subgroups defined by gender age cut at either 50 years of age or 65 years of age and for origin, Caucasian or non-Caucasian uniformly lower mortality was observed with drotrecogin alfa (activated) compared to placebo.

Lower mortality with drotrecogin alfa (activated) was, also, observed for patients enrolled in Europe, North America and for the remaining countries grouped together as other.

Investigators in the United States enrolled the largest number of patients of any individual country. The administration of drotrecogin alfa (activated) was, also, associated with an improvement in cardiovascular function as evidenced by a reduction in time averaged CV-SOFA scores and an increase in the number of vasopressor free days compared to placebo patients. There were, also, fewer deaths in the drotrecogin alfa (activated) group from septic shock.

The administration of drotrecogin alfa (activated) also improved respiratory function, again as evidenced by a reduction in time-averaged respiratory SOFA scores and an increase in ventilator-free days compared to placebo-treated patients, and there were fewer deaths from respiratory failure in the drotrecogin alfa (activated) group.

A comparison of 28-day survivors between treatment groups indicated that drotrecogin alfa (activated) patients had similar patient location and functional status as compared to placebo-treated patients.

The only adverse drug reaction associated with drotrecogin alfa (activated) was an increase in bleeding and this graph displays the percent of patients in each treatment group that experienced a bleeding event reported as a serious adverse event either during the study drug infusion period or during the 28-day study period.

Over the course of the 28-day study period 13 more patients of the drotrecogin alfa (activated) experienced a serious adverse event that was of a bleeding nature.

We analyzed the types of serious bleeding events either by the type of event or by whether the event was considered to be procedure related or non-procedure related. The difference in bleeding events between the two treatment groups resulted predominantly from procedure-related bleeding events. The types of non-procedure related or the incidence of non-procedure related or if you will spontaneous bleeding events was actually similar between the two treatment groups.

An analysis of the remaining safety data indicated no other safety concerns. There was a similar incidence of serious thrombotic events in both treatment groups with approximately 3 percent of placebo patients experiencing a thrombotic event reported as a serious adverse event versus 2 percent of patients in the drotrecogin alfa (activated) group.

There was a similar incidence of post-baseline infections. There was a very low incidence of anti-APC antibody formation and when detected the level was low and non-neutralizing, and there were not other safety concerns identified based on analysis of other adverse events, other serious adverse events and analysis of organ function or analysis of the central laboratory data.

Since completion of the pivotal Phase III study we have initiated a number of other clinical studies of drotrecogin alfa (activated) in patients with severe sepsis. Protocol EVBC is a treatment use protocol sometimes referred to as a compassionate use protocol and studies EBVE, EBVF and EVBG are open-label studies being conducted worldwide.

Both protocols employ very similar inclusion and exclusion criteria as utilized in the pivotal Phase III study. In the compassionate use protocol EVBC approximately 185 patients have received drotrecogin alfa (activated). The current 28-day all-cause mortality rate is 21 percent although it is important to note that not all patients have completed the 28-day follow-up period.

Approximately 3.2 percent of patients have experienced a serious bleeding event during the study drug infusion period.

Five hundred and eighty patients have received drotrecogin alfa (activated) under our open label studies. The current 28-day all-cause mortality rate is 19 percent. Again, the same caveat applies. Not all patients have completed the 28-day study period, and the percent of patients experiencing a serious adverse event, a bleeding event reported as a serious adverse event during the study drug infusion period is 2.1 percent. Both values are somewhat similar to what we observed in the pivotal Phase III trial.

We have looked very carefully at all of the intracranial hemorrhage events that have occurred in our ongoing studies through an adjudication process that employs two external independent neuroradiologists and an external independent neurologist who review in a blinded fashion all of the events that have occurred.

Our numbers will differ a little bit from Dr. Lindblad's because some of the intracranial hemorrhages that have been reported to date have been adjudicated as not being intracranial hemorrhages.

However, there were three patients in the ongoing trials who experienced a cerebral hemorrhage that was fatal during the infusion period. One patients experienced hemorrhagic infarct that was fatal during the post-infusion period. This event occurred on day 14 while the patient was receiving heparin for dialysis.

There have been a number of non-fatal intracranial hemorrhages which are predominantly hemorrhagic infarct, so, is stroke with hemorrhagic transformation and in these three cases these are small petechial hemorrhages, and there have been three small subarachnoid hemorrhages reported.

For those patients experiencing a cerebral hemorrhage during the study drug infusion period these events always occur in the setting of severe thrombocytopenia usually with platelet counts less than 30,000.

To assess the benefit/risk for patients with severe thrombocytopenia we went back to the pivotal Phase III study, the EVAD study and we looked at the mortality rates for patient populations defined by those having a platelet count of less than 50,000 at baseline, a platelet count of less than 50,000 at some time during the study drug infusion period or a platelet count of less than 30,000 either at baseline or during the study drug infusion period, and there were 40 patients who had a platelet count of less than 50,000 at baseline. Although the numbers are small the mortality rate for the placebo group was 63 percent and for the drotrecogin alfa (activated) group 25 percent.

For patients who had a minimum platelet count during the study drug infusion period of less than 50,000 mortality rate was 54 percent versus 24 percent and there a total of 113 patients in this subgroup, and finally, for the population that had a minimum platelet count of less than 30,000 either at baseline or during the study drug infusion period the mortality rate for the placebo group was 84 percent and for the drotrecogin alfa (activated) group was 33 percent. So even in the setting of severe thrombocytopenia there may still be a favorable benefit/risk profile for drotrecogin alfa (activated) given the fairly dismal prognosis for patients with severe consumptive coagulopathy and severe thrombocytopenia.

In conclusion drotrecogin alfa (activated) administered to patients with severe sepsis substantially reduces 28-day, all-cause mortality. The administration of drotrecogin alfa (activated) also improves cardiovascular and respiratory function which may explain in part the improved survival associated with its use.

There is an increased risk of serious bleeding events although it is infrequent, and many of the events seem to be related to vessel trauma or occur in the setting of severe coagulopathy and taken together these data support the very favorable benefit/risk profile for drotrecogin alfa (activated) as a therapy for patients with severe sepsis.

I would like to now turn over the podium to Dr. Helterbrand who will review for you a formal benefit/risk assessment of drotrecogin alfa (activated) as therapy for patients with severe sepsis.

DR. HELTERBRAND: Good morning. My name is Jeff Helterbrand, and I am the Senior Statistical Scientist on the Xigris Product Development Team.

A formal evidence-based benefit/risk assessment of Xigris in the treatment of patients with severe sepsis was conducted using the pivotal Phase III trial results.

We will begin this presentation with an assessment of the benefit/risk profile for Xigris for the overall population of patients enrolled in the study. Then we will discuss what the trial results suggest regarding potential differential effects across subgroups, both in terms of bleeding risk and in terms of the Xigris survival benefit.

This benefit/risk analysis will show that Xigris is associated with a positive benefit/risk profile across the diverse population of patients enrolled in the study.

In the remainder of the presentation we will take the opportunity to specifically address six questions that have been posed by the agency to the Advisory Committee that are related to subgroups, namely, those questions related to patients without laboratory evidence of DIC, low-dose heparin exposure and less severe disease patients.

In the benefit/risk assessment each patient's outcome can be classified into one of three outcome categories. The first and best outcome is the patient survived 28 days and did not experience a serious bleeding event.

The higher percentage of Xigris patients compared to placebo patients experienced this optimal outcome. The second outcome is the patient survived the 28 days but did experience a non-fatal serious bleeding event in that time window. There were 18 Xigris and 8 placebo patients in this category.

The third outcome is that the patient died. In commonly applied benefit/risk assessment models each of these three possible outcomes are seeing the value from the patient's perspective with the greatest value being assigned to the optimal outcome and the least value being assigned to the worst outcome. In this model one must determine what value to assign to the middle outcome relative to the other two outcomes.

Intuitively this value should be assigned based on the number of additional serious bleeding events in survivors one would be willing to accept in order to save one additional life.

As this value for the middle outcome approaches zero, the one is essentially equating a non-fatal serious bleeding event to death. Alternatively as this value approaches one, then one is following the philosophy that the preservation of life is of greater importance than virtually any non-fatal risk.

This figure applies the benefit/risk model to the overall Phase III trial results for Xigris. Due to the magnitude of improvement in survival associated with Xigris and the relatively smaller increased risk of non-fatal serious bleeds the key message is that regardless of how one assesses the number of additional serious bleeding events in survivors one would be willing to accept to save an additional life the pivotal Phase III trial results demonstrate a highly favorable benefit/risk profile associated with Xigris.

Next we turn to subgroup analyses. Before proceeding it is important to reiterate the often-cited caveats associated with interpreting subgroup analyses. First, the pivotal Phase III trial as with most trials was sized to detect a treatment benefit for the entire population only and not for subgroups, and as you know, no trial can ensure definitive statistical evidence of a benefit in all subgroups.

Additionally when one is trying to interpret the results of individual subgroup analyses they must be interpreted in the context of the multiplicity of analyses that have been performed. Analyses from over 70 subgroups are presented in the Lilly briefing document and in this presentation, and with this in mind it is really important that we point out that it is not Lilly's intention to conclude greater efficacy in selected subgroups based solely on exploratory subgroup analyses.

There are some fundamental differences between the Lilly briefing document and the agency briefing document in the manner in which the consistency across subgroups was assessed, and these differences may lead to some confusion among readers. So, I will take a few moments here to specifically describe Lilly's approach.

In the briefing document and in the biologics license application we relied on two commonly applied measures for subgroup results namely relative risk and its close cousin odds ratios.

As stated in one of the mostly widely referenced books on categorical data analysis the odds ratio scale is the most generally accepted scale to perform interaction analyses across subgroups.

The agency briefing document does focus on a different risk scale by comparing absolute risk reductions across subgroups. Lilly's analytic approach for subgroup analyses follows commonly accepted methods. We focus on within subgroup relative risk confidence intervals and on interaction tests that are based on odds ratios.

However, it is important to emphasize that these approaches do not overcome the fact that subgroup analyses are exploratory in nature and not confirmatory. However, these approaches do assess the statistical evidence supporting any hypothesis that may be conjectured based on exploratory subgroup analyses.

With respect to bleeding since there were so few serious bleeding events in the study to begin with, the ability to detect differential effects across subgroups is limited. Indeed, when we actually include all serious bleeding events during the 28-day study period and include non-procedure related and procedure related events there is still limited ability to detect a differential effect with respect to serious bleeding risk, and indeed no clinically relevant differential effects were observed. Indeed based on these analyses what we have here is that there was no evidence of an exceptionally higher increased risk of bleeding associated with treatment in a particular subgroup.

In order to have more discriminatory power we actually, also, did a similar analysis on all treatment emergent bleeding events. However, again, no clinically relevant differential effects were observed.

Thus as much as the pivotal trial results can suggest from a statistical perspective the increased relative risk of bleeding with treatment is consistent across subgroups.

Turning to survival extensive subgroup mortality analyses were, also, conducted. This slide from the briefing document displays the mortality results for subgroups defined based on patient demographics, recent surgery status and site and type of infection.

There is a considerable amount of information on this slide. However, for each subgroup there are two key points to look for. First, one should note whether the relative risk point estimate for the subgroup lies to the left of the vertical unity line indicating that lower mortality was observed with Xigris compared to placebo within that subgroup.

The second point to look for is whether the relative risk 95 percent confidence interval for the subgroup contains the point estimate for the overall trial indicating that subgroup result consistent with the overall trial results.

Dr. Macias already reviewed the uniformly lower mortality observed with Xigris compared to placebo across all subgroups defined based on patient demographics. In addition, lower mortality was observed with Xigris for patients who did and did not have a surgery prior to the start of study drug administration and for the subgroup of patients with lung, intra-abdominal and quote, unquote, other sites of infection.

Similar mortality rates were observed in the two treatment groups for the subgroup of patients who had urinary tract classified as their presumed primary site of infection by the investigator.

In addition uniformly lower mortality was observed with Xigris regardless of the type of bacterial infection. As illustrated by their 95 percent intervals all summary results presented on this figure were consistent with the overall trial.

The following two slides recreated from the briefing document display mortality results based on subgroups defined by clinical measures of disease severity. As you know, the clinical diagnosis of a patient's condition in the decision to treat the patient is typically based on multiple measures of disease severity, and therefore it is important to consider how multiple measures describe a patient's condition and how these measures actually show evidence supporting a beneficial effect with Xigris across these measures.

With respect to APACHE II scores lower mortality was observed with Xigris compared to placebo for patients in the second, third, and fourth APACHE II quartiles. The mortality rate for treatment was higher than for placebo in patients in the first APACHE II quartile. However, as noted by the broad width of the 95th percent relative risk confidence interval containing the point estimate for the overall trial it does meet the consistency criteria.

We will discuss this observation in further detail when we specifically address a couple of the agency's questions to the Advisory Committee in a few moments.

Importantly uniformly lower mortality with Xigris as compared to placebo is observed across all subgroups defined by the various measures of cardiovascular organ function collected in the trial and by the various measures of respiratory organ dysfunction measured in this trial.

Furthermore lower mortality was observed with Xigris compared to placebo for all subgroups defined by measures of hematologic, renal, metabolic, hepatic or based on the number of organ failures present at baseline.

As illustrated by their confidence intervals all subgroup results based on clinical measures of disease severity that were presented on this figure and on the previous figure were consistent with the results of the overall trial.

The final subgroup figure reproduced from the briefing document displays the mortality results for subgroups defined based on biochemical measures of disease severity.

Notice that lower mortality was observed with Xigris compared to placebo across all these subgroups defined by these measures.

There are three key points, however, that can be made from this graphic. First, in the secondary objectives of the trial protocol there was only one subgroup for which there was a priori conjecture that a differential effect on mortality may be observed, specifically a greater treatment effect was hypothesized for protein C deficient patients compared to non-protein C deficient patients.

In final analysis a survival benefit was evident in both subgroups. Second, in the context of the agency's questions regarding DIC note that a beneficial effect with Xigris is observed in patients with normal protein C levels, normal prothrombin times, normal APTT levels in those patients with platelet counts above the lower limit of normal and for patients with normal anti-thrombin levels.

This implies that a survival benefit with Xigris is present in patients who generally would not be classified as having a clinical diagnosis of DIC, and finally, the only subgroup of all 70 subgroups assessed with a relative risk observation inconsistent with the overall trial results was the first IL-6 quartile where we saw much lower mortality with Xigris than for placebo.

This subgroup includes those patients with the lowest baseline IL-6 levels, patients, therefore with less severe disease as assessed by this marker.

Thus, to summarize our overall mortality subgroup findings, lower mortality was observed with Xigris compared to placebo for nearly all or 68 of the 70 subgroups assessed, the lone exceptions being the first APACHE II quartile and the relatively small subgroup of patients who had urinary tract infection classified as their presumed primary site of infection by the investigator.

Importantly, a consistent treatment effect with Xigris was observed for nearly all or 69 of the 70 subgroups assessed. A lower relative risk estimate in favor of Xigris was observed for those patients in the first IL-6 quartile, that is patients with the least inflammation by this marker and therefore the least disease severity where a 53 percent reduction in relative risk of death was observed with Xigris compared to placebo.

Thus, from a statistical perspective we conclude that a consistent treatment effect on the relative risk of bleeding and on the relative risk of death is observed with Xigris across subgroups as can be assessed by the trial results.

When this is accounted for in a formal benefit/risk analysis Xigris is associated with a favorable benefit/risk profile across the diverse population of patients that were enrolled in the pivotal Phase III study, that is from a population viewpoint for this devastating disease the demonstrated life-saving capability of Xigris outweighs the risks associated with its use.

Now, this completes the formal benefit/risk assessment, and we will turn directly to addressing six questions that were posed by the agency to the Advisory Committee that are related to subgroups.

Due to the limited time of this core presentation we will be happy to address any of these questions in further detail in the question and answer session.

Next slide, please?

The agency has posed questions No. 4 and No. 5 to the Committee based on the subgroup results in patients in whom DIC status at baseline was absent or unknown, and it is important to clarify a few key points regarding this analysis

Here we display the clinical trial definition of non-overt DIC used in the study. This definition is based on laboratory markers and does not take into account clinical signs of DIC.

As shown in the table accompanying Question No. 4, there were 115 patients who were classified as having their DIC status at baseline as absent or unknown. A total of 113 of these 115 patients did not have biochemical data available at baseline to assess their status. Thus, the subgroup was really defined based on the absence of data and not based on the absence of a clinical condition.

So, when we only assess those patients who did have laboratory data available we find that 99.9 percent of the patients in the trial met the clinical trial definition of non-overt DIC.

A review of data from another recent sepsis trial for an anti-inflammatory agent with similar inclusion criteria actually had similar results. Thus, as Dr. Opal and Dr. Macias alluded to earlier the inclusion criteria employed in this study, namely infection, inflammatory response and associated organ dysfunction by themselves essentially defines a population with sepsis-associated coagulopathy.

Next, turning to heparin the agency has posed Question Nos. 6 and 7 regarding low-dose heparin exposure, and we have a few remarks related to these questions.

First, regarding bleeding risk similar rates of serious bleeding were observed in Xigris patients who did receive heparin and Xigris patients who did not receive heparin, and there no treatment by heparin interaction with respect to bleeding events.

Second, regarding mortality we note that uniformly lower mortality was observed with Xigris compared to placebo and all subgroups defined by either baseline or concomitant heparin exposure with relative risk reductions in excess of 10 percent in all cases.

A further point to make is that analyses based on subgroups defined based on concomitant heparin exposure as opposed to based on a pure baseline covariate are severely biased, and this statement is true for analyses of any concomitant medication where many patients are exposed to the concomitant medication for the first time after the start of study drug infusion, and indeed in this trial many patients moved from the no heparin group to the heparin group with their first post-baseline exposure, and this type of bias is widely discussed in the statistical literature.

Next slide, please?

Therefore to perform statistically valid analyses we adopted two approaches. The first approach and maybe the best approach from a purist perspective was to define our heparin subgroups based on baseline heparin exposure only.

When we look at the trial results from this perspective there is no treatment by heparin interaction and actually when we do non-randomized comparisons of heparin and non-heparin patients within the two treatment groups again there is no evidence that low-dose heparin affects mortality in either of the two treatment groups.

The second approach which incorporates post-baseline heparin exposure in an unbiased manner is to use a Cox regression model with heparin exposure expressed as a time-dependent covariate when this approach is used, again, there is no statistical evidence to support a treatment by heparin interaction and furthermore there is no statistical evidence that low-dose heparin affects mortality in either of the two treatment groups.

Therefore we conclude that any conjectures that may be made regarding the effects of low-dose heparin based on exploratory subgroup analyses are speculations and are not compelling supportive from the statistical evidence perspective.

The agency has posed questions No. 2 and No. 3 to the Committee regarding the treatment of Xigris in patients with relatively less severe disease.

Importantly in Question No. 3, the agency has challenged the Committee to advise whether the indication for Xigris should be limited to a subset of the population enrolled in the pivotal Phase III trial.

Here we review the evidence supporting the beneficial effect with Xigris in patients with relatively less severe disease, and we have three key points for the Committee to consider. First from a statistical perspective the observed variation in relative risk estimates observed across subgroups is in harmony with random chance alone if treatment were uniformly beneficial at a constant 20 percent relative risk reduction across all subgroups.

As was discussed in Lilly's briefing document due to the multiplicity of analyses performed we would have expected high mortality for the effective treatment arm for five of the 70 subgroups assessed, and as we discussed already we saw that for two subgroups.

Second, a survival benefit with Xigris is evident in less severe patients almost uniformly across the totality of measures of disease severity that were collected in the trial, and third, a survival benefit with Xigris is evident in patients with less disease severity within the first APACHE II quartile subgroup itself, and my last two slides will discuss these last two points.

This figure displays the relative risk in 95 percent confidence intervals for the lesser disease severity subgroups that were presented earlier.

For example, the following subgroups are included: The first APACHE II quartile, those patients with a single organ dysfunction, those patients with no evidence of shock at baseline, patients not on mechanical ventilation, those patients with less hepatic organ dysfunction as measured by SOFA, patients with normal activated partial thromboplasmin times and normal prothrombin times, patients with less respiratory organ dysfunction and again the patients with the lowest IL-6 levels indicating the least inflammation, patients in the first IL-6 quartile.

In total 21 subgroups defining patients with relatively less severe disease are presented on this graphic. Lower mortality is observed with Xigris compared to placebo for 20 of the 21 subgroups clearly demonstrating that survival benefit with Xigris is evident in less severe disease patients enrolled in the pivotal Phase III study.

Additionally for approximately half or 12 of the 21 subgroups we actually saw larger relative risk reductions within the subgroup itself than was observed for the overall trial, and this observation supports our consistency conclusion.

In line with the ICHE 9 guidelines when one observes an unusual result we explored results within the first APACHE II quartile subgroup itself and the survival benefit is evident in less severe disease patients within this subgroup.

In patients with fewer than three organ failures a 20 percent relative risk reduction was observed with Xigris compared to placebo. This relative risk reduction is identical to what was observed in the overall trial.

It is important to note that approximately 75 percent of the patients that make up the first APACHE II quartile had fewer than three organ failures at baseline. In patients with three or more organ failures at baseline higher mortality was observed with treatment compared to placebo, and this apparently drove the result for the entire subgroup as a whole.

Not that Xigris patients with three or more organ failures had higher mortality than Xigris patients with fewer than three organ failures as one would expect. However in the placebo group we see similar mortality rates for patients with three or more organ failures compared to patients with fewer than three organ failures, an apparent anomaly.

It is, also, noted that within the first APACHE II quartile similar beneficial effects are evident in patients with low IL-6 levels, normal prothrombin times and normal APTT levels within the first APACHE II quartile, and we would be happy to share this data with the Committee during the question and answer session.

Thus, with regard to disease severity we conclude that a survival benefit with Xigris is clearly evident in patients with less severe disease enrolled in the pivotal Phase III trial as assessed by the multiple measures of disease severity that can be used to assess the patient's condition.

In simple terms lower mortality is observed with Xigris in nearly all subgroups and in the one subgroup where we do not see lower mortality the subgroup itself is internally inconsistent with the less effect and less severe patient hypothesis.

Therefore based on many well-founded scientific principles the results of this trial support granting an indication for this life-saving treatment that includes all patients who meet the inclusion criteria studied in the pivotal Phase III trial.

I am now going to return the podium to Dr. Macias who will provide additional clinical perspectives related to the treatment by disease severity analyses.

DR. MACIAS: Thank you, Dr. Helterbrand. Before I review the pediatric data, I would like to make just a few comments about the treatment by disease severity analyses and those comments really relate to the treatment by APACHE observation, and we have looked at this observation quite extensively and have really had a difficult time if you will operationalizing the observation.

As Dr. Helterbrand has reviewed for you, the observation itself does not really reconcile with the treatment by disease of the rest of the treatment by disease severity analyses. Particularly it doesn't reconcile with the observation that in patients with the lowest IL-6 levels there is a clear treatment benefit indicating that patients with less inflammation do benefit from a drug that has anti-inflammatory properties.

In addition, it doesn't reconcile with the analysis by normal PT, normal PTT and normal platelet count indicating that patients that do not have abnormalities in the global measures of coagulation do benefit from a drug that has anticoagulant properties.

To further complicate the observation, the APACHE II data collected in the EVAD trial were not collected and the score was not calculated according to the published methodology. It was never our intent to use the APACHE score in the EVAD trial to predict mortality. It was simply used to assess the parity of baseline between the two treatment groups, and finally, the APACHE II score itself is rarely used in the making of individual patient treatment decisions.

In fact, to my knowledge there is no outcome prediction model that has ever been validated for the use of individual patient treatment decisions. However, what physicians do look at --

You can go to the next slide, please?

What physicians do look at is the number of failed organs that are present at baseline, whether or not the patient has cardiovascular dysfunction and if present what is the extent of that dysfunction and whether or not the patient has respiratory dysfunction, and again if present what is the extent of that respiratory dysfunction.

This slide shows us the treatment by number of organ failure analysis and regardless of the number of organ failures present at baseline and treatment benefit, regardless of the number of organ failures present at baseline lower mortality is observed with the drotrecogin alfa (activated) group compared to placebo.

The interaction P value is .93, and despite the finding that there is no treatment by number of organ failure, there is no interaction, there is a tendency for individuals to focus on the point estimate for the relative risk that is observed in patients with single organ failure. To explore that a bit further we separated that out into the population of patients who had single organ respiratory failure and single organ cardiovascular failure, the two most common types of organ dysfunction in patients with severe sepsis. These two subgroups constituted 85 percent of all patients with single organ failure and in this analysis, the point estimates are actually quite similar to what was observed in the overall trial.

In addition although this is a subgroup of a subgroup, the number of patients with single organ respiratory failure is actually quite similar to the total number of patients with four organ failures at baseline and is actually much larger than the number of patients that have five organ failures at baseline.

Physicians will, also, look and try to assess the severity of cardiovascular dysfunction at baseline. In the EVAD trial physicians were asked to assess cardiovascular dysfunction as defined in the inclusion criteria either within the 48-hour period, immediately preceding the administration of study drug or within the 6-hour period immediately preceding study drug and that assessment was a yes or a no.

Graded assessment of cardiovascular dysfunction at baseline was performed using the cardiovascular SOFA score and physicians were asked to record the worst SOFA score within the 24-hour period immediately preceding the administration of study drug, and in each instance lower mortality is observed with drotrecogin alfa (activated) compared to placebo.

We, also, generated two additional subgroups, an any shock, yes and an any shock, no, and the subgroup that is any shock, no is the population of patients that had no evidence of cardiovascular dysfunction within 48 hours of drug, a SOFA score of no greater than zero or one with 24 hours of drug and no evidence of cardiovascular dysfunction within 6 hours of drug, and when you look at the point estimates for any shock, yes, and any shock, no, they are actually quite similar to what you see in the overall population.

This slide shows us the graded scale for cardiovascular function at baseline. Again, this is the worst SOFA score obtained within the 24-hour period immediately preceding study drug with zero being the complete absence of cardiovascular dysfunction and four being the requirement for very high-dose vasopressor.

What you see is when you look at the population of patients and it has no or only mild cardiovascular dysfunction within the 24-hour period immediately preceding drug there is a clear treatment benefit.

These two slides demonstrate as we have looked at these data that there is no treatment by baseline cardiovascular status interaction related to the effect of drotrecogin alfa (activated).

This slide shows us the respiratory SOFA score, again, graded 0 to 4, 0 being complete absence of respiratory dysfunction, 4 being the worst respiratory dysfunction with a severe decline in PF ratio and the requirement for mechanical ventilation.

Again, when we look at the population of patients with no or only mild respiratory dysfunction, a treatment benefit is evident although the numbers are a bit small.

Again, as we look at these data that there is a treatment by respiratory status interaction related to the effect of drotrecogin alfa (activated), and finally when we look at the baseline characteristics for the population of patients that comprise the first APACHE quartile, what we see is that this population of patients is actually critically by almost every other measure of disease severity.

Sixty percent of the population have two or more organ failure. Seventy percent have respiratory failure. Sixty percent require mechanical ventilation. Fifty-six percent are in shock. Almost 50 percent require high-dose vasopressors, and 65 percent are severely protein C deficient.

Seventy percent of the patients in the first APACHE quartile have two or more organ failures and/or require the administration of high-dose vasopressors to support blood pressure.

To sum up the subgroup conclusions, the EVAD study tested one primary hypothesis, and the results of the study show that drotrecogin alfa (activated) significantly reduces mortality in the population of patients defined by the inclusion and exclusion criteria.

As Dr. Helterbrand has pointed out caution should be exercised in interpreting individual subgroup analyses, and as we look at the data in its totality we find no clear evidence to support a differential effect of drotrecogin alfa (activated) based on disease severity.

Moving on to the clinical experience with pediatric patients as most of you are aware the majority of drugs used by pediatric intensivists are not approved for use in the pediatric population. Our intent in our pediatric development program was to provide guidance to pediatric intensivists on the use of drotrecogin alfa (activated) on the assumption that if it were approved for use in the treatment of adults it would be used in pediatric patients with severe sepsis.

The development program was based on ICH guidelines and the Code of Federal Regulations and was developed in collaboration with our colleagues at the FDA.

The studies employ open label safety and pharmacokinetic studies, and therefore efficacy must be extrapolated from the adult trial according to the Code of Federal Regulations which reads, "Where the course of the disease and the effects of the drug are sufficiently similar in adult and pediatric patients FDA may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic results.

Approximately 180 pediatric patients have received drotrecogin alfa (activated) either in our study EVAO which is an open label PK, PD and safety study, in our compassionate use programs, EVAS or EVBC or in the ongoing open-label studies, EVBE, EVBF and EVBG.

EVAO was the primary pediatric study which we will discuss now. Eighty-three patients were enrolled in this study. Approximately 50 percent of the population was male; 67, 68 percent were Caucasian, and the primary site of infection was blood in 35 percent of the patients and lung in 20 percent of the patients

For comparison we provide the similar baseline characteristics for the adult population in EVAD. The patient age range enrolled in the EVAO study was from 38 weeks gestation to 18 years of age.

This slide shows abnormalities in baseline markers of coagulation, protein C, D dimer and anti-thrombin, and again for comparison similar findings of values from the adult trial are, also, provided.

Almost all patients had evidence of elevated D-dimer, abnormally reduced protein C and abnormally reduced anti-thrombin levels indicating that the systemic response to infection in the pediatric population is actually quite similar to the systemic response that you see in the adult population.

If time permits during the question and answer period we can provide some additional data on the profile of organ dysfunctions in the pediatric patient population.

This slide shows us on the ordinate clearance, weight-adjusted clearance and on the abscissa the age range from the youngest patient enrolled in the pediatric program to the oldest patient enrolled in the adult program, so, from age 5 days through age 99 years, showing that weight-adjusted clearance does not change with increasing age indicating that at least by age no dose adjustment is necessary with the administration of drotrecogin alfa (activated).

This slide displays for us the pharmacodynamic analysis. This column contains the analysis for the pediatric population and again, for comparison the similar analysis of the adult population now divided by the treated group and the placebo group.

As prospectively defined in the protocol, the primary pharmacodynamic marker that we would look at in the pediatric trial to compare the similarity of drug effect to the adult population was D-dimer. The percent decrease in median D-dimer was 26 percent, a value very similar to what we saw in the drotrecogin alfa (activated) treated adults and for comparison placebo-treated adults actually had an increase in D-dimer over the course of the study drug infusion period as opposed to decreases in D-dimer noted both in the pediatric population treated with drotrecogin alfa (activated) and in the adult population, also, treated with drotrecogin alfa (activated).

The administration of drotrecogin alfa (activated) to pediatric patients with severe sepsis was, also associated with an increase in protein C levels and an increase in anti-thrombin levels and these values for comparison are provided for both the drotrecogin alfa (activated) and placebo groups from the pivotal EVAD trial.

The safety data obtained in the study is discussed in the briefing document, but briefly turning to bleeding events reported as serious adverse events during the study drug infusion period two patients out of the 83 or 2.4 percent of patients experienced a bleeding event reported as a serious adverse event. Throughout the entire study period four patients experienced a similar event for a total percent of 4.8 percent, and during the study drug infusion this percentage is actually similar to what we observed in the adult trial for adult patients administered drotrecogin alfa (activated).

Looking at all the pediatric patients enrolled in all of the trials, a total of 182 patients, the current percent of patients experiencing a bleeding event reported as a serious adverse event during the study drug infusion period is 2.2 percent, again, a finding very similar to what we see in the adult trial.

In summary, the pediatric patients are similar to adult patients based on the use of similar inclusion criteria and the almost universal presence of coagulopathy. The effect of drotrecogin alfa (activated) is similar in adult and pediatric patients based upon the finding of similar pharmacokinetics, a similar pharmacodynamic effect of drotrecogin alfa (activated) on D-dimer and a similar safety profile.

The results of the pediatric study support drotrecogin alfa (activated) use in pediatric patients with severe sepsis. However, they require the extrapolation of efficacy from the well-controlled study in adult patients.

The overall conclusion to our presentation is that drotrecogin alfa (activated) reduces mortality in patients with severe sepsis and is associated with a favorable benefit/risk profile in patients with severe sepsis.

The 6.1 percent absolute reduction in mortality translates into a number needed to treat to save an additional life of 16 and this number compares favorably to the number needed to treat to save an additional life with streptokinase over placebo in the ISIS II trial or the number needed to treat to achieve the additional benefit of TPA over streptokinase in the GUSTO(?) trial.

As we have presented these data, we believe these data strongly support the approval of drotrecogin alfa (activated) for the proposed indications statement.

Thank you very much.

DR. RELLER: Thank you, Dr. Macias and colleagues from Eli Lilly for the company's presentation which is now open to questions from the Committee members.

Dr. Chesney?

