FOOD AND DRUG ADMINISTRATION

	CENTER FOR DRUG EVALUATION AND RESEARCH

	SIXTY-THIRD MEETING

	OF THE

	ONCOLOGIC DRUGS ADVISORY COMMITTEE

	8:07 a.m.

	Thursday, September 16, 1999

	Kennedy Ballroom
	Holiday Inn
	8777 Georgia Avenue
	Silver Spring, Maryland

	ATTENDEES

COMMITTEE MEMBERS:

RICHARD L. SCHILSKY, M.D., Chair
Associate Dean for Clinical Research
Biological Sciences Division
University of Chicago
The University of Chicago Medical Center
5841 South Maryland Avenue, MC1140
Chicago, Illinois  60637

KAREN M. TEMPLETON-SOMERS, PH.D., Executive Secretary
Advisors & Consultants Staff, HFD-21
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland  20857

DOUGLAS W. BLAYNEY, M.D.
Medical Director, Oncology Program
The Robert and Beverly Lewis Family
  Cancer Care Center
Pomona Valley Hospital Medical Center
1910 Royalty Drive
Pomona, California  91767

DAVID H. JOHNSON, M.D.
Director, Division of Medical Oncology
Department of Medicine
Vanderbilt University Medical School
1956 The Vanderbilt Clinic
Nashville, Tennessee  37232

DAVID P. KELSEN, M.D.
Chief, Gastrointestinal Oncology Service
Memorial Sloan-Kettering Cancer Center
1275 York Avenue
New York, New York  10021

SCOTT M. LIPPMAN, M.D.
Professor of Medicine and Cancer Prevention
The University of Texas M.D. Anderson Cancer Center
Department of Clinical Cancer Prevention
1515 Holcombe Boulevard, HMB 11.192c, Box 236
Houston, Texas  77030

	ATTENDEES  (Continued)

COMMITTEE MEMBERS:  (Continued)

KIM A. MARGOLIN, M.D.
Staff Physician
Department of Medical Oncology and
  Therapeutics Research
City of Hope National Medical Center
1500 East Duarte Road
Duarte, California  91010

STACY R. NERENSTONE, M.D.
Associate Clinical Professor
Oncology Associates, P.C.
Helen & Harry Gray Cancer Center
Hartford Hospital
85 Retreat Avenue
Hartford, Connecticut  06106

JODY L. PELUSI, F.N.P., PH.D., Consumer Representative
Cancer Program Coordinator
Maryvale Hospital
102 W. Campbell Avenue
Phoenix, Arizona  85031

DEREK RAGHAVAN, M.D., PH.D.
Associate Director
Head of Medical Oncology
University of Southern California
Norris Comprehensive Cancer Center
1441 Eastlake Avenue, Room 3450
Los Angeles, California  90033

COMMITTEE CONSULTANTS:

JAMES E. KROOK, M.D.
Principal Investigator
Duluth CCOP
400 East Third Street
Duluth, Minnesota  55805

KATHLEEN LAMBORN, PH.D.
Professor
Department of Neurological Surgery

University of California, San Francisco
350 Parnassus Street, Room 805, Box 0372
San Francisco, California  94143

	ATTENDEES  (Continued)

PATIENT REPRESENTATIVES:

SALLIE FORMAN - for UFT
Washington, D.C.

SANDRA ZOOK-FISCHLER - for Evacet
New York, New York

FOOD AND DRUG ADMINISTRATION STAFF:

RACHEL BEHRMAN, M.D., MPH
JULIE BEITZ, M.D.
PATRICIA CORTAZAR, M.D.
JOHN JOHNSON, M.D.
ROBERT JUSTICE, M.D.
ROBERT WHITE, M.D.
GRANT WILLIAMS, M.D.

ON BEHALF OF BRISTOL-MYERS SQUIBB:

STEVEN BENNER, M.D., M.H.S.
RENZO CANETTA, M.D.
JAMES CARMICHAEL, M.D., PH.D.
ROBERT DIASIO, M.D.
JOHN MACDONALD, M.D.
STEVE PIANTADOSI, M.D., PH.D.
DARYL SONNICHSEN, PHARM.D.

ON BEHALF OF THE LIPOSOME COMPANY:

JONATHAN ALEXANDER, M.D.
GERALD BATIST, M.D.
ANDREW JANOFF, PH.D.
GARY KOCH, PH.D.
LILY LEE, PH.D.
ROBERT LEONARD, M.D.
STEVE PIANTADOSI, M.D., PH.D.
JAMES SPEYER, M.D.
ERIC WINER, M.D.

	ATTENDEES  (Continued)

ALSO PRESENT:

DR. MICHAEL COHEN
LAURENCE F. DASPIT
LAURA MEEKER
MARGARET VOLPE
MARISSA WEISS, M.D.

	C O N T E N T S - MORNING SESSION

	NDA 21-053, UFT (tegafur and uracil) CAPSULES
	BRISTOL-MYERS SQUIBB COMPANY
	Indicated with leucovorin calcium tablets for the
	First-line Treatment of Metastatic Colorectal Cancer

AGENDA ITEM	PAGE

CONFLICT OF INTEREST STATEMENT
  by Dr. Karen Templeton-Somers	10

OPEN PUBLIC HEARING PRESENTATIONS
  by Dr. Michael Cohen	12
  by Mr. Laurence Daspit	14

BRISTOL-MYERS SQUIBB PRESENTATION
  Introduction - Dr. Renzo Canetta	17
  Chemotherapy for Metastatic Colorectal 
    Cancer - by Dr. John MacDonald	20
  UFT Development - by Dr. Robert Diasio	24
  Pivotal Study 011 - by Dr. Steven Benner	30
  Confirmatory Study - by Dr. James Carmichael	41
  Concluding Remarks - by Dr. Renzo Canetta	48

QUESTIONS FROM THE COMMITTEE	52

FDA PRESENTATION
  by Dr. Robert White	86

QUESTIONS FROM THE COMMITTEE	98

OPEN PUBLIC HEARING PRESENTATIONS
  by Hepatitis C Action & Advocacy Coalition	119

COMMITTEE DISCUSSION AND VOTE	126

	C O N T E N T S - AFTERNOON SESSION

	NDA 50-772 EVACET (doxorubicin HCl liposome injection)
	THE LIPOSOME COMPANY, INC.
	Indicated for the first-line Treatment of
	Metastatic Breast Cancer
	in Combination with Cyclophosphamide

AGENDA ITEM	PAGE

CONFLICT OF INTEREST STATEMENT
  by Dr. Karen Templeton-Somers	155

OPEN PUBLIC HEARING PRESENTATIONS
  by Marti Nelson Cancer Research Foundation	157
  by Dr. Michael Cohen	161
  by Ms. Margaret Volpe	165
  by Ms. Laura Meeker	166
  by National Coalition for Cancer Survivorship	168

THE LIPOSOME COMPANY, INC. PRESENTATION
  Introduction - by Dr. Lily Lee	170
  Preclinical Overview - by Dr. Andrew Janoff	172
  The Need for a Less Cardiotoxic 
    Anthracycline - by Dr. Eric Winer	174
  Study Designs - by Dr. Lily Lee	179
  Reduction in Cardiotoxicity - 
    by Dr. Jonathan Alexander	184
  Antitumor Efficacy - by Dr. Lily Lee	192
  Clinical Safety - by Dr. Gerald Batist	206
  Conclusion - by Dr. Lily Lee	211

QUESTIONS FROM THE COMMITTEE	213

FDA PRESENTATION
  by Dr. Patricia Cortazar	245

QUESTIONS FROM THE COMMITTEE	259

OPEN PUBLIC HEARING PRESENTATIONS
  by Dr. Marissa Weiss	276
  by Ms. Laura Meeker	279

COMMITTEE DISCUSSION AND VOTE	282

	P R O C E E D I N G S
	(8:07 a.m.)
DR. SCHILSKY:  Good morning, everyone.  If people can please be seated, we'd like to begin the meeting today.  Welcome to the 63rd meeting of the Oncologic Drugs Advisory Committee.  I am not sure if this is the first meeting that has ever occurred during a hurricane, but it must be one of the few.
Karen Somers has a few opening remarks before we have introductions.
DR. TEMPLETON-SOMERS:  We have some new members to welcome to the committee, and Dr. Schilsky is our new Chair, in case you hadn't noticed already.  The new members who are already present are Dr. Douglas Blayney and Dr. Jody Pelusi, who is our new Consumer Representative, and Dr. Scott Lippman, who is over here.  In addition, Dr. David Kelsen will be arriving late.  He was having trouble getting a plane from New York and will be coming by train this morning, but he should be here by around 9:00.
DR. SCHILSKY:  Thanks, Karen.

I think we'll go around the table and ask each of the committee members to introduce themselves, and why don't we start with one of the experienced members.  Dr. Raghavan.
DR. RAGHAVAN:  I'm Derek Raghavan, medical oncologist, USC.
DR. LAMBORN:  Kathleen Lamborn, biostatistician, UCSF.
MS. FORMAN:  Sallie Forman, Patient Representative.
DR. MARGOLIN:  Kim Margolin, medical oncology and hematology, City of Hope, California.
DR. LIPPMAN:  Scott Lippman, M.D. Anderson Cancer Center, medical oncology.
DR. SCHILSKY:  I'm Rich Schilsky.  I'm a medical oncologist with the University of Chicago.
DR. TEMPLETON-SOMERS:  Karen Somers, Executive Secretary to the committee, FDA.
DR. NERENSTONE:  Stacy Nerenstone, medical oncology, Hartford, Connecticut.
DR. DAVID JOHNSON:  And I'm Dave Johnson, medical oncologist at Vanderbilt University.
DR. PELUSI:  And I'm Jody Pelusi.  I'm a nurse practitioner in oncology in Arizona.

DR. KROOK:  Jim Krook.  I'm a medical oncologist from Duluth.  When Karen asked me to come back to ODAC, she said there was a drought.  She said, bring water.
(Laughter.)
DR. KROOK:  I brought it.  Don't complain.
(Laughter.)
DR. TEMPLETON-SOMERS:  Dr. Krook does not know moderation.
(Laughter.)
DR. BLAYNEY:  I'm Doug Blayney.  I'm a medical oncologist from Pomona, California.  And when I joined, they told me all the meetings were going to be in California.
(Laughter.)
DR. WHITE:  Robert White, FDA, oncology.
DR. JOHN JOHNSON:  John Johnson, clinical team leader, oncology.
DR. JUSTICE:  Bob Justice, acting Division Director, oncology.
DR. BEHRMAN:  Rachel Behrman, Deputy Office Director, FDA.
DR. SCHILSKY:  Thank you.
Karen has a conflict of interest statement.

DR. TEMPLETON-SOMERS:  The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a 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 interests 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 U.S.C. 208(b)(3), full waivers have been granted to Drs. Douglas Blayney, David Johnson, David Kelsen, Scott Lippman, Kim Margolin, Richard Schilsky, James Krook, and Kathleen Lamborn which permit them to participate in all official matters concerning UFT.
A copy of the waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, room 12A-30 of the Parklawn Building.

In addition, we would like to disclose for the record that Drs. Johnson, Lippman, and Schilsky have interests which do not constitute financial interests within the meaning of 18 U.S.C. 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 outweighs the concern that the integrity of the agency's programs and operations may be questioned.
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 interest fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.
Thank you.
DR. SCHILSKY:  Thank you, Karen.
We have two people listed on the agenda for the open public hearing.  Is Michael Cohen here?  Please come to a microphone and state your name and affiliation and whether you've received any financial support from any sponsor.

DR. COHEN:  Since I'm a pharmacist and not an electronic engineer, I'll start here.  My name is Michael Cohen.  As I said, I am a pharmacist and I head an organization called the Institute for Safe Medication Practices.  It's an independent, nonprofit organization.  The United States Pharmacopeia operates the medication errors reporting program in cooperation with our organization.  We're also FDA Med Watch partners.
We publish reports of medication errors that we receive from practitioners from around the country, and these are published in various journals and newsletters, including Oncology Times.  We have an ongoing feature in Oncology Times.
We also have our own publication called the ISMP Medication Safety Alert, which is faxed or e-mailed to hospitals around the country and other practice sites every two weeks.  The reason I mention that is I'd like to disclose that Bristol-Myers Oncology does help to sponsor that for some of the hospital organizations, so that it is available to them.

My comments are related to the potential for medication errors with the product that you're about to discuss.  Through the years, we have had some reports from practitioners of confusion when prescriptions are written for the drug leucovorin calcium with the product Leukeran, and that concerns us because the drug that you're about to approve, UFT, apparently will be prescribed with leucovorin calcium. 
We also have occasional problems where the drug is referred to as folinic acid, and again we have had reports from practitioners where folic acid was administered instead. 
About 25 percent of the reports that come to USP and FDA of medication errors have to do with labeling and packaging.  One of the things that we've always promoted, besides clear labeling and packaging obviously, is simplification.  That certainly is promoted by human factors experts as well.  I think it would be very important then to simplify things and instead of having to write two prescriptions for the drug and have a patient have to have two prescriptions filled, with the added possibility of confusion between leucovorin calcium and Leukeran, that the products be available and packaged together. 
And those are my comments and I'd like you to consider them.  Thank you very much.
DR. SCHILSKY:  Thank you very much.

Is Laurence Daspit here?  So, please come to the podium and state your name, affiliation, and whether you've received any financial support to be here.
MR. DASPIT:  I have a brief prepared text with some notes.
My name is Laurence Daspit.  I'm 54 years old, married with one son.  I live in Spring, Texas.  My wife and I are here at the courtesy of Bristol-Myers Company which paid our airfare, transportation, and lodging.
Also by way of disclosure, in December of 1996, I did a brief marketing video, for which I received $200.  That is the extent of any compensation to me from Bristol-Myers.
In May of 1995, I had surgery at M.D. Anderson Cancer Center to remove a cecal region -- cecal colon tumor.  Excuse my medical terminology.  I'm not a doctor.  During the surgery, biopsies established that the disease had spread to my abdominal lymph nodes and liver.  The surgeon opted not to remove the lesions from the liver.  He did remove the abdominal lymph nodes. 

After recovering from surgery, I had the opportunity to participate in a clinical trial of UFT with leucovorin.  I began taking these medications in late June of 1995.  I took UFT with leucovorin three times a day, as indicated, for 4 weeks followed by a week without medication.  After two rounds of medication, CT-scans of my abdomen and pelvic region, x-rays, and blood labs indicated no evidence of disease.
Because the treatment was an oral medication, our family was able to travel to France in November of 1995 and take other extended vacations.  The staff at M.D. Anderson arranged for the required weekly blood work to be done at local hospitals where we were vacationing.  The results were faxed back to the research nurse in Houston.
I continued to take the oral medication until mid-October of 1997.  I was on this therapy regimen for approximately 2 years and 3 months.  During that entire time, I do not recall missing a single day of work because of medication side effects.  I did miss time from work for scheduled diagnostic procedures. 
Well into each 4-week cycle, usually in the third or fourth week, I often did experience moderate diarrhea.  On the advice of the research nurse, who had monitored my therapy, I would skip doses as needed and use over-the-counter anti-diarrhea medication to control and restore normal bowel function.

Also well into each round, I did often experience bothersome but not debilitating fatigue.
In mid-October 1997, at the suggestion of the oncologist who was treating me, I stopped taking the medication.  I continue the schedule of diagnostic procedures, the CT-scans, the blood work, and the x-rays.
My most recent set of diagnostic procedures was in early May of this year.  Those procedures revealed no evidence of disease. 
I want to close by asking this panel to make this medication available to anyone who is diagnosed with metastatic colon cancer.  Long before hearing no evidence of disease and long before understanding complete response, this medication let me work productively, enjoy leisure with my family and friends, and start a regular routine of physical exercise that has resulted in the best annual physicals I've had in my adult life.  I'm asking you to please give others with this disease the same opportunity.
Thank you.
DR. SCHILSKY:  Thank you.
Is there anyone else who wishes to make a statement before the committee?
(No response.)

DR. SCHILSKY:  If not, we'll move on to the sponsor's presentation.  Dr. Canetta.
DR. CANETTA:  Good morning.  My name is Renzo Canetta.  I'm with the Clinical Oncology Group at Bristol-Myers Squibb.  We plan to present to you today the contents of our NDA for UFT capsules plus leucovorin tablets for the treatment of metastatic colorectal cancer.
This biomodulated treatment consists of UFT capsules that is a fixed combination of tegafur.  Tegafur is a prodrug of fluorouracil and uracil which is an inhibitor of the catabolic pathway of 5-FU.  And that contributes also to the increase of the levels of 5-FU when UFT is given.
The addition of leucovorin is meant to provide potentiation of the 5-FU effect.  Altogether, this approach allows an efficient oral delivery of 5-FU, and that is coupled with a significant reduction of its side effects.  That's resulting in an overall improvement of the therapeutic index for fluoropyrimidine therapy.

UFT was originally developed in Japan by the Taiho Pharmaceutical Company, and it was approved there in 1983.  In that country, UFT has been widely adopted for the treatment of several solid tumors, including metastatic colorectal cancer.  You see listed here the countries where the drug has been approved after Japan, and these are the countries that approved the drug before the beginning of the pivotal trials that we'll be discussing today in the U.S. 
The use of the drug in the U.S. and in Western Europe has been limited to clinical trials, and the only exception was Spain where the drug was approved in 1986.  Following the approval in Spain, the drug has been generally given in conjunction with leucovorin as a treatment for metastatic colorectal cancer.
The Taiho Company began the clinical development of this compound in this country, and phase I and phase II were conducted under IND for the combination of UFT and leucovorin.  In 1995, Bristol-Myers Squibb acquired the license to the compound.  

Throughout the entire development of UFT and leucovorin, a series of meetings were held involving the sponsor and the FDA.  As a result of these meetings, the registrational plan was developed with a stated goal to demonstrate equivalence and efficacy as measured by survival in comparison with the standard of care of intravenous 5-FU and leucovorin.  The definition of non-inferiority was included both in the study protocol and the analytical plan submitted as early as 1996 or 1997.
The NDA submission began in September 1998 before the number of events projected for the final survival analysis had occurred.  And a number of events were projected to occur early in 1999, and that is when the rolling NDA procedure was completed.
During the review period, an update of the survival analysis was agreed upon with the FDA.
The NDA contains two prospectively randomized trials.  As a matter of fact, the pivotal study is the largest randomized trial ever submitted to the FDA for registration of a drug for this indication.  
We believe that these studies have conclusively demonstrated that oral UFT and leucovorin produce equivalent survival effects to the standard of care, 5-FU and leucovorin given intravenously.  The oral UFT and leucovorin regimen is associated with clinically significant safety advantages.  These encompass myelosuppression, febrile neutropenia, infections, gastrointestinal symptoms, including both diarrhea and nausea and vomiting, mucositis and stomatitis, and the concomitant use of additional medications. 

Thus, overall oral UFT and leucovorin represents an important therapeutic advance for the treatment of the disease.
This morning's presentation will consist of a review of the chemotherapy for metastatic colorectal cancer, which will be given by Dr. Jack MacDonald from New York.  Dr. Bob Diasio from Birmingham, Alabama will present to you both the pharmacological and the clinical aspects of UFT development.  His presentation will be followed by the reporting of the results of the two randomized phase III trials.  Dr. Steve Benner from BMS will present the pivotal study 011 whose principal investigator was Dr. Richard Pazdur from the M.D. Anderson Cancer Center in Houston.  Dr. James Carmichael from Nottingham Hospital in the United Kingdom will present the results of the confirmatory study 012.  At the end I would add a few concluding remarks.
We are very pleased today to have with us as consultants both Dr. Steven Piantadosi from Johns Hopkins University and Dr. Barry Lembersky from the Allegheny General Hospital in Pittsburgh.
I'd like now to introduce Dr. John MacDonald from St. Vincent's Comprehensive Cancer Center in New York.

DR. MacDONALD:  Thank you very much.  Dr. Schilsky, committee members, ladies and gentlemen, good morning.  
I will review the use of chemotherapy in advanced colorectal cancer.  In this disease setting, intravenous 5-FU and leucovorin is the current standard of care.
Colorectal cancer is one of the leading causes of cancer mortality in the United States and throughout the world.  By American Cancer Society estimates, over 129,000 new cases will be diagnosed in the United States in 1999.  Each American has a 1 in 20 lifetime risk of developing colorectal cancer.  This year the disease will result in an estimated 56,000 deaths in the United States alone.  Of all the patients initially diagnosed with colorectal cancer, slightly over half will develop metastatic disease sometime during the course of their illness.  In the past, without therapy, survival for metastatic colorectal cancer has been well under 1 year, with many studies reporting survival of less than 6 months.

The results of these three randomized clinical trials comparing 5-FU/leucovorin based regimens to best supportive care are shown to highlight the impact of chemotherapy on survival.  Throughout the literature, the 5-FU/leucovorin based chemotherapy has been shown to result in median survivals of close to 1 year.  This survival benefit represents both the statistically significant and clinically meaningful impact of chemotherapy for patients with metastatic colorectal cancer.
Leucovorin modulated 5-FU regimens have emerged over time as the standard initial treatment for metastatic colorectal cancer.  A meta-analysis showed statistically significant increases in response rates for 5-FU/leucovorin regimens compared to 5-FU alone.  But at the time of this meta-analysis, improved response rates did not translate into a statistically significant improvement in median survival.
The studies included in the meta-analysis used a variety of 5-FU/leucovorin doses and schedules.  The studies which used a daily times 5 schedule administered 5‑FU at doses ranging from 370 to 400 milligrams per meter squared per day.  Several additional studies, not available at the time of the meta-analysis, however, have demonstrated the beneficial effect of adding leucovorin to 5-FU in prolonging survival.

In the metastatic setting, 5-FU in combination with leucovorin is the current standard of treatment.  In fact, 5-FU was approved in the U.S. in combination with leucovorin to prolong survival in the palliative treatment of patients with advanced colorectal cancer.  In the U.S., schedules developed at the Mayo Clinic and Roswell Park Cancer Institute are approved, but only the Mayo Clinic regimen is widely approved throughout the world.  In clinical practice, 5-FU/leucovorin has been the accepted standard for first-line treatment of metastatic colorectal cancer.  
While different schedules have continued to be used and debated, all of these included biomodulation of 5‑FU with the exception of continuous, uninterrupted 5-FU infusions.  This approach is not approved, however, and requires placement of a central venous catheter.
5-FU, combined with leucovorin, has also served as the backbone for new experimental drug regimens being evaluated in the treatment of metastatic colorectal cancer.

Among the leucovorin modulated 5-FU regimens, which have gained widespread acceptance, the regimen developed at the Mayo Clinic has been extensively studied through the North Central Cancer Treatment Group.  This regimen in most of its iterations employs a bolus 5-FU given at a dose of 425 milligrams per meter squared for 5 consecutive days.  This is accompanied by intravenous leucovorin at a dose of 20 milligrams per meter squared per day, also administered for 5 days.  As approved, the regimen is given at 4-week intervals for the first two cycles and then repeated at intervals of every 4 to 5 weeks. 
This regimen has continued up to the present time to serve as an internationally accepted comparator arm for phase III trials in advanced colorectal cancer.  Approximately two-thirds of the recently reported phase III trials have used the Mayo Clinic regimen as the comparator arm.  While proponents for other 5-FU regimens certainly exist, there's no question that the Mayo Clinic regimen is an accepted standard in clinical practice, as well as an internationally approved and recognized comparator arm for clinical trials.
Dr. Robert Diasio, Professor of Medicine, Chairman of Pharmacology at the University of Alabama at Birmingham, will now review for you the development of UFT and the results of phase I and phase II studies performed in the U.S. to develop the UFT/leucovorin regimen.
DR. DIASIO:  Thank you, Jack.  Good morning.

As we all know, 5-FU remains the backbone of treatment for metastatic colorectal cancer.  While the debate has continued for decades regarding the optimal schedule for administration of 5-FU, 5-FU modulated by leucovorin is now the standard in clinical practice and the basis for experimental combination regimens.
This morning I will describe for you the initial development of UFT and how, when combined with leucovorin, it was developed as a fluoropyrimidine regimen with distinct advantages over IV 5-FU and leucovorin.
UFT is a combination of tegafur, a 5-FU prodrug, and uracil.  Unlike 5-FU, tegafur is consistently well absorbed orally.  The uracil component, of course, has no antitumor activity by itself.  In combination with tegafur, however, uracil slows the breakdown of 5-FU.  Animal experiments, later confirmed by human studies, establish the 4 to 1 molar ratio as optimal in producing high tumor exposure to 5-FU with much lower concentrations in normal tissue.
Following oral administration of UFT, tegafur is converted to 5-FU.  The uracil component of UFT competes with 5-FU at the level of DPD.  The inhibition of DPD by uracil is reversible.

Tegafur was first synthesized in 1967 as a 5-FU prodrug in an effort to improve upon 5-FU.  Tegafur was tested in the U.S. using both IV and oral regimens.  These studies did not demonstrate any efficacy advantage compared with 5-FU.  In addition, with the high doses of tegafur needed to achieve therapeutic levels of 5-FU, unique tegafur associated toxicities were noted; in particular, CNS side effects were observed. 
Oral tegafur was studied in the treatment of metastatic colorectal cancer in the early 1980s.  Six randomized trials compared tegafur given t.i.d. for 21 days versus IV 5-FU.  In these studies, the tegafur treatment was not associated with an improvement in survival compared to 5-FU, and the results appeared inferior to the results of recent UFT/leucovorin trials.  The tegafur treatment was associated with significant toxicity, however, with over 33 percent of the courses being associated with CNS toxicity and 54 percent of the courses with nausea.  Based on this low therapeutic index, development of tegafur alone was discontinued within the U.S.

Due to the interest in Japan in oral therapy, development of tegafur continued there in combination with uracil as UFT.  The uracil component allowed the oral combination to achieve therapeutic levels of 5-FU in man without the toxicities associated with high levels of tegafur.  UFT has been widely used in Japan as chemotherapy for the treatment of several solid tumors.  The Japanese regimen was specifically developed to minimize toxicity and uses UFT alone at doses of 300 to 600 milligrams per day given twice daily, or t.i.d.  In Japan, this regimen has been successful as an active antitumor regimen with minimal associated side effects.
The clinical experience in Japan with UFT supports the conclusion that the drug is extremely safe.  UFT has been marketed in Japan for over 15 years.  In addition to clinical trials, post-marketing surveillance now includes over 20,000 patients treated.  
For UFT given, according to the Japanese label, the most common adverse events, considering all grades, are myelosuppression, anorexia, nausea, and diarrhea.  The occurrence of severe toxicity was very uncommon.  With this extensive clinical experience, the toxicity profile associated with UFT has been extremely well described.

In the U.S., UFT has been studied in combination with oral leucovorin to improve fluoropyrimidine treatment for colorectal cancer.  As many of us know, leucovorin calcium stabilizes the complex of FdUMP with thymidylate synthase improving efficacy.
The following clinical studies were performed in the U.S. to develop the UFT and leucovorin regimen and are contained within the FDA.  The clinical pharmacology of UFT plus leucovorin was evaluated in eight studies which enrolled a total of 110 patients.  These clinical pharmacology studies demonstrated rapid absorption of both tegafur and uracil.  Following each oral dose of UFT, a peak in plasma 5-FU concentration occurs and there is no significant accumulation of plasma 5-FU with repeated dosing.  Consequently, repeated oral dosing with UFT produces a repeated peak and trough pattern.
Initially a series of phase I studies using oral UFT combined with oral leucovorin were performed.  The UFT dose was divided into three doses per day.  These trials may be divided into those with low dose, or 15 milligrams per day, and high dose, or 150 milligrams per day, of leucovorin, also divided into three doses per day, given together with UFT.

Among all of these phase I studies, the maximum tolerated UFT dose with either low dose or high dose leucovorin, using a 14-day schedule as opposed to a 28-day schedule, was 350 milligrams per meter squared.  In all of these studies, toxicities were very consistent, and the dose-limiting toxicity for all studies was diarrhea.
The phase I experience suggested that no dose intensification could be achieved by using a shorter dosing period.  So, a 28-day schedule followed by 1 week of rest was chosen for the phase II studies.  
In the phase II trials, both high and low dose leucovorin schedules were taken forward.  The phase II studies were performed in previously untreated patients with metastatic colorectal cancer.  In the M.D. Anderson Cancer Center trial, the initial dose of 350 milligrams per meter squared was not well tolerated.  The dose was, therefore, decreased to 300 milligrams per meter squared per day in combination with high dose leucovorin.  
Ultimately, from the phase II experience, this cohort -- that is, those patients treated with high dose leucovorin and 300 milligrams per meter squared per day of UFT -- achieved the best results.  In this study, significant antitumor activity was observed, based on a response rate of 44 percent, and the regimen maintained an excellent safety profile.

In this next slide, the safety experience for the phase II studies is shown based on the UFT dose.  Those patients treated with a UFT dose of 350 milligrams per meter squared per day and either high or low dose leucovorin experienced an unacceptable incidence of severe toxicities, as you can see, including diarrhea, which occurred in 33 percent of the patients treated.  
The difference in the toxicities observed between the 350 milligram and the 300 milligram per meter squared dose is quite striking.  Here the incidence of diarrhea decreased up to 13 percent with no case of grade 4 diarrhea being reported.  When looking at all other toxicities as well, there was an obvious improvement in the safety profile associated with treatment at a dose of 300 milligrams per meter squared per day compared with those treated at the 350 milligrams per meter squared per day.
For the phase III trials, after consultation with the FDA, a leucovorin dose of 75 to 90 milligrams per day was chosen.  Oral leucovorin is clearly demonstrated to have saturable absorption.  As shown by this data taken from Straw, a leucovorin dose of 25 to 30 milligrams will produce bioavailability of over 90 percent.

The phase I and phase II trials demonstrated that the UFT in combination with leucovorin was a highly active regimen which was associated with an excellent safety profile.  This is the regimen taken forward for the phase III trials.  Dr. Benner from Bristol-Myers Squibb will now describe for you the results of the pivotal phase III trial comparing the UFT/leucovorin regimen to bolus 5‑FU and leucovorin.
DR. BENNER:  Good morning. 
The 011 study was designed to demonstrate the safety and efficacy of UFT combined with leucovorin.  Patients in the study had metastatic colorectal cancer and following enrollment were stratified by these criteria:  presence of a measurable lesion, performance status, prior adjuvant therapy, and institution.  None of the patients in this trial had received prior systemic therapy for metastatic disease.

The patients were randomized to receive a treatment with either UFT and leucovorin or 5-FU and leucovorin.  The UFT regimen was given as follows:  UFT at a dose of 300 milligrams per meter squared per day divided into three doses per day and given for 28 consecutive days.  This was followed by 1 week of rest.  At the same time patients took UFT, they also took leucovorin again for 28 days, followed by a week of rest.  The total daily dose of leucovorin was initially 75 milligrams in the United States, but when the study was expanded to include sites in Canada and Europe, the total daily dose was increased there to 90 milligrams per day due to the worldwide availability of a 15 milligram leucovorin tablet.
The control regimen was intravenous 5-FU and leucovorin given at 425 milligrams per meter squared per day for 5 days, leucovorin at 20 milligrams per meter squared per day for 5 days, with cycles repeated every 4 weeks.
The study was designed to demonstrate equivalence and survival for UFT/leucovorin compared with 5-FU and leucovorin.  At least 630 events were required per the protocol.  A conclusion of statistical equivalence was based on the lower bound of the 95.6 percent confidence interval exceeding 0.8 for the hazard ratio.

The criteria used for eligibility are straightforward and they're summarized here.  The patient population enrolled in the study had metastatic colorectal cancer, had at least a 6-month interval from any prior adjuvant therapy, and had not received prior systemic therapy for metastatic disease.  Patients had a performance status of less than or equal to 2 and adequate hematologic, renal, and hepatic laboratory tests.  The protocol was approved by each institution's review board and all patients gave informed consent prior to participation.
This slide illustrates the accrual by country with the number of sites in each country shown in parentheses.  This large study enrolled 816 patients, with the majority of patients being enrolled from centers in the United States.  Initially the study had included only centers in the United States, but as it was intended to serve a global registrational purpose, it was expanded to include Canada and Europe.  The 011 study is the largest registrational trial performed for this indication.
Patient characteristics at study entry are shown here.  As would be expected in a very large trial, the two treatment arms were well balanced with regard to these characteristics.  
About 60 percent of the patients enrolled were men.  
Most of the patients had a performance status of 0 or 1.
The median age for patients enrolled in the study was 64 years, with a wide range in age in both of the treatment arms.

Most of the patients had not received prior adjuvant therapy.  
89 percent of the UFT/leucovorin patients and 91 percent of the 5-FU/leucovorin patients had measurable disease at the time of study entry.
The liver was the most common site of metastatic disease, with 80 percent of the 5-FU/leucovorin patients and 79 percent of the UFT/leucovorin patients having liver metastases at study entry.
The two interim analyses and the per-protocol final analysis were preplanned and discussed with the FDA.  An O'Brien-Fleming adjustment was used for the significance level.  The first interim analysis, performed with 237 events, was described in the analysis plan and served as the basis for discussions regarding the possibility of an accelerated filing.  The analysis with 453 events was also described in the analysis plan and was performed just prior to the initiation of the rolling NDA.  The survival analysis performed with 640 events is the protocol-defined final analysis which was submitted with the NDA.

In preparation for ODAC, the FDA had agreed that it would be helpful to update the survival analysis and this analysis was performed using a cutoff date of June 20, 1999.  This analysis included 700 events.  This updated survival analysis allowed mature data from the prospective clinical trial to add in the assessment of efficacy.
At the time of the NDA submission, 320 deaths had occurred in each of the treatment arms.  With these 640 deaths reported, the median survival for UFT/leucovorin treated patients was 12.4 months and was 13.4 months in the 5-FU and leucovorin group.  The hazard ratio for survival 5-FU/leucovorin to UFT/leucovorin was 0.93 with a 95.6 percent confidence interval extending from 0.79 to 1.1.
Use of the 95.6 percent confidence interval resulted from the statistical penalty applied as a result of the previous planned interim analysis.  Consistent results were obtained following a preplanned analysis adjusted for potential prognostic factors.

For the updated analysis, an additional 60 deaths had occurred since the time of the final protocol analysis.  There were 351 deaths in the 5-FU and leucovorin arm and 349 deaths in the UFT/leucovorin arm.  The median survival was 12.4 months for UFT/leucovorin and 13.4 months for 5-FU/leucovorin.  The hazard ratio for 5-FU/leucovorin to UFT/leucovorin is 0.96, with a 95.6 percent confidence interval extending from 0.83 to 1.13.  In the updated survival analysis, there was no change in the median survival, but the confidence interval for the hazard ratio shifted further upwards supporting the conclusion of equivalence.
The most mature survival curve from the June 1999 analysis is shown here.  In these curves, the UFT is shown in yellow and 5-FU/leucovorin is shown in white.  With this follow-up period, the survival curve now appears quite mature with few censored events occurring prior to the median.  It is apparent from these curves that the results of the 011 trial, now reported with 700 events, clearly demonstrates equivalence in survival for UFT/leucovorin compared with 5-FU/leucovorin.
Results from a multivariate stratified Cox model are shown here.  Among the covariates, only age was a statistically significant factor and gender was of borderline significance.  The hazard ratios within the subsets, defined by age and by gender, were consistent with the equivalence of UFT/leucovorin to 5-FU/leucovorin.

707 of the 816 patients were observed to have developed progressive disease.  The median time to progression for UFT/leucovorin treated patients was 3.5 months and was 3.8 months for the 5-FU/leucovorin treated patients.  This finding was statistically different.  The clinical interpretation of this 9-day difference in time to progression, in the setting of unequal time to reassessment, is difficult, however. 
Efficacy results for the secondary endpoint of response rate are summarized here for all randomized patients.  There was no statistical difference in response rates in the two treatment arms and there was no difference between the two treatment arms and the percentage of patients achieving a complete response.
Comparing the two treatments, there are clear differences in hematologic toxicity.  The incidence of both leukopenia and neutropenia, whether "any," CTC grades 1 through 4, or "severe," CTC grades 3 and 4, were highly statistically different favoring the UFT and leucovorin treatment group.  The incidence of severe neutropenia, for example, was only 1 percent in the UFT/leucovorin treated patients compared with 56 percent in the 5-FU/leucovorin treated patients.  Throughout the presentation of the toxicity data, the worst toxicity reported is shown for each patient, regardless of any assessment of drug causality, and it includes all courses of treatment.

The difference between the two treatments in the incidence of myelosuppression translated into a clinically important benefit, none of the patients in the UFT/leucovorin treatment arm experienced febrile neutropenia compared with 13 percent of those patients treated with 5-FU and leucovorin, a highly statistically significant finding.
For infections there was also a lower incidence for both any infection and severe infections favoring UFT/leucovorin.
In the phase I trials, the dose-limiting toxicity for UFT and leucovorin was diarrhea, but as can be seen here, the incidence of diarrhea was no worse for the UFT/leucovorin treated patients than for those patients receiving 5-FU/leucovorin.  In fact, the incidence of any diarrhea was statistically lower for the UFT/leucovorin patients compared with the 5-FU/leucovorin patients.  The percentage of severe diarrhea was slightly higher for UFT/leucovorin, but this was not a statistically significant difference.

There was no significant difference between the two treatment arms in the incidence of severe nausea and vomiting, although patients on UFT/leucovorin were less likely to have any nausea and vomiting than those patients receiving 5-FU/leucovorin.  This occurred despite the fact that patients receiving UFT/leucovorin were much less likely to have received concomitant antiemetics.
Here the percentage of days with diarrhea is shown for both any toxicity on the top and severe toxicity here with the percentage of days across and the percentage of patients, the 0 grade favoring UFT/leucovorin.  And when you look across the percentage of days, there was actually a statistically shorter duration of any diarrhea favoring UFT/leucovorin, and there was no statistical difference when you looked at the percentage of days with severe diarrhea.

Among these important safety advantages for UFT/leucovorin compared with 5-FU/leucovorin is the marked reduction in stomatitis/mucositis.  There was a three-fold reduction in the occurrence of any stomatitis/mucositis favoring UFT/leucovorin treatment.  For more severe toxicities, as you know, grade 3 toxicity means patients are unable to eat because of pain and grade 4 means that patients require parenteral or enteral support to maintain their fluids.  You can see that there was a difference from only 1 percent of the UFT/leucovorin treated patients having severe stomatitis/mucositis to 19 percent of the 5‑FU/leucovorin treated patients.  These findings were both clinically and statistically highly significant.
Comparing another toxicity commonly associated with fluoropyrimidine regimens, it is clear that the incidence of hand-foot syndrome was low in both of the treatment groups with only 2 percent observed in the UFT/leucovorin arm.  This was actually statistically lower than seen with the IV 5-FU/leucovorin treatment.
There as no difference between the two treatment groups in the occurrence of elevated liver function with the exception of hyperbilirubinemia.  UFT/leucovorin patients were more likely to have an increase in bilirubin, whether any or severe, than patients receiving 5-FU/leucovorin.  This finding was isolated and there was no difference between the groups in reports of hepatomegaly or liver failure.  With the interruption of UFT and leucovorin, the elevation in bilirubin declined.  This laboratory finding of an increased occurrence of hyperbilirubinemia due to the UFT/leucovorin was the only case in this study where the toxicity appeared worse for UFT/leucovorin than it did for 5-FU/leucovorin.

In this slide, the use of concomitant medications during treatment is summarized.  As previously shown, the patients in the UFT/leucovorin arm enjoyed a favorable toxicity profile, and this toxicity profile corresponded to a marked reduction in the use of concomitant medications which was statistically significant for systemic anti-infectives, growth factors, antiemetics, and specifically for 5HT3 blockers.
Patients were highly compliant with the UFT and leucovorin oral outpatient regimen.  This summary of UFT compliance, taken from patient diaries of treatment and including all courses of treatment, shows that at least 89 percent of the patients treated with UFT took at least 90 percent of the prescribed dose.
This slide describes the percentage of patients with dose reductions.  As you can see here, at the start of course 2, the majority of UFT/leucovorin patients were able to continue the treatment as initially planned, but there was a significant percentage, 43 percent for cycle 2, 56 percent at cycle 3, in the 5-FU/leucovorin treated patients who required a dose reduction.

This looks specifically at dose delays, and you can see that across the two treatment arms, they look somewhat similar suggesting that despite the 28-day continuous treatment, that the patients were able to resume the UFT/leucovorin regimen on time as planned, although apparently some of the patients with 5-FU/leucovorin required delays despite the long interval off of treatment.
The dose intensity and relative dose intensity of 5-FU and tegafur as received by patients in the study is shown here.  The patients in this study received 93 percent of the planned tegafur dose.
This very large study, which enrolled 816 patients and in which 700 patients had been followed until the time of death, demonstrates clearly that as an initial treatment for metastatic colorectal cancer, UFT/leucovorin produces equivalent survival to 5-FU/leucovorin.  While producing equivalent survival, this oral regimen is associated with significant safety advantages, including reductions in severe myelosuppression, febrile neutropenia, infections, severe stomatitis and mucositis, as well as any stomatitis/mucositis, any diarrhea and nausea and vomiting, and the use of concomitant medications.
The second confirmatory phase III study was performed to support the 011 study and helped to serve as the basis for a global registration of UFT and leucovorin.  This study, the 012 study, will now be described in detail by Dr. James Carmichael from Nottingham City Hospital.
DR. CARMICHAEL:  Thank you.  Good morning.  

This study, the 012 study, was performed in a similar patient population to the 011 study.  Patients were enrolled who had metastatic colorectal cancer and who had not received prior chemotherapy for metastatic disease.  Patients were stratified by performance status, history of prior adjuvant therapy, and institution.  Patients assigned by random allocation to the UFT/leucovorin treatment arm received the same regimen as those patients in the 011 study.  For patients randomized to treatment with 5‑FU/leucovorin, the doses were the same as in the 011 trial, but the interval of retreatment was 35 days rather than 28 days so that the cycle lengths in the two treatment arms would be the same for the assessment of the primary endpoint of this trial, time to progression.
As shown here, the eligibility criteria were very similar in this study to the 011 study.
This slide illustrates the accrual to the study by country.  The number of centers participating in each country are shown in parentheses.  For the 012 study, in addition to accrual by sites in Canada, Western Europe, there were also sites in Poland, Australia, New Zealand, and Israel.  The study had a total accrual of 380 patients up to July 1997.

Treatment arms were well balanced with regard to patient characteristics at baseline.  In both treatment arms, the majority of patients were male, 67 percent and 64 percent, respectively.  Most patients had an excellent performance status of 0 or 1, and the median age of participants was 61 and 62 years, respectively.  As in study 011, there was a wide range in the age of patients at the time of enrollment, with a significant number of older patients being included in the trial.
23 percent of patients enrolled in each treatment arm had received prior adjuvant chemotherapy.  Almost all of the patients, 97 percent in each arm, had measurable disease.  As in study 011, most patients had liver metastases:  78 percent of the UFT and leucovorin treated patients and 77 percent on the 5-FU and leucovorin treated arm.
The efficacy results for survival at the time of submission of the new drug application are shown here.  The median survival for patients treated with UFT/leucovorin was 12.3 months compared to 10.3 months for those patients treated with 5-FU/leucovorin.  The hazard ratio of 5-FU/leucovorin to UFT/leucovorin was 1.16, with a 95 percent confidence interval extending from .93 to 1.46.

As in the 011 study following consultation with the FDA, the survival results for the 012 study were updated by determining the status of each patient as of June 20, 1999.  At the time of submission of the NDA, 302 patient deaths had been observed, whereas for this analysis, a further 24 deaths had been observed.  At this analysis, the median survival for the UFT/leucovorin patients was 12.2 months compared with 10.3 months for the 5-FU/leucovorin treated patients.  A hazard ratio of 5‑FU/leucovorin to UFT/leucovorin was 1.14, with a 95 percent confidence interval ranging from .92 to 1.42.  
Here the survival curves over time are shown with UFT/leucovorin shown in yellow.  With 161 deaths in the UFT/leucovorin arm and 165 deaths in the 5‑FU/leucovorin arm, the pattern of the curves look quite similar.  It is also clear from examination of these curves that the curves are quite stable with very few censored events at early time points.  These results are very supportive of the conclusion of equivalent survival as demonstrated in study 011.

This slide illustrates the curves for time to progression in the two treatment arms, which again appear very similar.  At the time of this analysis, 320 of the 380 patients entered into the study had progressed.  The median time to progression for the UFT and leucovorin treated patients was 3.4 months, compared to 3.3 months for the 5‑FU/leucovorin treated patients.  This difference was not statistically significantly different.
Results for the secondary endpoint of response rate are shown here.  There were no statistically significant differences between the objective response rate seen for UFT/leucovorin and the 5-FU/leucovorin treated arms.  There were, however, statistically significant reductions in the instance of leukopenia and neutropenia, both covering all grades of toxicity and, more importantly, severer grades 3 and 4 toxicities, favoring those patients treated with UFT/leucovorin compared to those patients treated with intravenous therapy.  As in the 011 study, severe myelosuppression was uncommon in the UFT/leucovorin regimen.

The reduction in myelosuppression again led to a clinically significant outcome.  Only 1 percent of the UFT/leucovorin patients experienced febrile neutropenia compared to 8 percent in patients treated with bolus 5‑FU/leucovorin.  For infection, there was a lower incidence overall for the UFT/leucovorin treated patients compared to the 5-FU/leucovorin arm, although no statistically significant difference was detected in the incidence of severe infection.
There were no significant differences in the incidence of the most common UFT/leucovorin associated toxicity, diarrhea.  The percentages for any grade of diarrhea were lower amongst the UFT/leucovorin treated patients than for 5-FU/leucovorin treated patients.  However, the percentage of patients experiencing severe diarrhea was higher for the UFT/leucovorin patients although neither of these differences achieved statistical significance.
The incidence of nausea and vomiting, either any grade or severe, was similar in the two treatment groups.  The duration of GI toxicity, when it occurred, was similar between the two treatment arms.

One of the major safety advantages associated with the UFT/leucovorin regimen was the dramatic reduction in the incidence of stomatitis and mucositis.  Despite the lower dose intensity of the 5-FU/leucovorin arm used in this study, stomatitis was still a major problem with this regimen.  55 percent of the 5-FU/leucovorin treated patients, compared to only 18 percent of the UFT/leucovorin treated patients, experienced some stomatitis or mucositis during the course of their therapy.  For severe symptoms of stomatitis or mucositis, which is an extremely painful and debilitating side effect, only 2 percent of the UFT/leucovorin, compared to 16 percent of the 5‑FU/leucovorin treated patients, experienced this severe toxicity.  Both of these findings were not only clinically but also highly statistically significant and these findings were consistent with those findings observed in study 011.
The incidence of hand-foot syndrome was extremely low in both treatment groups.  There was no statistical difference between the two treatment arms.
The incidence of elevated liver function tests is illustrated here.  There was no difference between the two treatment arms in the incidence of any or severe elevations in alkaline phosphatase or transaminases.  The percentages of elevated bilirubin were higher for both categories, i.e., all grades or severe toxicities, for the UFT/leucovorin treated patients compared with the 5‑FU/leucovorin arm.  In this study, however, the findings did not reach statistical significance.

Overall the safety findings of the 012 study are consistent with the larger 011 study with the only trend towards worsening toxicity for the UFT/leucovorin treated patients being an isolated elevation in bilirubin levels.
This slide illustrates the percentage of patients receiving concomitant medications during the study.  There were statistically significant reductions in the use of antiemetics, including 5HT3 blockers, for patients receiving UFT/leucovorin compared with the bolus intravenous arm.  The use of anxiolytics was also lower amongst the UFT/leucovorin treated patients.
This slide shows the percentage of patients requiring dose reductions or a delay in retreatment.  Patients were better able to tolerate the dosing regimen of 5-FU/leucovorin given in study 012 compared to study 011.  In this study similar numbers of patients required dose reductions or dose delays in both treatment arms.
For example, UFT/leucovorin treated patients at course 4 required a dose modification in 38 percent of patients compared to 35 percent of patients on the 5‑FU/leucovorin arm.  