DR. CHESNEY: I had three questions. The first is, maybe I can give all three, and then the response. Were the APACHE scores determined when the patient first presented or were they determined at the time the infusion was started, and the second on Page 27 which is the intracranial hemorrhage summary, the top slide, I wondered why there were only 185 patients in the treatment use group instead of the 850, and the third on Page 22, I wondered with the bottom slide if you could just explain how that cumulative mortality graph works? I am sorry, I don't understand it very well.

DR. MACIAS: Okay, I am a little bit of a loss because I don't have the briefing document to look at the two to answer your second two questions. However, and maybe somebody could bring me the briefing document very quickly, but to answer your first question the APACHE score was calculated on data obtained -- thank you very much. I am sorry, this one and this one, okay. The APACHE II score was calculated based on data obtained within the 24-hour period immediately preceding the administration of study drug. If the patient were in the hospital for less than 24 hours prior to the administration of drug, in other words, they were enrolled in the emergency room, then the 24-hour period was truncated, and data collection for the APACHE II score was stopped at the time study drug was administered.

It was not collected for the first 24-hour period immediately following entry to the ICU.

To answer your second question which relates to how the cumulative mortality rate is, this is the 28-day cumulative 28-day all-cause mortality for each of the days throughout the entire 2-year study period, and then to address your third question which is the ICH which is Slide 53, we have two ongoing studies.

One is what I termed here as just the open label. It is really three studies being conducted globally, but they all use the same inclusion/exclusion criteria. Five hundred and eighty patients have been enrolled in that study to date, and there have been two cerebral hemorrhages that have occurred during the study drug infusion period.

In addition there are 185 patients that have been enrolled in the treatment use protocol which is what we call, you know, otherwise called the compassionate use program and there has been one patient who had a cerebral hemorrhage during the infusion and one patient who suffered a hemorrhagic infarct on day 14, again, while receiving heparin during an intermittent dialysis procedure.

DR. SUFFREDINI: I had three questions. Can you comment on the use of adjunctive steroids, stress dose steroids in the trial; was that controlled for, and was that data collected?

DR. MACIAS: Patient specific treatment protocols were not dictated by the protocol. So, it was not controlled for. However, approximately 30 to 35 percent of patients did receive some type of steroid, either at baseline or during the study drug infusion period. We did not record the dose of the drug being administered. We only have the fact that they received steroid and the type of steroid. There was no influence of the use or non-use of steroids on the outcome of the trial.

DR. SUFFREDINI: Can you comment on the issue of blinding in terms of the infusion of the, if your activated protein C will alter the activated partial thromboplastin time? If this was monitored during the infusion to decide whether the rate was too fast or too little, how did you achieve blinding in the study in terms of the providers' care of the patient?

DR. MACIAS: Activated protein C does influence the APTT assay depending upon the particular assay being employed and the reagents being employed. So, the effect is actually quite variable from site to site. In addition, the decay of APC in plasma is really quite rapid and begins to decay within minutes following the collection of the sample.

So, by the time the sample gets to the hospital laboratory and actually gets run the influence is really quite variable, and you would not be able to look to see whether or not the patient was receiving drug based upon a local laboratory APTT measurement.

DR. SUFFREDINI: So, it would be unlikely that a provider in terms of routine monitoring of the PTT in that 4-day infusion period would be knowledgeable whether or not the patient was getting the drug?

DR. MACIAS: Absolutely. That statement is correct.

DR. SUFFREDINI: A last question, if I may, I am curious as to I guess the rationale in terms of the amended protocol, and I wonder if you could comment on the significant changes that went into the amended protocol in terms of the types of patients that were being involved, what the incentive was, what the determination from the trial sponsors was that made those changes; why did they occur and why weren't they initiated at the beginning of the protocol?

DR. MACIAS: With respect to the type of patients being enrolled, and I think Dr. Forsyth will review some of the other objectives of the amendment, but predominantly with respect to what we were trying to achieve with respect to patient population the major attempt of the amendment was to further clarify for investigators that they should not enroll patients in the study who had a high probability of dying from their underlying non-sepsis related disease within the 28-day study period.

That exclusion criteria was contained with the original protocol. However, as we monitored in a blinded fashion the sepsis histories we were beginning to see that patients with significant underlying non-sepsis-related disease where the patient would be assumed not to be able to survive 28 days were being enrolled in the study. That was the intent of the amendment was to remind physicians that we are, I won't say saddled with, but the primary end point is 28-day all-cause mortality, and that patients dying from non-sepsis-related disease are generating noise.

DR. SUFFREDINI: But in the event that one did not do that, if they were evenly distributed across the study, would that have sort of in a sense washed itself out in the final mix?

DR. MACIAS: It takes away from your power. You have to increase sample size to adjust for it. In addition when I showed you the slide to try to assess the impact of the amendment on the overall outcome of the trial we felt that the best way to do that was to try to control for the side effect and to look at sites that participated under the original amendment and participated under the amended version of the protocol, and when we look at that analysis we really don't see that big of an impact, if really much of an impact at all on the outcome of the trial.

DR. RELLER: That series of questions and reply by Dr. Macias was from Dr. Anthony Suffredini.

Dr. Wald?

DR. WALD: Did you use mortality rates before and after the amendment was introduced?

DR. MACIAS: Yes, we did.

DR. WALD; And what did they show?

DR. MACIAS: Could you bring the slide up for me, please with mortality rates for all patients under the original and the amendment and, also, under the for sites enrolling under the original and the amended protocol, and you can bring the slide up for me, please?

This is the relative risk for all. This is now looking at the entire population of 1690 patients. This is the relative risk for patients enrolled under the original protocol .94, the relative risk for patients enrolled under the amended protocol. The interaction P value is .08, and then as we tried to explore this we looked at trying to control for the side effect. We looked at sites that participated under both the original and the amended versions of the protocol. The original relative risk for patients under the original was .87, and under the amended .77; the interaction P value is .5.

DR. WALD: Did you look specifically at the relative mortality rates in the two groups, the treated and the placebo group?

DR. MACIAS: Yes, the placebo mortality remains relatively constant over the course of the trial and the mortality rate is not there, but the mortality rate for the drotrecogin alfa (activated) population under the original enrollment in the original version is approximately 29 percent and under the amended version is approximately 24 percent. I am looking at Jeff for -- this just shows me the relative. I think it is about 24 percent, 23 percent.

DR. WALD: Was there ever any question about legitimacy of combining the two?

DR. MACIAS: We have looked very extensively at whether or not we felt that the amendment truly influenced outcome, and when we controlled for the site effect almost all the influence of the original versus the amendment went away. So, for example, can I see the slide with greater than 25, greater than 20, greater than 15 patients per site?

You can bring this up, please?

So, when we tried to control for the site, a site effect, we looked at sites that enrolled at least 25 patients, at least 20, 15, at least 10 and at least 5, and when you do that as you move down the interaction P values you don't see anything that is statistically significant, and as you look at the relative risks they begin to even out.

There is clearly as the trial progressed, I think physicians enrolled, I don't want to say better quality patients but more discriminating patients, patients that had a higher probability of dying from their severe sepsis and not from their underlying non-sepsis-related disease.

DR. RELLER: Dr. Peter Eichacker had a question from the NIH Critical Care Section.

DR. EICHACKER: You know, Bill, first a clarification because I am still confused. Was the infusion of the drug monitored with PTTs?

DR. MACIAS: No.

DR. EICHACKER: During the trial?

DR. MACIAS: No, it was not. There was no monitoring required for study drug administration.

DR. EICHACKER: Although during the Phase II study 50 percent of patients who received that dose of drug required a change in drug. I believe the --

DR. MACIAS: The way the study was done in Phase II, it was done with bedside monitoring of whole blood APTT, and the reason we used whole blood APTT is if you actually spent time to separate the plasma and sent it to the lab the effect of the APC would be gone.

So, during the Phase II study as we dose escalated we used a bedside monitor in whole blood to look at the APTT and the assay was obtained within 2 minutes of the sample being drawn. That is how the Phase II study was done, and then when we went to Phase III there was no monitoring.

DR. EICHACKER: All right, along those lines then, also, I am confused in the uncontrolled data that we were given talking about the incidence of intracerebral hemorrhage in the uncontrolled studies. I am seeing a number of 13 over 520 whereas the number that you showed was much smaller. Now, are these the same uncontrolled studies?

DR. MACIAS: For clarity, the number that Dr. Lindblad will report is the 13 events that have been reported to the agency as serious adverse events by the number, his 580 that he had at the time that he made his slides, the smaller number. The current numbers that I show you in my slide are the updated figures as of September 30. To look at all the intracranial hemorrhages that have occurred in the ongoing studies we put in place an external adjudication committee, and as the committed has adjudicated the intracranial hemorrhages 3 out of the 13 were adjudicated as not being intracranial hemorrhages.

So, the current number that we have is 10 as of September 30, and then we just gave you the total number of patients that had been exposed to study drug on that date. That is where our number came from. That is why it is a little bit different than Bob's.

DR. EICHACKER: One last question, and that has to do with the drug preparation and the change in the drug preparation. First of all, when was that instituted over the time of the study, and what was the change in the drug?

DR. MACIAS: It was instituted approximately at the same time as the amendment, and the change in the drug was just, and I will actually ask Ralph Riggins if he can just provide the crisp clean answer; otherwise, I will have to get clarity to my answer.

DR. RIGGINS(?): Yes, the process change in the manufacturing process for the drug was simply creating a new master cell bank from existing working cell bank by expanding the single cell isolate and then a minor adjustment in the way the drug substance is frozen after purification.

DR. MACIAS: And I think out of interest, could I see the BDS2, BDS2-plus slide by greater than four patients per site, greater than four and three? This goes back to the issue that we have just addressed when we tried to take care of the site effect.

Can you bring the slide up for me, please?

We did basically the same thing we did when we were trying to address the original amendment and that is to get the best idea of whether there was an influence of the amendment or the change. We looked at sites that enrolled both under the original and the amendment or dosed patients with BDS2 which is the material used early and BDS2-plus, the material used late, and if you look at sites dosed at least four patients of each and very similar mortality rates and this is the corresponding placebo rate, four and three, again very similar mortality rates, the corresponding placebo rate and then greater or equal to three at both sites.

When you start to go below that and start putting sites that did one patient, then you begin to see differences in sorting that out at the time of the amendment. It was really quite difficult.

Slide off, please?

DR. RELLER: Dr. Rotello?

DR. ROTELLO: As related to heparin, when you look at the two placebo groups on those receiving low-dose heparin and not receiving low-dose heparin there seems to be some mortality effect afforded by heparin alone. Have you substratified that population at all, and do you have any information on patients receiving full-dose heparin?

DR. MACIAS: Full-dose heparin was excluded from the protocol. Basically you either had prophylactic dose or below by the protocol, and I will as Dr. Helterbrand to address your question about whether heparin works in the placebo group.

DR. HELTERBRAND: Could I have slide 334, please?

To specifically address your question we did, indeed, look within the placebo group and looked at patients who did get low-dose heparin and those patients who did not get low-dose heparin.

Slide on, please?

Now, again, we have to remind everybody that this is a non-randomized comparison in the sense that patients in the placebo group were not randomly assigned to receive low-dose heparin or not receive low-dose heparin. So, there could be a patient selection bias, but nonetheless, it is interesting to look at.

As I referred to in the core presentation we did a Cox regression analysis looking at baseline, either looking at the analysis when the heparin groups were defined either by baseline exposure or using a time-dependent covariate in a Cox regression model.

When we look at baseline heparin exposure only and do no stratification for any measure of disease severity you see a relative rate of death of .94. That means just a 6 percent relative reduction observed, and it is clearly not statistically significant. It is very broad confidence interval, and the P value is very high there.

If we adjust for one measure of disease severity such as APACHE II quartile again there is very little evidence to suggest that heparin is having any effect on mortality in the placebo group.

In addition, if we actually do take the approach of, also, including patients in the heparin group who get heparin post-baseline using a Cox regression model, again, what you see here is no evidence that low-dose heparin has any effect on mortality in the placebo group.

DR. RELLER: Dr. Mumford?

DR. MUMFORD: How much overlap was there in the patients in the first APACHE II quartile and the patients in the lowest IL-6 quartile? They are being described as if they are both indicators of relatively mild illness, but do they in fact represent the same patients?

DR. MACIAS: Jeff, could you provide the answer t that? The first APACHE quartile does contain a lot of the patients in the lowest IL-6 quartile. I don't have the specific number.

DR. HELTERBRAND: I am going to look at 347 to attempt to answer your question.

Slide on, please?

This is one of the analyses that we said we would be happy to share with you later on where we look within the first APACHE II quartile and look at patients below the median IL-6 level and above the median IL-6 level. So, as you can see there, there are 433 patients that made up the first APACHE II quartile, and if I do the math correctly here I come up with 258 patients who had IL-6 levels below the median level, and as you can see, again, in people with IL-6 levels within the first APACHE quartile we see a relative risk reduction, again of 20 percent consistent with the overall trial results.

DR. RELLER: Dr. Warren?

DR. WARREN; Since there was a change in the way the drug was made do you have a release test that you use in house of some sort and is there, also, some sort of a, can you go back into the baboons or something to assure yourself that there had been no change in the drug function?

DR. MACIAS: There is extensive in vitro testing on the pharmaceutical product indicating no difference between the two compounds.

DR. WARREN: Can you describe what those, are they all hematological testing or --

DR. MACIAS: I will ask Ralph Riggins, could you please provide the answer to this?

DR. RIGGINS: Yes, we have done extensive not only physical-chemical but structural analysis in addition to coagulation-based activity assays and by all measures there is no difference between the preparations, and there is really no difference in the preparation of the drug other than the minor changes that I mentioned.

DR. RELLER: Dr. Cross?

DR. CROSS: I am still trying to get a handle on the impact of the change in exclusion criteria, on the patient population. What I would like to know is was there any difference in terms of the relative distribution of patients who developed sepsis outside or at least inside the hospital after a few days versus those who may have been hospitalized for a longer period of time. Perhaps one measure of that may be how many days the patient was in the hospital before receiving the treatment.

DR. MACIAS: Could you bring up on the monitor down here for me the profile for original versus amendment?

I believe as the, and that doesn't include the data that I need. I believe as the protocol progressed more patients came from home as opposed to being transferred from an outside institution or coming from a nursing home.

I don't think we have the analysis of that number of patients developing in-hospital, if you will, nosocomial sepsis versus non-nosocomial sepsis.

Yes, you can bring the slide up for me, please?

This is the slide that I was referring to. As you move through the study there is a little bit higher percentage of the patients that came from home, kind of a similar percent that came from another acute care facility, but then as you move through the study a little bit less that came from the skilled nursing facility, and then you looked at the population of patients without disabilities.

So, there were some changes as the protocol progressed.

Slide off, please?

DR. CROSS: But when you say, "Came from home," is that within a certain period of time? I am trying to --

DR. MACIAS: Oh, immediately prior to hospitalization.

DR. CROSS: Right. For example, as you excluded, for example, immunocompromised patients I would imagine you would have fewer patients who may be seen let us say in a tertiary care facility who are there for a while who then after a week or two then develop sepsis.

DR. MACIAS: Yes.

DR. CROSS: I would imagine a consequence of that amendment is that you would have fewer of those patients.

DR. MACIAS: It was clearly, that hospital location was where the patient came from at the time that they came into the hospital. So, theoretically they could have been at another institution a week earlier, been discharged to home and then popped into that hospital.

DR. RELLER: Dr. Christie-Samuel?

DR. CHRISTIE-SAMUEL: Did you look at the treatment effect stratified by APACHE score and age?

DR. MACIAS: By APACHE score and coupled by age?

DR. CHRISTIE-SAMUEL: Younger patients.

DR. MACIAS: Jeff, obviously the APACHE includes an age component. I don't think we did an analysis of APACHE II by age separately.

DR. HELTERBRAND: I guess I have a number of responses I could make. First of all, as we have shown with age there is really no interaction in terms of treatment effect by age on the relative risk of death. We did do a multivariate analysis that includes age and APACHE score as well as various other measures to try to take into account the multiplicity of clinical and biochemical measures that we collected in this trial in order to assess, you know, if we do all take all those variables into account what happens when you put them in a multivariate model, and it did include age, and it did include APACHE II scores, and what we came up with was a constant 40 percent increase in the survival with Xigris compared to placebo.

So, only in the multivariate sense have we done it, and it came out to a result of no interaction in the multivariate model.

DR. RELLER: Dr. Ramirez?

DR. RAMIREZ: Yes, two questions. I would like to go back to the amendment. According to the data that we have before the protocol was amended we have a difference in mortality of 2 percent, with the placebo 30 percent mortality and with the study drug 28 percent mortality, and after the amendment was performed we have placebo 31 percent mortality and the study drug 22 percent mortality and this decreased mortality rate of 7 percent before the amendment and 29 percent after the amendment. This is extremely significant.

I would like to re-ask the question. Is the only explanation that we have for this difference in mortality before the amendment and after the amendment the explanation of the enrollment site? Were there any other possible explanations?

DR. MACIAS: I think it is actually a combination of things. I think there clearly is over the course of the entire trial an improvement in the enrollment of discriminating patients, patients in whom the effect of the drug would be more evident because of the exclusion of patients likely to die from underlying non-sepsis-related diseases, and I think that occurs throughout the entire 2-year study period, but there clearly is an effect of site, and when you try to control for that effect of site and you look at only sites that participated under the original and participated under the amendment there is not a significant interaction.

DR. RAMIREZ: And the second question, during the amendment protocol there was an exclusion criteria, the exclusion criteria No. 17, and the presence of the first sepsis-induced organ failure of greater than 24. That was prior to the start of window two, and the question is in the first protocol there was any time for the beginning of organ failure or during the first part of the protocol the patient can be enrolled regardless of the time of initiation of organ failure?

DR. MACIAS: Under the original protocol no. The answer to that is no. There was not a restriction. At the time you met all inclusion and no exclusion criteria there was not a limit to the duration of that organ failure. However the vast majority of patients were enrolled within 24 hours of organ failure because it is the organ failure, the development of the organ failure that is basically allowing you to meet the inclusion criteria.

In other words, the patient gets infected first, then has SIRS(?) and then the organ failure allows you to complete that. When we did a fairly extensive analysis of treatment by duration of organ failure there is no difference, and maybe we could pull that up very quickly, the mortality by duration of organ failure, and there was no interaction present, and if we don't have it is not necessary to pull it up real quick.

DR. RAMIREZ: This exclusion criteria 17 was at the time when we see this great advantage of the drug. It would be fair to say that we are defining in the natural history of severe sepsis that the finding in the population that early onset severe sepsis because we are saying that a patient should be included within 24 hours of the first organ failure because in my mind you have a patient in intensive care unit. You have 6, 7, 10 days of organ failure and an average period of 7 days in some studies, but we are saying here that the person that developed the respiratory insufficiency or cardiovascular insufficiency more than 24 hours is already too late to be enrolled in the study. This was part of the criteria, and I am trying to see if the second part with such a great benefit is because we are looking in the natural history of the disease at patients with early progression, early severe sepsis even though the severity is there, this is in the natural history early severe sepsis because this is important when we look at indication because severe sepsis, often severe sepsis would imply well, I can have organ dysfunction for any number of days, but this protocol is telling me that you need to have only 24 hours.

DR. MACIAS: Could I have the slide with the schematic of the study design from the core presentation, and I think your point is actually a very extremely important point, but I would like to, if you can bring the slide up, please?

This is the window in which the patient had to meet all inclusion and no exclusion criteria and they had to do that within a 24-hour period.

At the moment in time within this window that the patient met all inclusion and no exclusion criteria, the organ failure could be no older, as you say, not present for longer than 24 hours but from this point to the start of study drug an additional 24-hour period was allowed to obtain informed consent, randomly assign the patient and initiate study drug. So, the maximum duration of organ failure could be 48 hours. However, approximately 75 percent of the patients received study drug within 24 hours of the onset of first sepsis-induced organ failure.

When we looked at treatment by duration of organ failure over that 48-hour period there was no interaction. In other words patients enrolled with organ failure greater than 24 hours had similar benefit than patients enrolled with less than 24 hours with an organ dysfunction, and we could provide those, Jeff, if you have those exact numbers.

DR. HELTERBRAND: Right, roughly, as Dr. Macias pointed out, roughly one-quarter of the patients had organ failure for longer than 24 hours before they started using study drug.

DR. RAMIREZ: But longer than 24 hours but less than 48 hours?

DR. MACIAS: Yes.

DR. HELTERBRAND: The majority were less than 48 hours. That is correct and in the group that had longer than 24 hours a 30 percent relative risk reduction with Xigris was observed.

DR. MACIAS: I think it is an extremely important point that we were not enrolling patients in the trial who had organ failure for 5 and 6 and 7 days prior to the administration of study drug.

DR. RELLER: Dr. Archer?

DR. ARCHER: More than one-half of the patients' infections was lung. How was pneumonia differentiated from ARDS?

DR. MACIAS: Pneumonia was defined in the protocol by chest x-ray consistent with pneumonia and the presence of purulent sputum and that was the guideline that we gave the investigators in the protocol and in the case report form. There was no further differentiation.

DR. RELLER: Dr. O'Fallon?

DR. O'FALLON: I think there will be many statistical questions. Let me ask one?

DR. MACIAS: Should I switch places with the statistician?

DR. O'FALLON: We can find out. We have heard in the last half hour or so I suppose two or three dozen references to the fact that there were no statistically significant interactions. Those are kind of useless statements unless we have some sort of a power statement regarding how likely it was that you could have detected such interactions, and those of us who do this kind of thing for our livelihood know that that likelihood is almost certainly very, very small.

So, any answer about power of the interaction effects would be useful at different times here.

DR. MACIAS: Are you asking for an answer? Because then I can turn it over to Dr. Helterbrand.

DR. O'FALLON: I have implied there are many of them. So, if he gives me one answer, I will have to know which one of the statements it applies to.

DR. HELTERBRAND: To speak to Dr. O'Fallon's question, indeed interaction analyses are typically lower powered because you are going into subjects and some of the subjects that we are talking about here today are 100 patients, a 200-patient subgroup, sometimes up to 400 patients and again they will have limited power, and that is why it was important for us to really look at it from a couple of perspectives, looking at it both in terms of interaction test and kind of follow the concepts of the exploratory data analysis by looking at the 95 percent confidence intervals and saying, "Do the confidence intervals contain the point estimate of the overall trial?" Again, those are, also, somewhat underpowered types of analyses, but that is why we took multiple approaches that are generally accepted in statistical literature to try to assess evidence of differential effects across subgroups.

DR. RELLER: Dr. Fleming?

DR. FLEMING: Many issues to discuss here, and time won't allow, but I would like to ask just two questions at this point that relate to the amendments and certainly strongly endorse Dr. O'Fallon's comment that he just made.

What is very apparent when you look at the amendment is that your thoughts about the motivation were fully justified, i.e., you were targeting the intention of excluding those patients with non-sepsis-related disease because if these people had a high rate of risk of death and treatment couldn't affect them it would dilute your odds ratio.

This is exactly what we see. I don't need to see a test for interaction to know whether it is significant or not significant. It is very apparent that after the amendment the estimate of the treatment effect is much larger. The overall death rates are much less. So, you did, in fact accomplish exactly what your intention was. My question was the first of my two questions then is if, in fact, you are excluding these patients that won't in fact likely benefit has your label, how has your label accounted for this?

DR. MACIAS: I think there are two points to it. One is as a point of clarity, we didn't exclude patients with underlying non-sepsis-related diseases. What we excluded or who we excluded were patients with non-sepsis-related diseases in whom the investigator would assess the patient as being at high likelihood of dying within the 28-day study period.

That was what we excluded.

DR. FLEMING: Is your label accordingly excluding such patients? I don't see that it is. The second question, can you assure us at the time that this amendment was made that no one from within Lilly had access to the code and let me go a bit further to say that it is not just that you amended the eligibility, you, also, amended your primary end point. So, if in fact someone from within Lilly had the code could you clarify who that was and could you clarify who was doing the ethically necessary safety monitoring because this code, this amendment was not done until about 8 months after the initiation of the trial. So, I am assuming ethically somebody should have been monitoring the two intervention groups for relative safety.

Did anybody within Lilly have access to that code?

DR. MACIAS: With respect to monitoring safety we monitored safety in a blinded fashion. However, the pharmaco-vigilance group at Lilly had the option to unblind individual patients who experienced a serious adverse event throughout the course of the study, and that group is separate from our group, but they had the option to unblind individual patients.

DR. FLEMING: So, am I to understand then that there was not an independent, non-Lilly assessment of relative safety issues during the first 8 months of this trial?

DR. MACIAS: No, there was. Jeff, do you want to answer very quickly, and then I will --

DR. HELTERBRAND: I mean for that particular question I think it is true that the monitoring was going on by Lilly, and then once we had the interim analyses, of course, our Data Safety Monitoring Board did review all the efficacy and the safety data both at the first interim and at the second interim analysis.

DR. FLEMING: At least I would like to call to the FDA's attention two issues that to me are major concerns. One is that it is apparent that Lilly was assuming the responsibility as opposed to an external committee for early safety monitoring and secondly, there was access to this code within Lilly, and we had a change in the primary end point during, well into the course of the study.

DR. HELTERBRAND: Actually I would like to speak to that because I think it might make sense to understand the organizational structure of how this trial was conducted, and it was conducted in a manner to optimize the integrity of the resulting data and the inferences that could be drawn.

Can I please have Slide 354?

This is a schematic. There are really three key points to make to Dr. Fleming's point. First, patient treatment assignments were provided pharmacists at the investigative site by Covance(?) which was a contract research organization via central randomization center and treatment assignments were retained by Covance during the trial, and it is important to point out that data management was performed at Lilly without access to patient treatment assignments. We did not have that access.

However, as Dr. Macias has pointed out, for regulatory safety reporting purposes we actually, our pharmaco-vigilance group did have the opportunity to unblind patients if there was a study drug related death, study drug related as assessed by the investigator or a study drug related unexpected event and there were approximately 10 unblindings of this trial. However, it is important to reiterate that Lilly did not have access to patient treatment assignments during the conduct of the study.

So, what we actually did is we did our data management without access to patient treatment codes, built the data sets without treatment assignments and then shipped them to an external statistical services organization, Pat O'Meara(?) and Associates who then married the data up with the actual treatment assignments that were contained at the external contract research organization. Dr. O'Meara then produced the prospectively defined analyses based on our interim analyses and then once he prepared the interim analysis report he provided them to our independent external Data Safety Monitoring Board.

If I could have the next slide, please?

That included the following individuals, Dr. Opal, who presented to you this morning was our Chairman. Dr. Abraham, Dr. Lowery, Dr. Wittus was our statistician involved in our Data Safety Monitoring Board. They reviewed both the safety data and the efficacy data and followed the O'Brien-Fleming methods in terms of for trial stopping rules, and so, just a point of clarification, Lilly did not have treatment assignments during the conduct of this trial, only when it was necessary for regulatory reporting purposes did our pharmaco-vigilance group have the opportunity to call Covance, get unblinded and that occurred approximately 10 times.

DR. SIEGEL: I would like to address that question, also, from a somewhat other angle.

We, as you know, our concerned especially when a company is dealing with preparing data reports for data monitoring which is a typical practice about those potential biases and one way is to look at whether the decisions that were made might have reflected such biases.

In that regard, regarding the MT(?) criteria if you could look at the FDA slide in the bottom right hand corner of Page 7 we divided the patients who had been treated pre-amendment to those who fell in a group that was now being excluded, the patients you expressed concern about who had a high risk of mortality based on the physician's assessment independent of sepsis.

If you look at that group with the new criteria excluded the first line in that table, the relative risk in that group is .8 similar to the overall study population in favor of treatment.

If you look at patients treated to that point in time in the other, in the complementary group, those who would have been eligible even under the final criteria there is little evidence of a drug effect.

So, in fact, their change in eligibility was excluding the group that provided the most evidence of drug effect to date. That, also, has some bearing as to whether one would want to exclude those patients in the labeling even though they were ultimately excluded in the entry criteria. The little data are present and obviously the numbers are small, suggesting that there isn't a differential effect there and further suggest that it wasn't out of knowing bias that that change was made.

A little bit different in terms of the study sites that were excluded. Interestingly the study sites that were small that were excluded were not showing a very good drug effect as it turned out. That is why when you see the analysis of same sites you don't see the differences in the first and second half that you do when you include those sites. However, by any way we can look at it, there is little to suggest that those sites were excluded other than for valid reasons.

They were, in fact, enrolling at a much lower rate than other studies. The third issue you mentioned is end point changes, and I think the fundamental end point didn't change. There was some change in how protein C, I guess would be, levels would be included into the end point and whether that was primary or secondary and my recollection although maybe the company can answer this, I think the data have been analyzed both ways, and I don't think it made a profound difference in the final analysis or even much of a difference at all.

DR. MACIAS: No, it did not. The change in the amendment with respect to the primary analysis, we kept the primary analysis which was 28-day all-cause mortality for all treated patients, so patients exposed to drug for any length of time. The original stratifications were age, APACHE and quote, unquote, presence of shock within 6 hours.

We modified the shock to change it to baseline protein C level and so the final analysis was an analysis stratified by age, APACHE, protein C, but we did provide in the final study report submitted to the agency the analysis that was the original prospectively defined analysis of age, APACHE and shock status. It made no difference.

DR. RELLER: Question from Dr. Murray.

DR. MURRAY: Sort of two questions. One is a follow-up on the previous question relating to the proposed labeling by Lilly. Would the proposal be that people with organ failure more than 48 hours not be administered the drug since that is how it was studied and then the second question which is totally unrelated but is more for curiosity, if you have any longer-term follow-up to the 28 days to see if people that did survive that had not gone back home were back to a more functional status?

DR. MACIAS: To answer the first question, from a restriction standpoint we would not propose that we would restrict it 48 hours, but the label would reflect the fact that patients were enrolled in the study within 48 hours of the onset of their organ dysfunction.

The reason for that is I don't think we believe that if a patient has organ dysfunction for 47 hours he would be eligible and for 50 hours he would be ineligible which is I think very different than TPA and stroke where if you have a stroke syndrome for 3 hours you might benefit and when you have stroke syndrome for 6 hours you don't benefit. So, I think there would be a reflection, we would recommend reflection of the duration of organ failure in the clinical trial section of the label but not a restriction for the reasons I have expressed.

With respect to follow-up beyond 28 days, we have currently initiated the follow-up protocol to EVAD. So, it will follow up all survivors in the EVAD protocol up through I think for some patients a minimum of 1 year but for patients enrolled early follow-up will be longer.

It will assess eventual hospital disposition for all hospitalized patients on day 28 along with survival status.

DR. RELLER: Dr. Suffredini?

DR. SUFFREDINI: In terms of other aspects of the study that were changed the placebo was changed. Can you comment on why that would be the case?

DR. MACIAS: Very early in the course of the study we were made aware that since activated protein C is a protein that if you perturb the solution too much you would get foaming, and the original placebo was saline. So, immediately following the start of the study sites were instructed to wrap all bags, the bag and the tubing so they could not visually see whether or not the solution foamed or didn't foam, and then at the amendment we elected to institute albumin, low-dose albumin to provide the same foaming just to improve the blind.

DR. SUFFREDINI: And they were considered to be comparable in terms of their foaming, the duration of foaming or were they still wrapped?

DR. MACIAS: We left them wrapped, but the duration of the, the amount of albumin contained within the saline produced the same amount of foaming as the other solution, but we still continued to wrap except in France where albumin was not allowed to be used as the placebo.

DR. SUFFREDINI: I guess there are at least four factors that changed between Part A and Part B of the study and in terms of the change in the DNR rate in the treatment group that diminished significantly but that wasn't shared by the placebo group which certainly may have a significant effect in terms of the 28-day mortality.

Can you comment on that?

DR. MACIAS: Yes, I think it is very difficult to interpret the DNR rates between the two groups because the DNR rate may reflect the fact that you gave them placebo and not effective therapy. The incident rate of making someone -- DNR may go down in the setting of an effective therapy.

DR. RELLER: Dr. Leggett?

DR. LEGGETT: A couple of questions. In terms of the survival benefit, it appeared that most of the time in the Kaplan-Myer curve that the survival benefit happened after the infusion. So, I would take that sort of physiologically to mean as you, I think tried to show that it was less organ dysfunction down the road, and you made the statement in, I cannot remember the slide where the post-5-day-infection rates, post-baseline infection rates were the same. Was the post-baseline mortality from those infections the same as part of that first question?

The second part of that first question is when people went back and looked at these patients in terms of other routine care, were the assessments of optimal or appropriate antibiotics in the two groups controlled for or looked at to see if that could be a potential confounding variable much like the steroid question?

DR. MACIAS: The answer to the very first question which is what were the mortality rates between treatment groups for patients having a post-baseline new infection, did we look at that, Jeff, do you remember? I don't think we looked at that. We can look at that for you today.

To answer your second question, and that is the appropriateness of antibiotics, all of the case report forms were reviewed by our Clinical Evaluation Committee and appropriateness of antibiotic therapy was adjudicated by the CEC.