Nevertheless, even with the better tolerated 5‑FU/leucovorin schedule used in the 012 study, significant safety advantages were again observed favoring the UFT/leucovorin compared with the bolus regimen.
The dose intensity of 5-FU and tegafur are shown here.  The median 5-FU dose intensity of 418 milligrams per meter squared per week as delivered in this study compares to the 011 with a median dose intensity of 452 milligrams per meter squared per week, a reduction of only 8 percent.  The median delivered dose intensity of tegafur is 1,542 milligrams per meter squared per week, which compares with 1,555 milligrams per meter squared per week in the 011 study.  In this particular study, the 012 study, you can see that the relative delivered dose intensity was over 90 percent on both treatment arms.
The 012 study of 380 patients confirms the conclusion that, as an initial treatment for metastatic colorectal cancer, UFT/leucovorin produces equivalent survival to 5-FU/leucovorin.  This equivalent efficacy is achieved with a regimen which results in significant advantages in safety and in patient tolerability.  These advantages include reductions in severe myelosuppression, febrile neutropenia, infection, stomatitis or mucositis, and less use of concomitant medication.

Dr. Renzo Canetta from the Bristol-Myers Squibb Pharmaceutical Research Institute will now make a few concluding remarks. 
DR. CANETTA:  Thank you, Jim.
As you've noticed by now, despite the differences of countless investigators and protocols, the consistency of the efficacy results obtained with oral UFT and leucovorin is quite striking.  In both trials, the median survival exceeded 1 year, and the other efficacy endpoints were quite similar, thus supporting the predictability and the reliability of the efficacy effects of this compound.
For what we believe is the clinically most relevant efficacy endpoint -- and that is survival -- the hazard ratios of .96 and of 1.14 and the narrow variability of the confidence interval fully support the evidence that oral UFT and leucovorin is equivalent in effect to the current standard of care of intravenous 5-FU and leucovorin.

Now, you've seen this slide before presented by Dr. MacDonald and we add the results of our two trials here.  Now, it is important to point out that the evidence that supports equivalence is based upon a very large database.  We are talking about almost 1,200 patients here, about the same size of several other the meta-analyses in the treatment of the disease.
Now, not only was the survival in the pivotal trial and the confirmatory trial comparable to the 5-FU and leucovorin arm, but it was also comparable to the 5-FU and leucovorin arm of all these trials that have been reported before.  One thing that is important to point out is that all these trials that showed an advantage in survival for 5-FU and leucovorin in fact used a lower dosage than the one that was used for 5-FU and leucovorin in our pivotal trials.  Here we used 425 milligrams per square meter.  The Mayo clinic trial started with 370 milligrams per square meter, and only after the first time that patients were treated increased the dosage.  This study used 370.  These two trials used 400 milligrams per square meter.
The other thing that appears from this trial is that UFT and leucovorin appears to provide survival that looks better than the 5-FU alone treatment using these historical controls.

The more aggressive dose regimen used in study 011 required in fact a rapid reduction of the dosage and delays in the treatment.  That is, when you look at the delivered dose intensity, there isn't much difference between the two control arms of the two trials, and there is a mere 8 percent actual difference in dose intensity delivered between the two trials.
Now, the consistency of the results observed for efficacy is actually evident when you look at safety.  No matter how intense was the 5-FU treatment delivered in the control arm, the UFT and leucovorin always came up with significantly reduced toxicity, and that is important for these categories that have clinical importance.  This is not only lab test results and involves febrile neutropenia, severe infections, and severe mucositis across the two trials.
Now, the similarity of these findings is fairly remarkable, particularly if you keep in mind the fact that the vast majority of these investigators had no prior experience with UFT and leucovorin, and experience teaches us that one would expect that this profile would even be better as investigators gain more familiarity with the newer treatment.

Incidence of gastrointestinal toxicities both for diarrhea and nausea and vomiting was significantly lower for UFT and leucovorin in study 011.  The elevations of bilirubin were significantly higher.  However, the clinical impact of this observation was minimal.  Only 1 patient -- and that patient was in study 011 -- discontinued the treatment because of bilirubin elevation.  Only 1 patient in study 011 had elevated ALT values and only 1 patient in study 012 had elevated ALT values concomitantly with elevated bilirubin.  3 patients with  elevated bilirubin also had elevated ALT values in this arm of this study.
The hand-foot syndrome with UFT and leucovorin was significantly reduced in study 011, and actually was not observed at all in study 012.
In conclusion, what we believe is that oral UFT and oral leucovorin constitutes an important therapeutic advance in the treatment of metastatic colorectal cancer.  Survival has been conclusively demonstrated to be equivalent to the standard of care in a large and well-conducted series of studies.  The improvements in the safety profile for many toxicities are not only statistically significant, but are also clinically significant.  

Finally, giving the option of an oral regimen constitutes an important alternative for the patients that are affected by this disease, and this is particularly true in view of the reliability and predictability of the effects of this treatment.
Thus, we propose that UFT capsules and leucovorin tablets be indicated for the treatment of first-line metastatic colorectal cancer, and we recommend the dosage of 300 milligrams per square meter divided in three daily doses for UFT accompanied by a dosage of 90 milligrams per day divided in three daily doses for leucovorin, and the entire course to be repeated at intervals of 5 weeks.
Thank you for your attention.  I would be happy to field the questions.
DR. SCHILSKY:  Thank you very much.
Questions from the committee?
Let me start off with one question.  I'm curious to know if there have been any comparative trials between tegafur and UFT that might help to discern the importance of the uracil to the combination.
DR. CANETTA:  Dr. Benner will address this question.

DR. BENNER:  There were some small randomized trials that were performed in Japan at the time that UFT was developed, but these studies were not specifically in metastatic colorectal cancer.  There's one in breast cancer.  And they tended to look in these small trials relatively similar.
The reason we don't think that that contribution needs to be further assessed now is because of the clear past experience with tegafur alone in this country where the tegafur, when given as an oral regimen that produced survivals that appear worse than what we achieve now with 5-FU/leucovorin or with UFT/leucovorin in metastatic colorectal cancer, was associated with significant toxicities, so much so that the development of tegafur alone as an oral drug was abandoned in the U.S.
DR. SCHILSKY:  Other questions?  Dr. Johnson?
DR. DAVID JOHNSON:  I have basically three questions.  The first question has to do with the breakdown of data relative to prior adjuvant 5-FU therapy and how did that subset of patients fare as compared to those who had not received prior 5-FU.
The second question I have, while you look that up, has to do with second-line chemotherapy, and I'd like to know the subset analysis of those individuals who received second-line irinotecan and/or oxaliplatin. 

And then the third question I have, while you look that one up, has to do with the mechanism of hyperbilirubinemia and what implications that has for drug-drug interactions and what sort of cautions we should be looking to in the package insert.
DR. BENNER:  What we're looking for is a slide that will show you that the percentage of patients who received secondary chemotherapy in both the 011 and the 012 studies was actually very well balanced with regards to the percentage of patients receiving secondary chemotherapy.  We do not know the specific types of secondary chemotherapy in the 011 study, but we do have that data for the 012 study.
What you can see, again, when you look specifically at the 012 study for the patients receiving secondary chemotherapy, that the regimens used were very similar within the two treatment arms so that the exposure to irinotecan and oxaliplatin actually look very well balanced across the two treatments.
DR. DAVID JOHNSON:  Do you know in these 150 or so patients, from the point at which they were switched to their second treatment, what happened to these 150 patients?

DR. BENNER:  Actually we'll ask Dr. Piantadosi to go through a landmark analysis.
DR. PIANTADOSI:  Thank you.  I'm Steve Piantadosi from Johns Hopkins Oncology Center and a consultant to the sponsor on this drug.
We've looked very carefully at the effects of secondary chemotherapy not broken down by these particular drugs but any secondary chemotherapy, and I want to show you a couple of analyses that reflect on this that may be somewhat surprising.  
The first slide is U12 which shows a proportional hazards model effect taking secondary chemotherapy as a time-dependent effect; that is, we model the effect of secondary chemotherapy when it occurred during the follow-up period and then its effect subsequently on the outcome of the patient with survival as the outcome here.

What you can see from this slide, first of all, is that the use of secondary chemotherapy has a hazard ratio estimate that's greater than 1, indicating that it is a risk factor for failure in these patients and that it's interaction with the treatment group is not significant either in terms of where the hazard ratio lies or the p value, indicating that this effect of secondary chemotherapy, being an adverse risk factor, is the same in both treatment groups.
The next slide, U13, shows without the interaction, and since it was not significant, it was removed, supporting this as a risk factor.  This seems backwards and so what we did were some additional exploratory analyses to try to understand why this would happen. 
The next slide is U34 which shows a landmark analysis, stepping now away from the regressions but to a more traditional Kaplan-Meier approach.  The treatment groups have been collapsed because the effect of secondary chemotherapy is the same in both treatment groups.  What you see here is at each landmark time in 3-month intervals, we have taken those patients who received secondary chemotherapy at or before that time, so that it is a baseline risk factor with respect to this time, and looked at the subsequent outcome of those patients.  And in this study, in 011, in all cases secondary chemotherapy is an adverse risk factor for outcome.

Now, there are a couple of different interpretations of this, and the one that I favor is that when patients take a turn for the worse, it's evident clinically and they go on second line chemotherapy which probably has relatively little effect.  Those patients who haven't taken a turn for the worse and don't need it are ultimately going to do better. 
A second interpretation would be that second-line chemotherapy is in fact beneficial and that these patients would have done even worse had they not received it.
And, of course, a third interpretation is that they were doing marginally worse and that second-line chemotherapy is harmful.
But the point is, with respect to the empirical evidence in the data, it's a risk factor for adverse outcome.
DR. SCHILSKY:  Don't you still have one question that still hasn't been answered?
DR. DAVID JOHNSON:  Well, actually two, but I think Steve is going to the next one.
DR. BENNER:  This is a slide that looks at your first question with regards to the impact of prior adjuvant therapy.  You can see that only a minority of the patients in the studies had received adjuvant chemotherapy and that the hazard ratios are very close.

So, these are the survival curves for the subset of patients that received prior adjuvant therapy.
Again, survival curves, UFT/leucovorin in yellow for patients who had not received prior adjuvant chemotherapy.
Now, Daryl Sonnichsen from BMS will address your question about the bilirubin.
DR. SONNICHSEN:  Daryl Sonnichsen, clinical pharmacology.
With regards to your question about elevated bilirubins, we looked at possible pharmacological rationales for that.  Preclinically in rats, the biliary excretion of tegafur and uracil is minimal.  Tegafur and uracil metabolites accounted for about 3 percent and less than 1 percent of the radioactive dose that was excreted in the bile of rats.  Of those metabolites that are excreted in the bile, tegafur and fluorureidoproprionic acid, or FUPA, accounted for 90 percent of radioactivity. 
In a study of 18 patients treated with UFT/leucovorin therapy, no associations between steady state pharmacokinetics and the incidence of course 1 elevation in bilirubin were noted, and I'll show you two figures following this to demonstrate that.

We did not come up with an apparent pharmacologic rationale for the development of this elevated bilirubin for this drug.  What we know is that the tegafur and uracil do not appear to be substrates for transporters that may interfere with bilirubin at the level of the liver, unlike drugs such as protease inhibitors or cyclosporin.  It does not have that pharmacology, so we wouldn't expect those.
Related to possible mechanisms of interactions, again we would expect that this is an isolated bilirubin.  It did not have clinical sequelae.  It would need to be monitored in those drugs more clearly in drugs that have a preponderance for bilirubin, but beyond that we don't have any further recommendations.
And can I just show the next two figures just to show that in those patients with an elevated bilirubin in course 1, the AUCs for tegafur and plasma versus those that did not occur, the incidence, there was no apparent association.
And the next slide shows the same figure for 5‑FU exposures.  No apparent association.

DR. CANETTA:  So, to summarize in a nutshell the three questions, the three answers would be the outcome in the patients who got adjuvant chemotherapy is equivalent in both subsets for whatever treatment was given.  
For secondary chemotherapy, basically the same approach was used in both arms in both the trials.  The 012 reflects the fact that oxaliplatin in study 011 were available in Europe.  011 we don't have the data.  Obviously, oxaliplatin is not available in this country.  But basically the investigators were equipoised and they proceeded in the same way whether the patient had been randomized to 5-FU/leucovorin or to UFT/leucovorin.
And finally, for the bilirubin, we don't know clearly the mechanism by which this elevation occurred, and yet what is important to say is that more than 80 percent of the patients that had elevated bilirubin could continue to receive UFT/leucovorin and their value of bilirubin went back down.  Of the 20 percent whose values did not go back, the vast majority had documented progressive disease in the liver, and it's difficult to separate out liver disease from these abnormalities.
The other thing, as I said before, elevation in liver enzymes did not seem to predict or accompany this type of bilirubin elevations.
DR. SCHILSKY:  Dr. Krook.

DR. KROOK:  I won't quite do what Dr. Johnson did.  I think I have three questions also, but I'll try to do one at a time. 
One of the things that was done with the study was a quality of life, and what we've seen here at least presented so far is toxicity, bilirubins, febrile neutropenia.  What was the feeling of the people who were involved, the quality of life?  Did the people who took the  5-FU/leucovorin have a poorer quality of life as far as they're concerned?  At least I didn't see you present the quality of life.
DR. BENNER:  For the 011 studies, the FLIC questionnaire was used as the subjective assessment of quality of life, and there were no statistical differences between the two treatment arms with regard to the scores on the FLIC questionnaire.  This was despite the overwhelming safety advantages that I've shown you with regard to the CTC grading.

One possible explanation for that may be the fact that the FLIC questionnaire specifically addresses the quality of life for the patients in the 2 weeks preceding the questionnaire.  You can see that those patients would have been 7 days from their last dose of UFT/leucovorin but would have been a much longer time, 22 days from their last dose of 5-FU, and it may be because of the IV regimen which causes severe toxicities associated with the nadir that the patients have recovered, and by the time the instrument was given, it was not able to detect the difference in quality of life.
DR. KROOK:  What I think you're telling me, at least using that instrument, at least from the way it looks, there is not a difference in what the patient perceives, although there's a difference in timing, and then we have to interpret that also.  Okay?
DR. BENNER:  That's correct.  Using that instrument, there was no difference between the two arms.
DR. KROOK:  And second is kind of a related question.  The gentlemen at the open public hearing spoke how he was able to continue to do things.  Were most of the people able to continue with their daily activities?  And then the issue of the contribution of leucovorin.  But the first one I think is, were most of the people able to continue their daily activities?
DR. BENNER:  We'll pull up the figure. 

DR. KROOK:  I've got a comment.  At least dealing with a lot of these people, it's nice that they can do their daily activities, do trips, but my perception is that either arm could perhaps do this.
DR. BENNER:  So, this shows the time to the worsening performance status in the 011 study for the two treatment arms with the majority of patients starting out with a performance status of 0 or 1.
DR. KROOK:  Now, they were measured at time of evaluation, not --
DR. BENNER:  This would have been reassessed at the start of each cycle.
DR. KROOK:  Of each cycle, okay.
Following up on the chairperson's question, what is the advantage or disadvantage of leucovorin?  We heard again from the open public hearing the gentleman who was a pharmacist say leucovorin is a potential mixup.  Do you have any studies which suggest -- I saw what was presented -- the addition of leucovorin, perhaps the contribution with or without that?  Obviously, if you have to take two pills, that's a problem, and all the things that were commented on.

DR. BENNER:  When looking at the early preclinical experiment, the animal models suggested that animals that had been treated with UFT combined with leucovorin had a higher complete response rate than those treated with UFT alone.  So, it was felt that because what we were trying to do was to replace 5-FU/leucovorin with another fluoropyrimidine and that for all fluoropyrimidine regimens used for metastatic colorectal cancer, leucovorin is an important component with the exception of continuous, uninterrupted infusions, that given preclinical evidence that it added to the efficacy, as well as the existing clinical evidence for 5-FU and leucovorin, that it was most appropriate to develop it with leucovorin, and that the early results of the phase I and II studies showed response rates and a toxicity profile that suggested that the regimen had significant advantages.
DR. CANETTA:  Yes.  Dr. Carmichael wanted to make a comment on the daily quality of life.  Since he's treated patients, I think it's appropriate for him to comment.
DR. CARMICHAEL:  I think the issue that you were making was what was the impact on the daily life of people.
DR. KROOK:  Right.

DR. CARMICHAEL:  And what I would say is the majority of patients through most of the time, as you can see from the quality of life data, because the same in our study, the 012 study, there were no obvious differences in quality of life globally.  But I think where it did make an impact was in patients who had grade 2 or 3 stomatitis, and the number of days with stomatitis was substantially less in patients who were having the oral therapy.  So, I think in a situation where you've got more mobility away from the clinic, as well as that you've got less days with quite a debilitating toxicity that does impact the quality of life, then that does have a significant impact for patients.
What we did see even more so in our study, the problem of interpretation, was the fact that we were out 30 days following the last 5-FU dose at the time of the quality of life assessment compared to only 7 days after UFT/leucovorin.
DR. SCHILSKY:  Dr. Margolin.
DR. MARGOLIN:  I have what I think is just one question, but it may be a little bit complex and it may be best left for the FDA reviewer.  I'll let you decide Dr. Schilsky.

The question has to do with the study design and the choice of the type of 5-FU and leucovorin regimen, its toxicity, and the comparison of toxicities with the UFT/leucovorin.  Presumably the agreement with the FDA in the initial phase III study design was that showing equivalence or inferiority not lower than a certain level would be acceptable, but presumably that would also require a significant lowering of toxicities that must have been quantitated in some way and we haven't really heard that.  We've just heard that the survivals were equivalent and that the toxicity was less in some systems for UFT and leucovorin.  So, one of the questions is that and maybe that's best left to the FDA reviewer.

But the other question is the choice of the 5‑FU and leucovorin regimen.  The Roswell Park regimen is given once a week, usually 6 weeks out of every 8.  That has been my experience and interpretation that one has a much better handle on patients when treating them that way because you assess them weekly.  If you don't see them, you leave parameters for the nurses, and at the first sign of lowering of counts or mucous membrane toxicity, you have a chance to alter your therapy.  And if you give 5 days in a row of therapy and then stop for 3 or 4 weeks, you are basically stuck with whatever toxicities you're going to see from those 5 days that are already gone.  I would think that we might see different outcomes here if the other regimen had been used, and I'd like the sponsor to address that.
DR. CANETTA:  I'll take a quick shot at the questions starting from the second one, the choice of the so-called Mayo regimen as the control arm.  Obviously we have dealt with the FDA, but we deal also with regulatory agencies around the world.  And the reality is that the Roswell Park regimen is not approved outside of this country.  Several countries only accept the Mayo Clinic regimen. 
Honestly, we've been told that we could bias the trial against the control arm if we came in with a weekly type of regimen because the type of comments that we were presented was that the Mayo Clinic is short in time and then leaves the patient alone for a longer period of time.  You can take it at face value.

The reality, though, is that we are doing a comparison of UFT/leucovorin versus the Roswell Park regimen.  This has been done in the adjuvant setting.  It's a very large trial by NASBP, and I should say adjuvant setting for colon cancer.  That trial has closed accrual with 1,600 patients.  Obviously the results have not yet been publicly disclosed.  I think that trial will give us a sense of what is the relative effect of UFT/leucovorin versus the Roswell Park.  
I think also it will give us some sense of the effect of UFT/leucovorin on the liver function because we've been dealing here with patients that do not have up front a severe liver impairment or a liver impairment related to the disease.
Going back to the first question, the discussion all along with the FDA was on the .8 to lower boundaries.  There was no established statistical goal for showing improvement in safety.  Obviously the phase I and phase II program had been accurate at M.D. Anderson and other institutions to give us a sense that that would have offered safety advantages in addition of the convenience advantages.  Again, once again, if we put that in the protocol, we would have been accused of being biased because everybody would say oral treatment may be better accepted by the patients than intravenous treatment.  But there was no stipulation in the protocol for advantages in safety, and yet the advantages in safety were vast, even exceeding our expectations.
DR. SCHILSKY:  Ms. Forman?

MS. FORMAN:  There's a lot of emphasis put on convenience for this drug which is a good goal, but traditionally I think patients who are receiving the 5-FU treatment have a prescribed routine for seeing their physician and a certain level of care and testing that takes place.  And probably not only is that helpful medically, but it is also a good support system for the patient.
My question is what are you prescribing in this regard for patients who -- assuming this drug is approved, what level of care and follow-up and testing is going to be recommended and how is that going to be done?
DR. CANETTA:  Two comments.  First of all, I think that if you wanted the philosophy of going towards oral therapy, go towards what we think should be our overall philosophy:  patients become more responsible about their own treatment.  And in these particular trials, patients were responsibilized.  They were asked to look for diarrhea, were carefully educated and instructed not to play the hero, discontinue UFT at the first signs of diarrhea.  They were contacted on a weekly basis by phone by nurses.  So, I think that overall there was a more continuous responsibilization of the patient.

In terms of what we plan to do should this drug be approved, obviously as part of the package insert, we have prepared also a patient instruction booklet that will go through all the type of different things that the patient receiving this drug should be looking for.
DR. SCHILSKY:  Dr. Lamborn.
DR. LAMBORN:  I have a couple of questions just to understand the data.  The guideline of the primary analysis was a demonstration that the hazard ratio was above .8, if I understand correctly.  Obviously, if we are going to use that as a primary measure, it would be important to know the validity of the hazard ratio in terms of the modeling, and I wondered what had been looked at there.
DR. PIANTADOSI:  Steve Piantadosi, consultant.
We were also concerned about this issue and it had been raised early on by the FDA.  I have a couple of analyses that reflect on this.  The first one is slide J14.

This slide shows on the horizontal axis follow-up time and on the vertical axis the estimate of the actual hazards in the two treatment groups.  The motivation for the question is that the model that's used to estimate the hazard ratio is assuming proportionality of those hazards, which in this kind of display would be reflected by two parallel lines.
Now, one can look at this picture and say these lines are not parallel to one another, but we have several comments here.
Number one, these curves are drawn in the presence of near identity of the hazards in the two treatment groups, so that in fact they really are on top of one another.  Had they been separated by a large treatment effect, they in fact would have been roughly parallel to one another. 
In spite of that, there's a fix-up if you disbelieve that the hazards are proportional over all time.  For example, the agency noted that the survival curves crossed at approximately 24 months, and so we performed an analysis that estimated two different hazard ratios, one prior to 24 months and a second after 24 months, so that we'd be examining one hazard ratio during this period of time and another hazard ratio later.  That analysis is shown on the next slide, which is J13.
I am sorry.  Before we do that, this is the test, an explicit test of your question, nonproportionality the test rejects showing that the usual procedure for testing demonstrates the hazards are not proportional. 

The fix-up or the analyses I referred to are shown on the next slide, which is beginning with J13.  Actually let's skip J13 and go straight to J18.
So, in this analysis, we use the same model but we allow for two different hazard ratios, one early before 24 months and one late.  You can see what happens.  Before 24 months, we have a hazard ratio estimate that approximates that that we see in the entire study.  It's over .9 the lower bound, in spite of the fact that this estimate is based on substantially fewer events than the total, only the early events, is roughly equivalent to the regulatory objective.  The late hazard ratio, after 24 months, is actually in favor of the UFT arm and the lower bound is almost demonstrating statistical superiority in the later time period. 
The analyses that were presented originally in a sense average these two hazard ratios, which I personally don't think is inappropriate.  But nevertheless, this is the answer to your question.

DR. LAMBORN:  While you're up there, I'll ask you a second question, which others might also wish to comment on.  Often in demonstrating non-inferiority, a one-sided confidence interval is used, and I noticed that in this case the more conservative two-sided confidence interval was specified.  I wondered if there was a reason for that.
DR. PIANTADOSI:  Not a very good reason, and that may be appropriate in this setting. 
I appreciate the regulatory vagaries in trying to define the appropriate hurdle for equivalence.  The one-sided bound I think was chosen initially and, if I remember correctly, was specified in the protocol.  The two-sided was used to be conservative primarily, and in addition the adjustment for that confidence bound, because of the interim analysis, is also an attempt to be conservative.