Approximately 88 percent of patients received appropriate antibiotic therapy within 24 hours of the diagnosis of severe sepsis, and the proportion was equal between the two treatment groups, and by 48 hours 92 to 93 percent of patients had received appropriate antibiotic therapy.

You can bring the slide up?

This slide just shows you the relative risk associated with drotrecogin alfa (activated) for patients who had received appropriate therapy within the 48-hour period.

DR. LEGGETT: I knew that. I was talking specifically about the post-baseline infections, in other words, afterwards.

DR. MACIAS: Dr. Levy, could you remind me? The adequacy of antibiotics was adjudicated for the original infection. I don't believe it was adjudicated for subsequent infections.

DR. LEVY: That is correct.

DR. LEGGETT: The next simple question, was the same D-dimer test, I understand there are several or at least a couple of them, was the single test done for everything or was it site specific and variable?

DR. MACIAS: Those were central laboratory data. So, it was the same for all patients.

DR. LEGGETT: I noticed in terms of infection there was a relatively low number of blood culture sites of infection. Does that mean those were primary intravascular infections and not sort of bacteremia related with pneumonia, for instance?

DR. MACIAS: No, what you are looking at there I think is just blood culture positive.

DR. LEGGETT: So, only 10 percent of this group was blood culture positive basically?

DR. MACIAS: Jeff, could you --

DR. LEGGETT: Because that seems to be a pretty low number for severe sepsis.

DR. MACIAS: Could I see the treatment analysis by blood culture positive, blood culture negative?

DR. HELTERBRAND: Positive blood culture is about 30 percent of the population, but we can show the slide with the data.

DR. MACIAS: You can bring that up for me, please?

DR. LEGGETT: So, this Page 18, Slide 36 is primary, okay.

DR. MACIAS: I am sorry. I think I misunderstood what you were asking me, but you can look at this slide and you can see that between the two treatment groups approximately, well, 266 patients of the drotrecogin alfa (activated) and 275 of the placebo group had positive blood cultures. That is the relative risk. The remaining patients of course, had negative blood cultures. That is the relative risk, and then since we are here you can look at whether they had any culture positive or had no culture positive and this is the relative risk.

DR. LEGGETT: Final question, in comparing the pediatric group in terms of demographics to the adult group I noticed that the types of infections were different. In the adult group your UTI mortality was much lower as we would expect from other mortalities. In the pediatric group which had relatively more kinds of infections, Slide 91, do we know about relative mortality in pediatric groups or in other adult sepsis groups, relative to the mortalities of central nervous system and the blood site of infection as opposed to lung?

DR. MACIAS: For pediatric patients in general?

DR. LEGGETT: Either pediatric or other adult things looking at those questions since to me these demographics do not match up.

DR. MACIAS: Brett, would you like to address an estimated mortality rate for pediatric patients with central nervous system infection?

DR. GIROIR: The estimated mortality rates in this trial according to the Pediatric Index of Mortality for CNS infections was approximately 18 percent. The overall mortality in pediatric patients in this trial really matches previous experience in pediatrics that the overall mortality rate despite similar numbers of organ failure and similar severity of illness is less in the pediatric population than it is in adults, and one might conjecture the reasons for that.

DR. MACIAS: That is Dr. Giroir. I am sorry, I should have probably introduced you rather than saying just, "Brett, could you go to the microphone," and Dr. Giroir has been the principal investigator for the Pediatric Development Program at Lilly.

DR. RELLER: We will have two final questions, then a 10-minute break and the FDA presentation. Dr. O'Fallon?

DR. O'FALLON: Dr. Fleming has assured me that you used the O'Brien-Fleming rules properly which is excellent to hear

DR. MACIAS: I have to ask Dr. Helterbrand that question.

DR. O'FALLON: The coincidence of the change in the protocol at approximately the same time that the first interim analysis was performed has bothered me as I read this material, and the fundamental question is, and I assume that the Committee when they did the second interim analysis did understand that there had been major changes in the protocol and attempted to take that into account as they made their recommendations. Is that correct?

DR. MACIAS: Dr. Opal, would you like to address that question, please?

Dr. Opal was the Chairman of the DMSB.

DR. OPAL: Yes, we were aware of the protocol amendment and did take that into consideration in looking at the data.

DR. RELLER: Dr. Ebert?

DR. EBERT: This is a follow-up question to a comment by Dr. Helterbrand. I wanted to get a little more information about the multivariate analysis that you referred to. Were you able to in a multivariate manner determine what risk factors or measures of severity of the illness were important in determining mortality or were related to the mortality and where did drug treatment fall as far as the relative measure on impact on mortality?

DR. HELTERBRAND: Yes, please, slide on?

Just to give brief details, we used a common approach to model selection using stepwise multiple logistic regression. Intuitively covariates are included in this model based on their explanatory value as you alluded to earlier.

Next slide, please?

We actually considered 21 different variables for inclusion in the model, including some patient demographics, some baseline data in terms of patient location, morbidity status, functional dependency status, infection site and type and surgical status, several clinical markers of disease severity and several biochemical markers of disease severity to be considered.

Next slide?

We, also, considered all two-factor interactions to be included in the model such as an age-by-treatment interaction if it had been present or an age by gender. So, they were all included in the stepwise procedure. We used the Schwartz(?) criterion to select our method or to select our final model, and we used forward and backward steps as is customly done in stepwise regression.

We, also, used the goodness of fit statistic, the most commonly used one which is the Honemere-Lamenshaw(?) chi square statistic.

Next slide, please?

Here is your point which is what were the results. The following covariates were retained in the model, age, APACHE II score, prothrombin time and we did the IL-6 on a log scale due to its distribution, dependency status and whether you have urosepsis or not.

The goodness of fit statistic to support the model's adequacy was .50. So, it supports the model's accuracy I suppose and basically this model estimated a constant 40.2 percent increase in the odds of survival with Xigris across the population. Importantly no interaction terms were included and no treatment by covariate interactions were included in the resulting model.

DR. RELLER: This concludes the Lilly presentation and the discussion related thereto.

We will have a 10-minute break. Please return promptly after that for the start of the FDA presentation.

(Brief recess.)

Agenda Item: FDA Presentations

DR. RELLER: We will begin with Dr. Linda Forsyth who is an officer with the Center for Biologics Evaluation and Research, FDA.

Dr. Forsyth?

DR. FORSYTH: Thank you very much.

Good morning. My name is Dr. Linda Forsyth. I am a medical officer in the Center for Biologics. This presentation is divided into two parts. I will begin by presenting the efficacy. Dr. Robert Lindblad will follow me and present an overview of the pediatric program and follow with the adult safety data.

As you have already heard the sponsor is proposing drotrecogin alfa or rhAPC recombinant human activated protein C be indicated for the treatment of pediatric and adult patients with sepsis associated with acute organ dysfunction or severe sepsis and that treatment with rhAPC reduces mortality in patients with severe sepsis.

The sponsor has conducted a number of trials. As you can see this includes a number of small Phase I uncontrolled trials. These included clinical, pharmacology studies, studies with end-stage renal disease, patients with protein C deficiency and purpura fulminans.

The sponsor, also, conducted a single-controlled Phase II trial of 131 patients with severe sepsis. A single randomized controlled trial, Phase III trial was performed in 1690 patients. A pediatric study was performed in 83 children with severe sepsis and finally there occurred ongoing uncontrolled trials having enrolled over 500 patients thus far.

The focus of my presentation will be on the Phase III data, but I will begin this section with a few Phase II slides.

So, again, the Phase II study was a randomized placebo-controlled dose-ranging multicenter trial. The study was conducted in 131 patients with severe sepsis; rhAPC was given in four different doses. This was given as a continuous intravenous infusion for either 48 or 96 hours. The outcomes measured in this trial were pharmacodynamic and pharmacokinetic as well as safety.

This table shows mortality from the Phase II study. As you can see 29 percent of the patients receiving any dose of rhAPC died compared to 34 percent of the patients receiving placebo.

This result was not statistically significant. Dr. Lindblad will describe the safety data in his presentation. The sponsor has already shown the pharmacodynamic and pharmacokinetic data from the study which I will not go into here. The dose for the Phase III trial was chosen due to the pharmacodynamic effects based on D-dimers in the Phase II trial, and just to recap what you have already heard from the sponsor, the Phase III study designated as EVAD was a randomized double-blind, single-dose, placebo-controlled, multicenter trial. The dose administered was 24 micrograms per kilo as a continuous 96-hour intravenous infusion in patients with severe sepsis.

Two thousand two hundred and eighty patients were originally planned for enrollment into the study. The diagnosis for severe sepsis was defined as patients meeting three or four systemic inflammatory response syndrome criteria, plus at least one organ failure and suspected or proven infection.

Patients that were at a high risk of bleeding were excluded from the study. Again, the primary efficacy end point for the study was 28-day all-cause mortality. The primary efficacy analysis included Cochran-Mantel-Haenszel test stratified by pre-infusion APACHE II quartile, age class, that is than 60 years of age and over 60 years of age and protein C activity class.

There were two planned interim analyses prospectively defined, identified by the sponsor. The first interim analysis occurred after 760 patients were treated. The second interim analysis occurred after 1520 patients were treated in June 2000.

The O'Brien-Fleming boundary for the alfa thinning function was specified as .0002 and .0118 respectively. The sponsor identified a number of secondary analyses of mortality treatment shown here, including protein C activity and notably APACHE II along with others.

In the next several slides I will present the patient demographics between the two treatment groups, rhAPC and placebo.

This slide shows that age, gender and ethnic origin were well balanced. There were a large number of pre-existing patient conditions in both treatment groups. Of note most were similar. However, there were some minor imbalances.

This slide highlights a number of the minor differences such as with hypertension, with myocardial infarction and congestive cardiomyopathy as well as others such as chronic obstructive pulmonary disease and cancer.

This slide displays the recent surgical history of patients between the treatment groups. Patients were grouped as to whether they had no history of surgery, required emergency surgery before study drug was administered or whether elective surgery was performed.

These groups were well balanced, and this slide presents measures of disease severity. Of note, both treatment groups had a mean APACHE score of 25. Also, there were slight differences in the number of patients who required mechanical ventilation in shock and with the use of vasopressors.

And lastly, this slide shows the distribution of the number of organ failures between the treatment groups. Both treatment groups are relatively well balanced.

In this table we have presented the results of the primary advocacy end points for the Phase III trial, again, to remind you the primary efficacy end point, 28-day, all-cause mortality as seen in the last column was reduced in patients that received rhAPC. Twenty-four point seven percent of the patients with severe sepsis died compared to 30.8 percent of the patients that were on placebo. The total number of patients was 1690, and the P value was significant at .005.

This study was stopped at the second interim analysis. These same data are depicted graphically in this Kaplan-Myer curve. As shown already by the sponsor we have in our curve we have the red line represented by rhAPC, the green line by placebo.

Time is presented in days on the X axis and percent survival on the Y axis. As can be seen a clear separation occurs approximately at the end of the first week.

The percent survival scale from the sponsor slightly differed from what we have we have presented here.

As mentioned earlier the sponsor has identified a number of important secondary end points evaluating mortality by patient subgroups. I am now going to review data from a number of these secondary analyses. We will look at age, disease severity, hematologic parameters and also look at the use of heparin.

We will first set off with patient age as highlighted on this slide. The sponsor prospectively defined in their analytic plan to test for treatment effect by patient age using a cutoff point of 60 years of age as shown in this slide. In the first column this can be seen.

There is a treatment effect in rhAPC in both less than 60 and over than or equal to 60 years of age. However, as seen in the column with the mortality difference the treatment was slightly greater in the older age group with 5 and 7 percent mortality difference respectively.

These same data are shown graphically in this slide. Age in years is plotted on the X axis. Percent mortality is presented on the Y axis and/or the number of patients are shown in brackets below.

There appears to be a greater treatment effect in patients over 50 years of age compared to younger patients. At both ends of the curve, however, you will note there are a small number of patients.

I will now present data on disease severity starting with the APACHE II scores, then will address organ failure and finally shock.

APACHE II or acute physiology and chronic health evaluation is a scoring system developed as a predictor of mortality described by Dr. Knause(?).

In the ICU setting it is comprised of three components, acute physiologic measurements, age and chronic health status. The higher the APACHE score the more severe the disease.

We evaluated the relationship between treatment benefit and disease severity defined by APACHE II as displayed in this slide. In the first column in this table we have the APACHE II scores divided into quartiles. The first quartile consists of APACHE scores between 3 and 19, the second between 20 and 24, the third between 25 and 29 and the fourth between 30 and 53.

As you know, APACHE II is designed to predict the likelihood of mortality. We have the mortality in each of APACHE quartile for the placebo patients and as would be expected there is an increase in mortality as the APACHE scores increase, 12 percent and we can see it moves down to 26 percent, 36 percent and finally 49 percent. Thus, the APACHE II score did, indeed, predict mortality in this population.

In this column in the rhAPC mortality column we have presented the mortality on rhAPC and once again we can see there is an increase in mortality as we go down. The difference in percent mortality between rhAPC and placebo arms is shown in the third column from the right in percentage. There is a 3 percent higher mortality in the APC arm, in the first APACHE quartile seen here and then a 4 percent lower mortality in rhAPC in the second APACHE II quartile. In the third APACHE quartile we can see a 12 percent reduction and finally an 11 percent reduction, lower mortality in the fourth quartile.

So, as we can see the largest rhAPC effects are in the third and fourth quartiles. The second column from the right is relative risks. We have the corresponding relative risks of death and next to that the 95 percent confidence intervals. Here, too, the data suggest that the greatest rhAPC benefit is in the higher quartiles.

These data suggest an interaction between treatment and APACHE II quartiles of .009. Again, these same data are depicted graphically but this time on the X axis the APACHE scores are divided into finer intervals of 5 units.

Again, rhAPC is in red and placebo in green. The N's in each APACHE interval appear in parentheses below. So, again, those patients with more severe disease appear to have somewhat more of a treatment benefit than those patients with less severe disease.

There are a few patients on either side, you can see here, of the curve of the APACHE scores. So, little can be made of these data.

In this slide we combined the first and second APACHE quartiles and the third and the fourth APACHE quartiles together. As can be seen in the first row here the first and second APACHE quartiles were combined representing an APACHE score of under 25. In the second row this combined the second and fourth APACHE quartiles together and this represented an APACHE score of 25 or above.

The mortality difference in percentage here presented in the third column from the right we can see there is virtually no difference in the mortality between rhAPC and placebo in the combined first and second quartiles; however, among patients in the third and fourth quartiles the combined APACHE difference or mortality difference, excuse me, was 13 percent.

Another way to capture disease severity and treatment benefit was to investigate the number of organ failures that occurred at baseline.

The first column shows the number of organ failures. Next, looking at the placebo column right here, there is an increase in the mortality rates with the greater number of organ failures as can be seen in this manner.

A similar trend actually occurs with the rhAPC mortality rates. The mortality difference in the third column from the right between rhAPC and placebo show an increase in mortality differences with an increased number of organ failures.

Patients with fewer organ failures at baseline have a suggestion of less of a benefit than with higher. These same data are depicted graphically again here. The likelihood of benefit appeared to be greater when patients presented with a greater number of organ failures and on to the next slide.

In this slide we have a table that displays mortality as a function of shock. Approximately 70 percent of the patients were in shock as defined by the sponsor within a 6-hour period preceding study drug administration.

In this table we can see mortality as a function of shock. Patients in shock showed a greater difference in mortality on rhAPC versus placebo. Those patients not in shock appeared to show a somewhat small difference.

Next in summary of the treatment effect by APACHE II and organ failure and shock we looked at the predicted values of relative risks and their 95 percent confidence intervals for APACHE and the number of organ failures and shock at baseline.

The data in this slide show the relative risk of death represented by the yellow points and their 95 percent confidence intervals in red.

A logarithmic scale is on the X axis and on the Y axis you need to take the various subgroups. One represents no treatment benefit. Anything to the right the placebo is better and anything to the left the treatment with rhAPC is better, except in the first quartile with a relative risk above one in the first APACHE quartile. The other APACHE quartiles show treatment benefit less than one. Patients with one organ failure or without shock had a relative risk of close to one. All others showed more treatment benefit with relative risk less than one.

So, in summary patients with more severe disease may suggest a greater treatment effect.

Now, we will proceed to look at hematologic parameters as highlighted here. This slide shows treatment effect as a function of protein C levels at baseline. One might postulate that the relative benefits of recombinant APC therapy be related to the deficiency of this protein in the serum.

In this table there are two main points. Relatively few patients were not protein C deficient at baseline. Also, there appears to be no relationship between protein C deficiency and treatment with rhAPC.

The unknown category was in a small number of patients who did not have tests performed due to laboratory error. So, it was unknown whether the patient was protein deficient or not.

We evaluated treatment benefit by disseminated intravascular coagulation or DIC. The majority of patients in this trial, over 90 percent had laboratory evidence of DIC at study entry. This was defined by the presence of at least two of four laboratory findings as the sponsor has previously defined today.

There were 115 patients in which DIC was unknown or absent. In 113 patients of this group this was due to insufficient laboratory data available to determine DIC. Of the small number of patients there appears to be a limited treatment effect in this group.

Finally, the use of heparin. Use of therapeutic heparin was an exclusion criteria. Low-dose heparin was permitted in the trial and about two-thirds of the patients received heparin. In this analysis we explored whether the use of heparin impacted the size of mortality benefits attributable to rhAPC. RhAPC mortality results in patients on low-dose heparin were compared to those in patients not on low-dose heparin.

Low-dose heparin use was categorized in two different manners, use at baseline as shown at the top and during infusion underneath.

While the second group, that is the group that includes patients who had heparin begun during the study drug administration is the group of greatest interest inclusion of such patients may introduce biases if the use of study drug influenced the decision to start heparin. Therefore both analyses are shown.

As can be seen the mortality effect of rhAPC was 3 to 4 percent in patients on low-dose heparin by either approach, whether it is baseline or during infusion.

In contrast the mortality of effect of rhAPC was considerably higher in patients that were not on low-dose heparin. You can see the difference is 9 to 15.

So, to summarize mortality in patients who received rhAPC was lower than placebo regardless of whether low-dose heparin was used or not, but treatment benefit was several-fold greater in patients that were not on low-dose heparin. However, the study to note was not designed to assess whether low-dose heparin should be used with rhAPC.

I would now like to switch gears and focus not only on mortality but on morbidity. Since 20-day all-cause mortality does not reflect all outcomes of treatment benefit it is important not only to look at the number of patients alive but at their treatment status and evidence of comorbidity.

Shown here in this slide is a side-by-side comparison of morbidity and functional status at day 28 compared between rhAPC and placebo. Mortality is shown in red. In green we have a side-by-side comparison of ICU status at day 28.

In yellow patients that are still hospitalized at the end of the study are shown. Violet is patients that are in a nursing home and navy in a discharged home.

In the rhAPC arm there was as you can see approximately a 6 percent difference of fewer patients who died on study. At day 28 this group had about a 2-1/2 percent number of more patients that were alive in the ICU and alive in hospital.

Also, about a 1 percent difference occurred in patients that were discharged to a nursing home or to home.

Finally, before I conclude with the summary of efficacy I would like to focus on the changes that were made to the protocol by the sponsor. These occurred while the study was still blinded and before the first interim analysis was conducted. The sponsor made two sets of changes in July 1999.

They altered their analytic time and they clarified their inclusion and exclusion criteria and they eliminated protein C deficiency and septic shock from the Cochran-Mantel-Haenszel test.

The sponsor changed the inclusion and exclusion criteria to clarify certain parameters. This was done to clarify definitions and better eliminate patients with chronic or comorbid disease. These patients were not likely to respond from acute therapy of severe sepsis in the sponsor's evaluation.

Listed here are some of the criteria that were modified. These include excluding patients that were more likely to bleed such as patients with esophageal varices or cirrhosis. They also excluded patients that were more likely to die and patients with other underlying disease such as malignancies and, also, they further clarified their organ failure eligibility for the trial.

These are the results of the changes between the original and amended protocol. There were a few relative modest differences between the original as compared to the amended version of the protocol.

In the amendment there were fewer patients with malignancies that were immunosuppresed that had the withdrawal of life support, with chronic APACHE health points and with non-sepsis-related disease as well as at nursing home facilities.

Also, of note a few points, the IL-6 median level was slightly higher in the amended protocol compared to the original. The mean APACHE scores between the original and the amended version were the same at 25. Acidosis was more common under the original protocol compared to the amended.

We, also, looked at the differences between the number of "do not resuscitate" orders under the original versus the amended version of the protocol.

As can be seen the placebo rates were similar. However, the number of patients in the first half of the study or in the original protocol on rhAPC it was 16 percent compared to 10 percent in the second half of the study or under the amendment.

This may reflect differences in mortality as on the next slide. Here as previous touched upon this table displays mortality data stratified by the original and the amended versions of the protocol. As we can see there were 720 patients that were enrolled in the original protocol and 920 under the amendment.

The placebo rates between the two protocol versions are similar. However, in the rhAPC arm there was a 28 percent difference in mortality under the original protocol compared to 22 percent in the amended version of the protocol. As noted we, also, have the P values here of .0055 or .057. Under the original protocol and under the amended protocol we have a P value of .00012.

It is, however, important to review not just the individual landmark analyses of the data for specific patients but to look over the entirety of the survival curves as a function of study day.

Shown in this table as the sponsor has already shown are the mortality rates in each arm on day 1 and really on a day-to-day basis as the study was conducted.

On the X axis we have the dates throughout the study. On the Y we have the mortality rates depicted for each study arm reflecting 28-day observation and therapy.

Let me go ahead and point out a few salient features. Line A represents the time the first patient was enrolled under the amended version of the protocol.

Line B occurs when the first interim analysis occurred and Line C when the second interim analysis occurred.

Of note, there was a separation of the curves before the protocol amendment was implemented in favor of benefit for rhAPC. These curves continued to separate throughout as the study progressed.

This curve was conducted in 1690 patients and slightly differs from the sponsor's curve presented earlier today as the numbers differ. The sponsor apparently was using a number of sites, of 99 sites and 1493 patients, and furthermore we conducted a sensitivity analysis evaluation for those patients that were enrolled in the original protocol, but would have been excluded from the amended protocol.

There were a total of 81 patients or 11 percent that did not meet new inclusion criteria for the amended protocol that would have met the original protocol.

Despite the 81 patients who did not meet the inclusion criteria they continued to show treatment effect. So, in summary there was a benefit in the 28-day all-cause mortality. The mortality rate on rhAPC was 24.7 percent versus the 30.8 percent on placebo with a P value of .005.

Finally treatment benefit was more predominant in the following groups of patients, in the third and fourth APACHE quartiles compared to the first and second, in patients with laboratory evidence of DIC compared to those without and also in patients receiving heparin, oh, not on heparin, excuse me, compared to those receiving low-dose heparin, in age groups over 50 years of age compared to not and in greater than two organ failures at baseline compared to patients without or single organ failure and finally, in patients with shock compared to patients without shock.

Next, Dr. Lindblad will present pediatric and safety data.

DR. LINDBLAD: I was going to start off with good morning, but I think I will start with good afternoon.

I would like to present data on both the pediatric patient population studied by the sponsor and the adult safety in the Phase II and Phase III trials.

This will be followed by immunogenicity data and a summary of the presentation. It is important to note that there are no randomized placebo-controlled trials in the pediatric patient population. The uncontrolled pediatric study was ongoing at the time of the BLA submission and the final report has not yet been filed with the agency.

The sponsor is seeking a pediatric indication based on demonstrating the similarity of pediatric sepsis to adult sepsis. This is based on the sponsor's premise that the disease characteristics, the pharmacokinetics and pharmacodynamic data as previously described by the sponsor are the same, as well an adequate safety database at the recommended dose and duration of treatment.

Since APACHE II scores are not used in pediatric patients the pediatric index of mortality was used. In addition to the pediatric index of mortality disease severity can be estimated by the number of organ failures and the overall mortality that was observed.

The total pediatric safety database consists of 121 patients. The sponsor presented a slightly higher number based on the ongoing trials. The pediatric patient population was studied primarily in an 83 patient safety and pharmacokinetic pharmacodynamic sepsis trial as previously described by the sponsor.

An additional 14 pediatric patients were enrolled in the study of patients with purpura fulminans and finally there are ongoing safety open-labeled trials that have enrolled at my time 24 additional pediatric patients.

These next slides compare the 83 pediatric patients enrolled in the primary pediatric sepsis trial to the adult patients enrolled in the Phase III trial.

The first two slides have a pediatric database of 32 patients. These patients were enrolled after a protocol amendment that added both hematologic and renal organ failure and more closely mirrored the adult study. The last three slides are based on the entire 83 pediatric patients enrolled in the study.

This first slide based on the 32 patients enrolled after the amendment compares the type of organ failure seen in the pediatric patients compared to the adult patients.

Pediatric patients had cardiovascular organ failure more often and respiratory organ failure less often when compared to the adults.

In addition renal failure was less common in the pediatric patients compared to the adult patients.

The next slide, also, based on the 32 patients enrolled after the amendment shows the number of organ failures in pediatric sepsis compared to adult sepsis.

This is one marker of disease severity, and it shows a shift to a single organ failure for the pediatric patients as compared to multiple organ failure in the adult patients in the Phase III trial.

The next slide, based on the 83 patient pediatric database compares the primary sites of infection in the pediatric population versus the adult population. The primary site of infection was blood followed by pneumonia and meningitis for the pediatric patients.

Blood and CNS primary sites of infection are uncommon in adult patients. As would be expected adult patients had primarily pneumonia, intra-abdominal and urinary tract infections.

Again, based on the 83 patient pediatric database the type of pathogen is more often gram negative as compared to gram positive in the adult patients.

The pediatric index of mortality was used in the pediatric sepsis study. This index was developed to predict mortality in the intensive care unit. The pediatric index of mortality score in the pediatric patients was 11 percent overall.

The APACHE II score was used in adults and estimated a mortality of 25 percent. Though these scoring systems cannot be compared directly they suggest a less ill pediatric population.

The mortality data in the pediatric study was determined at day 14. For comparative purposes the 14-day mortality figure was, also, used from the adult trial.

The 14-day mortality for the pediatric patients was 10 percent compared to 20 percent in the adult patients. This, again, suggests a pediatric patient population that is less ill than the adult patient population.

Moving next into the safety data for the pediatric patients a comparison of safety parameters between the pediatric and adult patients reveals similar overall rates of serious bleeding events, bleeding adverse events, serious adverse events and adverse events between the pediatric and adult patients.

Specific pediatric safety events included one intracranial hemorrhage. The patient, a 14-year-old with meningococcemia died on study day 13 with a CT scan revealing a right frontal parenchymal hematoma of uncertain age but perhaps a week old. The rhAPC had been stopped 10 hours into the infusion due to anisocoria.

Additionally there were three serious bleeding events noted in the study for a rate of 3.6 percent.

In summary there was a small uncontrolled pediatric database on which to draw any conclusions. Drug effects as reflected by the PKPD data presented by the sponsor and bleeding events were similar between the pediatric and adult patients studied.

There was one intracranial hemorrhage. However, the sepsis disease parameters in the pediatric patients are different than those in the adult patients studied.

The pediatric sepsis patients more commonly had cardiovascular organ failure versus both cardiovascular and respiratory organ failures as was seen in the adults. Pediatric patients had a single organ failure more often than multiple organ failures.

The primary sites of infection were blood followed by lung and CNS for the pediatric population versus lung, intra-abdominal and urinary tract infections for adults, and finally the 14-day mortality in the pediatric patient population was 10 percent versus a 14-day mortality of 20 percent in the adult patients treated with rhAPC.

Next, I will present the adult safety data starting with the Phase II trial. The patient population chosen for this trial as well as for the Phase III trial excluded patients that were at high risk for bleeding events. These exclusions included major surgery within 12 hours or an anticipated major surgery, GI bleeding within 6 weeks of study entry, trauma patients at increased risk for bleeding and patients with congenital bleeding diathesis. Additionally, patients treated with greater than 650 milligrams of aspirin within 3 days of entry, therapeutic heparin or warfarin within 7 days were excluded.

In the Phase II study specific criteria were used to start and stop the infusion based on the type of procedure and coagulation status.

The infusion was stopped for invasive procedures and restarted immediately after minimally invasive procedures and up to 12 hours after major surgery. The coagulation parameters used to start and stop the infusion included two or more consecutive activated partial thromboplastin times greater than 100 seconds or an INR greater than 3 or a platelet count less than 15,000.

For the Phase II trial the 28-day mortality was divided into groups based on several factors including the duration of the infusion. RhAPC was administered initially in a dose escalation scheme as described by the sponsor.

All dose groups were sequentially enrolled and received a 48-hour infusion. After safety review new groups were sequentially enrolled and received a 96-hour infusion. The 30-microgram-per-kilogram-per-hour dose was not studied in the 96-hour infusion.

Though the numbers are small there was a suggestion of a higher 28-day mortality in the patients receiving a 96-hour infusion compared to the 48-hour infusion. The overall mortality in the placebo group was 34 percent.

As noted on this next slide there was a higher incidence of serious adverse events in patients that received a study drug for 96 hours than those that received the infusion for 48 hours. The placebo rate was 24 percent.

Three significant bleeding events occurred, two in the 48-hour infusion group and one in the 96-hour infusion group. There were no intracranial hemorrhages.

Next, I will turn to the adult safety data in the Phase III trial. In the Phase III trial there were four deaths attributable to bleeding which occurred during the infusion period. The infusion period was defined as the start of the study drug through completion plus the next calendar day.

All four deaths occurred in the rhAPC-treated patients. Two of these deaths were due to intracranial hemorrhages representing a rate of 0.2 percent. There was one fatal pulmonary hemorrhage and one death related to an intrathoracic bleed in a patient that had been involved in a significant motor vehicle accident 3 days prior to being enrolled in the study.

On August 28, of this year, the company submitted additional preliminary data regarding intracranial hemorrhages in ongoing post-Phase III safety studies. These studies which are separate from the Phase III trial have similar entry criteria to minimize the risk of bleeding.

Despite these measures 13 new intracranial hemorrhages have been reported with 8 of those occurring during the infusion time period. The remainder occurred between days 7 through 13.

For those bleeds occurring during the infusion the event rate is 1.5 percent. This compares to a rate of 0.2 percent in the Phase III trial.

No other safety data has been submitted related to this patient population in these ongoing studies. The sponsor has, also, been evaluating this data on an ongoing basis. So, there may be updated information from the sponsor related to these events that has not been formally reviewed by the agency.

Serious bleeding events were defined in the Phase III trial as any intracranial bleed, any life-threatening bleed, transfusion of greater than or equal to 2 units of packed red blood cells in the Phase II trial or greater than or equal to three units of packed red blood cells on two consecutive days for the Phase III trial or they would meet other criteria for a serious adverse event such as a life-threatening event, prolongation of hospitalization, persistent or significant disability, congenital anomaly or birth defect, an event that results in cancer or an event that suggests a significant hazard, contraindication or side effect.

The number of total serious bleeding events during the infusion period was 20 in the rhAPC treated group compared to 8 in the placebo arm. Their GI bleeds were fairly balanced. There was a greater number of intrathoracic bleeds, retroperitoneal bleeds, intracranial hemorrhages and genitourinary bleeds in the rhAPC-treated patients versus the placebo patients.

Adverse events occurring during the infusion period revealed almost twice the rate of serious bleeding events and bleeding adverse events in the rhAPC-treated patients compared to placebo patients.

The rhAPC and placebo groups were similar with respect to the number of serious adverse events and adverse events.

As was shown in Dr. Forsyth's presentation mortality on treatment was not lower than placebo in the first APACHE II quartile.

This slide shows both the bleeding adverse events and serious bleeding events in the first APACHE II quartile. In a population where rhAPC was not associated with a lower mortality it was associated with more frequent bleeding events. There were 38 bleeding adverse events in the rhAPC arm versus 17 in the placebo arm and 9 serious bleeding events for the rhAPC-treated subjects versus none in the placebo group.

This resulted in a treatment difference of 9 percent for bleeding adverse events and 4 percent for serious bleeding events.

During the 28-day study period multiple transfusions of packed red blood cells fresh frozen plasma and platelets were given. These numbers, again, highlight the greater bleeding incidence in the rhAPC-treated patients as manifested by the greater number of required transfusions.

One must keep in mind that a greater proportion of the rhAPC-treated patients survived to day 28. This would potentially increase the total number of transfusions given in the rhAPC-treated arm.

Subjects with laboratory evidence of DIC as defined by the sponsor represented over 90 percent of the patients studied. It is unknown how many people were not in DIC as the remaining patients had insufficient data to establish the diagnosis.

The overall rate of serious bleeding events was similar between those that were in DIC and those where the DIC status was unknown.