There's a lot of fixation on that lower confidence bound, and quite honestly, I'm not sure that it's a big worry, whether it's .82, .8, or .79.  The agency is quite concerned about it, as evidenced by the preamble to their questions.  But in fact, there's very little evidence in the data that support values of a hazard ratio at the lower confidence bound, as you know.  The data are supporting very strongly a hazard ratio of around .95, and while we should have a look at the precision with which that hazard ratio is estimated, there's just as much support for a beneficial hazard ratio as there is for a harmful hazard ratio.  So, I don't know that we need to focus too much on the lower bound.
DR. LAMBORN:  I have one remaining question, back to a general one, which is the second study.  Initially time to progression was stated as the primary endpoint, which I assume meant that when the study started, you thought in fact that you would have a beneficial effect versus the regimen that you had selected there.  So, I'd like a comment on the fact that that sort of slipped away.
DR. CANETTA:  The second study was a confirmatory study and was a smaller study.  It was designed with the notion at the time of it being not yet a meta-analysis, but several comparisons of continuous infusion regimens of 5-FU versus bolus regimens of 5-FU.  And those trials, after being reported, although they did not show a survival advantage consistently, at least the dose at reported time to progression seemed to imply a time-to-progression advantage.
The other concern was the fact that with the disparity in the retreatment regimen in the first study, we needed to make sure that we had a study that addressed the time to progression issue at the appropriate time without reassessment bias.

DR. LAMBORN:  Yes, but my question is one of the questions that has been posed is whether the control regimen in the second study was less than an optimal control, and the fact that you anticipated an improvement in time to progression would imply that you also felt that this was in some ways a suboptimal regimen.  So, I'm trying to understand because you did indicate you expected to have improvement, not equivalence.
DR. CANETTA:  No.  As I said, that was not the thinking.  The thinking was that UFT and leucovorin would provide a more continuous exposure to the active moiety ultimately delivered, 5-FU, more like a continuous infusion, not mimicking a continuous infusion, but providing sort of mini-boluses to the patient.  And if UFT/leucovorin behaved like a continuous infusion type of regimen, it could have shown a superiority in time to progression.  
But we didn't believe that the 012 control arm was suboptimal.  In fact, what has been used reflects what is the actual practice in several clinics around the world.  And in fact, the dose intensity that has been administered supports that notion.

DR. SCHILSKY:  Maybe let me just restate Dr. Lamborn's question because I still don't think you answered it.  The briefing documents indicate that the analysis plan, the statistical design of the 012 study, was based on a hypothesis that there would be a superior time to progression for the UFT/leucovorin arm.  The study, as the data have been presented, indicates that that hypothesis is rejected, that in fact superiority was not achieved.  So, I think that's at the heart of your question.  In fact, it does lead to some other questions I guess about whether the study was sufficiently powered to accurately give us any other estimates since it was designed as a superiority trial.
DR. CANETTA:  Again, the primary endpoint of that trial was, indeed, the time to progression, and that's how the sample size of the trial was calculated.  In a regulatory type of environment, survival is the endpoint that is required, and this trial provides supportive evidence for that effect.
DR. SCHILSKY:  Dr. Nerenstone.
DR. NERENSTONE:  I just have two brief questions.

The first is neurotoxicity in the early evaluation of UFT was dose-limiting and a problem.  What was that neurotoxicity and was it looked for in these larger trials and what was found? 
DR. CANETTA:  I'm sorry.  If I understand correctly your question?
DR. NERENSTONE:  Neurotoxicity was discussed as being one of the reasons that UFT development did not continue forward in early --
DR. CANETTA:  I'm sorry.  Tegafur.
DR. NERENSTONE:  Sorry.  Tegafur.  Was that looked at in these larger trials and what was the result?
DR. CANETTA:  In fact, we happen to have the data because Mead Johnson, which is a subsidiary of Bristol-Myers Squibb, supported the IND for tegafur, and these data have been filed with the FDA as part of the IND for tegafur, and we pointed out these results.
Can we see the slide?
DR. BENNER:  Under that IND, tegafur was studied in these six trials, some of which had a 2 to 1 randomization with a larger proportion of patients being assigned to treatment with the tegafur.  That's why there's an imbalance with 127 patients treated with tegafur.

The patients enrolled compared to the current experience.  The age is very similar.  These are patients with metastatic colorectal cancer.  There was at this time an inclusion of patients with worse performance status than had been seen in our current clinical trials.
7 percent of these patients out of all of the tegafur treated patients had a prior chemotherapy prior to the tegafur.  The percentage of liver involvement was lower than in our trials where it was close to 80 percent.
Tegafur was given for 21 days split t.i.d.
Here looking at CNS toxicities.  At the time the toxicities were assessed, this was prior to the CTC scale, and all grades were included.  You can see that the CNS toxicities included headaches and dizziness predominantly, although some patients were reported to have confusion as well associated with the tegafur.
DR. SCHILSKY:  Steven, I'm sorry to interrupt, but in the interest of time, could you just comment on the incidence of neurotoxicity in the 011 and 012 studies.  I think that's what we really want to know, the neurotoxicity for the UFT/leucovorin.

DR. BENNER:  The incidence was lower.  I'm trying to pull up the exact percentage for you.  The reason for that is that when you give the tegafur, as it's converted to 5-FU, the 5-FU is rapidly catabolized.  So, when you have to give enough tegafur to get therapeutic plasma levels of 5-FU when you use it alone, you have a much higher concentration of tegafur, as you saw from the previous studies, and that is what contributes to the CNS toxicities that are seen with tegafur but not seen, as you can see, here, a lower incidence for the UFT/leucovorin.  In comparison, in those trials I showed you, 33 percent of the patients treated with tegafur had a CNS toxicity at each course.
DR. SCHILSKY:  That says peripheral nervous system.  Do you have data on central nervous system toxicity?
DR. BENNER:  You can see here for the two phase III trials pooled together.
DR. NERENSTONE:  I guess my only other concern is that because these are good performance status patients and you saw perhaps a higher incidence in poor performance status patients, if this oral medication is approved, you may actually be treating much worse performance status patients than here, and that might be something that needs to be talked about as a warning in terms of looking for problems in the future.

DR. CANETTA:  We actually believe that there is a pharmacological reason why tegafur alone induces this type of toxicity.  If you want, we can run through preclinical and clinical PK data demonstrating that it has nothing to do with performance status.
DR. NERENSTONE:  No, that's not necessary at this point.
My other question is probably a more philosophical one.  Somebody questioned the role of leucovorin, whether it was needed at all.  I actually have a different question.  The phase II study upon which the UFT dose was based, which was study 5, used a 500 milligrams per meter squared dose, but it used 150 milligrams of leucovorin.  At that dose in the phase II study, a 44 percent response rate was seen, and that was the reason it was taken to the phase III trial. 
However, in the phase III trial -- and I understand your reasoning -- the dose of leucovorin was halved or even more reduced.  In fact, your response rate was 11 percent.  

We're certainly used to seeing diminished results when you go from small numbers of phase II to a larger phase III, but a quartering of the response rate seems to be a bit dramatic.  Do you have any thoughts about why that happened?
As a clinician, quite honestly, an 11 percent response rate in metastatic colon cancer is not very encouraging.
DR. CANETTA:  We share your opinion of the relative value of response rate in this particular setting.  Yet, the way we operate, particularly for a phase III trial, we are quite paranoid about reassessing response rates.  So, the response rates that you see reflect the fact that we had responses confirmed with subsequent CT-scans and so on.
The reality, when you go back to the issue of the phase II, the phase II trials were done in single and highly qualified institutions, and the dosage of leucovorin that was given was actually a super-saturating dosage.  When we discussed the design of the phase III trial with the agency, we did address the issue of the fact that the dosage of 25 to 30 milligrams 3 times a day would result in total absorption of leucovorin.

Now, going back for one second to the leucovorin issue, obviously when we designed the trial, we wanted to make sure that UFT and leucovorin given orally was at least as good as the best accepted control arm.  That is why we chose IV 5-FU and leucovorin as a control arm, not to be accused to be biased against the control arm.  And we were aware of these trials that were maturing after the meta-analysis indicating there was a potential advantage for 5-FU and leucovorin over 5-FU alone.  So, we simply wanted to make sure that the control arm was the, quote/unquote, most active and certainly the most accepted control regimen.
DR. SCHILSKY:  We're running a little behind, so I'm going to ask for questions from Dr. Raghavan and Dr. Kelsen and, Scott, if you have a burning question, we'll give you the last word.  So, Derek?
DR. RAGHAVAN:  I'm still confused which is, I guess, a chronic state of mind, but there's one major issue I don't understand. 
I'm happy to accept that 11 months versus the 10 months comes out in my mind as about a year, and so I don't want to fight about median survival values. 

But I'm very puzzled about a drug that is introduced for convenience, and I think it's pretty obvious that an oral drug is more convenient than a parenteral drug.  If a more convenient drug, which has less mucositis and less myelosuppression, et cetera, is available, I don't understand why measured quality of life doesn't improve.  The issue of how we measure quality of life has been covered extensively in the external reviews of what we do at this committee, and yet I'm still puzzled as to why there isn't a substantial measured difference in the patient preference of one drug versus the other.  Could you talk about that in detail?
DR. CANETTA:  I think that we share your puzzlement.  Certainly there are two issues that are worth repeating again.  Actually I should say three issues.
First of all, the instrument that was used focused on the last few days before the instrument was filled, and again the recollection of 5-FU toxicity might have been exceeding those few days specified by the instrument.
The second thing, for this trial, as I said before, patients who received UFT and leucovorin were very, very intensively educated to look out for certain side effects because, again, they were responsible for their therapy.

The third thing that pops to mind -- and in fact, I'll comment in a second about that -- the UFT and leucovorin patients or the 5-FU and leucovorin patients did not really have access to know what life would have been like in the other arm.  And that's one of the biases that is always built in in these quality of life type of assessments.  We were surprised that the diarrhea was actually inferior in incidence for UFT and leucovorin as compared to 5-FU/leucovorin given that way.  
We have designed a study that actually is going on right now with URTC, and that study is designed with a crossover design after only one course of therapy so that patients get randomized to receive UFT/leucovorin versus IV 5-FU/leucovorin.  After course 1, they are crossed over, and after course 2, they sort of give their opinion about which type of treatment was better.  Obviously, there are a number of issues of this type of design that wouldn't fly as a pivotal trial, but that shows that we are very serious about this issue of quality of life.  
That trial is completing accrual right now.  We don't have yet the data available.  At the end of the second course of therapy, patients will be given the opportunity to choose how they want to continue their treatment, and these are patients with metastatic colorectal cancer.

DR. SCHILSKY:  Dr. Kelsen, glad you could make it.
DR. KELSEN:  Thank you.  First a comment and then my question, which will be very brief.
One possible other alternative explanation is that the UFT/leucovorin might be slightly less efficacious but less toxic and, therefore, the quality of life will even out because progressors will have a deterioration of their quality of life.  However, because it's less toxic, that will not be apparent as readily.  Therefore, the net effect of quality of life will be even if you accepted a hypothesis, which we haven't shown yet, that there is slightly decreased efficacy.

My question relates to something that's going to be discussed later or certainly has been raised, and that's the difference in outcome by site of treatment, namely continental United States versus the extra-U.S. sites in the 011 trial in which there appear to be a substantial difference in outcome.  Could you comment on your view of the difference in outcome on the basis of where the patient was treated and particularly on the possibility in the dose rate administration of fluorouracil/leucovorin, if that really could possibly be an explanation since the differences percent-wise don't look that huge to me?
DR. CANETTA:  Yes.  As they pull out the slide, if I can comment on your comment, your comment is actually confuted by the results of 011 where there was, again looking at the hazard ratio, the possibility of more efficacy for UFT/leucovorin.  So, one has to see the whole thing in the entire picture. 
We don't submit or suggest that UFT/leucovorin is more efficacious.  For us, all the evidence of the data points to equivalence.
Let me discuss the differences in the 011 study.  This is the 011 study only, split by patients who were accrued in the U.S. and patients who were accrued outside of the U.S.
Now, the important thing is that there's nothing special about passports.  This has to do simply with the fact that in the U.S. a 25-milligram tablet of leucovorin is available, and outside of the U.S., a 15-milligram tablet of leucovorin is available.  
When you look at these data, the other thing that you have to keep in mind is that you're talking about subset analyses.  That's important to keep in mind. 

Now, pretreatment characteristics.  There isn't much showing up in terms of differences by arm and by study in terms of what are the pretreatment characteristics.  
If I can have the next slide.  If you think of the factors that actually came out in the Cox regression analysis as being significant for survival, gender and age were factors in that analysis.  If you look at gender and age, there isn't really much of a difference in pretreatment characteristics between U.S. and non-U.S. patients.  So, at least in terms of pretreatment characteristics, we don't have much to say.
Now, the interesting thing, when you look at the dose intensity of 5-FU and of tegafur administered in the two subsets, it's kind of interesting the fact that the non-U.S. patients, indeed, seemed to have received more 5‑FU, and that would be sort of counter-deductive to the fact that these patients somehow received a suboptimal regimen by a different standard.  So, these are the data.

Next.  When you look into perspective -- again, this is a graphic that's a depiction of the hazard ratios for survival for the entire study, for the U.S. patients, and for the non-U.S. patients.  These are the data.  I don't think that when you put the whole thing into the general picture, that really points to any major difference between the two populations, again keeping in mind that this is a subset analysis.
DR. SCHILSKY:  Dr. Lippman, last question.
DR. LIPPMAN:  Yes.  I wonder if you could comment, under the concomitant medication use, on the differences in anxiolytic usage.  It was a little bit lower in the UFT/leucovorin arm in 011, but actually significantly lower in the 012 study.  I wonder if this relates to what we've been discussing about quality of life and particularly the issue of level of support and patient comfort with frequent follow-ups into the clinic and the issues with the oral versus IV regimens.
DR. CANETTA:  I would ask Dr. Carmichael to show because it is in the 012 study there was a significant difference in anxiolytics.
DR. CARMICHAEL:  I think that was a surprising finding when we analyzed the data.  I think there were expectations of reductions in things like systemic anti-infectives and the other agents that were seen.  I don't think we have an explanation for why that may be.  They obviously were linked in with the nurse on a regular basis in terms of phone calls, which may have helped reduce their anxiety, and that may well have proved a factor.  

Whether or not the higher incidence of mucositis or stomatitis made patients require additional therapy in terms of pain control and/or anxiolytics is something that obviously needs to be looked at.  So, I don't have a definitive answer for it.  It is a numerical finding that was unexpected.
DR. SCHILSKY:  Thank you.
We're running considerably behind schedule.  Hopefully we can make up some time with the FDA presentation, but let's take a 15-minute break.  We will reconvene promptly at 10:30.
(Recess.)
DR. SCHILSKY:  We'd like to proceed with the FDA presentation.  Dr. White.
DR. WHITE:  Good morning.  I'm Dr. Robert White and I will be presenting for the FDA.
The committee recently indicated it does not want two complete presentations of the NDA and that the FDA should present only the points it believes should be emphasized.  I will try to do that. 
This is NDA 12-053, an application submitted by Bristol-Myers Squibb.  The drug is UFT capsules, uracil and tegafur.

Here is the FDA review team responsible for reviewing this application for safety and efficacy:  medical, chemistry, pharmacology, pharmacokinetics, and statistics.  There were two medical officers contributing to this review.  Dr. Robert White reviewed study 11 and Dr. Martin Cohen reviewed study 12.  Dr. John Johnson was team leader.  Special appreciation to Mrs. Leslie Vaccari, the project manager, for coordinating the review of this application.
The proposed indication is UFT capsules plus leucovorin calcium tablets are indicated for the first-line treatment of metastatic colorectal cancer.
The pivotal trials.  There were two randomized  controlled trials submitted to support the indication. 
The first trial was study 11 reviewed by Dr. Robert White.  This was a multi-center, phase III study of 5-FU or UFT in combination with leucovorin in patients with previously untreated metastatic colorectal cancer.  This was an equivalency trial.  The primary endpoint was survival.  816 patients were accrued to this trial.  Patients were recruited from the United States, Canada, Europe, and Israel.

The second trial was study 12 reviewed by Dr. Martin Cohen.  This was a randomized comparative study of oral UFT plus leucovorin versus parenteral 5-FU plus leucovorin in patients with metastatic colorectal cancer.  This was a superiority trial.  The primary endpoint was time to progression.  380 patients were accrued.  Patients were recruited from Canada, Europe, Israel, Australia, and New Zealand.  No United States sites were used in this trial.
Both trials compared oral UFT/leucovorin to intravenous 5-FU/leucovorin.  There were some differences which I will point out now. 
The UFT regimen was identical in both pivotal trials.  Patients received UFT 300 milligrams per meter squared in three divided doses.  In the United States sites, leucovorin 75 milligrams per day, also divided in three doses, was given.  In the non-U.S. sites, 90 milligrams per day of leucovorin was given.  I want to point everybody to the red here.  These are our emphasis points.
All medication was administered orally for 28 days.  After the 28th day of therapy, patients rested 1 week and then resumed treatment.

On the 5-FU/leucovorin arm in both pivotal trials, patients received 5-FU 425 milligrams per meter squared and leucovorin 20 milligrams per meter squared IV for 5 days.  In study 11, patients repeated the dose every 4 weeks.  In study 12, they repeated their dose every 5 weeks.  The 5-FU/leucovorin in study 11 was 25 percent more dose intense than in study 12.
This brings us to the first FDA point.  In study 11, the control arm, 5-FU/leucovorin, was 25 percent more dose intense than in study 12.
Now, this slide summarizes efficacy results of response, time to progression, and survival.  The emphasis points are here in red, and I want to direct everybody's eyes there.
In study 11, the response rate to 5-FU was 15 percent.  In study 11, the response rate to UFT/leucovorin was 12 percent.  
With regard to time to progression, the median time to progression on 5-FU was 3.8 months, and it was 3.5 months on UFT/leucovorin.  This did reach statistical significance with a p value of 0.011. 
This brings us to the second FDA point.  In study 11, UFT/leucovorin was statistically inferior in time to progression.

Back to our efficacy table.  In study 11, the median survival of 5-FU/leucovorin was 13.4 and on UFT/leucovorin it was 12.4.  This result, favoring the 5‑FU/leucovorin arm, did not reach statistical significance with a p value of .391.
The hazard ratio was 0.933, with a lower bound of the 95 percent confidence interval of the hazard ratio of 0.794.
Now for the results in study 12.  The response rate to UFT/leucovorin was 11 percent; to 5-FU/leucovorin, it was 9 percent.  This also did not reach statistical significance.
With regard to time to progression, the median survival time on the UFT/leucovorin was 3.4 months and 3.3 months.  This did not reach statistical significance, but recall this was a superiority trial with time to progression as the primary endpoint.
The median times to survival were 12.3 months on UFT/leucovorin and 10.3 months on 5-FU/leucovorin.  And this also did not reach statistical significance.
Now, the hazard ratio in this case was 1.162 with a lower bound for the 95 confidence interval on that hazard ratio of 0.925.

Now, let me show the committee something that the FDA finds of interest, and again the emphasis is on these numbers in red.  If we focus from that last slide on the UFT/leucovorin arm and look at, again, response rate, time to progression, and survival, the duplication or replication of the response rates, time to progression, and survival are striking.  The response rates were 12 percent and 11 percent.  The times to progression were 3.5 and 3.4 months.  The median survival times were 12.4 months and 12.3 months.
Now, if we focus on the 5-FU/leucovorin arm, we do not find the same duplication and replication.  The response rates were 15 percent and 9 percent.  The times to progression were 3.8 months and 3.3 months.  The median survival times were 13.4 months and 10.3 months.
5-FU/leucovorin appears worse on study 12.  Recall that study 12 had less 5-FU dose intensity.

The next FDA point.  Although cross study comparisons are problematic, the results with UFT/leucovorin are almost identical in study 11 and study 12.  The difference in results in study 11 and study 12 may be due to the differing 5-FU/leucovorin control regimens.  This possibility must be considered.  The advice of the committee is sought on this issue.
Now, this table shows the survival analyses that were done during study 11.  There was an unplanned analysis at 237 deaths, with the hope of showing superior results with UFT/leucovorin regimens and submitting the NDA early.  There was a planned interim analysis at 453 deaths.  The protocol-specified analysis was at 630 deaths.  The applicant final analysis was at 640 deaths.  An additional unplanned analysis was done at 700 deaths after the final analysis had been submitted. 
The lower bound of the hazard ratio for survival at the protocol-defined final analysis was 0.785 and at the applicant final analysis was 0.794.
The true lower bound on the hazard ratio is uncertain.  In order to illustrate the problem with the uncertainty of a 95 percent confidence interval on the lower bound of the hazard ratio, here is a survival graph from study 11 when 700 deaths have occurred.  The upper curve is 5-FU/leucovorin and the lower curve is UFT/leucovorin.  Note at approximately 24 months the survival curves cross.  This makes the lower bound of the 95 percent confidence interval on the hazard ratio uncertain.  

Also, this is a time when few patients remain on treatment.  Over 75 percent of patients have progressed at this time.  Even at 12 months, only 26 of 816 patients remain on therapy.  There were 19 on UFT and 7 on 5-FU.  So, it is doubtful that the crossing of the curves at 24 months is a treatment effect with treatment so far removed.
Now, for the next FDA point.  In study 11, the lower bound of the two-sided 95 percent confidence interval on the hazard ratio for survival is uncertain because the survival curves cross at approximately 12.4 months.  The FDA believes the highest lower bound that can be supported is approximately 0.80.

The lower bound on the 95 percent confidence interval on the hazard ratio is important because it gives an estimate of how much of the survival time of the 5‑FU/leucovorin arm may be lost with UFT/leucovorin treatment.  This slide shows how much of the survival time of the control, 5-FU/leucovorin regimen, may be lost with the use of UFT/leucovorin in study 11.  Assuming a lower bound of the 95 percent confidence interval of 0.8, that means that 20 percent of the control 5-FU survival time may be lost.  The median survival, as shown on this slide, on the control 5-FU/leucovorin regimen is 13.4 months.  Thus, 2.68 months of median survival time may be lost with the use of UFT/leucovorin in study 11.
To assess the equivalence of two treatments, we must first know the effect of the control.  Then we must decide how much of the control efficacy we're willing to lose and still call the treatments equivalent.  The best information on effect of 5-FU/leucovorin control regimen comes from studies assessing the contribution of leucovorin to 5-FU.  5-FU alone is not shown to have any effect on survival.
This table shows the results of 8 such studies and one meta-analysis.  The effect on median survival ranges from 0 to 4.3 months.  Assume that each of these studies represents true effect of the 5-FU/leucovorin control regimen.  The column on the right here shows the amount of efficacy that may be lost in study 11 by using the UFT/leucovorin regimen.  The range is from 62 percent to 536 percent.  If the true effect of the 5-FU/leucovorin regimen is less than 2.68 months, then the UFT regimen may be a placebo or worse than a placebo in its effect on median survival time.

This brings us to the next FDA point.  In study 11, most or all of the efficacy of the 5-FU/leucovorin control regimen may be lost with UFT/leucovorin.
Now, recall that in study 12, the UFT/leucovorin arm was identical to the UFT/leucovorin arm in study 11.  It was the 5-FU/leucovorin arm in study 12 that was less dose intense with an every 5-week schedule instead of an every 4-week schedule.  The 5-FU/leucovorin arm in study 11 is 25 percent more dose intense.
Another FDA point.  In study 12, there are insufficient data on the efficacy of the 5-FU/leucovorin control regimen to assess whether UFT/leucovorin has an effect on survival based on equivalence to the 5‑FU/leucovorin control.  The advice of the committee is sought on this issue.
Now, the applicant submitted the following analysis, and this was their final analysis at 640 deaths from study 11 and they subsetted it by geographic site.  The survival results in U.S. sites strongly favor 5‑FU/leucovorin.  However, in non-U.S. sites, they strongly favor or lean toward UFT/leucovorin.