This rate was twice as high in the rhAPC-treated patients versus the placebo patients. Adverse bleeding events in relationship to baseline coagulation factors are presented next. This data is pooled from the Phase II and Phase III trials. This yields a total of 940 patients in the rhAPC arm versus 881 in the placebo arms.

The actual numbers in each group vary slightly because of patients that had incomplete laboratory evaluations.

For those subjects treated with the rhAPC and a baseline APTT less than 2 times the upper limit of normal the adverse bleeding event rate was 18 percent compared to a 20 percent rate in patients with an APTT greater than 2 times the upper limit of normal.

Both of these are greater than the corresponding placebo rates of 11 and 14 percent respectively.

For subjects with a PT greater than 1.2 times the upper limit of normal there was an increased risk of bleeding in the rhAPC group compared to placebo and compared to subjects that received rhAPC with a PT of less than 1.2 times the upper limit of normal.

A few subjects had platelet counts less than 50,000. In subjects with a platelet count greater than 50,000 there was an increased risk of bleeding in the rhAPC subjects when compared to placebo. There was, also, an increased bleeding risk in the few patients with platelet counts below 50,000 in both the placebo arm and the rhAPC arm.

The next two slides present the serious bleeding events on slide 1 and the bleeding adverse events on slide 2 in those patients treated with heparin while receiving rhAPC or placebo.

Therapeutic heparin was an exclusion criterion for the study. Low-dose heparin was permitted. With a potential for synergistic activity between heparin and rhAPC safety data were reviewed.

The rate of serious bleeding events was increased in the rhAPC-treated patients compared to placebo regardless of receiving heparin.

There was, also, an increased rate of bleeding adverse events for all patients receiving rhAPC whether or not they received heparin.

Reviewing data in subgroups based on gender, origin and age no differences in safety profile were observed.

Using pooled data from the Phase II and III trials patients were grouped based on their surgical status, either having had emergency surgery or elective surgery. These patient characteristics were obtained from the APACHE II assessment and were not prospectively defined.

Other than recording the APACHE II score at the entry of the trial the timing of the surgical procedure is unknown.

Though the numbers are small and the confidence intervals are large no mortality benefit was observed in the emergency postoperative patients. This was not true in the patients that were postoperative from elective surgery.

There was a similar rate of bleeding events in the rhAPC group regardless of their emergent or elected postoperative status.

RhAPC steady state concentrations were obtained in 326 patients. These steady state levels were divided in half, those at or below the median and those above the median.

The ranges went from 14 to 45 nanograms per ml and 45.1 to 391 nanograms per ml. The mortality, the number of patients with greater than or equal to one serious adverse event or greater than or equal to one serious adverse event during the infusion period was greater for patients with higher steady state levels than lower steady state levels.

This was, also, true for patients with serious bleeding events throughout the 28-day study period and during the infusion period.

Moving next to immunogenicity, combining the Phase II and III trials 942 patients received rhAPC. Of those 942 patients 370 patients had adequate blood samples to evaluate immunogenicity. This included a baseline sample and a sample on or after study day 12. The testing was done in a tiered manner. The first tier was a chemiluminescent binding assay. If this was positive it was followed by an inhibition chemiluminescent binding assay.

If that was positive an anti-APC neutralizing antibody test was performed. There are outstanding issues regarding the sensitivity, specificity and quantification of the assays. Based on this it is difficult to assess the true incidence of anti-APC antibodies.

Recognizing some limitations of these assays results were obtained in 370 patients. Of these 370 patients five had positive tier 1 testing determined by the chemiluminescent binding assay. Two of these five patients had positive tier 2 inhibition tests. Neither of these two subjects tested positive for anti-APC neutralizing antibodies.

Of the two subjects with the anti-APC antibodies determined by a positive tier 2 inhibition test one was in the Phase II study and the other in the Phase III study. The subject in the Phase II study had no clinical sequelae.

The subject in the Phase III study developed superficial and deep venous thrombosis in the 28-day study period. This patient was alive at day 28 but on further follow-up this subject died on day 36 of multi-organ failure. There were no further reported thrombotic events.

The overall incidence of deep thrombophlebitis reported in the Phase III trial was 7 cases for an incidence of 0.4 percent.

Three of these cases occurred in the rhAPC treated patients. There was a higher overall rate of thrombotic events as presented by the sponsor.

In summary for the pediatric summary there were no controlled studies. No controlled studies were performed in the pediatric population to support efficacy, and there is a limited patient population from which to draw any conclusions.

In comparing pediatric to adult data drug effects as reflected by the pharmacokinetics and pharmacodynamics were similar. However, the disease characteristics reflected by the type of infections and organisms and the type and number of organ failures are different.

Additionally, the mortality rate in the pediatric study was half of the rate observed in the adult Phase III trial. This low mortality rate is coupled with a similar rate of complications including deleting events and the occurrence of an intracranial hemorrhage.

This is important in assessing the benefit versus the risk in the pediatric population.

In summarizing the adult safety data it is important to reiterate that patients in this trial were selected to minimize the risk of bleeding. The major safety concern with rhAPC is the bleeding risk. This is reflected with a higher rate of bleeding adverse events during the infusion of 19 percent in the rhAPC-treated patients compared to 11 percent in the placebo group and an increased rate of serious bleeding events, 2 percent in the rhAPC-treated patients versus 1 percent in the placebo-treated patients.

In the Phase III trial four deaths attributed to bleeding occurred during the infusion period, all in the rhAPC-treated patients. Two of these were intracranial hemorrhages.

For rhAPC-treated patients this yields a rate of .2 percent for intracranial hemorrhages during the infusion period in the Phase III trial. In subsequent preliminary data submitted in late August open-labeled safety trials have enrolled 520 patients. Thirteen new intracranial hemorrhages have been reported, 8 occurring during the infusion period. This yields a rate for intracranial hemorrhages of 1.5 percent during the infusion period.

The sponsor has been assessing these cases on an ongoing basis, but these data, again, have not been formally reviewed by the agency.

One patients with anti-APC antibodies developed superficial and deep vein thrombi. This patient died at day 36 of multi-organ failure. Other than the increased risk of bleeding no other patterns of adverse events were observed when comparing the rhAPC-treated patients to the placebo-treated patients.

In conclusion, sepsis is a difficult condition in which to detect adverse events due to the large and varied number of events associated with sepsis itself. In evaluating products for the treatment of sepsis important safety events can easily be attributed to the underlying illness.

There is a clearly identified increased risk of bleeding in patients treated with rhAPC. Intracranial hemorrhages were identified in only two patients treated with rhAPC in the Phase III trial.

New data suggest this may under-represent the actual rate. Additional intracranial hemorrhages may go undetected in situations where CT scan for practical reasons is not performed.

Thus, it is unclear what the true rate of intracranial hemorrhages may be. Other major bleeding events occurring in contained non-visible sites could be difficult to detect for the same reasons. Though major bleeding events were identified, the risk of these events remains somewhat uncertain.

Thank you.

DR. RELLER: We have heard the FDA presentation.

Are there questions from the Committee?

Dr. Fleming?

DR. FLEMING: I had one question of Dr.Forsyth and one of Dr. Lindblad. Let me start with Dr. Lindblad, but while I do could Dr. Forsyth raise the slide about functional status at day 28 while I am asking the question of Dr. Lindblad?

Dr. Lindblad, one of the key issues as we look at the lowest APACHE II group is this SAE bleeding. You noted there were 9 cases versus 0, and that is certainly going to be important as we are looking at benefit-to-risk.

Can you tell us the survival status of those nine?

DR. LINDBLAD: Actually I can look that up for you and give that up to you. I don't have that right at my fingertips.

DR. FLEMING: Okay, it would be helpful to get that.

Could we have that functional status slide? If we are having trouble digging it up, could we go to another question and then we will come back to my question?

DR. RELLER: Dr. Suffredini?

DR. SUFFREDINI: I wonder if Dr. Lindblad could address the issue of whether the changes that were made in the protocol in terms of part two in terms of the changes in malignancy, acute MI, acidosis, etc., were distributed equally across both the treatment and the placebo group?

DR. LINDBLAD: Could you repeat the question?

DR. SUFFREDINI: Sure, I will try one more time. Let me repeat the question? I am sorry. In terms of the changes that occurred in the protocol from part 1 to part 2 were the changes that occurred in terms of malignancy, acute MI, acidosis, etc., hypertension, were they equally distributed across the treatment and the placebo groups?

DR. FORSYTH: As far as I know they were distributed appropriately.

DR. SUFFREDINI: But we don't have formal data on that?

DR. FORSYTH: No, we don't.

DR. ZWIGERMAN(?): We can dig up those final numbers. This is Bill Zwigerman, the Chief of the Branch. Yes, they were equally distributed between the two arms of the study but Dr. Forsyth pointed out on her slide that there were differences between the first and second half, if you will of the protocol.

DR. RELLER: Dr. Carcillo?

DR. CARCILLO: I have a question for Dr. Lindblad, please? Do you know if there were any children who were receiving activated protein C who died after 14 days in the pediatric ICU that were not included in your 10 percent mortality at 14 days?

DR. LINDBLAD: No, I don't know that. One of the difficulties with the pediatric study is the adult study was stopped early. The pediatric study was not finished. The initial submission included only 54 patients in that study. Subsequent data was provided and actually that I saw for the first time in the briefing document as well, too, so that it is an ongoing process. The final study report hasn't been finished. The sponsor may have some data to address that.

DR. RELLER: Let us come back to Dr. Fleming's question about the functional status for Dr. Forsyth.

DR. FLEMING: While the slide is being put back up, let me compliment the designers of the trial for one very important feature, and that is the study was providing uniform follow-up of survival through day 28, and in some of the historical trials there had been debates as to whether 7 days or 14 days is enough follow-up, and what we saw was that in fact there were one-third additional deaths that occurred during that second 2-week interval and I think the informativeness of this study is greatly strengthened by the duration of 28 days, and yet even at 28 days I had done some hand calculations, and I was delighted to see this slide because they exactly bring out the hand calculations. Twenty-eight days is critically important in survival status, but there is more to the status than just that figure would indicate.

What we can see is, and what we focused on is the difference in the red, that there are 6.1 percent fewer deaths which numerically is a difference of 49 additional deaths in placebo and yet the green and the yellow groups there are those that are hospitalized and there are exactly 46 additional treatment patients in the hospital.

So, essentially what this translates into then is a 6.1 percent reduction in death, but of that 6.1 percent 5.1 percent are in the hospital.

So, it is not as though we are in essence increasing by 6.1 the percent of people who are home. Essentially for the most part the prevented deaths are people who were in the hospital. Clearly it is better to be in the hospital than to be dead, and yet it is unclear exactly what this will translate into in terms of overall effect, and the reason this is important as well, and we will come back to this later on is that this study does meet the standard for strength of evidence for a positive study for a single positive study and that is of course, though on survival, and if you in essence though subtract off in some subjective sense the fact that you are hospitalized you could readily if you subtract off anything meaningful be moving to a level where this wouldn't be significant.

Clearly the study isn't remotely significant in the number of people who are alive out of the hospital because there is only a 1 percent difference.

Is there anything known about what the implications are, in essence that what we are doing really is keeping people alive but in the hospital what those implications are?

DR. SIEGEL: You noted that there had been calls for a study. I should say that really over the last 10 years while there have been calls in some cases for primary end points at 7 days and 14 days, in fact, there have been calls for 2-or-6-month follow-up for some of the reasons you mentioned and I think that some people have conceptualized sepsis as a relatively acute event that you either die from or recover from, and this study would suggest, however, since only 10 percent of these patients I think were in hospital prior to entry to development of sepsis, 80 percent were at home, that in fact there is a substantial rate of chronic sequelae. I think the point is well taken. I don't have any data to indicate what will happen to those 5 percent of patients obviously. I think that is an interesting question that struck us as well in the analysis.

DR. RELLER: That was Dr. Siegel responding to Dr. Fleming's question.

Dr. Warren?

DR. WARREN; I had two questions relating to the first and the second half of the study. The first was did you analyze bleeding comparing the first and second half of the study? We saw there was a large difference in efficacy, but was the bleeding equivalent across the study and similarly because I guess there was a change in the way the drug was made. Were the antibody levels also different between the first and second half of the study because one might imagine that that would a sensitive way to pick up differences in glycosylation?

DR. LINDBLAD: I actually had looked at some of the bleeding differences between the first half and the second half and could not discern any differences between them, and as far as the antibody levels, as I alluded to there are some issues with the assays that we are working out and the overall detection of the antibodies was so low that I don't think that that is going to be helpful for us at this point.

DR. RELLER: Dr. Rotello?

DR. ROTELLO: Two questions related to the scoring. APACHE II has been validated at the time of admission to ICU, and I was curious what the census of your patients when they had their APACHE II done at baseline were and was that coincident with the time of admission to the ICU, and No. 2, the APACHE split into two separate parts acute physiology and chronic health evaluation. Some of the criteria that changed in the second part of the study would have been patients who received points for chronic health evaluation. So, the same number of APACHE points could be weighted differently based on their proportion from chronic health evaluation versus acute score and would relate to a different mortality.

DR. SIEGEL: Let me comment on that? We tried actually to get a handle on the question of to what extent the APACHE was measured within the first 24 hours of ICU admission. I am not sure that exact information is available. I talked to the review staff and talked to the Lilly staff, and we may be able to get a better handle on that.

What we do know is that at the time they developed sepsis as I understand it only 10 percent of these patients were in the hospital. So, most of these patients are coming in septic, being admitted to the hospital and probably being admitted to the ICU relatively early in the course of having their APACHE done. It is probably, one would guess although I can't say with any degree of firmness that it is a relatively limited number of patients who had their assessment after being in the ICU for an extended period of time.

It is worth noting in this study as was pointed out in Dr. Forsyth's presentation and in virtually every other study we have seen and if the APACHE II or other risk measures that are similarly validated are measured at the time of study entry or within a window prior to study entry, the APACHE in this study did although no measure the way it was optimized which is measured at time of entry, did in fact serve as a powerful predictor of mortality with the 12 percent mortality in the low quartile and a 49 percent I think it was in the high quartile and graded values before this, and we have seen that in a number of other trials in which it has been used at entry, and so it may not be optimized for that, but it certainly is an important mortality predictor.

There is a couple of things I wanted to say, as well for the FDA presentation regarding the APACHE and the issue of risk and regarding some of the Lilly comments in particular.

We agree with the comments by Lilly that these variations could have arisen by chance and that the study was under powered for subgroup analysis and as Dr. O'Fallon mentioned under powered for interaction analysis as well, and that doesn't mean of course that subgroup differences don't exist or interactions don't exist. It means unfortunately that it is hard to tell because if they exist they still might not be statistically significant, and the questions we are asking the Committee about this analysis are not at all should we conclude that an interaction exists or there is a problem. The questions are simply is there a strong enough suggestion and are the implications of potential interaction important enough that they should be addressed somehow by further studies in particular.

In that regard we look, you can look at the data, and that is what has been looked at, but when you look at it of course, when you look at subset analyses which have been perhaps appropriately criticized at various times in this meeting and at many meetings, is biological plausibility, prospectivity and strengthening consistency of the suggestion of an effect and to comment just quickly on each of those, on biological plausibility sepsis is an extremely diverse syndrome.

People working in sepsis have been tackling on the fact that the underlying disease of the patients varies, the organ involved, the organism involved, the physiologic response involved varies and importantly you can integrate some of those factors and others into a severity risk. The severity risk has long been recognized as having the potential for being one of the more important factors and in the ACCP reprint that is in your folder, ACCP SCCM consensus reprint in which the definition for septic shock that was used was discussed there is an important recommendation that the newest terminology, quote, should be used with risk stratification or probability risk estimation techniques, and the rationale for that was that accurate identification of pretreatment risk can improve the position of evaluation of new therapies. Such risk estimation can also be useful in monitoring the utilization of new therapies and in refining the indications for specific treatments by identifying risk levels where certain therapies appear to be efficacious.

So, suffice it to say over the ensuring years of many trials and before many analyses have and many investigators have at least postulated that this could be an important interaction.

From a mechanistic point of view it is not hard to postulate a couple of ways in which that can be important. If you have a benefit that is proportional to risk so that you lower mortality proportional to the risk by 4 percent if it starts at 40 and by 1 percent if it starts at 1, but you have a safety risk that is constant then that safety risk can overwhelm the benefit in low-risk patients and not in high-risk patients.

You could, also, have a different pathophysiology in low-risk patients than in high-risk patients. It could be a surrogate for other factors that indicate different drug effects.

As far as prospectivity and those things speak somewhat to the general idea of prospectivity it is worth noting in this trial that the covariates looked at and notably APACHE II were prespecified. There were many prespecified covariates in this trial.

We did ask the sponsor to rank order them. I think the APACHE was fourth or fifth. It was pretty high behind some involving protein C level and coagulopathy state which were, of course, also, prespecified for obvious reasons as potential important covariates.

As far as the strengthening consistency of the suggestion Lilly showed you some slides within that first APACHE quartile that suggest, I think they looked at SOFA scores, number of organ failures, and maybe IL-6 that suggest that it looked like the higher risk groups were the groups where, that the lower risk groups, if anything had the most benefit or the higher risk groups had the most suggestion of a reverse effect and suggested that there is an inconsistency in the data there.

I am concerned about that sort of analysis. I think that you are talking about a group that has a relatively low total risk in the first quartile and that is fixed, and if you subdivide them by other measures, measures other than APACHE you can have unanticipated effects.

So, people who have high-risk because of organ failure are likely to have very few other risk points or they wouldn't still be in that APACHE or people who have low IL-6 levels but their organs are failing because you have to have organ failure to be in the trial might be more apt to have coagulopathies.

You get into some funny aberrancies. I don't know the latter is the case, but it certainly -- so, we have looked at that analysis subdividing APACHE quartile by APACHE, subdividing it into octiles, and it is worth noting there that the lowest octile showed 3.9 percent higher mortality on rhAPC with a relative risk of 1.32 and the second octile showed a 2.0 higher on rhAPC with a relative risk of 1.17. So, that suggests that within that there is a consistency in direction, and finally although a great number of analyses were shown to suggest that that was not a consistent effect of low risk it is worth noting that as we look at the data several that we think are perhaps the most important to look at are confirmatory of a suggestion of a

risk-related interaction.

Over the years of sepsis study shock and organ failure have been perhaps the most commonly, perhaps more recently with IL-6 touted predictors of possible interactions with the mortality effects and shock and organ failure were both very powerful predictors not only of mortality but also suggested in both cases larger treatment effects in the more severely affected than the less severely affected patients.

It has recently come to light in discussions with Lilly that shock interesting, you know on the one hand they showed cardiovascular SOFAs and we showed shock. Interestingly if you look at their slides the shock was actually a much better, shock within 6 hours was a much better predictor of risk level than, that is Page 41 of their slides, than cardiovascular SOFA which I guess was within 24 hours. Whether it is the time difference or something else I don't know, and we haven't yet fully reconciled why we see those differences.

So, I will just leave it at that, but I did want to put in some other perspectives, again not to suggest that these subset analyses drive toward any conclusion but just to lay the background as to why we notwithstanding the issues they raised, why we think it is important to discuss whether they merit further study.

DR. RELLER: Two final questions, and then we will break for lunch.

Dr. Suffredini and then Dr. Lilly.

DR. SUFFREDINI: I wonder if Dr. Forsyth could address the issue. I guess I am concerned about your conclusion that the treatment was efficacious with laboratory evidence of DIC, and my concern is that the definition as used by the sponsor is certainly not robust in terms of the two out of four parameters that are used are really very common abnormalities that one would see in any patient that goes into ICU and certainly don't meet the criteria that most textbooks would use for DIC and what a practitioner would consider severe disseminated intravascular coagulation.

So, it is not surprising since there is not a discriminating factor DIC the definition used was so broad. It is really not DIC. It is an abnormality in coagulation perhaps, but that is really not DIC, and so, my concern is in terms of labeling or in terms of how the practitioner would look at this and use it in someone with profound DIC. I am not sure if the data exist to tell us that that would be useful or not.

DR. FORSYTH: I totally agree with you and as far as the no standard definition of DIC we certainly understand that and this is the way that the sponsor has proposed to address the issue of DIC but I agree with you on that. That is an issue.

As far as labeling is concerned, we have been struggling with this issue.

DR. SIEGEL: We are going to take your advice, of course, on how we should address that in labeling, but this is not DIC. I think the slides say DIC but it is clear. It was called DIC in the trial criteria, but we agree it is not DIC, and the issues as will be brought out in the question are twofold.

One is is there a difference in treatment in patients who do have certain types of coagulopathy and not and there is not much data here to suggest that. The other is this is somehow a select patient population that has such a high incidence of coagulopathy that in some way we need to alert people that we don't know about the impact in patients who might not have all these abnormalities and we are seeking your expertise on that question.

As you heard for Lilly they looked at at least one other trial at the number of people who met these criteria and it was quite similar, and we have looked at the platelet criteria and found it similar in other trials.

DR. RELLER: Thank you, Dr. Siegel.

Dr. Lilly, and then we will break for lunch. There will be additional discussion and just before lunch I want to point out a few things on the revised schedule.

DR. LILLY: Can you or can you not account for the excess mortality in the lowest APACHE quartile by the reported bleeding related SAEs?

DR. LINDBLAD: That gets into Dr. Fleming's question, I think, and of the nine serious adverse events four of them resulted in death in the 28-day study period. So, it doesn't entirely account for it.

DR. SIEGEL: I am not sure. It is very easy to address that sort of question. It is my perception and we have seen this in other ICU trials like if you are in the ICU on a ventilator, say and on pressor agents and you suddenly crash and you are septic and you suddenly crash and die the likelihood that someone is going to do a postmortem to see whether that death was related to an ICH or not is probably pretty small, and so I am not sure.

If ICHs for example were accounting for a few percent extra mortality you might pick them up in survivors but in patients who are critically ill I am not sure. I mean this has always been an issue even in the MI trials.

Within those who die it may be difficult to know what the true incidence of serious or for that matter if they, even if their blood pressure dropped because of a sudden major hemorrhage internally it may not always be known I would think.

DR. RELLER: Thank you. It is time for lunch.

The public hearing we estimate will be approximately one-half hour. Since we are breaking for lunch late we will skip the afternoon break.

We will be back on schedule, and we will have continuous discussion and then addressing the questions.

For the Committee members there is a reserved table, if you are interested in the restaurant.

We will reconvene promptly at 2 o'clock.

Thank you.

(Thereupon, at 1 p.m., a recess was taken until 2 p.m., the same day.)

P R O C E E D I N G S [2:00 p.m.]

DR. RELLER: As people gather around the table and take their seats, I want to remind members of the advisory committee to speak naturally about six to eight inches from the microphone with the red circle on. If you are too far back, it encourages vibration and we are getting excellent audio help to try to minimize that so that we have clarity of the transmission of questions and comments and discussion.

We will open this afternoon's session with an open public -- comments in an open public hearing. I would remind the speakers that if there are any current or previous financial involvement of any kind with any firm whose products are presented now or compete with those products, that they appropriately would comment on that financial involvement.

Agenda Item: Open Public Hearing

Our first speaker this afternoon in the open public hearing is Dr. William Lyons, who will speak from the podium, as will the other speakers in this session.

Dr. Lyons.

DR. LYONS: Dr. Reller, members of the advisory committee, ladies and gentlemen, I am Dr. William Lyons, a surgeon from Falls Church, Virginia. I wish to present to this gathering quite a different view of sepsis and the possibility of XIGRIS interacting with it. The view will be a lot more clinical than the statistical presentation that we have heard.

Now, I think this committee should be quite circumspect in their deliberations on the approval for this drug. I believe that there are many solid reasons why it should not approved. Now, in the first place, if XIGRIS is approved for sepsis, then it is going to be used in a great number of related entities, off label, so to speak. Immediately, one can see the possibilities for indiscriminate and excessive use.

Now, secondly, the medical establishment doesn't really understand sepsis. Take a person as prominent as John Mannick of Harvard Medical school. Only last month in The Journal of the American College of Surgeons he said that sepsis is this perplexing syndrome and he has been working on sepsis for about 20 years.

Kenneth Brigham from Vanderbilt, for example, 15 years ago, referred to the respiratory failure of sepsis as a complete mystery. I have seen nothing in the literature that he has gone back on that. Brochard and Abraham and Matthay in the past year have asked this question in publications. What is ARDS? Of course we know that is the lung failure that is part of sepsis.

Well, what is sepsis. Arthur Baue, a prolific but respected surgical writer, only this past year said that it is neither a disease nor a syndrome. Well, for heaven's sake, what is it? Well, we can say this that there is no satisfactory definition for sepsis.

We used to think that sepsis meant to the public and to the physicians alike some sort of infection. Today, the definitions, if we have -- such as they are of sepsis, do not include infection even. So, sepsis is like pornography in a way. It is very hard to define but everybody thinks they know it when they see it.

So, I don't know, that is no basis for the development of a new drug, a specific drug for a so-called specific illness that we don't really understand. From a clinical standpoint, sepsis is basically a nosocomial problem and it refers to an inflammatory process of some kind throughout our body, following an episode of trauma or major surgery or severe infection.

Perhaps half of the cases have a significant infection. Dr. Porter, though, down at the University of Virginia says whether they are infected or not, they are going to follow the same clinical course. Of course, an awful lot of these patients have DIC, as you have heard, and, furthermore, they have a tendency to be very anemic and they often need transfusions, even in the absence of bleeding.

They accumulate a great deal of fluid in their lungs, for example, and in their body in general. Finally, they do have a rise in the pulmonary vascular resistance, due to the fluid in their lungs.

Now, may I have the first slide, please?

Those who haven't seen the clinical picture of sepsis, here is the typical picture here. You can see the infiltrates centrally located in both lungs and evenly distributed. The heart is small, so it is not a congenital heart disease. Those of you who can read x-rays can see that this patient is in respiratory failure. He has an endotracheal tube in place and he would die without this support.

He also has two subclavian catheters. You can see one coming up here and another one over here probably for dialysis, for example, and, of course, the electrocardiographic electrodes.

Next slide, please.

Now, here is a typical ICU case in severe sepsis. Notice how distended he is, how full of fluid this man is. He has gained 50 pounds in just a few days before this picture was taken. He is on the ventilator. He is in complete respiratory failure. You see he is strapped down. So, I think we can assume he has got ICU psychosis, probably from a diminished cerebral profusion. His thighs are big and he has got the catheter in place and then a continuous IV.

May I have the next slide, please?

This is a patient, after discussing the problem with the doctor, who just couldn't quite convince him, maybe he couldn't convince himself what was going on with this patient. When he finished the discussion, then the patient's wife said, "But, Doctor, why does he look like the Michelin man?" Well, we learn a lot from our patients. That is why I developed that slide.

You can take the slide off, please.

Now, with regard to the generalized inflammation, what does XIGRIS do for the inflammation? Well, we have had other drugs like aspirin and ibuprofen used and they have known anti-inflammatory properties and, of course, they failed. The most powerful anti-inflammatory drug in the possession of the medical profession, cortisone, was tried some time back and it distinctly made the patients worse and increased the mortality rate.

Now, XIGRIS anti-inflammatory effect is basically unknown. It is not likely that it would even begin to approach steroids, for example, in effectiveness. XIGRIS is not an antibiotic for those cases that are infected. XIGRIS with its fibrinolytic properties is sure to complicate the care of people with sepsis and DIC, for example.

XIGRIS is not any kind of a hematinic or marrow stimulant that would improve the blood count of these people who become so anemic and often need transfusions. It is not a diuretic. It will not help the patient rid himself of the large amount of fluid that he has in his system. It does nothing, of course, to reduce the pulmonary vascular resistance and the pulmonary hypertension that so complicates the management of the blood pressure in these people with severe sepsis.

It would seem to me in going over these details that XIGRIS has very little going for it in its own right. It is a pity, too, because of the -- sepsis patients belong to a group of people in general in whom we expect recovery, the younger people in trauma and that sort of thing. So, it is a pity that we have no particular drug.

The John Mannick that I mentioned in the first part of the talk says that he -- he said that drugs are not going to be the answer and that prevention or prophylaxis is the way to control sepsis. Now, I personally think that the statistics that we have heard today are not particularly impressive.

What we have is a 6 percent reduction in the mortality rate from 31 let's say to 35. Manipulating this statistic is not going to make it any better. That is a 6 percent reduction in mortality and I submit that this is not a particularly impressive clinical number. The cohort recruited by Lilly would seem to be not as sick as the patients that usually command our serious attention in the ICU and in surgery, with a cohort control that had a mortality rate of what, 31 percent.

In general, these patients with serious sepsis have more mortality rates running much higher than that. There is no doubt that we have a very serious clinical public health problem here. There were 225,000 people a year dying of sepsis. You can see that the mortality of cancer of the breast, cancer of the prostate, AIDS and automobile accidents together do not equal the mortality rate from sepsis.

We actually have, in my opinion, a public health crisis with sepsis. Now, I think from concept to application to cost, and oh, my Lord, the cost, that XIGRIS is an unsound drug and I think I would recommend that its approval be denied.

Dr. Dellinger from Rush Medical School is quoted as having said that he knows of no academic physician who would not recommend that XIGRIS be approved. But, you know, that is part of the problem. Academia has had this problem under their aegis for the last 25 years and here we are in 2001 with no specific treatment for sepsis.

I submit that academia is in consternation over this and they are very anxious to have any kind of a new drug to try for awhile. I submit that this is not a satisfactory basis for approving a drug.

Dr. Reller.

DR. RELLER: Thank you, Dr. Lyons.

Our next speaker in the public hearing is Edward Wiginton.

MR. WIGINTON: Hello. My name is Ed Wiginton. I am a board member with the Meningitis Foundation of America and I want to thank the panel for their attention of sepsis and for the opportunity to speak before you today on behalf of the Meningitis Foundation of America.

My family was robbed of our son, Jason, by meningitis and the subsequent onset of sepsis. I have come to learn that sepsis moves quickly and knows no mercy. Jason was a happy, healthy, 14 year old boy in May 1998. He loved his younger twin brothers, the Detroit Red Wings, WWF wrestling, running track and was looking forward to starting his first summer job very soon.

One day after school he came home with what appeared to be a normal headache and flu. Nothing could have been further from the truth. The next morning, Jason's symptoms worsened. In addition to the high fever, he was now starting to bruise and develop a rash. We knew something was terribly wrong. My wife rushed Jason to the doctor's office and the time they arrived, new bruises were forming by the second.

The doctor recognized that the infection was taking over his body and rushed him to the hospital. From that point on, it went down hill fast. The doctors said that Jason had Meningococcal Septicemia. Due to the severity, the medical team decided to transport our son to a children's hospital in Detroit. Jason didn't even survive the transfer.

I can't begin to tell you what it is like to watch your child literally degenerate before your eyes and not be able to save him. Now I know first hand the devastation sepsis brings. I also know that decades have gone by without any new treatments and that physicians and families have little hope.

My wife and I have dedicated our lives to trying to prevent other parents from having to go through the ordeal we did and I am asking for your help.

This terrible disease affects hundreds of families everyday. Please do not let a day be wasted in an attempt to make new therapies, rather, new hope, available to fathers like me.

Thank you.

DR. RELLER: Thank you, Mr. Wiginton.

Our next speaker is Alvin Lever with the American College of Chest Physicians. Mr. Lever.

MR. LEVER: Thank you. I am pleased to be able to present before the FDA. First, as the executive vice president of American College of Chest Physicians, I do want to disclose that the college does receive unrestricted educational grants from Eli Lilly and our Chest Foundation also receives grants from the Lilly Foundation.

I also want to disclose, though, that I have not been paid, received any honorarium for this presentation. So, I wanted to make that clear.

I want to do two things. First of all, following our prior speaker, to give a very short personal story. My father died in an ICU of severe sepsis, multi-organ failure, 25 years ago. In that 25 years, we have not seen any increase or any improvement in decreasing the mortality from this dreaded problem.

There is a concern both of mine, as well as most of the members of the college. The American College of Chest Physicians has been long involved in this issue. I worked with Dr. Roger Bone in the development of the consensus statement that we did distribute to everybody as attachments to our documentation. It is an important issue. The statistics show for themselves and I will just say for myself that had I seen the statistics that were delivered this morning and my father presented today and I was asked for informed consent, I would definitely give it based on the benefit-to-risk ratios that I was demonstrated with today.

So, I think from that standpoint on a personal level, I would like to see this move forward. I think we need some solutions. You all know that we publish the journal Chest. We are very active in the education on sepsis and all critical care issues and had developed a consensus statement together with the Society of Critical Care Medicine.

It is also important to note that it is an ongoing problem that is constantly addressed in all of our meetings and this is as it appears one of the first opportunities to find something that might work. It is, therefore, my pleasure, though, to introduce Dr. Curtis Sessler, who is a past board member of our Board of Regents, on our education committee. He is a professor of medicine at the Virginia Commonwealth, medical director of critical care at the Medical College of Virginia, to speak on behalf of the membership and the leadership of the college.

Thank you.

DR. SESSLER: Good afternoon. I would lie to thank the FDA for the opportunity to offer a few comments on behalf of the membership of the American College of Chest Physicians. Sepsis is bad. Thank you.

You are supposed to laugh. Seriously, experts now estimate that 750,000 people in the United States will develop severe sepsis annually. These experts also estimate that more than 200,000 individuals will die as a result of this illness. It is considered to be the most common cause of death in non-cardiac ICUs.

Further, it is anticipated that by the end of the decade more than one million Americans will develop severe sepsis each year. The basic components of our management of severe sepsis have not really changed appreciably in many years. Management typically includes elimination of the infecting organism, shock resuscitation and support therapy for failing organs.

As a practicing critical care specialist for the past 16 years, I have seen my share of folks with severe sepsis and septic shock. Unfortunately, like many other clinicians, I have cared for numerous patients, who have succumbed to this illness, despite aggressive management with all available interventions and successful treatment of the underlying infection.

We know that considerable time and resources have been invested over the past several decades in search for new agents to modify the inflammatory response to infection that is thought to contribute greatly to the development of shock and organ failure. Clinical trials testing novel agents have uniformly had negative results in reducing sepsis-related mortality.

Many explanations have been offered for this apparent lack of efficacy. These include a variety of study design issues, insufficient sample size and the perhaps overly optimistic rationale that blocking the effects of a single pro-inflammatory cytokine will be sufficient. Recombinant human APC represents the first agent and new class of drugs that may improve the outcome of severe sepsis by altering its complex physiology at several levels. This combination of anti-inflammatory, anticoagulant and pro-fibrinolytic effects at the microvascular level may be important to ameliorate shock and organ dysfunction; thereby, improving the likelihood of survival.

I recently spoke not far from here on the topic of septic shock at the Washington Area Critical Care Society annual meeting. I started the discussion with a particular case presentation that I always use when I talk about septic shock, of a gentleman who developed septic shock several weeks after having undergone abdominal surgery.

I found this case to be particularly instructive for a number of different reasons. First, it is an absolutely classic presentation for septic shock with all the manifestations outlined in the definitions put forth by the consensus committee from the ACCP and the SECM.

Secondly, the patient had a good outcome, recovered fully and, third, the case is actually one of the first published cases of hospital acquired sepsis. It was published in the journal Archives of Internal Medicine in 1951. Yet, the management could very nearly pass for current day management.

One of the big exceptions was the antibiotic used was something called aureomycin. Never heard of it. But unfortunately this case does illustrate our relative lack of significant progress in sepsis management, despite the passage of in this case half a century.

In closing, the American College of Chest Physicians salutes the many scientists and clinical investigators in their ongoing search for new agents and techniques to improve outcomes of our patients, who have this common and devastating disorder. We also recognize the importance and support the role of a thorough review of the evidence for safety and efficacy so we can best use these new products.

Thank you.

DR. RELLER: Thank you, Dr. Sessler.

Our last presenter in this session is Thomas Smirniotopoulos. Dr. Smirniotopoulos.

DR. SMIRNIOTOPOULOS: Thank you for allowing me to speak. I am a practicing pulmonologist and critical care physician for 15 years in Alexandria. I also am a consultant to the U.S. Department of State for their pulmonary clinic, which I have done for that time.

My experience with sepsis dates back at least that length of time and my experience has been similar to what you just heard, that we have a difficult time managing many patients with sepsis. The mortality is very high. As you heard Dr. Lyons speak, sometimes we do see mortality as high as 50 percent. Lately, I think, the mortality is a little bit lower for our patients.

But we are constantly looking for something else to treat these people because we really are using everything that we have, every bit of our armamentarium, which we have to use we use on patients. We see patients continually deteriorating, especially when they develop multi-organ dysfunction syndrome.

We know that we are losing the battle. This new drug, activated protein C, only became available for my use after the September 11th terrorist attack, when I took care of a smoke inhalation victim from the Pentagon. This gentleman, who seemed to have simply laryngeal edema from smoke inhalation was doing fairly well and we were ready to extubate him.

However, on about the fourth day, he suddenly required 60 percent oxygen, 8 centimeters of PEET(?) and was developing diffuse ground glass interstitial infiltrates. Because I had been aware, watching this drug, waiting for it to come about, I was able to get this drug on compassionate use basis for this patient.

I have to say that I am very thankful to have been able to get this drug for this patient. He definitely benefited from this drug. I don't want to have to go through the red tape in the future that I had to go through for this patient to get this drug. I want to see this drug available. I agree with other speakers that we need to have some restraint on how this drug is used.

In our institution, we have implemented a protocol that is going to restrict the use. It is going to fairly well mimic the protocol that was used for the investigational study. Our belief is that this drug will be useful. It will be used for patients who have severe sepsis, who are going into organ failure. And I believe that it will benefit many of them. I am sure that not all of them will survive simply because of this drug.

But anything else that we can have that will help us to manage these severely ill patients, I think we have to have. I can't possibly imagine any reason why this drug shouldn't be made available. I hope it will be made available very soon. It was on September 11th that this panel, I believe, was originally going to convene and, of course, was cancelled, as have many of the other plans of many Americans been cancelled from that date.

But, hopefully, one thing that we can do here today is we can move forward with at least one weapon that we have to fight a serious problem in this country.

Thank you.

Agenda Item: Charge to the Committee, Introductions to Questions

DR. RELLER: The open public hearing is now closed and we turn to the questions and discussion. To aid in this process, I would remind the committee that our charge is not to approve or not approve anything, but rather to give our advice to the Agency in their responsibilities, including we will have some votes, but other portions, where there will be discussion that the content of the discussion as captured in the recording will be available for the Agency's consideration.

So, before we restrict the discussion to the committee members and take the votes, I want to make sure if there be any leftover questions from earlier or comments, that we get them made succinctly because thereafter things will move along better if we have the discussion within the committee itself.

Any questions to either FDA or to Lilly from committee members that we did not get to this morning? Yes, Dr. Archer.

DR. ARCHER: I had a question. I am not sure whether anybody will be able answer it or not. I just wanted to get an idea about how many sites were involved in the trial, approximately how many patients were enrolled into the protocol per site and if there is any idea of the patients that were available for entry, how many were approximately not entered into it? About what percentage of the patients with sepsis at the institutions contributing patients actually got entered into the trial?

Is there any way of knowing that data?

DR. RELLER: Dr. Macias.

DR. MACIAS: Thank you.

There were 165 sites that participated. The number of patients enrolled per site obviously varied and I think this morning we showed you an analysis by the number

-- the outcome by the number of sites, whether the sites enrolled greater than 25, greater than 20. So, it is really quite variable.

There were approximately 4,300 patients screened to enroll approximately 800, of which -- I am sorry -- 4,300 screened to enroll the 1,700 and some that were eventually randomized, of which 1,690 received drugs.

DR. RELLER: Dr. Ramirez.

DR. RAMIREZ: Just for my clarification, I understand that when the protocol was revised, the objective of the company was to decrease the number of patients with the syndrome that were not due to sepsis and the other idea was to decrease the number of patients that may have complications.

I still don't know -- what was the rationale to apply to now restrict the population just to organ disease function in the first 24 hours? What was the rationale to not to enroll patients -- the idea is for four days.

DR. MACIAS: Just to answer your question very briefly and to make a point of clarification from this morning's session, this is the cumulative mortality over time that was presented during the FDA document for all 1,690 patients. This point in time is the point at which the first patient was enrolled under the amendment and in October was the point at which the first DSMB meeting was conducted.

Lilly signed off on the protocol in March. So, Lilly was completely unaware of any of the data -- I just wanted to take a moment and assure you of that. We had not access to the treatment codes and were completely unaware of the data as we amended the protocol. It took us a few months to get the amendment set in place and then we signed off on the amendment on March 2nd.

With respect to limiting the duration of organ failure, the intent of the protocol had always been to limit the duration of organ failure to 24 hours. That was just not included in the original version of the protocol and it followed recommendations that had come out of the ibuprofen studies that Dr. Bernard had run, where at the time you meet inclusion criteria, the organ failure can be no more than 24 hours old and it just wasn't included in the original protocol. But that had always been the intent.

DR. RAMIREZ: But still the question is what is the rationale? I mean, are you thinking that if you go beyond 48 hours -- because in your comments, you mention that there was a question addressed to you regarding there was a need to indicate this drug only for 24, 48 hours, and you mentioned, well, I don't think that is going to be necessary because this drug is going to work even if the patient is at 48, 72 or four or five days.

Still, my question is what was the rationale of the company to put this exclusive criteria?

DR. MACIAS: I am going to ask Dr. Bernard to answer that question for us.

DR. BERNARD: Yes. In helping to coordinate the study and interpret the inclusion criteria, the kinds of problems we would run into would be a patient who had, say, blunt trauma to the chest in a car accident and for a week is on a ventilator and only a week later did they finally have fever and a white count. Now they meet in the 24 hour window, they meet the criteria for the study. That is not a sepsis-induced organ failure, but, yet, technically that patient under the original criteria could meet study criteria.

Do you follow what I am saying?

DR. RAMIREZ: Yes.

DR. BERNARD: So, we wanted to make sure that it was the organ failures which started the clock for getting the patient in the study, not temperature or heart rate or the surface criteria.

DR. RELLER: Dr. Wald.

DR. WALD: I wondered, did you do any separate analysis of the 970 patients that were enrolled after the amendment, either with regard to that first quartile APACHE outcome or with regard to the long term outcome at 28 days regarding home, hospital, ICU?

DR. MACIAS: We actually did look at the treatment by APACHE for patients enrolled under the amendment. In four patients enrolled under the amendment, lower mortality is observed in the Drotrecogin Alfa activated group for patients enrolled under the amended protocol.

If you would like the exact numbers, we can calculate those for you.

DR. WALD: Then with regard to the overall outcome, was that any different than for the entire group? You know, one might expect that if you were eliminating some of the patients with chronic illness, that, in fact, their 28 day outcome might have been improved, compared to placebo.

DR. MACIAS: You mean, in terms of disposition, whether they were home?

DR. WALD: Yes.

DR. MACIAS: I don't think we did that, but I think we can -- excuse me.

DR. RELLER: We will let Dr. Macias and his colleagues get that together. Give them a few minutes.

Then we will go to other questions. Yes?

DR. EICHACKER: Yes. I guess I can direct this to the FDA, but in your analysis of the data, is there a way to differentiate -- if the drug, the batch of drug was changed at the same time that the exclusion criteria were changed, is it possible to differentiate a drug effect versus an exclusion effect for the differences between the first half of the study and the second half of the study?

DR. SIEGEL: It was actually the new batches of drug were introduced at a somewhat different time at each clinical center. So, there is no single point in time, unlike, say, the protocol amendments, where they switched over from old drug to new drug. It depended on stocks and supplies at each center.

We made some efforts to try to, for example, identify the precise placebo group that was being given at any given center alongside, when they were getting the second batch of drugs and the company had some difficulty in analyzing data in that manner.

So, largely, our analyses are based on specific points in time when switchover occurred. I think the basic answer to the best of our ability to detect is that although it occurred over a period of time, the switchover in drug occurred at a point close enough in time to the change in the protocol that it would be hard to differentiate, you know, to identify patients who had experienced one change but not the other patient -- change, the numbers would so small as to not tell you anything.

So, what we wound up doing, just as looking at all the protocol changes, to see what implications they might have had and what they did have, we looked at drug changes and I think it came out in earlier conversations. Dr. Johnson can speak to this in more detail, but I do want to state and I know Lilly stated something similar, that we requested extensive types of analysis and testing.

I should note in a complex biological, you can't be sure in any lab testing that you fully know the physical, chemical nature of the product. We have seen changes occur in behavior of products that are beyond our ability to detect in physical, chemical characterization, but with that said, this product was rather extensively looked at and we were unable to detect any changes attributable to the development of the new master cell bank.

DR. RELLER: Dr. Macias.

DR. MACIAS: We don't have the specific analysis, but we are running it for you right now and will give you the patient disposition for all patients enrolled under the amended protocol in a few minutes.

DR. RELLER: Dr. Macias, if you can work out of another window, are there any things that -- questions that were asked before that you think were not adequately addressed earlier. Then we will come back to the specific issue that is being worked on.

DR. MACIAS: I would like to make one quick question, just to reiterate with the timing of the amendment that we clearly were unaware of any of the data and that the integrity of the study is absolutely intact. You can bring this slide up.

Then the other comment that I wanted to make dealt with the survival benefit in patients with less disease severity and we have looked at a whole host, as we have talked about earlier today, of measures of disease severity. The point of discussion from the Agency side tends to focus on these three up here. Yet, there are a whole host of them down here.

I just wanted to ask Dr. Mitchell Levy if he just wanted to make one brief comment about his interpretation of this particular treatment by disease severity analysis.

DR. LEVY: Well, I think what you see in terms of the problems and issues that have come up around the APACHE II score illustrates exactly why most clinicians don't use the APACHE II score in practice. The APACHE II score was established to relate to the severity and mortality prediction on the first day of the ICU and after that first day, it has not been validated and may not even be helpful.

So, if what you are doing is looking for patient population of low severity or prediction to survive, then, in fact, APACHE II score may not be -- a low APACHE II score may not be all that helpful. If you look at the subgroup of that APACHE II score, two-thirds of that group have a low IL6 level, which by another subgroup, in fact, had a survival benefit and a third had more than three organs down.

So, I don't think any critical care clinician would look at a patient with three organs down and say that that patient has a likelihood, a good likelihood, of survival. That is why I question the value of a subgroup analysis that looks at the first quartile of APACHE II score that is not calculated on the first ICU admission day.

DR. ARCHER: Can I ask one of the statisticians -- I am an statistical idiot -- these things cross one of these confidence intervals. What can we say about those intervals and that data?

DR. RELLER: Dr. O'Fallon.

DR. O'FALLON: Well, we certainly recognize that they cross one and they never made any point of the fact that they crossed one or didn't cross one. The point is that the point estimators, the little diamonds, are all to the left side of the one and many of them are right inside the confidence interval for the overall effect.

This is the worst of their several slides of this type. I basically like this method of analysis and prefer that to their claims --

DR. ARCHER: So, that is relevant then.

DR. O'FALLON: So, I think this is a relevant slide.

DR. ARCHER: All right. Thank you.

DR. RELLER: Dr. Bernard.

DR. BERNARD: I just wanted to make one comment about the operationalization of APACHE. From a clinical trialist perspective, we have been collecting APACHE scores for years. It is to try to show whether or not the groups are well-matched at baseline. That is the main purpose.

But as I have thought about how you might go about using this in clinical practice, it gets very, very difficult. The APACHE window is a moving window in these studies. So, if you look at the APACHE score today in a patient, it may be different than tomorrow. It may even be different in a couple of hours. So, this is critical in trying to give some guidance to the clinician, who is trying to figure out when to use this drug and when not to use the drug.

Are they really supposed to calculate in the package score on a moving window and mae some sense out of that because, of course, the study wasn't exactly done that way? So, just to even think about how you would design a clinical trial that would look at just this low APACHE score, well, what part of the course would you look at them? And what would you do if their score changed during the time that they were on the study, which will happen, of course?

So, this is a very difficult process to work through and think about how you would operationalize something that involved an APACHE score as part of the evaluation for treatment.

DR. RELLER: Dr. Siegel, you had something you wanted to say.

DR. SIEGEL: Just a comment on a couple of those comments. If I could refer you -- I don't know how easy it is to pull up the slides, but Lilly presented three slides on page 33 and 34 of their presentation of various -- their Slide No. 66, 67 and 68, that were all of those analyses that you just saw in terms of relative risk, based on what they term disease severity measures.

These three slides differ from that other slide in the way they are ordered. They show low and high risk, but most importantly, they also show the mortality rate. If you would look here at the placebo mortality rate in the first quartile of APACHE, it is 12 percent. There is not a single one of these predictors that identify the population anywhere close to that low a mortality, and particularly a population of that size; in fact, none even I think on any of the three slides.

If we could go to the next slide, you will see looking down the placebo column, that the lowest number there is 21 percent for one organ failure and the next slide, the lowest number there is 22 percent on the IL6. Again, that 12 percent on APACHE.

So, I think that APACHE was -- whether or not you think it is validated, APACHE was and it has been in every trial it has been used in, a very powerful predictor of mortality risk and identifier of low risk patients far better than any of these others.

Secondly, I would just take a little bit of exception at the notion that shock and organ failure were kind of cherry picked among the huge number of severity measures of those that seem to show this effect. I mean, obviously, there are some improved. There are others that could have and that didn't.

I would ask the committee to consider, though, they are not all of the same significance. Whether, for example, hepatic organ failure score of low versus high is as important as some of the others, those are, suffice to say, maybe not the only ones, but among -- organ failure and sepsis and shock have been among those most commonly and most frequently discussed and hypothesized as indicators of both outcome and treatment impact.

Yes, it is correct that they fall on the left side of the line. However, it is also correct that in the case of -- if we can go back a slide -- I don't know if that is possible, but in the case of one organ failure and we will talk about 19 1/2 versus 21.2 percent mortality, that, in fact, for both organ failure and shock, there is a supportive suggestion of a possible interaction.

DR. RELLER: Dr. Fleming.

DR. FLEMING: There are some really critically key issues here. Obviously, statistical interpretation is critical in these. I had assumed that since there are specific questions here that I would give my comments then, but would you prefer to get into this now because the sponsor and Dr. Siegel have jumped in in their interpretation?

DR. RELLER: Well, we definitely want to systematically go through all the questions and I would prefer to have the discussion in that context. But what we wanted to make sure that we got the comments from the persons who are not going to be voting out because once we get to the committee members, then to go back and forth, it just chews up a lot of time.

So, if there is something you want to ask of Lilly or CBER, now would be a good time. Otherwise, for your views and discussions, during the discussion.

DR. FLEMING: I will be delighted to follow your recommendation. I think you are right. Let's discuss them in the context of the question.

DR. RELLER: Okay. Please, go ahead, Dr. Suffredini.

DR. SUFFREDINI: If Dr. Macias could possibly address their role in the two studies and in the amendment summary, investigative sites had to contact a Vanderbilt coordinating center for questions about patient eligibility. And I wonder if you could clarify what that means in terms of from a practical point of view what are the guidelines that are being used to tell the investigator that, yes, they are eligible or they are not eligible.

DR. MACIAS: I will as Dr. Bernard to address that since he ran the coordinating center.

DR. BERNARD: There are a whole host of imponderables as you know, Tony, in critically ill patients, surgical patients, emergency admissions, where you can't deal with all the potential bleeding risks in the inclusions and exclusion criteria. So, when patients -- when clinical sites had questions about whether a patient was at an excess bleeding risk, they would call us and discuss it.

Many times it had to do with numbers, like what the pro-time was right now versus what it was before two units of fresh frozen plasma. We have all those guidelines written and we have submitted those to provide some guidance as to whether or not the patients were too far out on the coagulation cascade to be safe to be put in the study or if they were too close to surgical procedures or trauma and so forth.

DR. SUFFREDINI: I guess the concern I would have or it does bring up the question in terms of the subjective nature of this, which is a requirement in terms of is this person eligible or not in terms of applicability to a more general population? How difficult will that be in terms of determining whether someone because of your instincts or because of your subjectivity is eligible to receive the drug and to get benefit from it or not.

DR. BERNARD: Well, that is all I can tell you is that the exclusion criteria were the ones we were focusing on, not the inclusion criteria. There is some interpretation of the window. It is not that it is not objective. It is objective. But the time window is a problematic feature of all of these sepsis trials, as you know. You have been involved in many of them.

But it was more just trying to clarify the bleeding risk criteria for the sites and we had this written-in guidelines that we have submitted.

DR. RELLER: Dr. Munford, you had your hand up earlier.

DR. MUNFORD: Yes. Could we see the cumulative 28 day mortality over time figure again, please?

DR. MACIAS: Absolutely.

DR. MUNFORD: While he is producing that, this is a familiar graph and so the point that perplexes me is the following. After the amendment of the protocol and the beginning of the use of the new formulation of the drug, the outcome was clearly different. Whereas, the drug was not efficacious during the first part of this trial, which one might consider the first trial, then it did become efficacious or seemed to be efficacious in the second trial, but not for awhile.

So, beginning about the first of the year of 2000, they drug separated dramatically and progressively and I think the figure actually seems to underrepresent the efficacy of the drug, which must have been even better in order to produce those cumulative results.

The point that worries me is why did this happen. I mean, we are told that there is not a substantial difference between the product that is being used and we are told that there are subtle differences between the patient populations and who is being enrolled and so forth. But all of the sudden, something striking happened and if that had not happened, we would not be here.

My reservation is how do I know that the drug I get to give my patient is going to be the same -- have the same result that is seen in the last six months of the trial and not the result that was seen prior to that? Is there some way that we can be reassured about this? I guess that is more of a comment than a question, but if either FDA or the company has an answer, I would appreciate it.

DR. MACIAS: Dr. Munford, if I could answer the question or at least attempt to answer the question to your satisfaction, I will take the next slide, please. The way that we have tried to sort out whether or not there was an amendment of fact, was really to look at sites that enrolled under the original and the amendment, to control for the site effect.

As we stated earlier in the presentation, this is the point in time when the first patient was enrolled under the amended protocol and the last patient was enrolled under the original protocol. During this time period, this month in here, there was kind of the transition phase. I think as we look at these data, we clearly believe that there is a treatment benefit that is evident early in the course of the study before the protocol was ever amended or before there was a change in the CT material from the BDS2 to the BDS2+ material.

At this point in time, now all patients have been enrolled under the original protocol. The curves stay relatively flat, maybe float around a little bit and then continue to separate, but if you drew the line over the course of the entire trial, this is what you would see and there is a gradual decline in the placebo mortality over time. So, I think these data, if you control for the side effect, I think these data do allow you to draw conclusions that there really was a treatment benefit prior to the amendment or prior to the change.

DR. MUNFORD: I am sorry to be thick here, but what is the difference between that figure and the previous one, which --

DR. MACIAS: You can go back to the slide that is up there currently. Just leave it here. We are quite adaptive. This slide shows --

DR. MUNFORD: But you like this one better.

DR. MACIAS: This slide shows the sites that participated both under the original version of the protocol and the amended -- and this is basically a hundred of the 165 sites, but they enrolled almost 1,500 of the 1,690 patients. This allows us to try to -- at least try to attempt to control for side effect, so that we can look to see what the sites did when they were participating under the original and then what they did when they were participating under the amendment.

That is the difference, between --

DR. MUNFORD: But I guess part of my problem is that I would -- my hospital would not have been a chosen site for this study as a big academic city hospital, right?

DR. MACIAS: Why not?

DR. MUNFORD: Well, I don't think you have very many of those in the trial.

DR. MACIAS: No. There were quite a few academic medical centers in the trial.

DR. RELLER: Okay. Now, we have a line up patiently, Dr. Cross, Dr. Murray and then Dr. O'Fallon.

DR. CROSS: I wanted to talk about that figure that just disappeared.

DR. RELLER: About this figure, Alan? We will reverse the orders.

Dr. Murray is about this figure and then Dr. O'Fallon.

DR. MURRAY: I was just going to comment that the comment was made that the drug was phased in slowly at several sites, which would even further support Bob's idea that it took a few months for the more active compound to be used at enough sites for the curves to differentiate themselves more from each other. So, it is just a little disconcerting.

Has this compound been evaluated in animals to the extent that the original product was? I heard about in vitro and all sorts of analytical aspects of it, but it was also looked at in the animal models?

DR. MACIAS: Animal models of --

DR. MURRAY: Whatever the original compound -- however it was evolved -- evaluated.

DR. MACIAS: Excuse me for one second.

The BDS2+ material did not go through the same preclinical animal toxicology studies that the original material did.

DR. MURRAY: Weren't there some animal efficacy studies that --

DR. MACIAS: No. I will note, though, that pretty much by the end of August/September, all of the sites had been converted over. We can check that, but that is my memory, that by this point in time all sites are enrolling BDS+ patients and the curve stays still relatively flat.

DR. RELLER: Dr. O'Fallon.

DR. O'FALLON: I am glad to see that being a statistician is contagious here. So, we are getting some help.

This type of figure is notoriously very variable early on, where the denominators are like 1 and 2 and 3 early on. They should be very stable later on. So, the fact that the green line is still decreasing, even though we are well into a situation where if the rates were constant, we should have gotten to a stable level, I think, is the point that is being raised so that the actual efficacy of the drug seems to be improving to overwhelm the circumstances earlier in the thing.

I think that is the issue that is being raised here. Why do we not see a steady state flat line? Let's assume there is a difference between the white line and the green line. Why is the green line still decreasing?

DR. MACIAS: I think actually Dr. O'Fallon, you would see the general trend involved. No? The general trend for the placebo population is to also fall.

DR. RELLER: This we will come to in the committee discussion because what we will be -- after we get everything out on the table, then we want to hear how the committee members, the consultants, the guests, how they put this altogether. That is what we are after.

Dr. Cross.

DR. CROSS: I would like to ask either Dr. Forsythe or Dr. Siegel for some help on the material that was passed out to us earlier, which has Kaplan-Meyer(?) plots of the pre-amendment and post-amendment survival. It looks as if under the original Kaplan-Meyer process on page 46 of the handout, that is almost superimposable; whereas, there is a difference with the amendment. Yet, in the slide presentation, looking at the sensitivity analysis, which is the patients on pre-amendment not eligible under the post-amendment, looking at the difference between those two Kaplan-Meyer plots, I would have expected that those who were -- who did not meet the new criteria, would have had a higher mortality. But that was not the case.

I was just wondering how you can reconcile your sensitivity analysis with the results you presented in those two Kaplan-Meyers plots?

DR. SIEGEL: Well, the data speak for themselves. How to reconcile them, of course, is entirely speculative. The data in the -- I am not fully sure I understand the question. In terms of the sensitivity analysis in which we looked at the patients, who would have been excluded under the new protocol, the patients who would have been included under the new protocol, which is the large majority of them, showed a relative risk of .96. The overall relative risk before then was 28 percent versus 30 percent mortality or relative risk.

I am not going to calculate it, but that is why the Kaplan-Meyer looks so similar. You are looking at reaching at the end of Study 28 versus 30 percent mortality. Looking at the specific -- I think if I understand your question, the answer is that this analysis does not provide insight, if you are asking me to reconcile these, as to why these changes occurred, which is to say if you look at the group that was eligible in -- would have been eligible in the second half, if you look at them in the first half, the relative risk is .96, but in the second half, the relative risk is very low in that group and this does not -- so, it doesn't suggest that the entry criteria, at least based on this data analysis, account for the differences.

But if you are asking me how I account for them, I don't have an answer to that.

DR. RELLER: Dr. Fleming and then Dr. Chesney.

DR. FLEMING: Just a quick comment on this. There are two very important ways of looking at these data. Dr. Siegel earlier called our attention to looking at the original patients, splitting them out by those that would still have been eligible under the refinement and those that wouldn't. Those that wouldn't, as you were pointing out, still seemed to show benefit.

This is looking at a different issue on page 46 of the briefing document. This is looking at, if I am interpreting right, the original cohort and then the subsequent cohort. It clearly shows a time effect, but as Dr. Siegel would say, not a time effect that is so simply explained by the change in the eligibility criteria.

So, we are left with a very substantial change that at this point has not been explained.

DR. RELLER: Dr. Chesney.

DR. CHESNEY: This question is for the FDA. On page 3 of your presentation, the middle right hand slide, 'Serious bleeding events during the infusion period is very impressive." I probably should remember from everything we have heard and read what those serious bleeding effects were like in the post-infusion period.

Was there as striking a difference?

DR. LINDBLAD: The reason I focused on the infusion period is because I thought it was most relevant to the time frame of when the drug was effective or active, at least. There was continued bleeding events in both the placebo group and the treated groups past the infusion period, but they were fairly well balanced between the two groups. I think the overall numbers added 12 patients in one and 13 in the other so that the 28 day infusion bleeding event rate was higher but symmetrically higher for both groups.

DR. SIEGEL: I probably should ask for clarification. Please correct me if I am wrong, Dr. Lindblad. As defined in these slides, infusion period includes not only while the infusion is running, but I think what the next day to day and a half, depending on the time of day it was stopped. So, it includes essentially the period in which at least we anticipate there is sufficient drug on board to have an impact on coagulation. Whether there are long term, subtle effects that we don't know about of the drug, of course, we could only speculate.

DR. RELLER: Dr. Archer.

DR. ARCHER: I wonder if the sponsor could comment on one of the FDA slides that showed there was no difference in mortality as a function of protein C levels.

DR. MACIAS: The protein C status at baseline was the only a priori defined subgroup that we felt we might detect differential effect in. In fact, we thought people that were protein C deficient would benefit more from the administration of activate protein C. I think there is a clear treatment benefit regardless of your protein C status at baseline.

The way we rationalize that is when we administer activated protein C, we are really giving pharmacologic doses of a recombinant protein, to achieve pharmacologic concentrations. The concentration of APC in blood now is about 50 nanograms per ml. Basically, it is unmeasurable in the severe sepsis population and actually unmeasurable, at least by our assay, with the limit of detection of about 10 nanograms in healthy subjects.

So, I believe that what you are seeing is the pharmacologic benefit of achieving pharmacologic concentrations.

DR. SIEGEL: I would also like to address the question itself and something underlying the assumption of the question. That analysis you saw defined "deficient" and "not deficient." If you look at page 34 of our briefing document, there are pre-specified analyses that broke down protein C classification in more detail. Those might suggest that there are some interactions. Are those interaction P values underneath? I am not sure. There are P values underneath of 0, 0, 0, .00001 for unordered analysis of these different subgroups, but it is not a relatively straightforward situation.

In fact, the best relative risk was in those people with normal protein C and those people with the lowest protein C. So, if the question is is the evidence restricted to the population with abnormal protein, with protein C deficiency, that is what the slide we showed addressed. There is nothing to support that.

If the underlying assumption of your question as you worded it is is there any evidence suggesting that protein C might interact with drug effect? Well, there is certainly some suggestion, but in ways that, you know, would require a more complex hypotheses to try to get at.

DR. MACIAS: If it is helpful, we did the protein C analysis as a continuous variable and the interaction P value was .7.

DR. RELLER: Dr. Archer, do you have one final question before we hear the response to the functional status, the data that were being gathered by Dr. Macias? No. Okay.

Dr. Macias, the answer to the earlier query.

DR. MACIAS: I just wanted to make one quick question to help Dr. Murray and that is we did a fairly extensive pharmacokinetic analysis of the BDS2, BDS2+ data in the pivotal Phase 3 trial and the pharmacokinetics are absolutely the same between the BDS2 and BDS2 compound, just to help you with your question about had it been tested in other animals.

I believe Dr. Wald had two questions. The first one was what was the relative risk for the first APACHE quartile in patients under the amendment. The mortality for the APC group was 9.5 percent. The mortality for the placebo group was 13.9 percent and the relative risk is .68 for patients in the first APACHE quartile. That is about 250 patients.

The second question was what was the status of patient location and the distribution for home is 29 percent of patients and 29 percent of patients under the original protocol, 29 percent of patients in the placebo group, for home, 30 percent of the treated patients are home and under the amended, 31 percent of the placebo are at home and 32 percent of the treated are at home. So, the same absolute difference.

There is one additional point about the relative risk over time that might be helpful and throughout the course of the trial as we kind of alluded to, sites that didn't enroll well during the first part of the trial were discontinued. It is not that they enrolled necessarily bad patients, but they just didn't enroll any patients or enrolled one or two and those sites were discontinued.

Toward the end of the study, we actually had completed a separate, a different study with anti-inflammatory, but that protocol actually utilized the same inclusion criteria and many of those sites were actually then rolled over into our EVAV(?) study and that kind of happened in the last six months, eight months, of the trial.

That is about the only other thing that has really come up as we have looked at the mortality curves over time.

Then one last question, could we just make just one -- take a minute for Dr. Bernard just to address the pediatric question very quickly?

DR. RELLER: Final comment from Dr. Bernard and Lilly and we will have one question from Dr. Rotello and Dr. Fleming, you had a question -- no. Okay. Dr. Rotello, you had a question after this.

DR. BERNARD: Thank you, Dr. Lindblad, for your presentation. I want to make a couple points based on the questions which you asked in your presentation that were not brought out in the initial presentation.

First of all, there are no randomized control trials in pediatrics and we all agree to that. The real issue that pediatricians here can attest to is there really cannot be a randomized control trial in pediatrics with this indication.

Could I get Slide No. 86, please?

The reason is this. If we assume a 12.5 percent placebo mortality rate, that is assuming a drug effect of 20 percent relative risk reduction, an alpha two sided of .05 and even with 80 percent power, we would need a study of over 5,000 patients in order to prove in a randomized control trial that this would have an effect.

In contrast, because of the limited number of pediatric patients and the low incidence of severe sepsis. The largest trial ever done in pediatric critical care -- and this was a sepsis trial -- was 396 patients, which occurred over four years. A randomized trial cannot be done.