In study 11, the disparity in survival effect between U.S. and non-U.S. sites is a concern.  The UFT/leucovorin does poorly at U.S. sites.  This cannot be assessed in study 12 because it is entirely at non-U.S. sites.
Safety.  There's not much more the FDA has to add to the toxicity information presented by the applicant. This slide shows worst hematological toxicity for each patient at any time during the study.  5-FU/leucovorin has more hematological toxicity than UFT/leucovorin, reaching statistical significance in leukopenia, neutropenia, febrile neutropenia, and thrombocytopenia.  Across studies, the less dose intense 5-FU/leucovorin arm in study 12 may be trending toward less frequent hematological toxicity than the arm in study 11.
This slide shows worst non-hematological toxicity for each patient at any time during the study.  In study 11, any diarrhea, any nausea and vomiting, and any mucositis are statistically significantly reduced on the UFT/leucovorin arm.  Severe diarrhea and severe nausea and vomiting are trending to be less on the 5-FU/leucovorin arm.  Of course, this did not reach statistical significance.
In study 12, except for any and severe mucositis and any infection and skin toxicity, there were no significant differences between the UFT arm and the 5-FU arm.

With regard to bilirubin, all I have to say is any and severe hyperbilirubinemia are statistically more frequent on the UFT arm in study 11.
Summary.  In study 11, the control arm, 5‑FU/leucovorin, was 25 percent more dose intense than in study 12.  
In study 11, UFT/leucovorin was statistically inferior in time to progression.
Results with UFT/leucovorin are almost identical in study 11 and 12.  The difference in results in study 11 and study 12 may be due to the differing 5‑FU/leucovorin control regimens.  Although cross study comparisons are problematic, this possibility must be considered.  Again, the advice of the committee is sought on this issue.
In study 11, the lower bound of the two-sided 95 percent confidence interval on the hazard ratio for survival is uncertain because the survival curves cross at approximately 24 months.  The FDA believes the highest lower bound that can be supported is approximately 0.80.
In study 11, most or all of the efficacy of the 5-FU/leucovorin control regimen may be lost with UFT/leucovorin.

In study 12, there are insufficient data on the efficacy of the 5-FU/leucovorin control regimen to assess whether UFT/leucovorin has an effect on survival based on equivalence to the 5-FU/leucovorin control.  The advice of the committee is sought on this issue.
In study 11, the disparity in survival effect between U.S. and non-U.S. sites is a concern.  The UFT/leucovorin arm does poorly at U.S. sites.  This cannot be assessed in study 12 because it is entirely at non-U.S. sites.
And finally, we have one last slide that is added at the request of Dr. Temple.  It is not clear to the FDA that an oral formulation of a cytotoxic anticancer drug is an advantage over a parenteral formulation because of the uncertainty of the amount actually taken by the patient and the narrow safety margin.  This uncertainty is less important with drugs for other conditions where the safety margin is much greater.
And the slide that I contributed the most to:  The End.
(Laughter.)
DR. SCHILSKY:  Thank you very much for a very concise presentation.

We have time now for questions from the committee.  Dr. Kelsen.
DR. KELSEN:  One of the major points that you've made is that UFT/leucovorin may have less efficacy or lost efficacy in survival when compared to 5‑FU/leucovorin, and you went through a mathematical presentation of that.  My question is, why do you think UFT/leucovorin is a placebo when there are randomized studies of treatment versus best supportive care, at least initiating best supportive care?  There are not many of these.  There are four or five of them.  In most of those trials, the arm randomized to start with best supportive care with an option for later chemotherapy has a median survival of about 5 or 6 months.  The Nordic trial is an exception with a 9-month median survival, but the Nordic trial specified asymptomatic patients only.  And as I looked through this, it looked to me like most of these patients were either ECOG 1 or 2, not that many ECOG 0 and I don't know how many ECOGs were asymptomatic.  Therefore, the statement that it's a placebo or worse than -- it can't be worse than a placebo, but a placebo, I just wonder where you get that. 
DR. WHITE:  Yes.

DR. KELSEN:  Just let me follow up.  Because when you have this nice table that shows comparison to historical studies, which is always a little bit tricky, it seemed, if I understood this correctly, that you do the worst the smaller the difference between the observed arms, particularly that half month.  I understand the mathematics of it, but I'm wondering about the clinical applicability about that.  It sounds like the better you do, the worse your numbers are going to be.
DR. WHITE:  Yes.  We talked about this amongst ourselves.  This goes back to the basic efficacy of 5‑FU/leucovorin in this disease and it is felt to have no impact on survival.  That's the best answer I can give.
DR. KELSEN:  The view is that the standard of care arm, or at least a treatment that is widely prescribed, fluorouracil/leucovorin, if I just understood correctly, may not have any impact on survival.  Is that what you were just saying?
DR. WHITE:  No, 5-FU.
DR. KELSEN:  Yes, 5-FU.
DR. WHITE:  Yes, alone.

DR. KELSEN:  Well, the randomized trials are 5‑FU in a variety of combinations, MLF, 5-FU, leucovorin, and those studies show against no treatment a modest but felt to be clinically significant improvement in outcome.  That's not your feeling.
DR. WHITE:  I was making the comparison to 5-FU alone.
DR. KELSEN:  Okay.
DR. DAVID JOHNSON:  Rich, it might be worth doing a little historical review for purposes of this committee.
When you and I came on this committee initially several years ago, one of the very first things that we were asked to review was the utility of CPT-11 in this disease.  There was a lengthy, detailed discussion about the efficacy of 5-FU versus 5-FU plus leucovorin in colon cancer.  And randomized trials were presented, including SWOG data and others, which failed to really show a major survival advantage for the addition of leucovorin.  Yet, the committee at that time, this committee, accepted, I recall very vividly, this issue -- Dr. Bunn was the Chair of this committee at the time -- that 5-FU/leucovorin was a standard.  It didn't say the standard.  It said a standard for the treatment of this disease.

Now, whether or not one can show a difference between 5-FU plus leucovorin versus 5-FU of any major substance I think is debatable and was debatable at that time.  Some members of the committee, as I recall, wondered why the committee accepted 5-FU/leucovorin as a standard when it had not been shown to be superior in survival to 5‑FU.  The answer ultimately boiled down to a difference in response rates that were perceived but not proved to be related to improvement of quality of life.  If I can interject a little corporate memory into the discussion here, that's where we were at that time with that discussion.
In fairness, it seems to me -- I realize the committee has changed, and we can change our mind.  We are free to do that, but as I recall vividly, that was the issue and it seems to me that it's still valid today, those discussions that we held almost 3 and a half years ago now.
DR. SCHILSKY:  Thank you.  We can maybe ask you to take on the official role of committee historian.
(Laughter.)
DR. DAVID JOHNSON:  Well, in that regard, I actually had some comments then, if you wanted me to do that.
(Laughter.)

DR. SCHILSKY:  This has not been rehearsed in advance, ladies and gentlemen.
(Laughter.)
DR. DAVID JOHNSON:  No.  Because I actually think sometimes the corporate memory is helpful.  I assume that's the reason why the FDA asks us to serve more than one meeting at a time, although I have to confess sometimes it seems like it's one meeting at a time.
But, for example, I was very interested in this elaborate analysis regarding the certainty, if you will, of the lower bounds of the 95 percent confidence interval.  I appreciate the point that is being attempted to be made here, and this is by no means an effort to be flippant.  But the reality is those two curves on which this analysis was done are so precisely the same that it seems to me that it's a lot of effort for not really a clinically relevant issue in my opinion. 
Again, the corporate memory tells me that we have approved drugs, albeit maybe in an accelerated manner, with similar mechanisms of action with considerably less data than were presented in this randomized, I think well-conducted study.  And it seems to me that that really is what we as a committee ought to focus on.  

What did they do?  They took a standard that we accepted once before in a well conducted study.  I don't care if it was done in the U.S. candidly or in Canada.  I noticed Canada was on both sides of this, so they need an identity check.
(Laughter.)
DR. DAVID JOHNSON:  But the reality is this study was well done and I think proved the point that they set out to prove. 
Now, the second issue.  I agree with the points that were made.  The study did not meet the endpoint that it was designed to do.  But I think, as I see the sponsor's presentation, it's merely presented for supportive evidence, and you yourself pointed out the consistency of the data, in the UFT presentation.  In fact, it's shockingly consistent.
DR. WHITE:  Strikingly.
DR. DAVID JOHNSON:  Well, I would say shockingly.  I've never seen data this consistent from two studies like that.  And I think that's very powerful evidence in my mind.

One, I think, last corporate memory issue that's worth making is related to -- and one other point that I wanted to bring out was the issue of the placebo, whether this is a placebo or not.  I think the answer is clearly it is not a placebo, 5-FU/leucovorin, even if given poorly.  You might argue it was a poor way of giving a standard treatment, or you might argue it was a good way if you're looking at it from a toxicity perspective.  But I don't think that that impacts on the efficacy of the UFT, which I believe they have demonstrated at least is equivalent to a standard way in this country of giving 5‑FU/leucovorin, which we've previously accepted as a reasonably standard regimen.  That's how I see these data personally.
DR. SCHILSKY:  Thank you, David.
Dr. Raghavan.
DR. RAGHAVAN:  I guess that I run the risk of being like some of my procedural colleagues which is often wrong, but never in doubt.  I just am very perturbed by the presentation because it seems to me that it's totally missed the point.  

One looks at the survival curves, and as my distinguished southern colleague pointed out, they are very, very similar.  And one has just listened to an attempt to look at what might happen and if certain simulations occurred.  It's sort of, really effectively, a historically controlled statistical analysis, and I think it's actually not very valuable.
But what I think I would really like to have heard the FDA do is concentrate more on what I think is the fundamental issue.  There's an orally administered drug which has been designed to reduce the problems of having chemotherapy, and to me, treating a lot of patients, it's a no brainer.  Patients like to take things by mouth rather than get stuck with a needle and to take them at home rather than to come to a clinic.
So, I don't have a lot of interest in comparing 52 versus 53 versus 51 weeks and try to make sense of whether a benefit is lost when there is a large number of patients that are following identical survival curves.
But I'd be very interested, Dr. White, in your sense of the issues that we raised related to toxicity, which you kind of summarized just in one slide.  Give us the FDA's gestalt.  Does this make toxicity less?  Does it make it easier for patients to deal with fluoropyrimidines?

You know, the whole story of fluoropyrimidines, corporate memory or not, is somewhat like rearranging the deck chairs on the Titanic.  It's a small gain.  We've recognized that.  Dr. Johnson, Dr. Schilsky, and I were there 3 and a half years ago when we ground through whether 5-FU was good or bad and whether leucovorin added.  But the reality is the community in time has accepted 5‑FU/leucovorin as some form of standard. 
So, the thing I'm really interested in knowing about this product is what is the patient benefit from the perception of the FDA?  Is it easier to take?  Do they live better lives?  Is it better tolerated?  Can we not assess it from the data presented?
DR. WHITE:  Based on the quality of life assessment in study 11, there was no difference between the two arms.  So, the reduction of toxicity that's being claimed just didn't seem to result in improvement in quality of life.
DR. SCHILSKY:  Dr. Margolin.

DR. MARGOLIN:  I think that we need to be very careful how we interpret the information from the study about the quality of life which we actually didn't see presented but we had in some of the handouts -- and we haven't heard a statistical analysis of it either, which often breaks down its integrity -- versus the actual toxicities as measured by whatever toxicity scale was being used because in this study -- and I think somebody asked about this earlier and didn't get a full answer -- patients with this disease had a very short duration of treatment, a very short progression-free interval, and they were off therapy.  The value of quality of life analysis, when patients are falling off as quickly as they are, has to be quite limited and I think needs to be looked at quite differently than the actual toxicities of treatment.  
I think quality of life and the impact of an oral therapy versus a really relatively nontoxic IV chemotherapy are probably much more useful in a patient group that is benefiting over a much longer period of time, is being treated longer, or if it's adjuvant where everyone gets 6 months of therapy and then they go off, but otherwise they're well.
DR. SCHILSKY:  Dr. Krook.

DR. KROOK:  A couple of comments and back to the quality of life issues.  I am going to come back at Derek a little bit here, and maybe my statistician can help.  But if I'm correct, these people will take 12 pills a day 28 days out of each 35 days, which is 336 pills in a cycle.  I guess as an investigator I'm not sure that's easier than 5 days of 5-FU/leucovorin.  Now, maybe I've been around long enough that I've passed out enough 5‑FU/leucovorin, but it isn't that difficult.  So, if it comes down to an issue of what's easiest and convenient to the patient, I guess I plead with the sponsor, if this is made available, that we do something about the number of pills.  If I'm correct, it's 4 pills 3 times a day.  So, I think that that's something that I come back to.  I don't think taking that many pills is convenient.
Secondly, the quality of life scales that Dr. White or Dr. Johnson or Dr. Cohen -- I'm not sure who did them -- in the FDA document does show that at least that document is the same on both arms.  And I have a little bit of trouble rationalizing out that there's less side effects when I look at these quality of life, and that when we look at all, if and and, they come down I think the two regimes in both studies are equal in quality of life.  I don't think there's a benefit of one over the other.  And they appear to be similar in survival, however you look at it.  After that, I agree with Derek, I think we're starting to pick it apart.

Perhaps Dr. White would like to comment on the quality of life at least being the same.  That's what my question.  There isn't a difference when you look at the approved scales.
DR. WHITE:  Based on the claim in reduction in toxicity on UFT/leucovorin, I specifically looked to see whether that was going to translate into a quality of life improvement, and it wasn't there.
DR. KROOK:  And I think 336 pills -- again, we can't ask that, but cost-wise certainly that's a problem.  But somehow if this is available, I think that issue has to be dealt with.

DR. SCHILSKY:  Just one other comment on the quality of life issues.  Many of the reductions in toxicity were laboratory parameters, blood counts essentially.  I don't know that one would anticipate that a reduction in a blood count nadir would necessarily have a quality of life impact on a patient.  The number of febrile neutropenic events were different, but there were relatively few and they might not ultimately manifest themselves in a quality of life analysis.  And one might argue that the reduction in mucositis in the UFT arm was balanced by the increase in diarrhea in the UFT arm.  So, maybe there's a plausible explanation for why there might not be an overall difference in quality of life, that there's just some tradeoff in toxicity.  Some of the other toxicity reductions which the physician may appreciate as being potentially important may be, in a sense, unrecognizable to the patient.
I had one question for you, Dr. White.  I wonder if you could help answer the question that you said Dr. Temple posed on that slide that you put in there having to do with compliance.  So, was there information on compliance submitted in the NDA?
DR. WHITE:  Yes.
DR. SCHILSKY:  Did you look at it, and what's your assessment about compliance?
DR. WHITE:  Well, it depends on your definition.  And I made some comments on that in my review.  Patients on UFT had to take the medicine for 28 consecutive days, and to be fair with regard to the 5-FU/leucovorin arm, there were about 39 patients, or 10 percent of the patients, on UFT/leucovorin who missed 6 or more days of the medication.
DR. SCHILSKY:  Now, is that a compliance issue or is that a --

DR. WHITE:  Well, I thought it was a compliance issue.  I thought it was a compliance, that patients forgot, they missed.  So, I looked at those patients in detail in terms of toxicity, and to my shock, it appears, at least with the graphs I provided, to coincide with the onset of toxicity.
DR. SCHILSKY:  So, why were you shocked by that?
DR. WHITE:  Because I thought it was just going to be a simple compliance, and at least based on what they were saying, that it was reduced toxicity, I gave them the benefit of the doubt.
DR. SCHILSKY:  So, if I understand you correctly, you're saying that when patients missed doses, that it appeared that it was related to toxicity.  So, it may have been either a protocol-specified dose modification or just a recommendation from the physician that they skip doses.
DR. WHITE:  When patients missed 6 or more.  And I used that as a cutoff because that was being fair relative to missing a day of 5-FU.  What was the question again?

DR. SCHILSKY:  I'm just trying to get your insight as to whether these missed doses were patients just being noncompliant as in not following instructions or they were missing the doses because they were told to omit doses.
DR. WHITE:  At least with regard to the first course of therapy -- and that's where I felt everything was equal and that's where I focused on -- it seemed to be due to toxicity, although it seemed that the patient was on drug a day or 2 more after the onset of grade 2 toxicity which was the cutoff when they should have come off treatment or when the weekly telephone call came.
DR. SCHILSKY:  Ms. Forman.
MS. FORMAN:  Just to ask the question a different way, is there any evidence as to patients who either forgot to take the medication or some other circumstances rather than the reaction to the medication?  How many patients were in that category percentage-wise or numbers, whatever?
DR. WHITE:  Yes.  With regard to the first course, there were 95 patients who missed at least 1 day's worth of UFT.  In terms of why those patients who missed less than 5 days of UFT, that hasn't been examined yet.
DR. SCHILSKY:  Dr. Lippman.

DR. LIPPMAN:  I agree with Dr. Johnson's assessments of the survival equivalence and his comments regarding the standards, but a lot of this seems to be the apparent discrepancies perhaps between issues of convenience, quality of life, and toxicity grading.
Regarding compliance, again if you look at the table that was presented, the fact that 99 percent of the people took 80 percent or more of the medication seems pretty good, even given the number of pills.
Regarding the issue of whether there's clinically meaningful toxicity or we're just looking at grades -- because really there are impressive differences in toxicity grading.  Again, I come back to looking at some of the correlates like the concomitant medication use, which seems to clearly support the clinical importance of these toxicity grades.  Unless some of these antiemetics and so on are used prophylactically to a greater degree in one arm or the other -- and maybe there could be some comment -- if they're not being used prophylactically, this would seem to support the clinically meaningful differences in toxicity that were reported.

DR. WHITE:  Let me just make a comment about the UFT compliance that you were talking about.  When you look at the accessed database, there was, of course, compliance which only applied to UFT.  I spent a lot of time trying to figure out what that exactly meant.  I thought if I prescribed 28 days' worth of UFT and somebody took 80 percent, whatever that is, 23 out of 28 days, that's what that 80 percent meant.  That's not the case.  I have a case report form.
What I believe happened is if a patient was prescribed 28 days, but if they only took it for 6 days but took only, say, 5 and a half days, it was the 6 divided into the 5 and a half and not 28, which would have brought it down to 17 percent. 
So, those numbers that were presented relative to UFT compliance are inflated, and they don't match the dose intensity numbers that were included in the exact, same table.
DR. SCHILSKY:  Dr. Raghavan.
DR. RAGHAVAN:  Using the FDA tables, I think we still have a forest and trees problem, and I come back to the point because I think it's important, Dr. White.  You said that the measured quality of life didn't show a difference, and I accept that.  I think that the company goofed big time by not understanding the right indices of quality of life and how to apply them.  Listening to Dr. Canetta, I think that they recognize that.

But if you look at the data that you've analyzed, we're looking at severe leukopenia less than 1 or 2 percent versus 19 or 12 percent, worse figures for neutropenia, equivalently different figures for severe stomatitis.  Now, I defy any clinician or any patient to say that having a mouth fallout is a good thing.  Therefore, if you have severe stomatitis in 1 and 2 percent versus 19 and 16 percent, it seems to me a no brainer that quality of life is better in the people who don't get it.
So, therefore, I'm just really worried that the forest and trees issue here is that we're talking about small differences in survival where for metastatic disease the treatment is quite poor.  We have what looked to me like poor quality of life official measures, sort of, if I could say, patient controlled measures.  And I don't mean to demean those, but yet objective indices that go with poor quality of life that are vastly different.  
So, Dr. White, I'm surprised that you haven't expressed concern over that discrepancy.  It troubles me enormously because there are such big differences in the indices that I think make patients' lives worse.

I take Jim Krook's point that taking a lot of tablets is a bad thing.  On the other hand, showing up to a cancer center week after week after week and getting stuck where sometimes you get stuck three or four times is no picnic either.  
I'm just uneasy that, while we're getting very, very clever in looking at fine points, we're missing the big picture, which is that even though the company screwed it up, this looks like the medication actually causes less morbidity in a way that we're used to looking at traditionally, and all the very clever indices of quality of life seem to be letting us down.  I think this is going to come again and again at FDA.  So, I think we probably ought to nail it down today.
DR. SCHILSKY:  David.
DR. DAVID JOHNSON:  It's perhaps repetitious to say it again, but again just as a clinician taking care of patients, patients complain of mucositis, patients complain of nausea, patients complain of being anxious, and these are all parameters that I see the UFT arm doing better.
Again, the concomitant therapies -- maybe that's a recording phenomenon; i.e., the company was very careful to record all those data for 5-FU/leucovorin and were more casual or less diligent, but I sort of doubt that that's the case.  I think here that's good supportive evidence, as Dr. Lippman has said. 

For those reasons, it seems to me again that they've shown that is what they set out to do.  This is equivalent therapy.  At worst, toxicity similar.  As I see these data, the toxicity appears to be less. 
In terms of the convenience issue, I think some patients will find pills more convenient and some will find injections more convenient.  That's the way it is now for me with etoposide, and I'm glad I have that particular choice for patients.  I see patients that live 250 miles away from me and some that live a block away, and the trip to the clinic is easy for some and not for others.  This gives some flexibility in the ability to treat those patients, it seems to me.  That's the other "advantage" I see.
DR. SCHILSKY:  We've been blending our discussion and questions.  So, let me just bring us back for a moment to ask, does anyone have specific questions to the FDA regarding their presentation?  Because we will have additional time for discussion.
Dr. Margolin.

DR. MARGOLIN:  I guess it's just a reiteration of my original question that would have been to the FDA in the first place.  I didn't get an answer.  I know the FDA tries to be very rigorous, and generally when we recommend a new drug approval, it is with the requirement to show a clinical benefit either by survival or by some good surrogate for survival or quality of life. 
In this study, it seems that even in the design of the phase III, the FDA agreed to use in the pivotal study equivalence as clearly defined for the new drug without defining what improvement in the tolerability or the quality of life or the toxicity profile would be sufficient to allow only equivalence to make this drug approvable.  
And in the second trial, the supportive trial, the concept of progression-free survival as the endpoint we know is one that the FDA has been grappling with, although presumably that's an historical problem in that this study was agreed upon before the FDA started to revisit the value of progression-free survival.
DR. JUSTICE:  Well, there would be no requirement to demonstrate -- I mean, if the committee votes for approval, you're voting that the survival is equivalent or non-inferior, whatever terms you want to use.  You don't have to believe that it's less toxic to vote for approval. 

Does that answer your question?
DR. MARGOLIN:  No, because in previous meetings, it was always my impression that for a new drug to be approved, it had to be better than an existing drug.
DR. JUSTICE:  No, that's not true.
DR. SCHILSKY:  Dr. Blayney.
DR. BLAYNEY:  In the discussions about quality of life and toxicity, et cetera, it sort of hinges on the fundamental question where they measured equivalently.  I noticed in the UFT arm, a nurse or some study personnel at each site called the patient at least once a week.  Was that done in the control arm?
And second, were the biochemical and hematologic parameters measured equivalently in the control arm and the UFT arm?
DR. WHITE:  The laboratory interventions were done the same, as far as I remember.  I asked the company about whether the 5-FU/leucovorin arm was being called weekly, and based on what they told me, that was yes, that they were being called weekly.
DR. SCHILSKY:  Okay.  Any other questions for the FDA at this point?

DR. BLAYNEY:  Excuse me, Rich.  The other thing has to do with salvage or second-line treatment.  The FDA analysis made a point about the U.S. versus non-U.S. sites in terms of the efficacy of the control arm.  We were shown that in the 11 study 50 percent of the patients got some sort of salvage treatment.  Do you know if there was a difference in the salvage therapy or the second-line therapy between the U.S. and non-U.S. sites?
DR. WHITE:  We asked that question, and basically got the same numbers that you saw here.  But Bristol-Myers Squibb said that they didn't investigate and weren't required to collect what regimen the patients were put on.
DR. BLAYNEY:  But in terms of patients who received salvage therapy, was that subset analysis performed?
DR. WHITE:  Oh, I didn't perform that subset analysis.
DR. SCHILSKY:  I think we did see some data from the sponsor earlier about that point.