Even if you assume a 20 percent mortality rate, like for kids of Wiginton, who you heard testify, we would still need a trial of over 3,000 patients, which by the way if started today would end at the end or over my expected life expectancy as a human being. We are talking about trials that would occur over several decades.

I think that is why we have the wisdom in the law that is the law in the Code of Federal Regulations, which is Core Slide No. 88. Dr. Lindblad said we need to prove that they are the same in pediatrics and in adults and that is really not true. The statute says that we need to prove that they are sufficiently similar.

I would really suggest to you that these are sufficiently similar in most ways. Now, he brought up several different aspects, which he thought they were different.

Could I have Slide No. 129, please?

A major point was made in terms of organ dysfunctions. I will explain where this slide came from. The organ dysfunction data presented by the Agency was based off the inclusion criteria for the trial. The inclusion criteria for the trial were designed only to give great similarity between the adult and the pediatric study. We measured organ failure by typical organ failure indices that are known and routinely used in pediatrics that were not the same as the inclusion criteria of the trial.

This was prospectively defined. It is by Wilkinson in The Journal of Pediatrics, 1987. When you look at the data for real organ failure, the way pediatricians define it, what you see is there is great similarity. Yes, there is more cardiovascular than adults, but instead of being half the amount of respiratory organ failure, there is actually slightly more.

I would suggest that these are very, very similar. If you go to the next slide, please, if you look at the numbers who had one, two, three or four organ failures, what you see is that the pediatric patients did not have more one organ failure, but actually had almost the same or even more. In fact, the mean number of organ failures were 2.7 in pediatrics, which is very similar to that in adults.

Core Slide No. 92.

What is important is not that there are differences, but are the differences relevant. I would suggest to you, based on the data that the effect of Drotrecogin Alfa is independent of whether you have one, two, three, four organ failures. They were all within the point estimate. It is also independent of whether you have gram negative, gram positive or no culture infection.

Very importantly for pediatrics, the pathophysiology is the same. There are some differences, but the pathophysiology is the same. There is still a decrease in protein C levels, a universal increase in D dimer levels, as well as a drop in anti-thrombin III. The inflammation coagulation paradigm, the induction of innate immunity is the same.

Can I go back to back up Slide No. 92, please?

I use this slide as similarities of infection, not differences of infection. Again, Drotrecogin had an effect, whether it is gram positive, gram negative or mixed and the pediatric population is very similar. The reason you see more gram negatives is because of meningococcemia.

Pediatricians are enrolling patients who have a high risk of mortality, the kinds of sick patients that you heard about. Thirty percent of the patients in Part 2 of the study had fulminate meningococcemia. Now, again, we say is a blood stream infection. Of course, its origin is in the respiratory tract. But I would say that this is sufficiently similar and, remember, the adult Phase 3 data has results that are independent of the type of organism, which caused it.

The last couple of slides, please, No. 95.

There was a suggestion that the adverse events between the pediatric data and the adult data were the same and nothing could be further from the truth. In the adult data, all clinical manifestations -- I am sorry -- in the pediatric data, all clinical manifestations of severe sepsis were collected as adverse events. This is very different than the collection mechanisms that were done in the adult trials.

Could I have Slide 97, please?

For example, in the pediatric study, the most common adverse events were those that you see in sepsis, particularly thinking about 30 percent meningococcal disease, generalized edema, lung edema, oliguria bradycardia, hypokalemia, thrombocytopenia. These adverse events are all adverse events of severe sepsis.

Slide No. 101, please.

There was a bleeding risk in pediatric patients, but this also occurred in the patients who had the most organ dysfunction. In other words, there is no such thing as a free lunch. The sicker patients, which are more likely to benefit also had the higher risk of severe adverse events. If you look at all patients, the mean organ failures at baseline was 2.7. With SAEs(?) was 3.3. If they had a bleeding SAE, they had four organ failures in pediatrics, which is a very high number and, again, those who died were similar in the amount of organ failures.

So, there was no dissociation. There was clearly a relationship, again, on small numbers. But the sickest patients get the most adverse events and you would expect that.

Finally, Slide No. 101.

The child who, quote, died of an intracranial hemorrhage -- and, again, we could go through all four of the severe adverse events. Two of them occurred during the course of an infusion. This was documented on Day 13. Now, this may have been an intracranial hemorrhage associated with Drotrecogin Alfa. It may have been.

We do know, however, that in puerperal fulmanants with meningococcal disease, there is that baseline risk of intracranial hemorrhage, somewhere between 2 and 5 percent. That is precisely what we get when you combine the meningococcal patients and puerperal fulminants patients.

Of note, this patient had puerperal fulminants on multiple ionotropes(?) and a baseline platelet count of 26,000. Yes, that patient was at very high risk of bleeding, but also according to the data at very high risk of benefit. The drug was stopped due to anisocoria. But if there was thought to be a very large intracranial hemorrhage, I would point out one thing, that even after APC was stopped, the child was systemically heparinized for CVVH(?), which occurred for many, many days.

It was not until Study Day 13 that the intracranial hemorrhage was documented postmortem. So, this child did die with an intracranial hemorrhage. Whether it was associated with APC or not is of question. It might have been associated. It may not have been.

The child was heparinized and was at very high risk for intracranial hemorrhages, based on the baseline severity of illness. So, overall, the main point is this: The wisdom in the law is obvious. There cannot be randomized controlled pediatric trials due to numbers.

Are the populations sufficiently similar? Absolutely. The pathophysiology is extremely similar. The minor difference is in the types of organisms that cause that pathophysiology are irrelevant. The organ failure data, when you look at real pediatric organ failure scores are exact.

Thank you.

DR. RELLER: Dr. Rotello, did you have a question before we go to the questions and discussion?

DR. ROTELLO: Yes, one for the sponsor.

You have chosen to stratify your data by raw PACU(?) scores. There is not necessarily a linear correlation between a PACU score and predicted mortality. Have you calculated the predicted mortality for your group based on -- compared to actual mortality for both the study group and the placebo group?

DR. MACIAS: The way we collected the APACHE, we were not able to convert APACHE to predicted mortality. First, we didn't collect the APACHE within the first 24 hours of admission to the ICU and, second, we didn't collect the reason for ICU admission that you need to generate the coefficient that gets plugged into the equation because the intent was never to use the APACHE to predict mortality. The intent was to compare the baseline severity of illness.

DR. SENEFF: I am Mike Seneff. I am director of critical care at George Washington University. I just want to use one thing, Leo, to address that.

It has been made clear that APACHE II was not collected per the normal methodology in the study. This was referred to earlier and I just wanted to make sure that everybody was clear that this refers -- this slide looks at the first APACHE II quartile and looks at the location of the patients prior to hospitalization, not prior to randomization.

So, even though 83.5 percent of the Drotrecogin Alfa patients came in from home and 82 percent of the placebo patients came in from home, that was when they were hospitalized, not necessarily when they were randomized. So, they could have been in the hospital for five days before they got their APACHE II score. If those patients are not randomized appropriately across the two groups, that could lead to why the placebo mortality was so low in the first quartile.

So, the methodology here of this 20 year old system was not collected in this study as it was validated and calibrated in these studies that were done 20 years ago.

DR. RELLER: The time has come. I have already given the charge to the committee. We will deal with the questions and discussion related thereto.

Agenda Item: Discussion and Questions

The questions and the format are on our agenda sheets. I have been asked to read some sections as preludes to the question, so that we have this captured on the tapes, as well as serving as a focus for the discussion. I will point out where we expect discussion and those comments then being used by the Agency and I will delineate when we are going to have a vote on a specific question.

I. Patient entry criteria. Data supporting the efficacy of drotrecogin alfa (activated) were derived from a single Phase 3 randomized, placebo controlled trial of nearly 1,700 adult with severe sepsis. Treatment resulted in a significant reduction in Day 28 all cause mortality compared with placebo treated patients, 25 versus 31 percent.

Eligibility required meeting three or more SIRS criteria, at least one of five organ failure criteria and with evidence of infection. Midway through the trial, the eligibility criteria were modified to more clearly exclude patients, who had a high probability of dying from an underlying non-sepsis-related condition within the 28 day study period.

As a result of the modifications, fewer patients with malignancy, chronic APACHE II health points, those who were immunocompromised, et cetera, were enrolled.

Questions for discussion: Please comment on entry criteria and the implications of the modified criteria. Do the entry criteria define a population appropriately described as having severe sepsis?

We will go around the table of the voting members, which are all, except for FDA persons at the table, and will follow the pattern of left to right and then the next question will go the other direction.

Dr. Archer -- I am sorry -- Dr. Leggett is first.

DR. LEGGETT: In terms of comments about the entry criteria, they follow the things for SIRS and with the organ system failures in that 60 percent had four of the SIRS criteria. However, there was only one to two multi-organ system failures in 57 percent of the patients, mostly hypotension or respiratory criteria.

I note that we clinically have a very difficult time differentiating ARDS from pneumonia. I was a little concerned about that.

My feeling of the way things worked is we sort of have a sigmoid E-max curve in all of these biological functions. If you are off to the 80 percent or more most severe portion of that E-max curve or you are under the 20 percent or less, it is very difficult to show a change by the addition of a new drug. So, I think that the way they modified their protocol allowed them to move into that 20 to 80 percent relatively linear time frame of what kind of drug effects you would do and that allowed them to show a change and an improvement in outcome.

That still doesn't help us very much about real life situations of what we are going to do with that group, that is the 80 percent or above and the group that is 20 percent or below and, to me, the sponsor's interpretation is sort of at odds with the FDA's interpretation of what that lower group risk is.

We are still left without knowing what to do about that high risk group, who got kicked out of the original protocol. So, I think that, to me, even though this is called severe sepsis, it is in that middle range of severe sepsis, if you will.

DR. RELLER: Dr. Archer.

DR. ARCHER: Yes. Thank you.

I understand why the modification was made. I think it was appropriate in order to include more appropriate patients with sepsis in the protocol, but as was just said, I don't think that defines the group of patients, who are ultimately going to get this product if it is approved, which are the more severely ill patients and many of the kind that were kicked out of the study.

I don't know how to reconcile those two. I think that is part of the problem that we are going to be dealing with through the whole time talking about this product. So, I think it did define a population of patients with severe sepsis, but without underlying disease, but it may not have defined a population of patients that we see in the hospital as having severe sepsis.

DR. RELLER: This is not a vote. This is for discussion only.

Dr. Cross.

DR. CROSS: Well, clearly, patients here had satisfied entry criteria for severe sepsis. However, within that broad category, especially with the amendments made, I am not left with a good feeling of knowing whether or not there is a definable population, who would benefit from this drug.

Many of the patients who were excluded are precisely those who would be most likely treated in my large, academic center. There are those who are immunocompromised with underlying malignancy, et cetera, et cetera. So, although there were some entry criteria used here, it would not really define how it would be used in my hospital. I still am left with not knowing what were the reasons for the change halfway through the protocol, which resulted in the differences reported.

DR. RELLER: Dr. Chesney.

DR. CHESNEY: I thought the entry criteria did define a population described as having severe sepsis and I thought I heard Dr. Macias say that they didn't really change the criteria. They just tightened them up, if you will. I think the decisions or answers to the later on questions are going to be at either end of these populations, if that makes either sense, those who were excluded and those who are APACHE score II.

So, that is my comment.

DR. RELLER: Dr. Christie.

DR. CHRISTIE-SAMUELS: It seems to me that in real life that the patients that I see in ICU are much more ill than the patients that we are seeing here that were studied, based on cases, like 50, 60 percent in baseline populations. Whereas, I think the study is quite appropriate. They did everything they did with approval. The question is how do you generalize that a normal population that we take care of on a day to day basis? That would be my concern.

DR. RELLER: Dr. Ramirez.

DR. RAMIREZ: The question is to find a population with severe sepsis. That answer is clearly "yes." We just follow the recommendations that we use nowadays to define severe sepsis. The question is -- and Dr. Archer already asked this, from the pooled population of severe sepsis, not looking at inclusion criteria, but looking at the exclusion criteria, from the 100 percent of the population with severe sepsis, how many patients want to be excluded with these exclusion criteria.

The inclusion criteria is very clear to me on defined severe sepsis. The problem is that the exclusion criteria limited the number of patients with severe sepsis to a very selected group of patients. When we look at these selected group of patients, clearly defined they have severe sepsis and they were able to at least I think it was whatever to define these populations, the same population at any other time, compared with positive cultures, positive infection.

The inclusion criteria is clear. My problem is that it is too large an exclusion criteria. I have to translate these exclusion criteria to clinical practice, but I think that this is not part of the question. But there is an advantage for the patients that were defined according with the study protocol.

DR. RELLER: Dr. Ebert.

DR. EBERT: I agree with the previous panel members that suggested that the definitions are reasonable for a definition of severe sepsis, but that will have difficulty projecting these criteria onto an appropriate use for patients if and when this drug is approved.

One other addition is that there did appear to be a smaller percentage of patients in the treatment group after the protocol modifications, receiving activated protein C, who do not resuscitate patients. So, there may have been a greater emphasis on treating patients because of the smaller percentage that were do not resuscitate.

DR. RELLER: Dr. Wald.

DR. WALD: I think that the study did define an appropriate group of patients with severe sepsis. I think the challenge here will be like it is for many other drugs, for us to design and describe the patients who are most likely to benefit, rather than to use it indiscriminately and I think that is a -- we have for many other categories of drugs restrictions and we have either committees or groups that need to decide that a particular drug is indicated for a patient. I think we could handle it in the same way.

DR. RELLER: Dr. Wittner.

DR. WITTNER: I agree with what has been said before by the previous panelists. I do believe that this -- the study did define a population of patients, who should or who could benefit or might benefit from this protein C, activated protein C. The problem is who will in practice actually receive this medication is really the question in my mind, since I think some of the major criteria, at least at our hospital, such as immunosuppression, would be, I think, if those people are left out, we would lose a large percentage of the individuals in our group.

DR. RELLER: Dr. Murray.

DR. MURRAY: I agree and I think the real issues will come up in the labeling and the licensing and the criteria so that you do not set a precedent for future equivalent studies to be judged as equivalent for groups that haven't yet been shown to be efficacious.

DR. RELLER: Dr. Fleming.

DR. FLEMING: I think the entry criteria do define a population having severe sepsis in appropriate populations. The concerns that I have have been clearly articulated already. My general philosophy is clinical trials ought to be designed to obtain the relevant real world answers. Hence, we should tend toward inclusive eligibility criteria.

There should be a very close relationship between the eligibility criteria and what the label is. As I read page 2 of the executive summary, it is my sense that the sponsor is clearly asking for a wider indication and we have heard some of the specifics. We have heard specifically higher risk patients, I presume they would be restricted to higher risk for bleeding, pediatrics. So, I am particularly concerned if, in fact, there is an intention to use these data to justify a label that, in fact, is much more inclusive than what the eligibility criteria were in the trial.

DR. RELLER: Dr. O'Fallon.

DR. O'FALLON: I don't think I have anything to add to this question.

DR. RELLER: Dr. Munford.

DR. MUNFORD: Yes, I think the criteria did define a population with severe sepsis. However, it was a very narrowly defined population as others have said, may or may not extrapolate to the larger pool of patients with severe sepsis.

DR. RELLER: Dr. Rotello.

DR. ROTELLO: I agree with the previous panel members that these do define an appropriate population for sepsis. I do have issues with restricting patients' entry based on a disease process that might not result in their death during this hospital visit. I believe that that is more appropriate than the actual disease, the severity of it.

DR. RELLER: Dr. Warren.

DR. WARREN: It seems to me that since the entry criteria changed halfway through the trial and the efficacy also seemed to change, it will be difficult to come up with appropriate guidelines because if you eliminate those, such as immunosuppression, you are essentially doing a subgroup analysis, which is not really, perhaps, the best approach. On the other hand, if you include the entire group, then you are eliminating the fact that the efficacy was much greater with the second group defined.

DR. RELLER: Dr. Suffredini.

DR. SUFFREDINI: You know, my concern is that we basically have two studies. We have entry criteria for one, entry criteria for two. There are overlap certainly, but in terms of -- and they define a very sick group of patients, but in terms of generalizability, et cetera, we really are competing one against the other study, basically, and not until the second part of the study where there were many things changed, inclusion criteria, drug change, among other things, I think we have concerns about combining the two studies.

So, yes, the criteria defined a sick group of patients, but it is a moving target and I am not sure why the sponsors changed their target midway through the trial. In other words, with the knowledge that they have had with extensive clinical trial experience, why it had to be modified, I don't know the reason. I really don't -- I didn't really understand the rationale behind that.

DR. RELLER: Dr. Lilly.

DR. LILLY: I do find that infected patients with systemic inflammatory response syndrome and evidence of organ dysfunction to meet the criteria for severe sepsis. I would also like to point out that targeting this therapy to patients, who are going to die from sepsis is appropriate.

DR. RELLER: Dr. Carcillo.

DR. CARCILLO: I would like to for the most part limit my comments to the pediatric study, since that is my expertise and there really isn't enough information in the pediatric study for me to comment intelligently on this. Thank you.

DR. RELLER: Dr. Eichacker.

DR. EICHACKER: I think that the inclusion criteria in both parts of the study or in both studies do describe a sick group of septic patients. In terms of defining or in terms of assessing what the significance of the change in the exclusion criteria were, which was the big change between the first and the second part of the study, I don't know how to assess it because the agent changed also.

I don't know whether differences that we see in the second part of the study, how much of that is related to defining a group of patients better as opposed to potentially changing the drug. So, I don't know how to assess what happened to the inclusion criteria.

DR. RELLER: It seems to me we have basically two studies here and even though the study design may be appropriate in inclusion of sepsis in both groups, we have heard much that there is nothing to say that they couldn't be combined, but then we are left with quite different outcomes.

One of those two still baffles me. If they are really not so different, then why the differences? I am wondering if the first phase may not be more reflective of what physicians in intensive care units actually have to deal with.

II. Treatment effect in subgroups defined by disease severity. The reduction in mortality was not consistent against all prospectively defined patient subgroups. The data suggest that there may be a different mortality effect in less severely ill patients with better survival prognosis. Mortality in patients with the lowest APACHE score quartile was higher in the activated protein C group compared to placebo patients and a smaller treatment benefit was observed in those in the second APACHE II quartile compared with patients who were in the third and fourth quartiles, as shown in the table and the figure that is before you.

Question 2: This is for discussion and then we will come to 3, an actual recorded vote by committee member. So, for discussion.

Dr. Fleming -- we are going to come to each person.

DR. FLEMING: I am wondering if we could have permission to -- since, at least, I have withheld all statistical comments on the issue of subsets, could we -- and I don't want to answer the question yet, but would it be timely to give statistical discussion before we start answering the question? Since we have heard from Dr. Siegel, we have heard from Dr. Lindblad and we have heard from Dr. Helterbrand, but we haven't heard from the statisticians on the committee yet.

DR. RELLER: Why don't we do this? I will read the Question No. 2 and then we can have the statisticians comment go first. Would that take care of it?

DR. FLEMING: Good.

DR. RELLER: Please comment on the implications of the analysis of treatment effect and disease severity, the mortality by quartile subgroup analysis. Should the sponsor conduct further clinical controlled studies of the effects of the activated protein C in patients with severe sepsis and more favorable prognosis, lower APACHE II scores?

So, what we want here is the comment first from our biostatisticians on the committee and then how the rest of the committee members, guests see this.

Dr. Fleming, first.

DR. FLEMING: Great. Let me give -- let me ask my colleagues as I am beginning if you -- you might turn to pages 135 and 136 of the sponsor's briefing document. As you are doing so, my general sense is there is much wisdom in what we have heard from Dr. Helterbrand from the sponsor and there is much wisdom in what we have heard from Drs. Forsythe and Siegel from the FDA on this issue, the former giving us a sense to be incredibly cautious about interpreting lack of effects in these lower risk patients, the latter, the FDA commentators, raising key issues.

I think there is a lot of truth in what both of them are saying. First of all, Dr. Helterbrand is exactly right, that there is tremendous hazards to overinterpreting subgroup analyses. Far more often than not in my own sense, it is more heat than light. There is a lot more variability. You are breaking studies down into smaller numbers and the trials simply aren't designed to adequately address effects in those smaller numbers.

So, if you do have a common effect, clearly, when you look at subgroups, it is very likely that confidence intervals will overlap equality, as Dr. O'Fallon was pointing out. It is also even likely, as Dr. Helterbrand was pointing out, that you might see subgroups with point estimates that show no effect.

Conversely, however, there are those settings in which treatment effect truly does depend on patient characteristics and these subgroup analyses can be very insensitive to picking up those effects and the sponsor's argument that the APACHE II low group is something that we should ignore or not be overly concerned about because the confidence interval just barely includes a 20 percent reduction is a very insensitive test as well.

If there is, in fact, no effect, there is a very high chance, even if there is no effect, that that confidence interval will overlap a 20 percent reduction. So, where does that leave us? It leaves us possibly in a setting where it is very difficult to interpret subgroup analyses. So, should we not do them?

Well, I think that is absolutely indefensible because clearly there can be signals and there certainly be settings in which treatment effect and relative benefit to risk can depend on patient characteristics. There are a higher level of structure that we have to look into the data, though, to be able to have a better sense of separating the light from the heat.

Some of the criteria that we have looked at are strength of evidence and there has to be a lot more statistical evidence to justify a subgroup analysis; a second is biological plausibility, as Jay Siegel was talking about before lunch, and a third criterion is confirmation. What I would like to do is draw your attention to pages 135 and 136, acknowledging that these data are still from my own perspective somewhat troubling, but I do see more signal and confirmation here as was indicated in the FDA presentation. What I would like to draw your attention to is the right hand column on pages 135 and 136 because the right hand column tells you how effectively each of these covariates is really distinguishing a low risk group from a high risk group. What you will see is the vast majority of these covariates are not separating the population into groups that have more than a twofold difference in the risk of mortality.

So, indeed, Dr. Helterbrand is correct. If you look at all of the covariates that we are assessing here, then you can't simply see one subgroup that doesn't show an effect and overreact to that. But the fact of the matter is most of these covariates are not highly predictive, are not distinguishing low risk groups.

In fact, what stands out is that if you are looking on pages 135, clearly, the APACHE II covariate and the organ failure covariates are very effective in a risk gradient in establishing high risk groups and low risk groups in contrast to the IL6 on page 136, which is not nearly as effective in establishing high risk gradient and low risk gradient.

In addition, on page 4 of our handout from the FDA -- I won't call your attention -- you don't need to go to that, but, in fact, when you divide age up by decades, you also see a covariate that has substantial gradient. Interestingly, all three of those covariates that are the most effective in distinguishing truly low risk patients, i.e., those with one organ failure, those that are younger and the lowest APACHE II group do all show the same consistent signal of lesser effect.

It has been argued, ignore the APACHE II because it is not validated. I can't think of a better validation than the right hand column. Look at the actual data in the trial. In the data in the trial, did these patients by APACHE score have strikingly different survival? Much more so by APACHE than by IL6.

So, in essence, what I do see is a very -- I do see a consistent signal of validation. It doesn't prove anything to me, but it does -- this is a higher order of investigation that goes beyond Dr. Helterbrand's presentation. There is a consistent signal here that I see that, in fact, has been put forward in the FDA discussion.

Now, Question No. 2. How does this impact Question No. 2? Specifically, is there need for essentially further studies in these low risk patients. I would put forward in my own thinking several factors as I would try to answer that. First of all, what is benefit to risk?

These patients that are in the lowest APACHE II grouping have about a 12 percent mortality. Even if in truth there was a 20 percent reduction, that translates into two or three deaths per hundred people versus the six that we have been told about for the broader group. Two or three deaths is certainly relevant, but it is a smaller overall benefit. That is presuming that there is, in fact, as the sponsor would argue or as somebody who says there is a homogeneous effect would argue, that assumes that we have a 20 percent reduction.

Of course, as the data show, there is a 25 percent increase. So, there is a leap of faith there to argue that there would even be two deaths per 100 people. So, there is a smaller unmet need. It is still a significant need, but it is a smaller unmet need in that group.

Secondly, there is some consistency of evidence that in these lower risk patients, the effect may be much less. Thirdly, there is a non-trivial safety risk. That safety risk is in part represented by these SAE bleeds. There were nine of them. Four of those people died. That is a 2 percent death rate.

It may not be that those deaths with major bleeds were entirely mediated through the effect of the treatment, but if, in fact, they were substantially mediated so that you had four deaths, that is 2 percent, that would exactly offset the 2 percent benefit, which, in fact, we didn't see, but in a best case scenario, if we argued there wasn't an interaction, we would say would be there.

Finally, and I don't have a good sense about this, but the additional evidence of the 1 1/2 percent risk of intracranial bleeds that was referred to by the FDA in the more recent data also becomes more of a concern in a low risk population. The lower the risk the population, the lower the overall net benefit. Hence, the bigger concern with the level of side effect.

DR. RELLER: Thank you, Dr. Fleming.

Dr. O'Fallon. And for other members of the committee, I think we will have the comments from the statisticians and we are actually going to take on what are clearly succinct questions having to do with the need for

-- possible need for further studies and also the next question, we will have votes on both of those. So, everyone will have a chance to vote on these.

We will hear the overarching statistical comments and then anybody who has a general comment before we actually take the two votes here.

Dr. O'Fallon.

DR. O'FALLON: Dr. Fleming was nearly as eloquent as this when he came to work for me after the completion of his doctorate degree several years ago. How could I possibly add anything to that eloquent presentation?

DR. RELLER: Are there any other comments from committee members to other committee members having to do with things that they would like -- any other statistical comments? Okay.

Now we will go to Dr. Eichacker. The question that we will vote on next is as follows: Should the sponsor conduct further controlled clinical trials of the effects of drotrecogin alfa (activated) in patients with severe sepsis and a more favorable prognosis; for example, lower APACHE scores?

DR. EICHACKER: I am not going to add to what has already been said. I think that this is very important, not just because of the reasons that have been stated, but, again, I think this is a very difficult trial to interpret, given the way criteria changed and given the way drug changed. So, I think it is very important that it continue to be studied.

DR. RELLER: That is a yes?

DR. EICHACKER: That is a yes.

DR. CARCILLO: I think that the drug should be studied in a randomized controlled fashion in the low risk population of pediatrics. The reason I have been asked is because of our expertise in the epidemiology. There are, in fact, 45,000 to 47,000 cases of severe sepsis in children per year. Dr. Gerard(?) is really referring to meningococcus, which is only 1 to 2 percent of severe sepsis in the country.

DR. RELLER: Dr. Lilly.

DR. LILLY: I do not believe that there should be additional studies based on APACHE II scores, particularly not the way in which they were calculated by the sponsor. Such scores are not clinically applicable and would constitute a significant expense with very little real patient gain.

DR. RELLER: Dr. Suffredini.

DR. SUFFREDINI: My sense is that, yes, further trials should be done in terms of verifying what was seen in the second study and the issues of risk in terms of underlying risk, whether you are a high risk patient or a low risk patient needs to be examined because that is, in fact, what will be done in clinical practice.

DR. RELLER: That is a yes?

Dr. Warren.

DR. WARREN: I learned that the way to approach this is a hypothesis-driven trial and a confirmatory trial and I think that what we have seen is a hypothesis-driven trial that has given us some hypotheses. So, I believe that, yes, there should be further studies, but I am not sure they should only be in the subgroup of the lowest APACHE. I think they should be in defined groups that maybe has not been parsed out yet.

DR. RELLER: Dr. Rotello.

DR. ROTELLO: I find it very difficult to interpret the APACHE scores in the first portion of the study. You wind up having an APACHE score, which is weighted towards chronic health evaluation points. When you add the modified criteria, you eliminate some of those disease processes, which would give you chronic health evaluation points. So, that second portion is weighted toward the acute physiology of scale. I don't think they are comparable.

So, I think further studies do need to be done.

DR. RELLER: Dr. Munford.

DR. MUNFORD: Given the disparate results and the two phases of the trial and the fact that there is not an obvious explanation for these differences, I favor further study of this drug. I think that study should incorporate some estimate of disease severity, whether it is the APACHE II score or some other scoring or prognostic system. So, yes.

DR. RELLER: Dr. O'Fallon.

DR. O'FALLON: I am going to try to answer the question directly asked, in contrast to most of the answers that I have heard so far. Absolutely not. There is no evidence that the difference would be substantial enough for anything other than a huge, huge study, which would be impractical and expensive beyond belief, to make any progress. So, I do not believe that a study should be conducted on those with the APACHE II lower quartile scores, which is the way I read this.

DR. RELLER: Thank you.

Dr. Fleming.

DR. FLEMING: This is a difficult issue. I believe there is need for more data and whether or not that additional data is inclusive of higher risk or people with less favorable prognosis we will discussing later. I believe there is need for additional data in patients that are -- that have a more favorable prognosis. As Dr. O'Fallon points out, this would be an extremely significant undertaking with the very large sample size and maybe we can talk about that later. But I believe there is need for independent confirmation in more favorable prognosis patients and I would include in that the pediatric population.

DR. RELLER: Dr. Murray.

DR. MURRAY: Yes, I agree with that completely, except that I am not sure how it is going to be done and if it can be done and in the meantime, I think, yes, in an ideal world, I would love to see more data on that population, but can you really get it in any kind of reasonable fashion?

DR. RELLER: Dr. Wittner.

DR. WITTNER: I believe that further data should be acquired, especially for the lower APACHE group. I think it is necessary in view of the changes in the protocol, both in terms of the drug and in terms of the admission criteria.

DR. RELLER: Dr. Wald.

DR. WALD: I think if we were looking at just the patients who were entered into the amended protocol, we would not be having this dilemma because I think that the results were more striking and more consistent with each other. So, in that sense, I feel like this drug is getting a little bit of a bad rap for a very rocky beginning. Although the patient group was selected, again, I think that is all right. I think we have to be the judges of how we use a drug and that we can't not accept it because it is misused by others.

I think we sort of have to set the standard for the patients who are most likely to benefit. So, I feel comfortable with the drug as is if we write the right indications and I do think we need to do the specific study in pediatrics.

DR. RELLER: Dr. Ebert.

DR. EBERT: I do not feel that targeting a specific low risk population and conducting further studies in that population would be appropriate. Most of the data to date suggests that the higher risk populations are where we are seeing the greatest benefit and I agree with others that have said that this would take a very large study and may not show a difference.

DR. RELLER: Dr. Ramirez.

DR. RAMIREZ: I listened to the sponsor. I listened to the FDA and I think that I liked the consideration of the FDA that not only that decreased mortality has been clearly shown with the APACHE scores more than 25 when you have more than one organ failure with the patient in shock. I think that there is a population that we can collect in hospitalized patients with sepsis without shock with a lower APACHE score with just one organ failure to define because essentially this is going to use a statistical evaluation that still is unclear. But I agree that they are the most important indicators that relate to severity in favor of no advances in mortality who use the drug.

Then I would not only look at the APACHE but the other indicator of severity.

DR. RELLER: Dr. Christie.

DR. CHRISTIE-SAMUELS: My answer is yes. I would study patients with a more favorable prognosis. I think we would be able to get some more information, which might be a little bit more -- would be better extrapolated to children. I don't think we necessarily have to look at the APACHE. We could look at other things. We could look at severity of illness, more about the different types of organ function or malfunction and age.

Thank you.

DR. RELLER: Dr. Chesney.

DR. CHESNEY: To me, this is the crux of the issue of all the questions because I would be very reluctant to take a patient group that has a good outcome, the best possible outcome of all the groups and yet has from what I understand a worse outcome in terms of bleeding and significant adverse effects. So, I would either exclude patients who would fall into the APACHE first quartile from being able to use this drug or I would get more information.

DR. RELLER: Dr. Cross.

DR. CROSS: I appreciate the arguments on the -- that was an interesting biologic signal on the APACHE scores, but I would not do a study just to address that point, but I firmly believe we do need more data to find out whether or not the drug works. So, I think as part of a new acquisition of data, perhaps, the -- some appropriate assessment of risk might be incorporated into that kind of trial.

DR. RELLER: Dr. Archer.

DR. ARCHER: I am persuaded by the eloquence of the statisticians that it would be a waste of time and money to do answering specifically this question to go after just the APACHE I score population group. So, I would say no.

DR. RELLER: Dr. Leggett.

DR. LEGGETT: Last and probably least, a couple of points. I think the sponsor, I believe, this morning showed us a slide of how all the post hoc evaluation of subgroups then got turned -- was proven wrong on confirmatory trials. So, I think we are in the same problem here. Unless we do that confirmatory trial, we are not going to know. But I would not limit it to the low risk group as has been pointed out, because we would have to enroll too many people, which is why they amended the trial to begin with.

But I think that if we combined the covariates that were pointed out to be the ones that most differentiated the high risk, low risk and just go right down the median as was done in some of the FDA approvals, that might be a way to get patients into the trial and use smaller numbers.

In that regard of several things pointing out the same difference, the FDA on page 33 also shows that the groups that had a relative risk of less than .8 were those who had the most organ failures and they had the highest APACHE scores. So, I mean, I think there is yet more consistent data to say that we need to look at that farther.

My final question is is it possible for the FDA and the sponsors to get together after this and talk about something that disturbed me a little because I thought I heard the sponsors say there are actually three groups of patients in this trial because at the very end when we saw the drop in the mortality rate was when they started rolling in patients from other trials even though the inclusion were the same. So, now we have got three groups instead of two and that worries me.

So, I guess I think further study is needed and pediatric studies are needed.

DR. RELLER: Yes, for the record. But what I mean by "yes" is I am not convinced that there isn't a group of patients who may suffer harm rather than benefit from this drug. That may include pediatric patients, who start out with a lower risk in the first place. It think that needs to get sorted out. Whether it is sorted out by exclusion in labeling and is done postmarketing or whether it is done with additional studies that encompass the full range of risk up front, which would be my preference, there are other practical realities that have to go into that.

My worry is that there are patients we don't yet know exactly how to define that may not derive benefit.

Now, the mirror image of the Question 2 that we just had is Question 3 and we will answer it first and then we will come back to suggestions on how, depending on how the vote comes out, whether A or B is further delineated.

If licensed, should the indication for drotrecogin alfa (activated) be limited to the subset of patients with severe sepsis, who have a poorer prognosis?

Dr. Leggett.

DR. LEGGETT: Again, this is a mirror image of what I think I just tried to say and that is that we can't make any real life decisions knowingly well without -- by just doing subset analysis. So, I think that we should not just limit it to the patients with poorer prognosis.

DR. SIEGEL: I am sorry. Could you repeat that comment?

DR. LEGGETT: Like it not, the trial has been run. So, the question is we then further limit it based on just the poor prognosis, folks, we have done a post hoc analysis of subgroups. On the other hand, I think that the indications should, as closely as possible, mirror the entry criteria so that we should not expand the licensing beyond what was described in the entire group of this patient group.

DR. RELLER: We will come back to -- there will be more discussion of this issue depending on the weight of the committee, the prevailing opinion. But if this drug were licensed, should there be -- should its use be limited to those in the -- those with a poorer prognosis by some defined criteria, APACHE 2nd, 3rd, 4th quartile, et cetera?

Dr. Siegel, a little -- we are here for one purpose and that is to provide guidance to the Agency. So, you focus what you want to have answered and we will try to do the best we can.

DR. SIEGEL: Thank you.

Crafting questions is always very difficult. You never know how the discussion is going to go. I noticed on the last question, there were lots of "yeses" and several "noes," all for very different reasons. So, I wouldn't even know how to add those up in numbers.

But as far as this, of course, it is always difficult to figure out the right order to ask questions. We haven't yet asked about whether the drug should be approved because we wanted to make sure there was discussion of some of the other pertinent issues before we get there, but really what we are trying to get at here is a practical issue, which is that if this drug is approved, if we mae that decision based on our review on the advice of this committee, would the -- should the indication statement be simply severe sepsis as proposed by the company or should we somehow define a population within that that is more severe or somewhat more limited and then if so, how would that be described?

B just raises an issue that if there is a need for an indication that covers, particularly if it mentions the mortality benefit in a broad population, often it raises pragmatic issues in terms of then studying further studies in that population.

DR. RELLER: Does that help, Jim?

Basically, the way I see this question is it leaves open for the moment as to whether more studies are going to be done or recommended to get there, but, basically, given what we have now, could this be licensed as the sponsor requested or would want some constraints or focus on that to the higher risk groups? Now, how you do that, I think, is subject -- that is another issue.

Is that correct, Dr. Siegel? That is what you want?

DR. SIEGEL: That is correct. Assuming we can make a decision based on data available now to approve this, would the committee advise that it be approved as suggested for all severe sepsis or rather for some subset?

DR. RELLER: The way this question, this part, has been framed is for more severe sepsis. So, basically, a restricted approval, if approved at all. That is to try to clarify things.

Dr. Leggett.

DR. SIEGEL: We are cautious about the word "severe" simply because everybody in this trial, even those in the lowest quartile have severe sepsis as defined.

DR. RELLER: Dr. Leggett.

DR. LEGGETT: What I meant by that group is I agree if you can restrict it, but I think it is already being restricted by the lack of immunocompromise of the patients at higher risk of bleed and all that sort of thing. Patients with underlying diseases were excluded from the second half of the trial.

So, I think that in that sense, yes, it is restricted, but I do not think in the Part B that we should no longer conduct a placebo controlled trial in a population with less poor prognosis because that is exactly the question that you were trying to get at is is it really a 2 percent gain in a 1.5 percent intracranial hemorrhage.

DR. RELLER: Help Tom. He has to -- yes or a no?

DR. LEGGETT: Part A, it should be limited to the subset that they studied. I thought I had said that before. Part B is there should be further placebo controlled trials in the lower group.

DR. SIEGEL: So, an indication for the low risk group but they should be studied more.

DR. LEGGETT: Exactly. I don't think we should do the subset of only what was described as the higher -- the three and four APACHE II, greater than two organ failures. That, I think, is what we do as clinicians when we come up with our own guidelines for our own cities.

DR. RELLER: Dr. Archer.

DR. ARCHER: I think what he is trying to say is that, yes, it has to be restricted on the basis of the studies that have been completed so far. I mean, we have -- the data we have is limited by how the study was designed and I think it is going to have to be restricted to those patients who were studied. So, therefore, yes, there should be restrictions, yes, I think it should be restricted to the severest quartile, but that is going to still eliminate a lot of the sickest patients who have sepsis because they weren't studied. That is the immunocompromised patients, et cetera, et cetera.

That is the group on whom, I think, more studies are needed.

DR. SIEGEL: Let me provide a little bit of clarification about labeling here. You know, it is a general principle that people are reluctant to generalize beyond entry criteria of a trial. But I can assure you that the indication statement in the label on the way drugs are used are never strictly limited by the entry criteria. You are not likely to see an indication statement, it would certainly be pioneering, which included what the platelet levels and all other lab tests might need to be for most drugs, even those that are frequently used as an entry criteria.

I might hypothesize, although the advice of this committee might be persuasive otherwise, that it would be difficult to capture in an indication statement, per se, an indication statement for the drug, the exclusion of patients. One could conceivably write that it is contraindicated or not indicated in patients who have chronic underlying disease. We would rarely write a contraindication unless we thought there was harm and the limited data on 80 patients suggests that that is not the case.

So, we might well, since the committee is quite concerned about this, that if we approved the study, highlight that issue in the description of the clinical study. What this question is getting at -- and I know this committee is very concerned about the patients with underlying disease, but I would like to get clear advice n this question of what to do about the low risk patients, not low risk as defined by whether they had chronic, underlying disease, but low risk as defined by the various indicators, all within the group of this study.

If we approve the drug, should we write a broad indication for all severe sepsis, which I imagine would preclude studying low risk patients further or should we in some way modify that statement to indicate that it is indicated in the higher risk -- in higher risk, higher probability of poorer prognosis, poor prognosis for mortality, whatever wording one might choose or work out. So, in a way that might reflect, as clarified in the clinical study section these concerns that we have discussed about the risk predictors and the effect by risk predictor.

DR. RELLER: I am going to take the chairman's prerogative and record my vote as a possible model for how this might be tackled.

My answer is yes, because I am concerned that the lower risk group -- there is some effect of this drug and that effect is in the higher risk patients. I think that one has to reserve judgment on its utility in those assessed objectively somehow to be at lower risk in the first place. Basically, it is complementary to the first answer. So, the answer is yes, because I don't think the data allows a general approval at this time.

Dr. Archer.

DR. ARCHER: I think that is what I said earlier as well. I think that exactly mirrors what I said. Yes. Thank you.

DR. RELLER: Jim, is that the intent of where you want to go? We will let you think about it and we will get a yes or no later.

Dr. Cross.

DR. CROSS: I will follow the chairman and say yes. Having said that, I am reminded of similar types of meetings almost a decade ago with other anti-sepsis drugs, in which there was a very strong tendency not to go into the area of subgroup analysis, but rather to treat the whole population of, quote, septic-appearing patients.

But here I think that we do have -- I think there is something going on at both ends of the spectrum, both in the lower, less risky patient and in the more severe one. Furthermore, Dr. Fleming pointed out that we do have at least three separate things, which may be helpful to clinicians in the future, who may want to use this drug in terms of actually assessing degree of risk. That is the age APACHE score and organ failure.

So, I would say that, yes, a study ought to be done not just on the poor prognosis, but also on the less sick ones and trying to validate the utility at least of those three strong predictors, perhaps, of patient risk.

DR. RELLER: Thanks.

Dr. Chesney.

DR. CHESNEY: I would say yes, it should be restricted to those patients in the quartiles 2, 3 and 4, as defined by the study. I would put in the label that the group that were excluded in this study have not been studied. We really don't know what would happen in those patients that were excluded with the amended criteria.

DR. RELLER: Dr. Christie.

DR. CHRISTIE-SAMUELS: My answer is yes and definitely the patient -- that should be included are those who are in the third and fourth APACHE II quartile. Those who have laboratory evidence of DIC, those not on heparin, those who are over 50 years of age, those who have two or more organ failures and those who are in the lower risk group, there is a risk of hemorrhage. We are not sure.

DR. RELLER: Thank you.

Dr. Ramirez.

DR. RAMIREZ: My answer is yes. I just want to -- I have a problem with the question still limited to a subset of patients with severe sepsis who have a poor prognosis. We discussed that the second part of the protocol was an attempt to eliminate patients with more severe sepsis that was due to comorbidity. They were looking for patients with more severe sepsis that was due to sepsis and then their definition here of sepsis, severe sepsis, with poor prognosis, I would read this as my patient immunocompromised -- this is not the patient that we are discussing.

You can have severe sepsis due to the sepsis itself or severe sepsis due to your comorbidity and the patients with severe comorbidity were excluded, just to confuse a little that question.

DR. RELLER: Dr. Ebert.

DR. EBERT: Based on the information presented today, as well as the relative risk/benefit in the various risk groups, I would vote yes.

DR. RELLER: Dr. Wald.

DR. WALD: I think this is really tough to answer. I do feel somewhat persuaded by the data after the amendment was made that, in fact, this is not hazardous in the less severe groups. So, I would say I think more study is needed, but for the moment, I would, I think, recommend its use in all patients -- patients in severe sepsis who were studied.

DR. RELLER: Dr. Wittner.

DR. WITTNER: Who am I to argue with the group. I do believe that the protein C should be used with individuals in severe sepsis, who have the poorer prognosis, but I think more studies really need to be done on individuals who were in the late exclusion group, since I think these are a major component who we see in the ICUs.

DR. RELLER: Dr. Murray.

DR. MURRAY: I am going to vote no in terms of the restriction with respect to the APACHE, but I think that some sort of modifying statement, disclaimer, black box, something needs to be said that in that group, the data are -- cannot make a decision that there are data to the contrary.

But, yes, in terms of the exclusions for the patients that were not studied. I think that those -- there needs to be some continued exclusions on those and if this is a very expensive drug, I think that hospitals, HMOs and managing corporations -- it may be like enrolling a patient on a study to use this drug in someone. One may have to, indeed, go through a lengthy form. So, I think that there will be -- should be and probably will be other exclusions.

DR. RELLER: Dr. Fleming.

DR. FLEMING: If this is licensed, I would agree that there should be -- that the indication should be limited restricting to the -- ruling out those more seriously ill patients that were excluded by the eligibility criteria and also the patients that have the more favorable prognosis. I don't think the question specifically ties us down to whether that is the first quartile of the APACHE. I think that is something that we -- that I would advise be considered very carefully by the FDA, but I do believe that if licensed now, the indication should be limited to exclude those patients that would have the most favorable prognosis.

DR. O'FALLON: I also believe that it should be restricted. So, I am voting yes.

DR. RELLER: Dr. Munford.

DR. MUNFORD: I am going to be a contrarian, I suppose. If I would answer the question as written, that is, if licensed, should the drug be limited, I would say no. The reason is that -- it is a historical reason and I think that we need to be careful not to establish a double standard.

For all the previous trials in this field, the drugs have seemed like they were probably going to work, but not quite and subgroup analysis was done to try to figure out the groups in which the drug did work. Then subsequent trials were designed to test the hypothesis generated from the first trial and as Dr. Opal showed us this morning, no drug in this field has reproducibly protected patients with severe sepsis.

Here the situation is different. It looks like the drug may have worked and we are using subgroup analysis to try to figure out who it didn't work in. I don't think that is quite fair. I think if the drug is licensed, I think it needs to be licensed for use in essentially patients in whom it was tested and regardless of subgroup analysis, but I would emphasize two points.

One is I strongly favor more studies of this drug and, secondly, that if it is licensed, I strongly favor limiting the use of the drug to the patient population in which it was tested and not a more general license.

DR. RELLER: Dr. Rotello.

DR. ROTELLO: I also vote no. I believe that if it is licensed, it should not be restricted just for severe sepsis. I think basing a use of something on prognosis puts too much variability into the individual clinician's hands to deal with. Also, in those patients who have mild sepsis, there will be a subset of those who will progress to severe sepsis without any way to predict that. If you wait to treat those patients until they become severe, you have given them a much worse chance of survival.

DR. RELLER: Dr. Warren.

DR. WARREN: I also would vote no for very much the similar reasons as Dr. Munford has mentioned, that I think this was a hypothesis-driven trial ultimately. I would also like to point out that there are a lot of different subgroups that are similar. For instance, the drug didn't seem to work as well in the surgical patients as the medical patients and how will we decide based on this one particular group of APACHE as opposed to all of the other subgroups that we haven't even gotten to. Why this group? Why not exclude surgical patients? Why not exclude age?

So, for those reasons I vote no. But I do think there should be more studies.

DR. RELLER: Dr. Suffredini.

DR. SUFFREDINI: To the first part, I would vote yes. Yes, it should be limited and I think that while we talk about subgroup analysis, there is at least compelling information that age, organ failure, the severity of illness, as reflected by a score really makes your risk/ benefit ratio, it will vary with what your underlying problems are.

So, yes, I would limit it and to the Part B, I would yes and it should be restricted to patients with much poorer prognosis and we should study more of it. I mean, we need more information.

DR. RELLER: Dr. Lilly.

DR. LILLY: I agree with the sentiments of others that there should be better clinical science in this area. I vote no. I respectfully point out that the trial itself demonstrated that individuals who met these entry criteria have a substantial mortality benefit. The trial was not designed and I do not believe provides informative information on subgroup analysis.

Therefore, I think to put the overinterpretation in front of the interpretation is a mistake and that the labeling should allow patients who meet the entry criteria of this trial to have access to the drug.

DR. RELLER: Thank you, Dr. Lilly.

Dr. Carcillo.

DR. CARCILLO: I vote that in patient groups where there has been a randomized controlled trial done that there not be any limitations in its labeling. However, if the FDA were to decide to approve the drug in a population where a randomized control trial was not done, then I think that it should be expected that the possibility of increased intracranial hemorrhage should be discussed with the patient or the patient's family before prescription.

DR. EICHACKER: Again, to sound like a broken record, I look on this as two studies. We actually haven't been shown data or we have not been shown these subgroups for the two different parts of the study. So, I am not even sure we can say what the relationship is between severity and the effect of the drug, although I believe there probably is such an influence. I would have to say yes, but it is really not having seen the data that provides a basis for that answer.

DR. RELLER: Thank you.

The subparts A and B, most members have already commented on those. Is there any additional comment from any committee member on the A and B components of this question?

Like the sepsis syndrome that is very complicated, these questions and their interpretation, but I think we are actually getting there and we are moving in the right direction of getting things out on the table and we will be coming to a bottom line later.

Okay. Now, III, the treatment effect in patients with disseminated intravascular coagulation. Activated protein C has anti-thrombotic and pro-fibrinolytic analytic properties that may contribute to its mortality effects in patients with severe sepsis. Thus, one might see different effects in patients with sepsis who have DIC from those who do not. The majority of patients in the trial, more than 90 percent, had evidence -- and this has been brought up what the definition is -- let's leave it at evidence of altered coagulation -- at study entry, as defined by the presence of two or more of the following laboratory findings that are listed for you.

Now, of note, two individuals did not have altered coagulation at baseline and 113 in whom insufficient laboratory data were available to determine their status. There was little suggestion of treatment effect. So, where we want to go now is should Drotrecogin Alfa (activated) be further evaluated in controlled studies in patients with severe sepsis, who do not have laboratory evidence of DIC?

Dr. Siegel, could you clarify for us if -- we want something so that we don't get into a protracted debate on what constitutes DIC. Could you give us a standard or some definition or should we phrase it in terms of what was actually included in this trial?

DR. SIEGEL: I am glad you asked for that clarification. The question as became clear in the discussion earlier and in the review in recent weeks. What was called DIC, at least for the purpose of this analysis, is not even by rigor of lab criteria and certainly by clinical criteria, necessarily what would normally be diagnosed or even in a textbook definition of DIC.

The question we are basically asking with Question No. 4 is given that there is only 115 patients in the -- who didn't meet these criteria and even in those patients, we don't know that they didn't meet them, we -- in all but two of them, simply the lab tests were not available and given the concept raised by several speakers before, the drugs should be indicated for use in patients who are studied. The question is is there a population using these definitions, who don't meet these definitions, who either need to be studied or need to be excluded or I think one of the questions is do they really exist in significant numbers. That is something we have been trying to get at.

So, once again, I may not have made that black and white, but I guess the simple answer to your question is using the definitions that were used, is there a need for further study of people who didn't meet that criteria since so few were studied here or is it just not that important an issue?

DR. RELLER: Dr. Eichacker, comment, please.

DR. EICHACKER: I would say yes. I think that these reflect -- again, they are part of -- they reflect the severity of infection and to the extent, I believe, that the influence of severity of infection has to be studied here and this would be patients who don't have abnormalities of these parameters probably have very mild sepsis since I think that these generally reflect evolving sepsis.

So, I think, yes, they should be studied.

DR. RELLER: Dr. Carcillo.

DR. CARCILLO: I defer.

DR. RELLER: Dr. Lilly.

DR. LILLY: While more information in this group would be very desirable, their rarity makes study impractical.

DR. RELLER: Dr. Suffredini.

DR. SUFFREDINI: I would agree actually. I think this is a rare entity, that anyone who is infected will not have at least two of these four criteria. So, I think it is not an important question.

DR. RELLER: Dr. Warren.

DR. WARREN: I would agree. It is not an important question. I would point out, though, that we don't know whether this drug only works in the coagulation box. So, I think in future studies if there are some, it should studied -- there should not be a question. It should be studied in all patients. It shouldn't be necessarily an entry criteria.

DR. RELLER: Dr. Rotello.

DR. ROTELLO: I agree. I don't think any further evaluations are necessary. The rarity would make it impractical.

DR. RELLER: DR. Munford.

DR. MUNFORD: I don't think it deserves further study. I also -- I think we heard from the company this morning that almost all these unknown people simply didn't have measurements done. So, they very well may have met these criteria, too. So, I don't think it is a big issue.

DR. RELLER: Dr. O'Fallon.

DR. O'FALLON: The rarity makes it impossible and, therefore, they should be allowed to be treated in answering this question.

DR. RELLER: Dr. Fleming.

DR. FLEMING: I think what I am about to say has already just been said, but I believe it is -- these small numbers of people have unknown status, which I see as very different from having clear documentation of a different effect in a known cohort of patients without DIC.

My sense is there isn't sufficient evidence here to be restrictive in any way in a decision about approval. However, if future studies are done, as some of us have suggested would be useful, gathering additional data about this would certainly be useful as well if it is already planned to do future studies.

DR. RELLER: Thank you.

Dr. Murray.

DR. MURRAY: I agree. Nothing additional.

DR. WITTNER: Likewise. Nothing additional.

DR. RELLER: Wald.

DR. WALD: I agree.

DR. RELLER: I agree.

DR. EBERT: I also agree.

DR. RAMIREZ: I think that it won't be necessary. Now, the question is if these patients find out they don't have DIC according to the criteria or we don't know if they have DIC? What is the --

DR. SIEGEL: 113 of these 115 patients didn't have all the lab tests drawn. There have been some -- they were required by entry. So, it may well be that they are a random population. There has been some speculation that the lab tests are more likely to be drawn in people who are, for example, showing bleeding evidence of DIC. So, they may be less likely to have DIC, but in the most part, we just don't know.

DR. RAMIREZ: Because at the same time almost -- the low risk, low severity patients and then these patients -- we identified these patients low severity, also patients with no DIC and we agree that by definition if you have severe sepsis, you have to have low inflammatory activity. Then the lack of DIC can be a definition of the patient's non-severe sepsis. We are looking at the low severity patient with APACHE or lack of shock or just one organ failure. It may be that the definition of severe sepsis that we use in one organ failure is too sensitive and the patients don't have DIC because they don't have severe sepsis.

I agree that these need to be probably further studied, but not specific for indication for the drug.

DR. RELLER: Dr. Christie.

DR. CHRISTIE-SAMUELS: No. Rarity is impractical. However, in uncontrolled studies, yes.

DR. RELLER: Thank you.

Dr. Chesney.

DR. CHESNEY: I think they don't need to be further studied because they would fall in the low risk group and I would exclude the APACHE I from the indications.

DR. CROSS: I concur not to study them.

DR. RELLER: Dr. Archer.

DR. ARCHER: I agree.

DR. RELLER: Dr. Leggett.

DR. LEGGETT: I concur not to further study it and I would like to point out that the times I have been here, this committee has never been entirely inherently incoherent in its responses to different questions.

DR. RELLER: Dr. Siegel, do you want any comment from the committee members regarding a future -- when future studies are done of a different approach from what was done in terms of definition of altered coagulation? In other words is there a group of patients with a strict definition that would be generally acceptable for DIC that would be worthy of inclusion in future trials? Or do you have a sense of what you need to -- for this question?

DR. SIEGEL: At the heart of asking this question was, in fact, did they use the right definitions and did they treat a typical sepsis population or did they treat one that has a lot more coagulopathy than your typical population? I think those questions were asked.

As to how best to design future studies with respect to coagulopathy, I could imagine quite a lot of fruitful discussion of that issue with the expertise at this table that it is perhaps not a critical question to the decisions we are facing.

My inclination on your question would be to proceed through the rest of the questions and open the floor at the end for any further advice that any members of the committee would like to give on that or other related topics.

DR. RELLER: Thank you.

IV. Treatment effect and heparin use. Many patients received low dose heparin for prophylaxis of DVT. Both heparin and Drotrecogin Alfa (activated) have anti-thrombotic effects. Mortality was lower in patients who received the compound than in those receiving placebo regardless of whether low dose heparin was used, but the treatment effect was several fold greater in patients not on low dose heparin, as shown in the table.

If the differences in activated protein C in patients on low dose heparin, 3 to 4 percent, and patients not on low dose heparin, 9 to 15 percent, are real, then the question of whether to administer low dose heparin when using this compound could be very important. Potential mechanisms by which low dose heparin might influence the Drotrecogin Alfa (activated) effect include the low dose heparin may provide some benefits, leaving less residual benefit for the addition of the activated protein C and low dose heparin might abrogate some of the benefits of Drotrecogin Alfa (activated) perhaps through synergistic toxicity.

Question -- and we will vote on this -- should more studies be done addressing whether and how low dose heparin should be used in patients receiving Drotrecogin Alfa (activated)?

Dr. Leggett.

DR. LEGGETT: First, a point of clarification. Is this before consideration of licensure or afterwards or does it matter?

DR. SIEGEL: I think the question would be valid either way. Of course, if it is broadly licensed without further randomized studies -- no, I take that back. The studies we have potentially been looking at here are studies in which -- I mean, it could be worked into a controlled study but it could also be done in a study where all patients get APC and you randomize to whether to give low dose heparin or not.

So, this question would be fully relevant either way.

DR. LEGGETT: That was exactly where I was going because if I understood things correctly, this trial was not designed to look at the effect of low dose heparin and by doing it, we are once again going into this post hoc analysis, which bothers me.

There are other things that could be looked at, though, in the future and I think there could be a randomized trial, but, you know, if somebody comes up with protein S, can we throw protein S in there? You know, there are a lot of questions that could be talked about later, but in the view of whether this needs to be done before licensure is decided upon by you guys, I do not think it is necessary.

But the broader question, is this an important question to look at is what we are trying to --

DR. SIEGEL: I think so.

DR. RELLER: Dr. Archer.

DR. ARCHER: I think this is one thing that can be studied and should. I think the idea of a trial, everybody gets protein C and then you randomize them to get low dose heparin. It would be a good trial. I mean, this is a common therapy in these patients and I think it really does need to be studied. So, I would strongly say yes.

DR. RELLER: Dr. Cross.

DR. CROSS: I think it is an important question that ought to be studied, but not limiting the licensure issue.

DR. RELLER: Dr. Chesney.

DR. CHESNEY: I agree totally. I don't think it should limit licensure, but I think it could be studied after.

DR. RELLER: Dr. Christie.

DR. CHRISTIE-SAMUELS: I agree.

DR. RAMIREZ: Yes, I agree. It needs to be studied, but even though -- let me ask one question. Is the activated -- because I imagine that a low dose heparin in all these patients to prevent DVT and is the activated protein C prevent DVT by itself during infusion?

DR. RELLER: Dr. Macias.

The difference between DVT and the active compound at -- and placebo was 2 and 3 percent.

DR. MACIAS: At 3 percent of the placebo group, 2 percent in the Drotrecogin Alfa (activated) group.

DR. RAMIREZ: The placebo was receiving the low dose heparin?

DR. MACIAS: That analysis is for all patients, not split by those being treated or not being treated.

DR. RAMIREZ: Because I would not have spent too much money if I have it on anticoagulation and then I don't know if low dose heparin may be non-beneficial. I would just stop the low dose heparin while I give the drug and try to obtain this benefit without doing any further study.

DR. RELLER: Thank you, Dr. Ramirez.

Dr. Ebert.

DR. EBERT: I don't think that this is important for approval. However, it is something that we can randomize in a subsequent study. I think the results to date are compelling.

DR. RELLER: Dr. Wald.

DR. WALD: I agree.

DR. RELLER: Dr. Wittner.

DR. WITTNER: I believe it should be studied but it should not limit the approval of the drug.

DR. RELLER: Dr. Murray.

DR. MURRAY: Well, there is not even a hint of a benefit and, if anything, there might be a hint of an interference. So, I wouldn't let it hold up licensure. I am not sure it should be the sponsor's obligation to study that effect. It might be, perhaps, an NIH-driven study. But I am not -- looking at the data here, it looks like it would take a huge trial based on these data, huge, huge.

DR. RELLER: Dr. Fleming.

DR. FLEMING: As we look at this table of the contrast between the on heparin and not on heparin, where the distinction is greatest is during infusion. I strongly concur with the sponsor's comments that such analyses have to be viewed with great caution. Not only is it the subset issue, these are improper subgroups and it is extraordinarily difficult to interpret results such as that. So, I look in particular at the at baseline contrasts and agree with what I have heard from my colleagues. I don't see this as data that would alter licensure or labeling.

Certainly, however, if this were to be approved, subsequent studies that would explore refining the optimal way to use heparin in conjunction could certainly be done.

DR. RELLER: Dr. O'Fallon.

DR. O'FALLON: I think that is the critical point. Not necessary for licensure. As to whether other studies are necessary, I am not at all convinced.

DR. RELLER: Dr. Munford.

DR. MUNFORD: I would like to see this studied further, just as I would like to see possible interaction between APC and glucocorticoids studied in more detail, but I don't think that should influence the licensure.

DR. RELLER: Dr. Rotello.

DR. ROTELLO: I would also like to see this studied further but don't think it should affect licensure.

DR. RELLER: Dr. Warren.

DR. WARREN: I agree.

DR. RELLER: Dr. Suffredini.

DR. SUFFREDINI: I don't think it should limit the decision on licensure, but I would just bring, at least as I understood it, we have information based upon exposure to heparin, not total doses and a mixture of fractionated and unfractionated heparin were provided in the study. They were not designated. So, it is yet another confounding factor that needs to be looked at certainly in future studies.

So, I will leave it at that.

DR. RELLER: Thank you.

Dr. Lilly.

DR. LILLY: Because knowing whether there is an antagonistic interaction between these two drugs is so important, I believe that additional studies should be done, but that it should not hold up licensure of the drug.

DR. RELLER: Dr. Carcillo.

DR. CARCILLO: I would agree with the majority opinion.

DR. RELLER: Dr. Eichacker.

DR. EICHACKER: I agree.

DR. RELLER: Also.

Therapeutic heparin in sepsis-related DIC is controversial. I won't read through the entire paragraph. Were Drotrecogin Alfa (activated) approved, clinicians treating patients with severe sepsis and DIC will face a therapy choice of activated protein C or therapeutic heparin, but not both due to bleeding risks? Please discuss how such a choice might be made. Are there situations in which heparin use rather than activated protein C might be appropriate? Is there a need for further studies? If so, what type of studies would best address this question?

This is for discussion, comment.

Dr. Eichacker, your views. We will go around the table.

DR. EICHACKER: The issue about what the definition of DIC is here now becomes very important. DIC as it has been defined for the study is not something that someone would typically treat with therapeutic heparin. The use of therapeutic heparin in DIC is controversial when you meet the full criteria, I think.

So, at this point, I haven't seen any data to show -- I mean, there is no data that we have seen here looking at therapeutic heparin versus the effects of APC in true DIC, where you have fragmented red blood cells, a falling fibrinogen and the other criteria that go into a true diagnosis of DIC. I have seen no data to say whether APC would be the preferable to therapeutic heparin. You would have to do a trial. Therapeutic heparin is the standard therapy and if one is referring to other kinds of conditions, such as thrombophlebitis, et cetera, where you were making a decision between activated protein C and therapeutic heparin, again, at this time, therapeutic heparin is the standard and you would really have to compare the drug to that in a study if you were to answer the question.

DR. RELLER: Dr. Carcillo.

DR. CARCILLO: I defer.

DR. RELLER: Dr. Lilly.

DR. LILLY: I would prefer a clinical trial to an observational study.

DR. RELLER: Dr. Suffredini.

DR. SUFFREDINI: I think the concern about increased bleed with therapeutic heparin and either concomitant therapy or doing a tradeoff is going to require that you address -- of course, more data is always important to have, but, you know, with the current presentation that we have and the materials that we had, the use of transfusions, fresh blood from plasma, platelets, PRBCs, I mean, all those were increased in patients who were not on therapeutic heparin who received APC. It is a major concern in terms of bleeding risk and I think it has to be studied in a prospective fashion. We could do these tradeoffs.

DR. RELLER: Dr. Warren.

DR. WARREN: I essentially agree with that. I think, though, if the drug is licensed and a patient were to develop an absolute indication for therapeutic heparin, such as say a pulmonary embollist, then, in fact, one would need to stop the APC and use heparin because that is the treatment of choice.

DR. RELLER: Dr. Rotello.

DR. ROTELLO: I agree further studies need to be done. I feel that if you develop a condition that requires therapeutic heparin, the mortality of that condition weighed against the mortality of the acute sepsis needs to be considered before you can make a decision which drug to use.

DR. RELLER: Dr. Munford.

DR. MUNFORD: I agree. Nothing to add.

DR. RELLER: Dr. O'Fallon.

DR. O'FALLON: I have certainly heard many indications that suggest that this would be an extraordinarily complicated study to design, but perhaps one needs to be done.

DR. RELLER: Dr. Fleming.

DR. FLEMING: I defer.

DR. RELLER: Dr. Murray.

DR. MURRAY: I defer.

DR. RELLER: Dr. Wittner.

DR. WITTNER: I defer.

DR. RELLER: Wald.

DR. WALD: I defer.

DR. RELLER: Ebert.

DR. EBERT: I agree that a controlled study would be needed. Anything else would be speculative at this point.

DR. RELLER: Dr. Ramirez.

DR. RAMIREZ: How such a choice may be made and in a case of DIC, heparin will at least be controversial and we also have to wonder that activated protein C may be a better therapy for DIC than heparin itself because we are treating the cause of what is going to produce DIC. If I have a patient with sepsis and DIC and if I have the two choices, at this moment, I would consider a drug that probably is going to resolve the etiology.

Now, when we are looking at pulmonary embolism, it is a totally different story. Then these will be a definition that we have to consider what happened with the mortality of pulmonary embolism. For DIC, how the choice to be made, I will consider probably to stopping the heparin.

DR. RELLER: Dr. Christie.

DR. CHRISTIE-SAMUELS: Yes, I think an ICT should be done with regards to comparing heparin to APC in DIC truly defined.

DR. RELLER: Dr. Chesney.

DR. CHESNEY: I defer.

DR. RELLER: Cross.