DR. BLAYNEY:  But it was balanced in terms of treatment versus control arm but not U.S. sites versus non-U.S. sites, and in the FDA analysis, they made a point about the better performance of the control arm in the North American or U.S. sites.  I wonder if that could be explained by availability of effective -- if you agree there is effective salvage or second-line therapy on survival.
DR. WHITE:  What you've got in front of you is a draft review, so that may be something that we will go ahead and look into after the meeting.
DR. SCHILSKY:  Before we go into a more general discussion, Karen Somers has another public statement to be read to the committee.
DR. TEMPLETON-SOMERS:  This is a fax that has just been received today from the Hepatitis C Action & Advocacy Coalition.  Actually I'm not going to read the whole thing.  It came with a number of letters, and I'm just going to read the cover letter.
"To the FDA Advisory Committee for Oncology Drugs:
"We request that the following comments be read at the advisory committee meeting on September 16th for the consideration of Bristol-Myers Squibb's UFT, uracil/tegafur, fixed combination and leucovorin for the treatment of metastatic colorectal cancer. 

"As a coalition of patients and patient advocates, we strongly oppose the approval of the two-drug combination with UFT/leucovorin if Bristol is allowed to market the drug solely in a fixed combination package under the brand name Orzel while the drugs are unavailable separately.  This will lead in oncology to the same fiasco that now exists in hepatology with last year's unprecedented FDA approval of Schering-Plough's Rebetron combination therapy of Intron A, interferon alpha 2b, and Rebetol, ribavirin, bundled into a single package for the treatment of hepatitis C.  Tegafur is currently not approved in the U.S., just as ribavirin was not approved in oral form before Rebetron approval.  As a result of the approval of Rebetron, ribavirin is not available from Schering except in its fixed combination.

"There is no clinical reason for these oncology drugs to be packaged solely in combination.  Should the advisory committee find this combination treatment safe and effective for approval, we urge you to approve them to be available separately and labeled appropriately for use in combination.  Such approval is the norm for all HIV antivirals that must be used in combination.  The members of Bristol's team before you today are well aware of how their company has benefitted from HIV medications not being available only in bundled or combined forms.  Bristol's popular medication, Zerit, d4T, is often used in combinations containing Glaxo-Wellcome's Epivir, 3TC.  Glaxo markets Combivir, a single pill containing both 3TC and AZT, and other of its HIV antivirals.  Yet, both AZT and 3TC are marketed separately at no higher price than when they are combined as Combivir.  So, the physicians can individualize combination treatments, including combinations using Bristol's d4T.
"Bundling drugs together limits the ability of physicians to individualize treatment for patients when the dosage of one or both drugs must be altered from the fixed packaging.  Amounts of one or both drugs are often not used, an enormous waste of scarce health care resources.  Bundling also limits the use of appropriate and reasonable off-label combinations with one or both drugs as the HIV example illustrates. 

"Bundling impedes research as well.  Usually a competing drug company desires only one of the drugs of a bundled combination for research.  Either the competitor must purchase the entire combination package and waste the unwanted drug, or the competitor must submit its protocol to the company, revealing its strategy, something that most companies will not do and should not have to do.  Then they must await the license holding company's decision whether or not to grant the request.  The decision is not usually based on clinical research merit, but economics and market position of the license holder.  Bundling, therefore, impedes the development of promising novel treatment combinations that would be economically unfavorable to the license holder of a desired drug.
"Far from any safety or efficacy concerns, the primary reason the company desires to bundle its products is to hold third party payors, patients, and physicians hostage by forcing them to purchase both drugs and use fixed amounts of the drugs whether or not they are actually needed.  This scheme also allows the company to hide an inflated price for one or both drugs when separate sale of the drugs would make the unreasonableness of the prices transparent.  Escalating drug prices are the single largest contributing factor to the rising health care costs in the U.S. today.

"Despite continued calls from the hepatitis C community, Schering-Plough selfishly refuses to sell the ribavirin in its combination kit separately.  When Schering came before the FDA Antiviral Drug Advisory Committee in May of '98, it cited convenience as well as safety and clinical concerns to defend its desired bundling practice, just as we are sure Bristol is doing today for its drug.  The European Medicinal Evaluation Authority, in its review of Schering's application of interferon/ribavirin combination therapy for the European Union, saw through this rouse.  On May 7, 199, the EMEA approved the combination only when the two drugs are marketed separately and labeled appropriately for combination use.  Schering put ribavirin on the market in Europe separately as soon as it was allowed.  Clearly any safety concerns that Schering may have had were far outweighed by the economic interest to get the drugs to market any way it could.  We sadly suspect the same situation is occurring here.
"In the case of Schering's Rebetron, the FDA has expressed its willingness to unbundle the packaging of Rebetron and has written to Schering stating so.  However, once it approved the bundled package, Pandora's box was opened and the FDA lacks the regulatory authority to compel Schering to separate its drugs once on the market.  We urge you not to make the same mistake here.

"The American Medical Association's Council of Ethical and Judicial Affairs has publicly cited its concern over Schering's marketing practice.  Congressmembers Christopher Smith, Frank Pallone, and Nancy Pelosi have requested hearings on the matter.  Next week members of the HAAC and other HCV patient advocates will be meeting with staff of the House Subcommittee on Health and Environment and with officials of the Federal Trade Commission to urge actions on this matter.  In addition to the objections already cited, it is our view that bundling constitutes a form of tying under the Sherman Antitrust Act.  Bundling is nothing more than forcing the sale of one product by tying it to the sale of another. 

"Pharmaceutical manufacturers will argue either side of the bundling issue, depending on their individual economic advantage for the drugs in question.  Regardless of the clinical results, if a company owns the drugs they want used in combination, it will argue the need to bundle the packaging, i.e., Orzel.  If the combination requires use of a drug from a competitor, it will argue against it, i.e., Zerit.  But the third party payors, researchers, physicians, and patients all lose every time if bundling is allowed to stand.  Arguments of convenience, compliance, or dispensing errors have all been heard from Schering.  Bristol will probably even tell you they can conveniently make a few different dosage kits supposedly to meet individual needs.  Nonsense.  These arguments pale in comparison to the economic and treatment options that are lost if bundling is allowed to continue.  Physicians working with their patients, not drug companies, should have the control and flexibility of deciding what is the best dosing for their individual patients.  Individualization of treatment cannot be realistically achieved in a few fixed dosage combination drug kits.
"Bundling does not lead to greater safety or efficacy.  On the contrary, it detracts from both.  Attached to this letter, we have included a few testimonials from HCV patients to show how bundling has adversely affected them economically and therapeutically.  We ask that you read these as well.  We do not wish oncology patients to experience the pain that Rebetron has caused members of the hepatitis C community.
"We urge this committee to stop this bundling and tying scam here and now.  We ask that you strongly urge the FDA to deny approval to Orzel or any future bundled drug combination products unless the drug company is also compelled to market the drug separately in addition to the bundled package."

This is from Brian Klein from the Hepatitis C Action & Advocacy Coalition, and it came along with five anonymous letters which in the interest of time and avoiding redundancy, I will not read them here.  They will be available through the Freedom of Information Office next week if anyone would like to see them.
Thank you, and that's the end of our second open public hearing.
DR. CANETTA:  Are we allowed to make a comment, a very brief comment?
DR. SCHILSKY:  Perhaps you could just inform the committee about the plans for how the drug product would be marketed if it's approved.
DR. CANETTA:  It's very simple.  It's very short.
The NDA that you have being presented today is the NDA for UFT and leucovorin calcium tablets.  Bristol plans to market the two things separate.  Oral leucovorin is available on the market.  Bristol has an NDA approved already for oral leucovorin that will be marketed separately, and I think diffuses the whole issue.  We do not plan, though, to separate uracil for tegafur because there is a clinical reason not to do that.

DR. SCHILSKY:  Thank you for that clarification.
Before we go into the questions, I'd like to just ask if there's any general discussion that the committee members would like to have, having now heard a thorough presentation of this application.  Dr. Kelsen.
DR. KELSEN:  At the present time, there are advances in the treatment of this disease that really are important and they include drugs like irinotecan and oxaliplatin, but the data that we have right now, at least the preliminary data, is that both of those two agents are most effective when combined with fluorinated pyrimidines.  So, it's highly unlikely that, at least in the immediate future, fluorinated pyrimidine therapy is going to be abandoned, and therefore, this is an important issue as to whether there's a more convenient and less toxic way of giving the same drug.

It's especially important to me because that fluorinated pyrimidine therapy remains the linchpin of curative therapy.  We're not being asked to discuss curative treatment with this application today.  It's for palliative treatment of patients with metastatic disease, but the key role of curing people still revolves around FU/leucovorin or some other fluorinated pyrimidine in one combination or another.  CO6 may answer this question but we'll have to wait for that data.
This is more of a statement than a question.  I'm unimpressed with the comparison that we just heard that UFT is a placebo or worse than a placebo.  I don't think we ever actually got an answer to that table that we saw, although Dr. White might want to comment on it again during the discussion.  But the placebo-controlled trials pretty regularly, although they're small in number, give a very brief median survival of about a half a year, 5 to 6 months, with the one exception of the trial for totally asymptomatic patients, which was also inferior to UFT as historically controlled.  Therefore, I think the statement that UFT is acting as a placebo is very difficult to support.
I think what we should really focus in on is what has been discussed now.  Is this an equivalent agent?  I think the agent has some activity.  Fluorouracil leucovorin has modest activity and this drug has modest activity.  Is this drug equivalent and easier to give and less toxic?
DR. SCHILSKY:  Yes.

DR. BEHRMAN:  I'd just like to address that because you're right.  We're not asking you if this is a placebo.  We're trying to ask you how much uncertainty are you willing to accept because we do prefer the term "non-inferiority."  In other words, are you content or comfortable with the degree of inferiority that may be present?  Obviously, the worst case scenario would be that the drug has no effect and, therefore, would be equivalent to a placebo, but I think the words are getting confused a little bit.  We're not trying to ask you whether you believe it's a placebo or whether the added toxicity would make it worse than a placebo.
DR. KELSEN:  Do you believe that it has no effect at all?

DR. BEHRMAN:  Well, we're asking you the efficacy question.  We spent a lot of time talking about quality of life and comparative toxicity, and that's really not what we're asking you.  We're saying, given that the effect is small and the confidence interval is obviously not incredibly tight, are you comfortable that you're ruling out a significant -- decreasing the benefit significantly?  That's what we're asking you, not whether we believe it's a placebo or whether we believe it's inferior, but are you comfortable that it's essentially giving the same effect, although we understand that the effect is not that substantial.
DR. SCHILSKY:  So, we'll get to that specifically with, I think, the first question.
Any other general discussion anyone wishes to have?  Dr. Krook?
DR. KROOK:  Just the one question or comment of the U.S. versus the non-U.S.  In Bob White's document which was there, there's a statement which I guess I thought was interesting, that in the U.S. it was organized through a principal investigator who I believe in the Minnesota terminology is now a provider with an M.D. degree, and in Europe it was by a sponsor, medical monitor.  I don't know if that has anything to do with it, but that question comes up.  I think having been here the longest on this committee now, that question keeps coming up, U.S. versus non-U.S.  I don't have an answer, but as a principal investigator in clinical research, I always go into a study saying I don't know the answer.  Now, obviously if I'm being paid by someone, it may be different.  It's a comment, Rich.  Thank you.
DR. SCHILSKY:  Other comments?  Dr. Lamborn.

DR. LAMBORN:  Just to the question of the U.S. versus the non-U.S., as we saw the analyses earlier where the question was asked whether the differences observed could be just due to chance, as distinct from being statistically significant, it's my impression that in fact those kinds of differences were potentially just chance phenomenon.  I'm wondering if the FDA has done any analysis which would demonstrate other than that it is a chance phenomenon, including the potential that there would be an interaction, because I look at it and I say that it looks to me like it's just the luck of the draw.  Is there any demonstration that it's other than chance from the analyses done by the FDA?
DR. WHITE:  Well, the answer to that is no.
DR. SCHILSKY:  Dr. Johnson.

DR. JOHN JOHNSON:  Yes.  I just wanted to respond to Dr. Kelsen.  He has spoken about best supportive care twice now this morning.  In the slides that Dr. MacDonald used on page 2, he has a table there of three best supportive care studies.  In the first one, there is a total of 163 patients, and the difference in median survival is 2 months, which is similar to the many studies that the FDA showed.  The second study has a total of 40 patients, and it's mentioned that cisplatin was involved in that study.  And the third study has a total of 21 patients.  So, I don't think the FDA can give a lot of weight to studies that have a total of 40 patients and a total of 21 patients.
DR. KELSEN:  I don't know if that's a question.  I guess the Nordic trial, which is the trial that had asymptomatic patients in both arms, so the best population you could possibly have, had 183 patients in that trial.
DR. SCHILSKY:  Any other general comments?  Dr. Nerenstone?
DR. NERENSTONE:  I sort of want to ask our statistician a question.  In the study objectives for the trial 11, the first one was the equivalence of the two, and despite the very significant number of patients, the confidence interval was under the targeted .8 that they were looking for.  It came in at .79.

The secondary objectives -- and you can say it's close, but didn't quite meet it despite the very large number of patients.  The secondary objectives included the assessment of tumor response, which was the same; time to progression, which actually favored the 5-FU arm in a statistically significant way; safety and quality of life, which were probably no difference.  
How would you weight those in terms of primary endpoint and secondary endpoint when the one that's clearly statistically significant is in the opposite direction but is a secondary endpoint?  Or is there an answer to that?
DR. LAMBORN:  I'll have to think about it a little bit.  I think that you always start with the biggest issue being survival.  They put that as the primary endpoint.  I think that one of the things we have to be careful of -- and it was addressed earlier -- is when you try to use a model and you sort of arbitrarily say, well, it has to be 80 percent as good as an absolute assurance, remember that that lower bound, especially since they used a two-tailed test, says that we're 97.5 percent sure that that's the worst it could be.  Then you go back to what has been mentioned earlier.  If you then look at the curves and you look at the superimposability, just remember that's the absolute sort of worst case.  So, that's one piece of it to keep in mind.

I am in some ways more concerned that the time to progression is in an opposite direction, and you usually would hope that while -- and somebody else again referred to the fact that there has been a lot of discussion about time to progression and the ability to identify it.  And we have the problem that the assessment was done at different times, but the different times could conceivably be argued should have favored UFT. 
But I would then turn it back to the nonstatisticians in the group to say how would you interpret that if what you're seeing is a similarity in overall survival.  And I was, in fact, surprised that we didn't have more discussion of that earlier in the process.  Response for a number of reasons I'm much less -- I think it's the general consensus that that's less of importance in this situation.
Does that help?
DR. NERENSTONE:  Yes.
DR. SCHILSKY:  I think maybe we should just go on with the questions.  Ms. Forman?

MS. FORMAN:  I have a question of Dr. Johnson.  You had I think made a statement that said you have some patients that are 250 miles away from you and this might be a way to treat them because it is easier for them to get this treatment than travel to you.  How would you foresee the kinds of things that you would normally have to do in terms of their testing and following them and knowing where they are from the baseline right through the treatment to be sure that they are getting the best care, that they are not in jeopardy, that their levels of safety are monitored?  How would you handle that?  And any other doctor here who might be faced with that, I'd appreciate your response.
DR. DAVID JOHNSON:  Well, unfortunately, not everyone lives within real close proximity of Nashville.
(Laughter.)
DR. DAVID JOHNSON:  This is a problem irrespective of how one delivers the chemotherapy to the patient.  It doesn't matter whether you give it to them intravenously or orally.  It's a problem.
The question somewhat infers that if one gives oral therapy, one sends the patient out and says comes back and see me in a couple of months; whereas, if one gives intravenous therapy, one says, well, we'll be in close contact, we'll monitor you very carefully, et cetera. 

I don't really foresee a lot of difference in terms of the level of concern that I have for the patient, and I would do the same thing for the patient who's taking an oral drug and lives 250 miles away as I do for a patient who gets intravenous drug and lives 250 miles away.  We usually work with the patient's primary care physician in order to obtain laboratory data to monitor the patient when that is appropriate to do and to also monitor the patient's progress.  It's much more convenient again for a patient to drive down the street and get something done as opposed to driving 250 miles to get a CBC done, for example.  So, I don't really see the fact that their taking an oral drug makes them less well monitored.  In fact, perhaps quite the opposite.  Maybe we will monitor them more intensely.
I can tell you that the way we handle it at our institution, which I suspect is true for everyone around this table, is that our clinical nurses, not our research nurses, but our clinical nurses are responsible for contacting those individuals to keep in touch with them to find out exactly what toxicities they may have experienced.  And patients are educated before they leave, at any point during the course of their treatment, with specific indications to call us.  In fact, we give them information sheets that very clearly spell out the reasons that they need to call irrespective of day, time, et cetera.  So, I don't really see it being a whole lot different.  I do see it being much more convenient though from the patient's perspective.

Again, you wouldn't know this, but I can tell you from the standpoint of the provider of care -- and I don't like the Minnesota approach to provider with M.D. -- but I've been a recipient with an M.D. too of chemotherapy, and I can tell you right now -- and I took weekly chemotherapy that was injected -- if I had a choice again, if I ever have to do that again -- and I pray to God I do not have to -- and I have a choice between an oral and an injectable drug, I'll take an oral drug 100 percent of the time over an injectable drug.
DR. SCHILSKY:  Scott?

DR. LIPPMAN:  I guess I just wanted to follow up on the question I think that our statistician posed to us and no one really answered because I think we all know what the answer is but we should get it out since the FDA is asking us to address the efficacy question, and this issue of the significant difference in time to progression.  There have been very large discussions and I don't necessarily think we have to have that now.  It's maybe a useful marker in some cases, but in this case where you have a 9-day difference in time to progression, there are tremendous issues of ascertainment about when you actually check into that and get that data point.  So, I think it's sort of the same issue of looking at the survival curves to try to find possible differences.  They really are virtually identical.
DR. SCHILSKY:  It is a small difference.  The bias, though, is in favor of the control arm because there was less frequent evaluation by 1 week in the UFT arm.  So, the difference could actually be slightly greater than 9 days, but it's still going to be a small difference.
Yes.
DR. LAMBORN:  Just to clarify, if I had just seen the 9-day difference, I wouldn't have been asking this at all.  If you look at the curve, you see that there's sort of a sustained difference that becomes clear, moving beyond the median.  So, it was really looking at the whole curve again rather than just looking at the median which led me to say at least I was surprised that somebody hadn't brought it up.  That doesn't mean that I want to make a major additional issue of it, but just to clarify, it was not at the median that I was looking.

DR. SCHILSKY:  If I can offer again some historical perspective.  Typically we have always, in a sense, valued the survival endpoint as the absolute gold standard in evaluating new therapies.  In fact, as you know, we had lengthy discussion at the June meeting about the role of time to progression as an endpoint in metastatic breast cancer, a slightly different situation, but the committee rejected time to progression as an appropriate endpoint in metastatic breast cancer.  So, I think that here we have a large study with a clear ability to evaluate the survival endpoint easily, and we should, I think, focus on that a good deal.
Why don't we go on to the questions.  Now, we have what I believe to be the longest preamble that I've yet sent to a question.
(Laughter.)
DR. SCHILSKY:  So, the first eight pages of the questions represent a restatement essentially of the FDA's analysis of the data that Dr. White just reviewed with us.  I think it's probably not going to be necessary, since we just had all this presented, for the committee to spend a great deal of time reading this through again.  So, why don't we go directly to page 8 and the first question.
So, the question is, what percent of the survival effect of the control regimen would the committee be willing to lose with the UFT/leucovorin regimen and still call the UFT/leucovorin regimen equivalent to the control regimen? 

Does anyone want to take a stab at that one?  Dr. Margolin?
DR. MARGOLIN:  I'll take a stab.  I don't know if I have anything to lose.  It's really more of a comment.  I'm not going to give you my opinion on the percentage.  
I think the most difficult issue here is really for us to sort of determine how we really think fluorinated pyrimidine based therapy impacts on patients with metastatic colorectal cancer and whether that needs to be linked somehow with the response rate, which is very troublesomely low in both arms here in a very well executed study, and whether you really believe that somehow this therapy is helping a lot of people even though you can't measure that by objective responses.  So, that's really just more of a comment.  
I don't think that we can really come up with a percentage of the survival effect since we don't know what the survival effect is that we could be willing to lose and still call it equivalent.  We know the survivals are equivalent, and I don't think anyone on the committee would argue about that.

DR. SCHILSKY:  Well, I think that's what this question is actually addressing, is do we know that the survivals are equivalent, because the proposal is that the survival in the UFT arm could possibly be 20 percent worse.  Now, we've heard it stated, I think very nicely, that that is probably the worst case scenario and that there's a high level of confidence that it's not likely to be any worse than that.
Perhaps one way of thinking about this question would be if in fact that were the case -- and we don't really know how likely that is that that would be the case, but if that were the case -- would we be comfortable in still accepting this therapy as equivalent in efficacy.
DR. DAVID JOHNSON:  Yes.
DR. SCHILSKY:  So, instead of answering this question with a percentage, maybe since the focal point of the study was the 80 percent level, we can just have some discussion as to whether people would feel comfortable with that level.  Dr. Kelsen?

DR. KELSEN:  Yes, I think that that's a reasonable way of looking at this, that if the very worst thing happened and that the outcome was a difference of a month or 2 months in a patient who has very advanced disease and the tradeoff, which is not stated here, but sort of implicit to me, is that it's less toxic and at least gives the doctor, as Dr. Johnson said, the option of offering a patient an other alternative, yes, I think that that's a very reasonable thing to accept.
DR. SCHILSKY:  Dr. Raghavan.
DR. RAGHAVAN:  Yes, I agree with David Kelsen's view.  I think it's a contextual answer.  If you're talking carboplatinum versus cisplatinum in testicular cancer where you're talking very high proportional cure versus somewhat less high proportional cure, you accept different figures from a situation where the management is palliative and you're looking at convenience.  So, while I think the question as initially phrased is an odd one, I'd be happy to say 20 percent because 20 percent of a year in the broader context is not an awful lot of time.  
And I agree with David.  I think the evidence that we've seen -- look at the survival curves.  They're equivalent curves.  And you can do any amount of statistical mumbo-jumbo to hypothesize what might happen on a Tuesday at 3 o'clock, but the reality is these are identical curves, and there's no evidence on the table to suggest that there is a real difference. 

We spent a lot of time talking about what might happen in Europe and what might happen here, but it's all a hypothetical discussion.  If you actually look at the data presented, there's a minuscule difference, and I'm sort of surprised we're spending so much time on it. 
DR. SCHILSKY:  Yes.
DR. BEHRMAN:  The reason it was a concern to us is because it's not 20 percent of a year.  It's 20 percent of the difference between best supportive care versus, and we feel there is less room for error there.  So, that's why we're asking you.
DR. RAGHAVAN:  I do understand that, but I guess I'm looking at a more global picture.  Dr. Johnson is someone who should always be listened to carefully.  I hate to say it in his presence.
(Laughter.)
DR. RAGHAVAN:  Both John Johnson and Dave Johnson, but in this case Dave Johnson.  What he said is right.  We've got to be consistent in the committee, and the reality of the situation is we have an unhappy situation with the conventional treatment.  

David Kelsen made the point that even with really quite exciting new drugs that are there for gastrointestinal malignancies, fluoropyrimidines are not going to go away, and I think he's right.  So, therefore, having a convenient fluoropyrimidine is important, and even though the company have tried very hard to mask the convenience with the assays they've used, it seems to me that it emerges time and again.  So, therefore, I'm not too worried.  
Even if we accepted that the time to progression difference was 3 months, I think the big picture is what happens to patients, and time to progression is so evanescent that I don't think we're doing a bad thing if we let this drug through.
DR. SCHILSKY:  Any other comments on this? 
I think there is some consensus among the committee that 20 percent would be the answer to this question.  I don't know that we need to actually vote on that.  So, maybe we can just go on to the next question.
So, question 2, the results on the 5‑FU/leucovorin control arms in study 11 and study 12 appear different.  Can the better tumor response rate, time to progression, and survival on the 5-FU/leucovorin control arm in study 11 be explained by the 25 percent more dose intense FU/leucovorin control regimen used in study 11? 
Comments on that.  Dr. Kelsen.

DR. KELSEN:  Well, I think the answer to that is yes, it could, but in fact the numbers that were shown for both 011 and 012 are well within the range of what's been reported by many trials, including the SWOG multi-arm trial and a half a dozen others, for this type of regimen.  So, it's true it could be.  On the other hand, that's 5‑FU/leucovorin.
DR. SCHILSKY:  Dr. Krook.
DR. KROOK:  I would simply say yes, and I think there are other things that can do that as a reviewer.
DR. SCHILSKY:  Other comments?  Dr. Nerenstone.
DR. NERENSTONE:  I would say that supporting the fact that it's related to dose, the toxicity profile likewise is affected, and that seems to imply that perhaps dose is something that may be part of the reason.
DR. SCHILSKY:  So, I think the consensus answer there is yes, but there may be other factors as well that are more difficult to discern.
Question 3, part a.  Does the more dose intense every 28 day control FU/leucovorin regimen used in study 11 have an effect on survival? 
Dr. Kelsen.

DR. KELSEN:  Yes, it does have an effect on survival, but this implies because it is more dose dense, that it has an effect on our survival than the less dose dense every 5 week regimen, the infusional 5-FU?  There are large analyses that look at many different ways of giving 5-FU with many, many other drugs.  We talked about the repeatedly this morning.  I personally think the evidence is reasonably compelling that chemotherapy, including a fluorinated pyrimidine, is better than no chemotherapy or delayed chemotherapy, but the difference is modest.
DR. SCHILSKY:  Maybe you can go on just to give us your thoughts on part b, which is if FU/leucovorin does have an effect on survival, what is the magnitude of that effect?

DR. KELSEN:  Yes.  Then I'm going to fall back on the best data that I know, which is the best supportive care trials, such as the Nordic study, which is an MLF regimen if I remember.  It was a methotrexate, 5-FU, leucovorin I think.  I can check that.  And the magnitude of the difference in that study in asymptomatic patients was 9 months versus I think 14 months.  So, it's somewhere in the range of 2 to 4 months, depending on what you look at, that if you start therapy immediately, you get an improvement in median survival compared to if you either delay therapy since only 60 percent of the patients were treated or never treat the patient.  And that's the closest I can come.
DR. SCHILSKY:  Dr. Raghavan.
DR. RAGHAVAN:  I have the sneaky feeling that the FDA are trying to get us to create a standard today that they can look at for the future because that's is kind of what the question is asking.  Where does the 28-day control FU/LV fit into the big scheme of things?  I think the truth is that that wasn't the mission that we had coming in, so it's very hard to answer the question as phrased.  I'm not trying to be critical, but I just think that that wasn't the topic.  The topic was how does a new drug compare to a standard approach.  It happens there were two variants of the standard approach, and if you get out into the real world, there are 50 variants and they all give you a median survival and a long-term survival in metastatic disease that's very close, which is why we continue to argue whether 4 versus 5, 750, 350.  After 20 years, we still don't really know exactly the right way to use them, and I don't think today's deliberations will get you to that point.

DR. SCHILSKY:  I would just add from my own point of view that there are many trials, most of which have been reviewed here this morning, comparing 5‑FU/leucovorin against best supportive care, more trials comparing 5-FU/leucovorin to 5-FU.  Some of those trials show a survival advantage for 5-FU/leucovorin, some do not.  The meta-analysis that was performed does not show a survival advantage for 5-FU/leucovorin.  Those trials that show a survival advantage, the survival advantage is typically in the range of 3 to 5 months.  So, if you accept the notion that the preponderance of evidence is that there may be a survival advantage, it's going to be small.  It's going to be in the range of a few months, and it's probably very difficult to estimate it any more precisely than that.
Why don't we go on then?  Oh, we have a part c here.  Pardon me.  This is actually 12 questions in 5.
(Laughter.)
DR. SCHILSKY:  Part c.  If the every 28-day control FU/leucovorin regimen has a survival effect, does study 11 show the effect on survival of the UFT/leucovorin regimen is at least as good?  So, that's the question.  Is the survival with UFT/leucovorin in study 11 at least as good as the control regimen? 
Dr. Krook.

DR. KROOK:  I would say that my looking at the data, the answer should be yes.
DR. SCHILSKY:  Other comments? 
(No response.)
DR. SCHILSKY:  Anyone who dissents from that point of view?
(No response.)
DR. SCHILSKY:  I think at some point, we may ask for a show of hands on some of these questions.  These seem to be more sort of consensus questions.
Question 4.  Does the less dose intense every 35-day control FU/leucovorin regimen used in study 12 have an effect on survival? 
Dr. Kelsen.
DR. KELSEN:  I think my answers to 4a, b, and c would be similar to my answers to 3a, b, and c, based on the same data that we've talked about several times now, both randomized studies against a non-leucovorin containing 5-FU regimen or against no immediate treatment.  So, my estimate would again be several months.  It may be 3 months.  It may be 4 months, something in there, for a.  
What's the estimate of the survival effect as shown?  And the evidence as I've described.

And lastly, I think that the survival curves are equivalent.  So, the survival curves are equivalent.
DR. SCHILSKY:  Any other comments there?
(No response.)
DR. SCHILSKY:  Okay, let's continue.
I think we're getting the message across even without a formal vote.
Question 5.  The UFT capsule is a fixed combination.  The regulations require the contribution be shown for each active component of a fixed combination.  The fixed combination regulation is important and the FDA would not waive it without a compelling reason.  However, a waiver could be considered if the committee believes the UFT/leucovorin regimen is an important therapeutic advance compared to present therapy for patients with advanced metastatic colorectal cancer.  
The FDA did not believe this requirement to show the contribution of uracil to the UFT capsule had been met and requested more information.  Additional data on the contribution of uracil to the UFT capsule was recently submitted to this NDA, but the review of it has not yet been completed.

A, if the FDA concludes the contribution of uracil to UFT is adequately shown, is this NDA approvable?  For this I will ask for a show of hands.
Does anyone want to make a first stab at answering that?  Dr. Margolin?
DR. MARGOLIN:  Actually I just want to ask a clarification question.  I think the question means would this entire NDA meet the requirement for approvability.  Right?  I mean, otherwise this is the entire vote on the entire drug.  Right?
DR. BEHRMAN:  I'm sorry.  I don't understand.
DR. MARGOLIN:  Well, does this question just refer to if the uracil data are okay, can we then go ahead and answer the next questions, or is this the entire -- 
DR. BEHRMAN:  This is it.
DR. MARGOLIN:  This is it.
DR. BEHRMAN:  Yes.
DR. SCHILSKY:  This is the big one.
(Laughter.)
DR. SCHILSKY:  Dr. Nerenstone.

DR. NERENSTONE:  I just have sort of a question to the FDA, and it might be a little unusual.  I still am very uncomfortable about the difference between the U.S. results and the European results which I feel may, in fact, be significant.  I know subgroup analysis -- you get nervous about doing that, but they are very large groups of patients and they were stratified by being U.S. or not U.S.  If in fact this is approved, can we request that this table, showing the difference in the two groups, be included in the material that goes out?  Because I think individual physicians have to make up their own minds to decide whether in any individual case a decrease in median survival of 3 and a half months may be important for their patients to know.
DR. BEHRMAN:  If it was the recommendation of the committee, we would certainly consider putting that in the labeling, yes, in the clinical trials section.
DR. SCHILSKY:  Any comments about that?  Dr. Margolin?
DR. MARGOLIN:  I would argue against that unless we could find medical reason.  I think it would be misleading and perhaps lead to some misinterpretation of data.  I think you really do need to look at a study and not do the subgroups unless there is some really compelling biological or medical thing that explains it or unless the statistical difference is so great that you're forced to repeat the study or do something like that.
DR. SCHILSKY:  Dr. Lamborn?

DR. LAMBORN:  I'd also like to reiterate something that was said earlier, just a reminder that I think it could also be statistically misleading because even if we ignore the fact that this was a post hoc analysis, which is sort of where you're coming from when you say subgroup analysis, but even if it had been a preplanned analysis, the analysis says that these differences could simply be chance differences.  Again, unless there's a medical reason, unless there's something systematic that was found that could explain it, we do know that it could be just a chance phenomenon, and I would hate to see us make a major point of it in the labeling unless there's some other rationale.
DR. SCHILSKY:  Other discussion?
(No response.)
DR. SCHILSKY:  Okay, so back to the question.  If the FDA concludes the contribution of uracil to UFT is adequately shown, is this NDA approvable?  All those who would vote yes, raise your hand.
(A show of hands.)
DR. SCHILSKY:  12.
All those who vote no?
(No response.)

DR. SCHILSKY:  Any abstentions?
(No response.)
DR. SCHILSKY:  Part b.  If the FDA concludes the contribution of uracil is not adequately shown, a waiver could be considered if the committee believes the UFT/leucovorin regimen is an important therapeutic advance compared to present therapy for patients with advanced metastatic colorectal cancer.  Is the UFT/leucovorin regimen an important therapeutic advance compared to present therapy for patients with advanced metastatic colorectal cancer?
Any discussion on that?  Dr. Krook?
DR. KROOK:  My feeling on this is that, no, it's not an important therapeutic advance.  It's using again a prodrug.  At least it's not a therapeutic as I look at therapeutic.  I would argue that this vote should be no.
DR. SCHILSKY:  Other discussion, comments?
(No response.)
DR. SCHILSKY:  So, why don't we vote it?  Let me read it again.  Is the UFT/leucovorin regimen an important therapeutic advance compared to present therapy for patients with advanced metastatic colorectal cancer? All who would vote yes, raise your hand.

(No response.)
DR. SCHILSKY:  0.
All who would vote no?
(A show of hands.)
DR. SCHILSKY:  8 no.
Abstentions?
DR. SCHILSKY:  4 abstentions.
So, since the majority is that it is not an important therapeutic advance, we don't have to answer the part about if so, in what respects.
That concludes this morning's session.  We will take a break for lunch.  Why don't we plan to reconvene at 1:15.
(Whereupon, at 12:10 p.m., the committee was recessed, to reconvene at 1:15 p.m., this same day.)

	AFTERNOON SESSION
	(1:20 p.m.)
DR. SCHILSKY:  Good afternoon.  Welcome to the afternoon session of ODAC.  
We do have at least a couple new people seated around the table, so I thought I would briefly ask that we go around and have another brief round of introductions.  Dr. Raghavan?

DR. RAGHAVAN:  Derek Raghavan, medical oncologist, University of Southern California.
DR. LAMBORN:  Kathleen Lamborn, biostatistician, University of California, San Francisco.
DR. KELSEN:  David Kelsen, medical oncologist, Memorial Sloan-Kettering.
MS. ZOOK-FISCHLER:  Sandra Zook-Fischler, Patient Representative.
DR. MARGOLIN:  Kim Margolin, medical oncology and hematology, City of Hope, California.
DR. LIPPMAN:  Scott Lippman, medical oncologist, M.D. Anderson Cancer Center.
DR. SCHILSKY:  Rich Schilsky, medical oncologist, University of Chicago.
DR. TEMPLETON-SOMERS:  Karen Somers, Executive Secretary to the committee, FDA.
DR. NERENSTONE:  Stacy Nerenstone, medical oncology, Hartford, Connecticut.
DR. DAVID JOHNSON:  David Johnson, medical oncologist, Vanderbilt University.
DR. PELUSI:  Jody Pelusi, nurse practitioner, Phoenix, Arizona, and the Consumer Rep.

DR. KROOK:  Jim Krook, Duluth, Minnesota, medical oncologist.
DR. CORTAZAR:  Patricia Cortazar, FDA.
DR. WILLIAMS:  Grant Williams, FDA, medical team leader.
DR. BEITZ:  Julie Beitz, acting Deputy Division Director.
DR. BEHRMAN:  Rachel Behrman, Deputy Office Director.
DR. SCHILSKY:  Thank you.
I should also announce that Bill Gradishar, who was to be here as an ODAC consultant, was unable to make the trip because of the weather.  So, we will do our best to get by without Bill.
Let's go into the open public hearing.  We have a number of -- oh, I'm sorry.  Karen has a conflict of interest statement to read.
DR. TEMPLETON-SOMERS:  Again.  The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a 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 interests 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.
Dr. Douglas Blayney is excluded from participating in today's discussion and vote concerning Evacet.  
In addition, in accordance with 18 U.S.C. 208(b)(3), full waivers have been granted to Drs. William Gradishar, Kathleen Lamborn, and Stacy Nerenstone which permit them to participate in all official matters concerning Evacet.
A copy of the waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, room 12A-30 of the Parklawn Building.

In addition, we would like to disclose for the record that Dr. David Johnson has an interest which does not constitute a financial interest within the meaning of 18 U.S.C. 208(a) but which could create the appearance of a conflict.  The agency has determined, notwithstanding this interest, that the interests of the government in his participation outweighs the concern that the integrity of the agency's programs and operations may be questioned.
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 interest fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.
Thank you.
DR. SCHILSKY:  Thank you.  We have a number of individuals who have requested an opportunity to make statements to the committee.  So, I'll just take them in the order that they're listed here.  The first is I guess just a letter to be read from Robert Erwin representing the Marti Nelson Cancer Center.

DR. TEMPLETON-SOMERS:  "I am writing this letter in support of the application for approval of the liposomal doxorubicin formulation, Evacet, submitted by The Liposome Company.  I represent the Marti Nelson Cancer Research Foundation, a nonprofit organization that works with cancer patients and their physicians to assist in access to experimental therapies and enrollment in clinical trials.  We have no financial interest in The Liposome Company, nor in any other company developing and marketing products for cancer treatment.  Our short-term objective is to help people with cancer obtain improvements in both quantity and quality of life.
"My wife, Marti, died of breast cancer at the age of 40 and she suffered many of the adverse effects of cancer treatment, including cardiac toxicity.  I know first hand the importance of finding drugs that will be more effective against breast cancer than those available today, but I also know the importance of improving the safety of the drugs we currently have.  Safety in a chemotherapeutic is the difference between having the breath to sing a song, or not; the desire to eat a home-cooked meal, or not; the strength to climb a single flight of stairs, or not; or, in my wife, Marti's case, the strength to do the work she loved as a physician helping other people, or not.

"Given that over 40,000 U.S. women die of breast cancer each year, it is tragically clear that doxorubicin is not an ideal drug for the treatment of breast cancer.  Nonetheless, it is still one of the most efficacious drugs available and can provide extended life to many women with disease.  As all of you know, doxorubicin causes both acute and chronic cardiac toxicity which can be life-threatening.  After a cumulative dose of 500 milligrams per meter squared, 6 to 20 percent of patients will experience significant and irreversible cardiac toxicity.  This risk increases with prior radiotherapy.  Surviving breast cancer can be a very hollow victory at the cost of facing the day to day morbidity that results from chronic heart disease.
"Other adverse reactions, particularly mucositis, can limit a patient's ability to tolerate an optimally dose-intensive regimen.  Reducing the factors that cause a poor quality of life during, and too frequently long after, chemotherapy is an important research priority.  If this priority is adequately addressed, not only will the quality of life of cancer patients improve, but the probability of achieving optimal efficacy with current therapeutics will also increase.

"The development of newer generation antiemetics such as ondansetron and granisetron have significantly improved the quality of life experienced by most patients during chemotherapy with doxorubicin.  The use of dexrazoxane with doxorubicin reduces cardiac toxicity, but at the cost of reduced doxorubicin efficacy.  Although we have not seen data directly comparing Evacet to doxorubicin plus dexrazoxane, the data available suggest a favorable comparison, given the full maintenance of efficacy with Evacet.
"Approval of Evacet will provide another important option to the woman facing breast cancer, an option that might prove to be the difference between survival with debilitating morbidity and survival with normal health and full vigor.  The experience of the individual in the use of a pharmaceutical to combat a disease must never be lost in the coldness of the statistics.  It is the individual people who matter the most, in medicine as in life.

"In addition, approval of Evacet will provide physicians with greater flexibility in treating patients who are at higher risk for cardiac toxicity; and, if additional studies support the initial results obtained to date, the potential to achieve greater efficacy through the use of this novel doxorubicin formulation.  Although it is a small point, approval of this drug will also increase the competition in the oncologic drugs market leading ultimately to a better efficacy to price ratio.
"The Marti Nelson Cancer Research Foundation recommends the approval of Evacet for the treatment of metastatic breast cancer on the basis of its superior adverse effects profile with comparable efficacy to conventional doxorubicin.
"Respectfully submitted, Robert Erwin."
DR. SCHILSKY:  Thank you.
Next is Michael Cohen.  Would you please again state your name, affiliation, and whether you've received any financial support to be here?
DR. COHEN:  Yes.  My name is Michael from the Institute for Safe Medication Practices.  It's a nonprofit organization and we work in cooperation with the United States Pharmacopeia in their medication error reporting program.  We receive reports of medication errors and we publish them in various publications' journal columns, including the Oncology Times.
I have nothing to disclose with this company.  However, they did, more than 12 months ago, donate some funding to ISMP.  Other than that, there's nothing.

From time to time, we have had reports of mix-ups between doxorubicin products, the conventional doxorubicin and the doxorubicin liposomal injection product.  Doxil is the brand name.  And you know there is quite a dosing difference.  Because of the mix-ups, the company that manufactures Doxil at one point actually did make a package label change where they have on the front label panel now a statement that this is a liposomal product and that it is not to be substituted.  And there's a red band that goes across with that and it's very helpful in preventing mix-ups.
We actually have had mix-ups between other conventional products and liposomal products as well, amphotericin in particular.
So, we have the conventional product and the liposomal product already on the market for doxorubicin.  The dosing difference is dramatic.  The liposomal product currently is at about 20 milligrams per meter squared per dose, and the conventional product, more in the area of 60 to 75 milligrams per meter squared per dose.

Now we have the Evacet product which is being discussed today.  As many of you know, the dosing here is even higher than the conventional product, and so we at ISMP have a concern that the possibility certainly exists, since we have this history of mix-ups between the conventional and liposomal product in the past, that now we could have mix-ups between the two liposomal products.  And the dosing difference here is so dramatic that it could actually lead to a patient injury.
We would like to recommend that, if this product is approved, that along with the product, perhaps some enhancements of the generic name of the current liposomal product be considered.  However, the United States Pharmacopeia and the Food and Drug Administration, to my knowledge, is actually working now to look at the nomenclature of liposomal products in general.  I'm not sure how that would affect the current product or the product that is being discussed today.

I think there are some things that would be need to be done as far as preventing mix-ups between the two liposomal products in particular in this case.  I think the major problem that we see is with the product that is already on the market because if the dose is accidentally given in the higher dose -- in other words, instead of 20 milligrams per meter squared, more like 75 or 100 milligrams per meter squared is accidentally given -- and this could occur at the physician prescribing level.  This could occur at the nursing level.  It could occur at the pharmacy dispensing level, which is where we see many of these accidents.  There would be a disastrous result potentially. 
So, we'd like to recommend to FDA that, first of all, of course the nomenclature issue be considered with USP's Nomenclature Committee.
But second -- and there is precedence for this -- we would like to see something done, in addition to what is already present on the Doxil container, to further warn about the dosing differences between these products.  The precedent is with the amphotericin products now.  After several accidents where the liposomal product was ordered and the conventional product was dispensed in the higher liposomal amphotericin dose, the company was good enough to work with FDA and place a stop sign on the conventional amphotericin product which warns against using this without checking the dose appropriately.  We would like to see something similar done with the Doxil product.  But at the same time, we think that this is unusual and that some education needs to be done as well and other types of reminders.  

Early on we would like to see even stickers prepared by the companies and ask pharmacists to actually affix these to the containers, anything that can be done to prevent the mix-ups because I'm sure that it will happen without taking proper action.
Finally, in the interest of full disclosure -- and I immediately recognized this and mentioned it to Dr. Templeton right afterwards my appearance this morning -- I mentioned that BMS does help to sponsor the ISMP medication safety alert.  I should also mention that they have in the past helped to sponsor medication error prevention programs that ISMP has done. 
Thank you very much.
DR. SCHILSKY:  Next is Margaret Volpe representing the Y-ME National Breast Cancer Organization.  Again, please for the record state your name, affiliation, and whether you've received any financial support to be here. 
MS. VOLPE:  My name is Margaret Volpe.  I'm the Y-ME D.C. liaison, and we've received no financial support to be here in any way.

Thank you for allowing us to submit the statement to the committee.  I am here today on behalf of the Y-ME National Breast Cancer Organization to express our position regarding the potential approval of Evacet, liposomal doxorubicin, for the treatment of metastatic breast cancer.
Y-ME is the nation's premier source of support, education and information for women diagnosed with breast cancer, their families and communities.  Y-ME was started by two women diagnosed with breast cancer 20 years ago and offers two national, 24-hour hot lines in English and in Spanish.  In addition, Y-ME has 26 chapters nationwide, numerous publications in adult and teen workshops on the early detection of breast cancer.  
Y-ME has no financial connection to The Liposome Company.
Y-ME believes that women and men diagnosed with breast cancer should have access to as many treatment options as possible.  Doctors and patients should have choices.  We believe the approval of Evacet will help provide these choices.  Therefore, I speak on behalf of women living with metastatic breast cancer.
One of the most commonly used agents to combat breast cancer, doxorubicin, also carries a substantial risk of damage to the heart, cardiotoxicity.  For this reason, physicians often must limit their use of this drug to suboptimal doses.

Based upon the clinical studies presented at ASCO, Evacet represents a safer alternative to conventional doxorubicin while still being as effective against the cancer.  The availability of such a treatment would be an important step in our quest for safer chemotherapeutic agents.
Quality of life beyond chemotherapy is important.  Effective and relatively safe advances towards this end should be an option for women with metastatic breast cancer.
Thank you.
DR. SCHILSKY:  Thank you very much.
Next is Laura Meeker, and again please state your name, affiliation, and whether you've received any support to be here.
MS. MEEKER:  Hi.  My name is Laura Meeker.  I'm a public servant.  I represent myself.  I was recruited by my oncologist to come and talk about my own personal experiences with cancer and with treatment.  I have no financial interests in anything related to this meeting and have received no financial support whatever from anyone.

I am a 6 and a half year survivor.  I'm living with metastatic breast cancer.  I've had way more than the optimal doses of Adriamycin in an attempt at the beginning of my diagnosis to wipe out the cancer.  Unfortunately, that treatment had to be stopped without a total remission because I developed incredible cardiac toxicity.  I had congestive heart failure and cardiomyopathy to the point where, although I'm a public servant and I've continued to work during this entire time, there was a year in my life when I finally got to the office, I would plan my trips to the ladies' room 50 yards down the hall.  I could do about two of them a day.  Everyone came to me.  I could organize my thoughts and deliver good advice to my clients, but I was basically a vegetable body.  
I participated in two years of cardiac rehab three to four times a week and returned to close to normal but not close to what I used to be.  I was a scuba diver, an athletic person who loved hiking, and that has not been a part of my life recently, though I hope it will be.
In addition to that, I had CMF which did nothing.  So, it was the Adriamycin part of this FAC that treated me successfully and I finally had taxotere which put me into remission again.  Unfortunately, it's back in my bones, but I'm real happy to be here with bone metastases.  I can live with those. 

I'm not a scientist or a medical person, but I am a person who has been impacted by regular Adriamycin, both very positively -- it made it possible for me to live to be here -- and by the side effects of aggressive treatment which made it harder for me to be here. 
I'd love to answer any questions if anybody has any.
Thank you for the opportunity to be here. 
DR. SCHILSKY:  Thank you very much.
Finally, we have a statement submitted from Ellen Stovall from the National Coalition for Cancer Survivorship.
DR. TEMPLETON-SOMERS:  "This is a statement in support of oral anticancer drugs.