DR. CROSS: I think patients who -- well, I think, you know, the interaction has to be studied, but the patients who have an absolute indication for heparin, the physician will have to just balance the relative risk of not being on heparin versus being on the APC for sepsis.

DR. SIEGEL: I just want to make sure I understand so I understand the advice. A couple of people have said where there is an absolute or clear cut indication for heparin, one will have to balance the relative roles. Nobody is assuming that clinical DIC per se is such an indication. You are talking about pulmonary embolists or whatever and that is sort of what we wanted -- right. Okay.

DR. RELLER: Dr. Archer.

DR. ARCHER: Nothing.

DR. RELLER: Dr. Leggett.

DR. LEGGETT: Nothing to add.

DR. RELLER: The next two questions have to do with safety and they are for discussion questions. The overall assessment of the safety versus the benefit will come in the following question No. 10. So, for questions 8 and 9, a brief introduction.

Patients with severe sepsis were -- this is under Roman numeral V -- patients with severe sepsis, who were at increased risk for bleeding or excluded from the Phase 3 trial, including all of those in bullets listed. The number of patients experiencing serious adverse bleeding -- serious bleeding adverse effects during the Phase 3 study was 3.5 percent and those receiving Drotrecogin Alfa (activated) in 2 percent and those receiving placebo.

Then it goes on with further details. The essence we want to hear you comment on is given that the bleeding events are greatest during the infusion time, should further dose optimization studies be conducted; for example, fusion duration with the goal to minimize major bleeds while preserving efficacy?

Then, if licensed, should Drotrecogin Alfa be contraindicated in patients with conditions that led to exclusion from the Phase 3 trial because of high risk for bleeding? What if any other characteristics of patients at high risk for bleeding should be specifically identified in the product labeling?

So, what we could do here is go around, and Dr. Leggett starting, is say, one, do you need more studies for dosing and then what sort of constraints if it were licensed, would you put into the labeling regarding exclusion of patients at higher risk for bleeding?

Dr. Leggett.

DR. LEGGETT: Regarding No. 8, I do not think further optimization studies are necessary for licensing, but I would hope that people would continue to look at this, just as we started off with huge doses of AZT, which we no longer use because we found they were too toxic.

In terms of No. 9, I think as I stated before that the contraindication should be the same as it was in the Phase 3 trial for the high risk of bleeding. I cannot think of any other characteristics off the top of my head for -- to labeling because the person with the thrombocytopenia as the example is given is possibly the one who has got the most DIC for which the drug is probably going to work the best.

DR. RELLER: Thank you.

DR. ARCHER: I agree with what was just said. It seems to me that dose optimization has been done, at least to the extent that it could be. I don't think you should hold up licensing. I think another study looking at more dosing and bleeding would be a very difficult study to do and it should be looked at.

I think that if licensed, it should have the indications as we have said before that were done in the trials basically. Those patients excluded would have to be excluded in the label.

DR. RELLER: Dr. Cross.

DR. CROSS: I think the rationale for the dose presented seemed reasonable, but I also agree it would be very, very difficult to actually do the study suggested, but I think more information afterwards would certainly be useful. I think the exclusions ought to be those that were included in the study and I can't think at the time of any further characteristics of a high risk patient.

DR. RELLER: Dr. Chesney.

DR. CHESNEY: I concur with the previous speakers.

DR. RELLER: Dr. Christie.

DR. CHRISTIE-SAMUELS: No. I would address the issues of the labeling. I wouldn't do any definitive extra studies.

DR. RELLER: Dr. Ramirez.

DR. RAMIREZ: I agree. No extra studies. High rates for bleeding, somehow we need to identify -- the drug not to be used. These also bring the point in this drug is that we may use a drug, if we use it for the wrong indication, we may have a malpractice litigation because I am not aware of any of the antibiotics that we use for sepsis or any drug that usually we have a some side effect that may kill a patient. This is going to be something that -- I am sure the physician is going to be willing to look into the exclusion criteria because you may be using something that may damage the patient.

DR. RELLER: Thank you.

Dr. Ebert.

DR. EBERT: I don't believe such studies will be necessary for approval. However, there is a pretty impressive inter-individual variation in the elimination of the drug. In the Phase 2 studies, the investigators did have the option of reducing the dose in patients who had an elevated APTT, whole blood APTT.

I am not sure whether the patients in the Phase 3 study, who experienced bleeding had an elevated APTT or not, but certainly there I think there is no question that that potentially might be something to look at as far as dose modification.

DR. RELLER: Dr. Wald.

DR. WALD: I don't believe any further study is required for optimization, but I do believe that all of the exclusion criteria with regard to coagulopathy should be observed here.

DR. MURRAY: I agree with Dr. Wald.

DR. RELLER: Dr. Murray.

DR. MURRAY: I agree except I guess my concern is the exclusion for the platelets of less than 30,000, as was pointed out earlier, that might actually be of benefit. So, I would like to somehow get -- have some flexibility there perhaps. Perhaps contraindication is too strong for some of the exclusions, particularly that one.

DR. RELLER: Dr. Fleming.

DR. FLEMING: Clearly, it is an important issue to optimize benefit to risk with proper dose and schedule. With moderate sample sizes, we can probably look at how refinements in dose and schedule might alter safety. But, clearly, it will also potentially alter efficacy and then you are into very large scale trials. So, we are almost starting over again. We did have the data from the EVAA. It is a small Phase 2 study, but I found it interesting that at each of the dose levels, there was an indication of higher efficacy with the longer infusion period.

So, there is some -- there was some basis for them going to the schedule that they had chosen and I would anticipate that if we were able to reduce the bleeding, I would worry about in turn whether that might be reducing efficacy and it would be an extraordinarily hard thing then to address without doing another large trial.

The next question, No. 9, certainly, yes, I would say if licensed, the agent should be contraindicated in those conditions that were related to high risk for bleeding.

DR. RELLER: Dr. O'Fallon.

DR. O'FALLON: I agree.

DR. RELLER: Dr. Munford.

DR. MUNFORD: I agree.

DR. RELLER: Rotello.

DR. ROTELLO: I agree.

DR. RELLER: Dr. Warren.

DR. WARREN: I agree with Question 8. For Question 9, I would only raise a point that a lot of people are now being treated with steroids, both for ARDS and also there was actually a French trial suggesting it may be helpful, low dose steroids. Since a lot of the bleeding was due to GI bleeding, I think if it is licensed, it should be commented on and if it is not licensed, I think that should definitely be part of another trial because I think that (a) we don't know about synergistic either toxicity or synergistic benefit and I bet that physicians will try to use both.

DR. RELLER: Dr. Suffredini.

DR. SUFFREDINI: With regards to No. 8, it shouldn't hold up licensing, but I mean the issue of distinguishing between the anti-inflammatory effect and the anti-coagulant effect and dose optimization is something that, you know, needs to be looked at obviously. But I don't believe that it would require a substantial effort to address that issue.

I do agree that No. 9, that the exclusion criteria that we used in the Phase 3 trial for high risk patients should be kept in there. I guess my only concern about the issue about the platelets is that we haven't been provided data specifically in severe DIC with low platelet counts to tell us whether that was beneficial or harmful. We don't have any data on it.

So, I just don't know what to address with regards to that caveat that we have to be concerned about people with severe DIC. We have no data. So, I can't make an exception to what was already defined here as the exclusion criteria.

DR. RELLER: Thank you.

Dr. Lilly.

DR. LILLY: I do not believe additional dose optimization studies are necessary and I do believe that the document should be clear as to the exclusion criteria used in the trial.

DR. RELLER: Dr. Carcillo.

DR. CARCILLO: I would like to take a moment to just show the differences between babies and adults. A baby has about this much blood in their body, a newborn 3 kilo, and then by the time your child is a year of age, they have approximately three of these. Then you as an adult have approximately four of these. So, it is extremely important to address this question on an age-dependent basis.

A given amount of bleeding from a newborn can be catastrophic, but for me it would be considered a relatively easy event. From the standpoint of what I am seeing -- and, again, the data I know is not in its final form, but from Dr. Lindblad's production, we have bleeding instances that rival what we see with pediatric ECMO(?).

Now, let me say what those are. From what I see, there is a 21 percent instance of bleeding associated with the drug. There is a 5 percent of 4.8 percent incidence of serious bleeding. As Dr. Gerard pointed out, one of those was associated with meningococcemia, but even if you take out the meningococcemic and the meningococcemic patients, as predicted by the biological plausibility, you have a high bleeding risk.

Most bleeding risks are also compounded by age-dependent differences. As you know in children, we don't use heparin or subcutaneous heparin. They don't tend to have thrombosis. They tend more towards bleeding. So, I think, very importantly, this has to be looked at.

In terms of contraindication in patients because of high risk of bleeding, I think this needs to be looked at carefully as well.

DR. RELLER: Dr. Eichacker.

DR. EICHACKER: Yes, I don't think it necessarily deserves study but it is concerning that now that the drug in uncontrolled use is associated with an incidence of intracranial hemorrhage, which is almost ten times its rate during the study. It certainly has to be monitored if the drug was to be used because I don't know whether that is going to escalate as other people use it. It is a concern.

Yes, all the exclusion criteria should be included.

DR. RELLER: I agree, no further dosing studies with the appropriate exclusions in the labeling if it were approved, as has been mentioned earlier.

We are now at Question 10. Overall risk/benefit assessment. Do the available safety and efficacy data support an indication for the use of Drotrecogin Alfa (activated) in adult patients with severe sepsis with any of the limitations discussed above?

Dr. Eichacker?

DR. EICHACKER: My concerns about how the study unfolded, the change in inclusion criteria, the change in drug make this -- make it very difficult for me to say that this drug should be approved. I don't think it should be approved at this time. I think it has to be studied additionally.

DR. RELLER: Thank you.

Dr. Carcillo.

DR. CARCILLO: Well, I am a pediatrician. My viewpoint is from the study is yes.

DR. RELLER: Dr. Lilly.

DR. LILLY: I believe that there is convincing evidence that this drug saves lives and it should be improved.

DR. RELLER: Dr. Suffredini.

DR. SUFFREDINI: I think the combination of two studies confounds their interpretation of the data and I think a confirmatory trial should be performed.

DR. RELLER: So, that data as of the moment are not sufficient.

DR. SUFFREDINI: Not sufficient, right.

DR. RELLER: Dr. Warren.

DR. WARREN: I would say no. I think there should be a confirmatory trial. I am persuaded in part by the fact that I am concerned about the lack of a release test. In fact, if there was another trial, I would be concerned that the lot be very, very carefully studied in animal models because otherwise you could have a situation where we wouldn't even know how to interpret the next trial. So, if there was another trial, I would urge that there be animal testing of that lot.

DR. RELLER: Dr. Rotello.

DR. ROTELLO: I think, no at this point, pending delineation of some of the questions the panel has brought up in previous discussion.

DR. RELLER: Dr. Munford.

DR. MUNFORD: I agree.

DR. RELLER: Dr. O'Fallon.

DR. O'FALLON: My overall gestalt -- and statisticians, I suppose, aren't supposed to have gestalt. We are supposed to have data -- was positive in the sense that I thought there was persuasive evidence, but it says overall benefit/risk assessment and the concern I have is that the benefit/risk assessment was very, you know, kind of basic. We saw whether a person lived or died as being the only criteria and Dr. Fleming had us looking at a beautiful graphic with multiple colors in it that persuaded me to some extent that maybe we needed to see a little bit more of quality of life type of assessment.

My quality of life in the intensive care unit might not be a great deal better than in the coffin. I am not quite sure how I feel about that since I am hopefully not near either of those places personally. I think also that my gestalt is seriously confounded by the fact that the study does seem to really be two different studies as most of my previous colleagues have said.

It is a shame at this stage you all tell me that sepsis has been studied for 30 years, that we had to design a study that then had to be redesigned practically within the first year. So, I am really flipping a mental coin here at the moment, I guess. I am going to stay with my gestalt and say yes.

DR. RELLER: Dr. Fleming.

DR. FLEMING: Well, I hope the reasoning and justification for my answer here is going to be more useful to the FDA than my actual vote because my vote is yes and no.

[Laughter.]

Let me give my reasoning. I am most impressed by the fact that this was a very large study. We have addressed a number of concerns that have been clearly articulated about imperfections. At the same time, this was a major accomplishment and many aspects of the study were extremely well done. It yielded a significant result on survival. In the context of a myriad of such studies done in the past, it certainly has to be one of the most impressive from a favorable perspective.

What cautions me a bit about that, though, are some of the issues that have already been alluded to. One is the 6 percent difference in survival is in essence for the most part people are in the hospital. I don't know specifically what the implications of that would be, how much does that compromise the level of survival benefit?

Other endpoints we haven't discussed very much, organ function, effects on that, health economic impact effects. They are pretty modest. I might have hoped to have seen a bigger effect when I looked at those myriad of measures. So, those were -- those also somewhat tempered my sense of strength of efficacy.

Clearly, there is some risk that we have discussed greatly, the most important being the bleeds and I am more concerned from what I have heard today about the intracranial hemorrhage as well. I don't understand much about that because it was just presented to us today, but it does lead to some caution.

I think if I believed that these data are the truth, I probably would be persuaded more toward the yes side, but these are estimates. These are maybe very informative estimates, but these are estimates nevertheless. There are three factors that caution me about how reliable these estimates are.

One of them is the great discussion that we have had about consistencies and inconsistencies across subgroups. For the most part, much of the subgroup analysis discussion is more heat than light, but I do think there is signal there relative to the low risk patients.

We have also had a lot of discussion about the uncertainties as to whether in essence these are two trials based on time. If, in fact, we do break into the first group versus the second group, as was given in the briefing document, we have got a very nice positive study and we have got a negative study. Study results tend to be less persuasive when there are inconsistencies, any study if you subdivide enough and subgroups will show inconsistencies, but I think there are some real inconsistencies here.

A second point, this study was stopped early using very -- very appropriately using methods, nevertheless, when you do stop a study early, there is statistically some overestimate of the magnitude of treatment effect. So, from that perspective, it is probably modestly -- although that is maybe about a 10 percent. So, if we are estimating a 6, probably an unbiased estimate would be about a 5 to 5 1/2 percent improvement.

The final point, though, that concerns me, and I am a frequentist rather than an abasian(?), so in a certain sense I hate to bring this up, but I can't help but look and interpret these results in the context of historical evidence. We heard the sponsor earlier today talking about the interpretation of the data from previous trials, when validation studies were consistently negative.

Now, I think the essence appropriately of their point was that was, though, based on having seen data exploratory subgroups that couldn't be confirmed. Nevertheless, there is reason to argue that confirmatory trials are extremely trials are extremely valuable. We haven't discussed this today. What is your standard, FDA? Do you want two adequate and well-controlled trials or is one study enough?

This study at best meets the standards for strength of evidence of one positive trial. In the context of a myriad of previous agents that were found to be in essence negative, if you begin with the sense that the vast or a large majority of these agents, because of the incredible challenge of having a survival effect in this setting are likely to be negative. Then there is a fair -- it is called predictive probability -- there is a fairly high probability achieving a statistically significant positive result is actually a false positive.

When you do a confirmatory study, it will be negative. So, with these issues interpreting these data, I go back to what I said about three minutes ago. If these data I knew represented the truth, I would be persuaded towards supporting a recommendation of an approval, but an approval in a restricted manner as we have discussed earlier, which is at least from my perspective not including the ped population and the low risk that I believe those should be studied separately in another trial.

On the other hand, taking into account all of these other considerations of particular caution, I could be persuaded that the right answer is to do another trial in its entirety.

DR. RELLER: Dr. Murray.

DR. MURRAY: I think I am going to refine the being on the fence and go 60 percent yes, 40 percent no. But coming from the usually seen antibiotics, where there are confirmatory trials, that is probably, again, my hold up as well, that we haven't -- there isn't a confirmatory trial here. But I am still going to come down as a yes.

DR. SIEGEL: By the way, since you asked about the legal standard, I am sure many of you are aware we have a document about evidence of effectiveness for the Agency and there is not an absolute requirement that there be two trials showing efficacy. There is requirement for a trial and confirmatory evidence that can come from various sources. We discussed at some length settings in which one trial may be -- may suffice and that includes a compelling trial on a mortality endpoint that is often felt that it is unethical or impractical to try to do a second trial, once you have a compelling trial and a mortality endpoint.

I recognize that, you know, a lot of what this discussion goes around, a lot of what Dr. Fleming's comments addressed, is how compelling is this trial. So, a lot of the comments are suggesting that other trials are potentially feasible. But suffice it to say, there is not a black and white applicable standard here that says -- in our evidence of effectiveness that says there needs to be -- absolutely needs to be two trials or there only needs to be one.

DR. RELLER: Dr. Wittner.

DR. WITTNER: I am going to come down on no. I think the reasons for coming down on no is because I am concerned that there was a change in the drug in the middle of the trial and the change in the patient criteria. I am also somewhat concerned based on the functional status data that Dr. Forsythe showed, which gave some sense that perhaps that 6 percent differential is really not 6 percent.

DR. RELLER: Dr. Wald.

DR. WALD: I think this is very tough. I just feel that this drug was performing well and it sort of performed better and better as time went along and I am not sure exactly what that reflects, but I do think it is the truth. I think that if we don't approve it, we will be denying people who would benefit from it.

So, at least for my self consistency, I would vote to approve.

DR. RELLER: Dr. Ebert.

DR. EBERT: I think in an ideal world if we were able to approve this drug with the -- to the patients who were enrolled in this study with the restrictions that we have talked about, as far as restricting it to patients who would be at higher risk of mortality, I think this would be a no-brainer.

Unfortunately, my concern is that the ultimate use of this drug might include, first of all, the low risk population and also probably more importantly the patients who were excluded from the study and, therefore, I would vote no.

DR. RELLER: Dr. Ramirez.

DR. RAMIREZ: I think I was convinced in the discussion today that in the second part of the protocol, this drug was used in patients with severe sepsis without serious comorbid conditions, that the patients were previously healthy that then developed severe sepsis. This is usually one that you can clearly define severe sepsis with a source of infection.

These patients were sick because we see the advantage with severe APACHE scores. Then in my mind I see -- I don't see the multi-organ failure in the unit. In my mind I see the person arriving from the community, young person with trauma, sepsis or the pneumonia, sepsis and this group of patients that are in my mind, I have no question that for every five of these patients that are going to die, one is going to be saved by the drug.

The question here says with any of the limitations discussed above. If I can figure out to use the drug in the patients that were studied, my answer is yes.

DR. RELLER: Dr. Christie.

DR. CHRISTIE-SAMUELS: My answer is yes with postmarketing surveillance to look at bleeding issues and also to look at quality of life issues.

DR. RELLER: Dr. Chesney.

DR. CHESNEY: Like Dr. O'Fallon, my gestalt is yes and I feel like we need to move ahead with any potential treatment for sepsis, which everybody has articulated well, but we haven't done very much.

I have a bad feeling that this going to turn out just as all the other ones have, as Dr. Opal indicated, but I also appreciate what Dr. Ramirez said about the fact that if this drug is not limited in its use and if people ignore that, there could be very serious consequences for the patient and medical-legal issues. So that I would restrict it to patients with more serious disease; namely, the APACHE groups, 3 and 4 for sure and maybe 2, and I would exclude its use in the group that was excluded in the trial.

DR. RELLER: Dr. Cross.

DR. CROSS: I am concerned that there were two marked differences in the outcomes of the study done both before and after the amendment and we don't have any adequate explanation whether it is the difference in the drug, which is extremely hard to make or the patient population. In the absence of having an explanation for that, I do think we need a confirmatory trial. Before doing so, I would just like to echo the point that Dr. Warren made that we need to have some added -- the efficacy of this agent, perhaps, in an animal model before proceeding further with a large scale study.

DR. RELLER: Thank you.

Dr. Archer.

DR. ARCHER: I haven't heard anybody talk about costs and I haven't seen a cost benefit analysis. I realize you can't put a value on a human life and I am sure that is one of the considerations, but this is a real budget buster potentially and particularly for small hospitals, where it may not be as limited as it is in a big hospital, like some of the ones we work in. I mean, it may just be used fairly indiscriminately, I am afraid, if it -- so I would like to see some of the issues that were raised here and that are unknown so that we can clearly define how this drug should be used so that it can be used in the right circumstances and that can be enforced.

DR. RELLER: That is a yes or a no?

DR. ARCHER: That is a no.

DR. RELLER: Dr. Leggett.

DR. LEGGETT: It seems like we are going to go down this approvable path meeting after meeting with the 60 percent yes, 40 percent no, et cetera. I think that there is -- and the reason I think everybody is hesitant is that there is some pathophysiologic plausibility here. Then we are worried about the benefit versus risk, not only the bleed versus saving somebody's life, but, you know, the benefit of a hospital stay in a vegetative state versus dying or, you know, to characterize.

I think that one thing that I would like to have us consider as well is the different backgrounds of the people who made the statements. I was sort of surprised that generally in my hospital and I am sure elsewhere the infectious disease doctors tend to be the sticklers and the cowboys or the cardiologists and, you know, the critical care folks in some sense.

But in this case, probably the majority of the cowboys came down saying no and the majority of the sticklers said yes, maybe. So, I am sort of -- I don't know how to interpret that. But to point out another thing that we haven't talked about and that this is an interaction between a variety of fields that always interact a little bit hesitantly at times because we all have different legs of the elephant.

Whether there should be ongoing clinical monitoring, I think, is for sure. How that is best done, we can leave it up to the FDA and I think that a confirmatory trial should be done. If that cannot be done or judged not to be, then I would say yes, that it be approved.

I am in sort of the approval camp, sort of like, you know, in the sense that if it is feasible for all the reasons that we talked about in terms of the money before or doing a group of -- where you divide them down them down the median of the three different severity things that we talked about, 3 and 4 versus 1 and 2 of APACHE, three or more organ failure versus -- you know, and you can get to a small, not huge trial again. If that is feasible, then I would say that -- through the confirmatory trial before, if that is not feasible, then I would say go ahead and license.

DR. SIEGEL: Let me try to get some clarification on this point. If we don't approve it, I assume it would be feasible to study the same population or even a broader population, not excluding chronic disease. Are you suggesting -- but you would like to see us not approving it but studying only a subpopulation?

DR. LEGGETT: No, I would say approve it but if there is some way that we can get at further tests to in terms of the confirmatory trials, I would urge that be done for all the reasons that Dr. Fleming and Dr. O'Fallon pointed out.

DR. RELLER: There is one more vote and it is a no.

The WHO defined health as more than the absence of illness. As I heard these discussions today, there is more to life than absence of death. I suspect that there may be a winner here, but I would like to know it and not go down the same path that has been gone down before. There are basically two studies. There are many hesitations that have been voiced in the committee.

This is an opportunity to do it right and if those diverging, increasing of effectiveness that we saw in the latter half of the trial held up and stayed constant, then we would have a confirmatory trial and we would have the first effective agent for the kinds of patients described. I think that would be an incredibly valuable contribution. I do not believe that we are going to get there with that definitive answer if this is approved as is now.

The next item, pediatric studies. We are item No. VII. We are to the last several questions. I will not take the time at this hour to read all of the issues having to do with pediatrics. They were discussed at some length in the interchange that took place before we came to the questions.

So, we will now go to No. 11. This is for a vote. Is severe sepsis in children sufficiently similar to severe sepsis in adults, such that it would support extrapolation of the efficacy of Drotrecogin Alfa (activated) from adults to children, based on PK and PD data in lieu of adequate and well-controlled efficacy data in pediatric patients?

Dr. Leggett.

DR. LEGGETT: This is the sort of similar sort of vein as to what was said before. I think, yes, they may be pathophysiologically similar, but, no, in terms of the risk/benefit for all that sort of low risk population we have been talking about. I don't think they are similar and I think, therefore, that a trial needs to be done and if it is true that there are 45,000 cases per year in the pediatric group, I thin we ought to be able to come up with more than 300 in a trial.

DR. RELLER: Actually, for the sake of time, do you have -- on 12 and 13, do you have any additional comments to make on those components, Dr. Leggett?

DR. LEGGETT: D-dimer is not helpful, at least not in our hospital. Everybody is positive. So, I don't see that as being useful at all.

Then No. 11, I am sure the pediatrician can tell us more about the trial data, but I think I just already pointed to that.

DR. RELLER: Okay. So, as a format for the subsequent members for concluding our deliberations, yes or no with any comments on No. 11 and any comments on the subcomponents 12 and 13.

Dr. Archer.

DR. ARCHER: I defer to the pediatricians. I have heard conflicting data and I can't really decide on whether trials should be done. So, I respectfully defer.

DR. RELLER: Dr. Cross.

DR. CROSS: I would also defer to the pediatricians on that, but I would also like to point out that fairly large studies have been done on the pediatric population in sepsis, certainly, looking in terms of IV gammaglobulin. I assume that a similar type of patient population would be available for this study.

DR. RELLER: Dr. Chesney.

DR. CHESNEY: I would like it to go in the record that two internists deferred to a pediatrician.

[Laughter.]

I would like that framed and I would like a copy. They are forever my close friends.

I think this absolutely has to be studied in children and I wouldn't even pretend to know how to study it and I would leave the answers to 12 and 13 to my intensive care colleagues.

DR. RELLER: Dr. Christie.

DR. CHRISTIE-SAMUELS: I agree with the FDA summary, pediatric summary as presented, that these -- with regards to PK and PD effects and also the bleeding events. What is different with regards to organ failure, it is just one organ failure and the mortality. I think with regards to Question 12, I am not so sure that this is applicable. Question 13, I think Dr. Carcillo is going to give us something very interesting with regards to how this should be done. He alluded earlier on to the fact that we have a lot of patients, pediatric patients, who can be studied with sepsis and I would love to hear what he has to say on that.

DR. RELLER: Dr. Ramirez.

DR. RAMIREZ: I defer to the pediatricians.

DR. RELLER: Dr. Ebert.

DR. EBERT: Based on the safety data, I am not comfortable with extrapolating the results in adults to those in children. I think what we need is some type of a controlled trial to try to assess the true delta between treatment and no treatment and only then can we really assess the risk/benefit.

DR. RELLER: Dr. Wald.

DR. WALD: I agree that separate studies need to be done in the pediatric age group. Although the pathophysiology of sepsis is similar, I think the etiologies are different. There is a lot more bacteremic disease. There is a lot more viral sepsis. I think those deserve separate inquiry and I also think the risks of this drug in the children have not been well-delineated.

DR. RELLER: Dr. Wittner.

DR. WITTNER: I agree with Dr. Wald.

DR. MURRAY: I would just like to say that if the pediatricians deferred every time we were voting on adult disease, we wouldn't have very many votes. So, I will -- I do not think the drug should be approved in pediatrics right now. I think it will be out there for individual cases off label. I would like to see it studied.

DR. RELLER: Dr. Fleming.

DR. FLEMING: I would like to make a distinction between a partial and a total extrapolation. In essence, as I see it here, we are being asked to make a complete extrapolation. There is no controlled data and we are asking are these children sufficiently like the adults that we can completely extrapolate. I believe the answer to that is no.

However, I do concur that a partial extrapolation is going to be necessary and my sense is another trial should be done of some type and in that trial, I would hope the children would be an important representation. Three to 500 children in a study that has many more patients than that will allow us to make only a partial extrapolation in assessing benefit to risk. We will get a very good sense of the risk profile and we will also get a much better sense than we have right now about the extent to which what we see in the broader adult population applies to children.

I will just say as an aside, I am reminded of a number of years ago when I was serving as chair of the data monitoring committee that was looking at a placebo-controlled trial in meningococcemia and we were initially told it wasn't going to be possible to randomize kids in this setting or at best maybe 25 to 50 and that study successfully accrued more than 300 infants randomized to a placebo-controlled trial.

So, it is possible.

DR. ARCHER: Can I ask a question of pediatricians? If they think that there should be a differentiation made between neonates and children in general in terms of trials and in terms of sepsis and in terms of all the other things?

DR. RELLER: Drs. Chesney, Christie, Wald and Carcillo, neonates versus older children, separate studies. Yes? No?

DR. CHESNEY: I think they are very different populations.

DR. WALD: I agreed. It would need to be a separate study.

DR. RELLER: Dr. Carcillo, any comment?

DR. CARCILLO: Yes. I agree with the two distinguished colleagues and -- but at the end, I will go over why.

DR. RELLER: Dr. Christie.

DR. CHRISTIE-SAMUELS: Yes, they are different populations, both pathophysiologically and also with regards to the type of sepsis that they have, etiological and otherwise.

DR. RELLER: Thank you.

Dr. O'Fallon, Question 11 and comment on 12 and 13, if you wish.

DR. O'FALLON: Yes, we need additional study and I have no comments on the other two.

DR. RELLER: Dr. Munford.

DR. MUNFORD: Since I am not convinced that the drug works in adults, I certainly would not extend this to children. As regard 12 and 13, I will defer to my pediatrician colleagues.

DR. RELLER: Dr. Rotello.

DR. ROTELLO: I do believe further studies are necessary and I also will defer to the pediatricians for detail.

DR. RELLER: Dr. Warren.

DR. WARREN: I would agree with Dr. Gerard that in a population where the mortality is only 10 percent, it would be hard to get a mortality difference and I also think it will be hard to extrapolate. So, I guess I would come down with a notion that once it is proven in adults, then the pediatric population can be addressed.

DR. RELLER: Dr. Suffredini.

DR. SUFFREDINI: I would say with regards to 11, I would say no. I think to echo what Dr. Carcillo has said and will probably say is that the age specific consequences of things like the complications that just bleeds in a developing brain, et cetera, are significant and need to be studied very closely and very clearly.

I have no comments on 12 and 13.

DR. RELLER: Dr. Lilly.

DR. LILLY: I want to defer.

DR. RELLER: Dr. Carcillo.

DR. CARCILLO: In terms of No. 11, are children like adults sufficiently to use pharmacokinetics and pharmacodynamic data, I would like to first start by thanking the Agency for its drive to bring children into drug studies. I would also like to thank the Eli Lilly Company for including children in their studies and also the Congressmen and Congresswomen who have looked at trying to improve this possibility.

It turns out that just looking at pharmacokinetic or pharmacodynamic data is not sufficient. In this particular drug, we know, for example, that newborns have hemorrhagic diseases, which require vitamin K. We know that the time to stopping bleeding, the so-called PTPTT is poor and becomes shorter over time. We know that we do not give sub Q heparin to children to children who are in the NICU or the PICU because they don't get thrombophlebitis, myocardial infarctions or strokes.

If you think about it for a second if your baby is lying in the crib for the first year of life, they don't have any thrombosis, but if I was lying in a crib for a year without any heparin, I would have thrombosis.

In addition, there are differences in fibrinolysis in children. One of the ways that the child overcomes this is by something called Von Waldbran(?) fragments and platelets. There are a number of things, but suffice it to say simply showing that the clearance of protein C is the same across age groups is not enough.

So, let me just address this question because I think the Eli Lilly Company is a very reputable company and very interested in children. So, here is some of the data. Basically, what is being asked for is indication for severe sepsis, not meningococcemia puerperal fulminants and that is very important to understand. That is really the difference in opinion between Dr. Gerard and I in terms of how long it will take to have a study.

Severe sepsis is an infection, plus an organ failure. Now, in 1995, the case fatality rate in our country was 10.3 percent and that is the article with Derek Angus as the primary investigator. In 1999, it is down to 9 percent. However, the burden to the United States is increasing. Presently, we have gone from 42,000 infants and children to 48,000 nationally who are infected.

Now, in terms of the potential market of this, the national total hospital days increased by 6 percent, from 1.3 million too 1.4 million days and total costs increased by 28 percent, from 1.7 billion to 2.2 billion. So, in looking at this as an agency, if you feel that you can have a mortality outcome, you can certainly have an outcome in terms of decreasing costs, morbidity.

In the trial that Dr. Gerard has led with another drug, which I will not mention, they looked at outcome scores at the time. So, I think the concept that a drug that could cause bleeding and harmful side effects cannot be tested in children because we don't have good outcome variables.

So, there are no surrogate pharmacodynamic or pharmacokinetic variables. This disease should be studied in a randomized controlled fashion.

DR. RELLER: Dr. Eichacker.

DR. EICHACKER: I agree with Dr. Munford. I think we have to find out whether it works in adults first before we start to test it in children.

DR. RELLER: I think there may be some compounds and situations where one might provide children the benefit of drugs without going through extensive trials. I do not think for the reasons mentioned this is one of them.

I have no comment on 12 and 13.

We have come to the end of our deliberations. From the FDA, are there any issues that we have not tried to provide at least some guidance for you that you would like addressed?

DR. SIEGEL: Thank you very much. There were very thorough and extremely informative discussions.

DR. RELLER: I would now in closing like to thank Eli Lilly for their succinct and thorough presentation and for the members of the advisory committee, guests, consultants for sticking with the program to the very end and for the thorough discussions and thoughtful considerations.

Our meeting is adjourned.

[Whereupon, at 5:35 p.m., the meeting was concluded.]