"The undersigned organizations provide educational advocacy and other services to people with cancer, their families, and their caregivers.  People with cancer are desperate to have access to new anticancer medicines, not only for the sake of more effective treatment, but also in support of better quality of life, including less toxic and more convenient modes of therapy.  Most current anticancer drugs are accompanied by potentially serious side effects and because they are administered intravenously, they require the involvement of a physician, nurse, or other cancer specialist.  While careful monitoring of patients receiving any type of chemotherapy is an important factor, intravenous administration of drugs can, by itself, create a hardship for patients living in remote, rural areas not directly served by a cancer specialist.
"The availability of oral anticancer medications with improved toxicity profiles and efficacy at least equivalent to intravenous alternatives is an important step for cancer patients.  If an oral compound under review by the Food and Drug Administration exhibits efficacy that is undiminished in comparison to the intravenous drug alternative, demonstration of reduced toxicity or other contributions to quality of life should be given great weight in the deliberations of reviewers.  Aside from the benefits of reduced toxicity, quality of life for cancer patients can be enhanced and should be valued along with other improvements in care. 

"Cancer is a highly individualized disease and the more treatment options available, the better, so long as neither safety nor efficacy is sacrificed.  Moreover, patient convenience and quality of life are important considerations that should argue for the availability of oral drug alternatives. 
"We encourage the Food and Drug Administration to take these patient oriented concerns into account in its review of any oral anticancer medications proposed for marketing approval.  
"The National Coalition for Cancer Survivorship, American Cancer Society, Cancer Care, Incorporated, Cancer Research Foundation of America, Cure for Lymphoma Foundation, Kidney Cancer Association, Oncology Nursing Society, and USTOO International."
DR. SCHILSKY:  Thank you.  Is there anyone else who wishes to make a statement to the committee?
(No response.)
DR. SCHILSKY:  If not, we'll move directly to the sponsor's presentation. We are running a bit behind, but the sponsor will have the full hour available to them.  So, Dr. Lee?
DR. LEE:  Good afternoon, Dr. Schilsky and members of the advisory committee, Dr. Williams and members of the FDA review team.  We're very pleased to be here today to present the data from the NDA for TLC D-99.

The indication that we're seeking today is for TLC D-99 for the first-line treatment of metastatic breast cancer in combination with cyclophosphamide.
The recommended dose with D-99 is at 60 to 75 milligrams per meter squared in combination with cyclophosphamide at 600 milligrams per meter squared administered every 3 weeks.
After my introduction, Dr. Andy Janoff from The Liposome Company will present a preclinical overview.  Dr. Eric Winer from the Dana-Farber Institute will present the need for a less cardiotoxic anthracycline.  We will then present an overview of the study designs for the three phase III studies.  Dr. Jonathan Alexander from Danbury Hospital and Yale University will present the findings for the significance reduction in cardiotoxicity.  We will then present the findings on the preservation of antitumor efficacy.  Dr. Jerry Batist from McGill University will present the findings from the clinical safety profile.  I will then return to provide a conclusion for the sponsor's presentation.

The following consultants covering areas of medical oncology, biostatistics, and cardiology are either participating in the TLC D-99 clinical program or have helped with the preparation of the NDA.  Many of them are present with us today and they are available to answer questions.
The data presented today will demonstrate that TLC D-99 is safe and effective for the treatment of metastatic breast cancer.  TLC D-99 provides clinical benefits to breast cancer patients by improving upon the therapeutic index of doxorubicin.  Doxorubicin remains a mainstay for the treatment of breast cancer.  However, as we just heard from the public statements, doxorubicin is associated with well documented cardiotoxicity, a dose-limiting toxicity that could be permanently disabling or potentially fatal to patients who are undergoing doxorubicin treatment.
Our data will demonstrate that TLC D-99 is significantly less cardiotoxic than doxorubicin.  TLC D-99 also has significantly less mucositis and diarrhea, acute toxicities which could interfere with the daily activities of patients who are undergoing doxorubicin after every cycle.  Importantly, TLC D-99 delivers antitumor efficacy that is comparable to that of doxorubicin. 
We will now begin our presentation with a preclinical overview by Dr. Andy Janoff.

DR. JANOFF:  Dr. Lee, good afternoon.  It's my job today to give you an overview of our preclinical program and provide you a framework in which to evaluate our clinical data, so I'd like to start, if I could, with the rationale for D-99, which is based on the well-known ability of liposomes to alter the biodistribution of drugs.  With this in mind, we set out to design a system that would decrease doxorubicin's cardiotoxicity, decrease its GI toxicity, but maintain antitumor efficacy.
Now, to create D-99, we created doxorubicin citrate complex which we anchor securely in the interior of 100 nanometer liposomes.  We engineer these systems to persist in the circulation which limits the peak availability of doxorubicin to cardiac and GI tissue, but ensures effective delivery to tumor tissue.  We don't pegylate D-99, so it doesn't persist in the circulation long enough to extravasate into dermal tissue which is a biodistribution well known to produce palmar-plantar erythrodysesthesia. 
On the next slide you see after a single -- this is a 1.5 milligram per kilogram IV push in the dog.  More D-99 relative to doxorubicin persists in the circulation.  This is particularly true at early time points.

Now, in these studies, we used whole body autoradiography to map the biodistribution of both D-99 and doxorubicin, and the next slide you see that these lines are reversed, less D-99 relative to doxorubicin, is delivered to myocardial tissue.  This diminished myocardial exposure to doxorubicin correlated with profoundly diminished cardiotoxicities preclinically as judged histologically, and this was predictive of our clinical data. 
In a similar fashion, the diminished intestinal mucosal exposure to doxorubicin also correlated with diminished GI toxicities preclinically.  Again, this was predictive of our clinical data.
Now, to look at the antitumor efficacy of D-99, we evaluated 5 murine tumors, and we found that in each case D-99 was at least as effective as doxorubicin.  
We also had the opportunity to look at a human tumor xenograft and that data is on the next slide.  This is a human mammary carcinoma, and as judged by tumor growth inhibition relative to control, D-99 was at least as effective as doxorubicin.  

So, in conclusion, in our preclinical program, we were able to show that D-99 reduced the cardiotoxicity, reduced the GI toxicity of doxorubicin without impacting efficacy.  And importantly, there was no evidence of PPE in any of our preclinical models, consistent with the fact that D-99 is not pegylated.  
So, it was against this background with this data that the company made the decision to enter into clinical trials, and you'll hear that data set next in the hour or later on in the hour.  But up next is Dr. Winer.  He'll discuss the need for a less cardiotoxic anthracycline.  
DR. WINER:  Good afternoon.  I just want to spend about 4 or 5 minutes talking about the need for a less cardiotoxic anthracycline in the treatment of patients with metastatic breast cancer.
As everyone knows, doxorubicin is an important drug in the treatment of patients with breast cancer, but it is limited by its cardiac toxicity.  Doxorubicin results in the generation of iron-mediated intracellular free radicals.  These free radicals damage cardiac myocytes.  Myocyte damage occurs with each and every dose.  It's initially subclinical but ultimately leads to dose-dependent cardiac dysfunction.

Cardiac dysfunction is rare, although it occurs occasionally in patients who receive less than a cumulative dose of 300 milligrams per meter squared.  Above this dose, it becomes much more prevalent.  I think over the past few years we've learned that cardiotoxicity with anthracyclines probably occurs at somewhat lower doses than perhaps many of us thought 5 and 10 years ago.  
These are data from a trial published by Dr. Swain and colleagues in the Journal of Clinical Oncology two years ago and demonstrate the cardiotoxicity with FAC chemotherapy in patients with metastatic breast cancer.  In this slide, a cardiac event refers to either the development of CHF or a substantial fall in ejection fraction.  As you can see, at approximately a cumulative dose of 300 milligrams per meter squared, cardiac events become more common, becoming much more common after 400 to 450 milligrams per meter squared.

These are more recent data.  This is a trial published by Chan and colleagues this past summer in the JCO and compared docetaxel and doxorubicin in patients with metastatic breast cancer.  A total of 163 patients received doxorubicin in this trial.  All patients had baseline determinations of their ejection fraction, a subsequent determination later in the course of the study, and the dose of doxorubicin was actually capped in the study at a little more than 500 milligrams per meter squared. 
Despite that, there were 6 patients in the trial who developed clinical CHF.  CHF developed in the range of 400 to 450 milligrams per meter squared and there were 3 patients who died of this toxicity.  I think this just highlights the ongoing importance of this problem as we take care of patients with breast cancer.
Now, a less cardiotoxic anthracycline could potentially be beneficial to all women with metastatic breast cancer.  I just want to touch for a minute upon a subpopulation, that is, women who have had prior exposure to anthracyclines in the adjuvant setting.

These are data lent to me by Jane Weeks at my own institution from the National Cancer Center Network database and demonstrate the number of patients with stage I and stage II breast cancer who are presently receiving anthracycline containing regimens.  As shown on this slide, at least within NCCN centers over the course of the past two years or so, 61 percent of patients with stage I breast cancer received an adjuvant anthracycline-containing regimen and over 85 percent of stage II breast cancer patients.  Obviously, a lot of women in the early disease setting are receiving adjuvant anthracyclines.
Despite adjuvant therapy, at least some of these women will, unfortunately, ultimately develop metastatic disease, and anthracycline may be of benefit at least in some proportion of them.  Unfortunately, if a woman has received adjuvant anthracycline therapy, it takes a very limited number of cycles before she reaches a cardiotoxic dose with doxorubicin.  And the availability of a less cardiotoxic anthracycline both in this patient population and in the broader patient population potentially provides patients and physicians greater flexibility in making determinations of how long to continue therapy with somewhat less concern about cardiotoxicity.
There are other available means to reduce cardiotoxicity in patients with breast cancer who are receiving doxorubicin-based therapy.  

Dexrazoxane is commercially available.  It is approved for use in women who have received cumulative doses of doxorubicin greater than 300 milligrams per meter squared.  It does, at least to a limited extent, add toxicity.  It is another drug adding on to the regimen.  In addition, there have been concerns about possible interference with efficacy.  
In some centers, prolonged infusions of doxorubicin, such as 96-hour infusions, are used, and these have been shown to reduce cardiotoxicity with anthracyclines.  Such infusions require a central catheter and a pump.  The bottom line is that outside of a few very specialized centers that have used this kind of approach for a long time, this is not a commonly used practice, at least in the U.S.

Now, there are reasons to be even more concerned about cardiotoxicity with anthracyclines now than a few years ago.  The trials with herceptin where it was demonstrated that the combination of doxorubicin and Herceptin resulted in a very unacceptable rate of cardiotoxicity highlight this point.  In addition, we know that there are women who have been treated with prior doxorubicin and are now receiving Herceptin who developed cardiotoxicity as well.  There are certain schedules when doxorubicin and paclitaxel have been combined where there appears to be excess cardiotoxicity.  And these are both areas -- and I would say particularly the area in terms of Herceptin -- where future trials are warranted, and in fact there are future trials that are now beginning to enroll patients looking at these combinations.
Finally, although in the adjuvant setting, cardiotoxicity is not a major problem when we cap doses of doxorubicin at 240 or 300 milligrams per meter squared, this is still a concern to physicians and a concern to patients.  We really don't have long long-term data in terms of safety of doxorubicin in this setting, and ultimately a less cardiotoxic anthracycline has a real role in trials in the adjuvant setting.
So, having said that, I do believe there's a role for a less cardiotoxic anthracycline in patients with breast cancer.  I believe there's a role for D-99 in the treatment of patients with breast cancer, and I say that as one who participated in these trials and as a clinician who does this on a daily basis.
Thanks.  I want to turn this back over to Dr. Lee.

DR. LEE:  Over 1,000 patients were treated in the TLC D-99 clinical program.  11 phase I/II studies were conducted, followed by 4 phase II studies in first-line metastatic breast cancer.  The centerpiece of our submission is three phase III randomized, comparative studies in the first-line treatment of metastatic breast cancer.
The four phase II trials conducted in the metastatic breast cancer patients showed a response rate ranging from 43 percent to 73 percent, clearly indicating a high level of antitumor activity.  Results from these studies indicate that 60 to 75 milligrams per meter squared provides encouraging safety and efficacy results and, hence, form the basis for the dose regimen to be studied in the phase III program.
The objectives and primary endpoints for the phase III programs are to demonstrate that TLC D-99 significantly reduces cardiotoxicity while preserving the antitumor efficacy of doxorubicin.
Three randomized studies were conducted.  Study 1 is our pivotal study conducted in combination regimens.  Our pivotal trial demonstrates the significant reduction in cardiotoxicity, as well as the preservation of antitumor efficacy.  

Each of these endpoints were reproduced in an independent study.  Study 2 is a single agent regimen study that provides confirmatory evidence for the reduction in cardiotoxicity.  Study 3 is another combination regimen study that provides confirmatory evidence for the preservation of antitumor efficacy in combination regimens.
I will now provide an overview of the study designs for these three studies and then the data for the two primary endpoints will be presented in subsequent presentations.
Study 1 is a study comparing the combination of D-99 plus cyclophosphamide to equal doses of doxorubicin plus cyclophosphamide.  Randomization was stratified by prior doxorubicin.  Prior adjuvant doxorubicin was allowed up to a maximum of 300 milligrams per meter squared.  Patients were to be treated every 3 weeks until disease progression or significant toxicity.  No dose escalation was allowed in this study.
Patients could not have been treated for the metastatic disease with prior chemotherapy.  Patients must have had bidimensionally measurable disease, ECOG performance status of 0 to 2, left ventricular ejection fraction at baseline greater than 50 percent, and no prior history of congestive heart failure.

The planned sample size for this study was 288 patients.  This was based on an 80 percent power to rule out a one-sided difference of 15 percent in response rates.  Three interim analyses were planned, but due to rapid enrollment into this study, only the first interim analysis was performed.  The study enrolled the full sample size as planned and the total number of patients was 297.
Study 2 is a study comparing single agent treatment of D-99 to the same dose of single agent doxorubicin.  The study design was very similar to that in study 1 except that in this study dose escalation was allowed at an increment of 15 milligrams per meter squared up to a maximum of 105 milligrams per meter squared.
Eligibility criteria were identical to that in study 1.  
As in study 1, the planned sample size was 288 patients with three planned interim analyses.  

The stopping rules were defined according to the O'Brien-Fleming stopping rule, with an overall type 1 error of 0.05.  It is important to note that this study was not prematurely stopped.  Rather it was stopped per protocol.  At the third interim analysis, the study had met both protocol-specified endpoints for early stopping.  The interim analysis results were discussed with the FDA and the agency agreed that the protocol endpoints were met for early stopping and that it was up to the company to decide to stop enrollment.  After the meeting with the agency, the sponsor stopped enrollment into the study as called for by the protocol.  The final sample size was 224 patients.
The D-99 clinical program was international in scope.  Study 3 compared the combination of D-99 plus cyclophosphamide to equal doses of epirubicin plus cyclophosphamide.  
The objective of this study was to demonstrate that antitumor efficacy at equal doses of these treatments was comparable.  
In this study no prior anthracycline was allowed and patients were treated up to a maximum of 8 cycles.  
With a maximum of 600 milligrams per meter squared, it was expected that there would be a low incidence of cardiotoxicity with both treatment arms.  Therefore, cardiotoxicity is not an endpoint in this study.
Eligibility criteria were identical to that in study 1 except that no prior anthracycline was allowed. 

As in the pivotal study, the sample size was 288 patients.  No interim analysis was planned or conducted.  This study was terminated because of resource considerations.  The final sample size was 160 patients.  The study was stopped without any knowledge of the study results.  The integrity of the study was maintained and the outcome of this study was not biased by the early termination.
Dr. Jonathan Alexander will now present our findings on the reduction of cardiotoxicity, focusing on results from study 1 and the confirmatory evidence from study 2.  Dr. Alexander had reviewed the cardiotoxicity results from these two studies on a treatment blinded basis.
Thank you.
DR. ALEXANDER:  Thank you, Dr. Lee.  My name is Jonathan Alexander.  I'm a clinical cardiologist at Danbury Hospital and Yale University.  It is my distinct privilege to present the reduction in cardiotoxicity data for TLC D‑99.
As described by Dr. Lee, two phase III trials were designed to determined if TLC D-99 was associated with less cardiotoxicity compared with conventional doxorubicin in the treatment of patients with metastatic breast cancer.

The primary endpoint in assessing cardiotoxicity in both trials was a reduction in the left ventricular ejection fraction, as determined by serial MUGA scans.  Guidelines developed by myself and the Yale University Nuclear Cardiology Laboratory were used to monitor therapy.  These have shown that a drop in ejection fraction can be a preclinical indicator for stopping doxorubicin in an attempt to reduce the severity of cardiotoxicity and limit the incidence of congestive heart failure.
Therapy was to be discontinued if the left ventricular ejection fraction fell by greater than or equal to 10 ejection fraction units to a level less than normal or greater than or equal to 20 ejection fraction units within the normal range.  If detected, therapy was to be discontinued. 
Additionally, at each clinic visit, patients were carefully monitored for signs and symptoms of congestive heart failure, and again if detected, it would be stopped.

In study 2, the protocol initially required that endomyocardial biopsy be performed after patients had received a cumulative lifetime dose of 425 milligrams per meter squared of doxorubicin.  A score of 2.5 or 3 on the Billingham scale, which I will define, required that treatment be discontinued.  Approximately 1 year after initiation of this trial and after careful review of the data with the FDA, the protocol was amended to discontinue use of this invasive procedure.
All of the participating institutions were required to submit their MUGA studies for standardization to the core laboratory at Yale University with subsequent certification.  All MUGA scans were read blinded to the patient's treatment.  If the scans were felt to be technically inadequate, they were asked to be repeated.  To minimize the risk of congestive heart failure, results were provided to the site prior to the next scheduled dose of anthracycline therapy.
In studies 1 and 2, MUGA scans were to be performed at baseline, before the next cycle after exceeding 300 milligrams per meter squared, 400 milligrams per meter squared, before each dosing after 500 milligrams per meter squared, at the end of the study, and 3 months after termination of the study.

My role was to review records of all patients reported to have congestive heart failure and those whose left ventricular ejection fraction fell to a level of less than 30 percent.  This value was chosen because the incidence of congestive heart failure rises significantly in these patients.  Charts were reviewed carefully to see if criteria for congestive heart failure was met.  Confirmatory evidence was also reviewed, including results of chest x-rays and echocardiograms. 
In study 2, endomyocardial biopsies were read blinded to treatment by Dr. Margaret Billingham of Stanford University, who developed the pathologic scoring system used to assess doxorubicin-induced cardiac damage.  Grade 2.5 is defined as 26 to 35 percent of involvement of the myocytes.  These patients have a 10 to 25 percent risk of developing heart failure with an additional 100 milligrams per meter squared of anthracycline.  A score of 3 defines a more diffuse cellular injury with greater than 35 percent of myocytes affected.  These patients have a greater than 25 percent risk of developing heart failure with any additional challenge of anthracycline.
In the initial phase of this study, both the biopsy and MUGA scans were obtained at a dose of 425 milligrams per meter squared of doxorubicin.

Study drug exposure in study 1 is depicted on this slide.  Although all of the overall differences in drug exposure were not statistically significant, the range in the D-99 group was higher.  In addition, more patients were treated with greater than or equal to 8 cycles of therapy.
The prevalence of recognized cardiac risk factors for cardiotoxicity was similar in both arms.  These included older age, prior exposure to doxorubicin, cardiac irradiation, and prior cardiac disease.  One-third of patients in both arms had one or more risk factors for cardiotoxicity, a finding similar to other patients treated with metastatic breast cancer.  The patients with these risk factors form a subgroup at high risk for cardiotoxicity.  
The relationship between the total cumulative dose of doxorubicin, the incidence of significant left ventricular ejection fraction change, and congestive heart failure is shown for the D-99 and doxorubicin group in this slide.  21 percent of the patients receiving doxorubicin had protocol-defined cardiac toxicity compared with 6 percent in the D-99 arm.  This occurred despite the higher cumulative doses of doxorubicin in the D-99 arm.  In addition, there were 5 cases of congestive heart failure with doxorubicin, none with D-99.

It's important to note that the majority of the change in ejection fraction, as well as the congestive heart failure, occurred in a dosage range of between 300 and 500 milligrams per meter squared, a dosage range frequently used to treat patients with metastatic breast cancer.
The difference between the estimated median cumulative lifetime dose of doxorubicin at the first occurrence of protocol-defined cardiac toxicity was statistically significant, as shown on this Kaplan-Meier analysis with a p value of .0001.  
The hazards ratio of 5 indicates that patients treated with doxorubicin were 5 times more likely to develop cardiac toxicity than those treated with D-99.  Cardiac toxicity was first evident at between 300 and 400 milligrams per meter squared of doxorubicin where the curves begin to separate.
In single-agent study 2, both arms received a median of 4 cycles of therapy.  There was a significantly higher range in the D-99 group, and a significantly greater portion of patients were treated with greater than or equal to 8 cycles in the D-99 arm.

The prevalence of cardiac risk factors was again noted to be similar in both arms, as shown in study 1.  Up to 50 percent of patients in this study had one or more cardiac risk factors for cardiotoxicity, again representing a high risk group.
A similar analysis comparing the two arms with regard to cumulative dose of doxorubicin, significant change in ejection fraction, and incidence of congestive heart failure is shown here for study 2.  The difference between the 28 percent in the doxorubicin arm and 13 percent in the D-99 arm was statistically significant.  9 patients with doxorubicin had heart failure, only 2 with D‑99.  Cardiac toxicity tended to occur at higher cumulative doses of doxorubicin in the combination trial, which is a finding consistent with doxorubicin's labeling which cites an increased risk of cardiotoxicity when doxorubicin is given with cyclophosphamide.
As in study 1, a Kaplan-Meier analysis for the estimated median cumulative lifetime dose of doxorubicin at the first occurrence of cardiac toxicity was performed, and the difference between the two groups is statistically significant.  

The hazards ratio of 3.7 indicates that patients receiving doxorubicin were over 3 and a half times more likely to develop cardiotoxicity compared with D-99, and in these curves, the separation is at about 450 milligrams per meter squared when cardiotoxicity was first seen.
Before amending the protocol to delete the requirement for endomyocardial biopsies, 36 patients, 19 receiving D-99 and 17 receiving doxorubicin, qualified for the procedure.  70 percent of the patients with doxorubicin had scores of 2.5 or greater in contrast with 5 in the D-99 arm.  Importantly, none of the D-99 patients had grade 3 cardiac toxicity.  
Thus, determined from either a functional standpoint using MUGA scans or with endomyocardial biopsies, it appears that D-99 is significantly less cardiotoxic compared with conventional doxorubicin.  These two differing methodologies support the same conclusion.
A meta-analysis of the high risk group of patients, those with one or more cardiac risk factors, was performed.  On this Kaplan-Meier analysis, the difference between the D-99 group and the doxorubicin group was statistically significant with a p value of .0001.  In this high group of patients, those receiving doxorubicin were greater than 6 times more likely to develop cardiac toxicity compared with D-99, using the hazards ratio.

In the third phase III trial comparing D-99 to epirubicin, cardiac toxicity was not a primary endpoint since it was anticipated that these anthracyclines would be relatively cardiac sparing when capped at a dose of 600 milligrams per meter squared.  Indeed, as shown here, 12 percent of the patients with D-99, 10 percent with epirubicin, developed a significant change in ejection fraction as determined by echocardiography.  No patient in either group developed congestive heart failure.
Hazards ratio on the corresponding 95 percent confidence limits for studies 1 and 2 are presented here.  There's a highly statistically significant difference in cardiac toxicity with a p value of .0001 for study number 1 and .0002 for study number 2.  The hazards ratios, indicated here between 3.7 and 5 again, indicate that patients treated with doxorubicin were 3.7 to 5 times more likely to develop cardiac toxicity than those treated with TLC D-99.

A review of the entire database of 542 patients with predominantly solid tumors who were treated with D-99 at a starting dose of less than 100 milligrams per meter squared was reviewed.  8 patients, or 1.5 percent, developed congestive heart failure.  As shown here, it is estimated that the cumulative dose of TLC D-99 was associated with a 5 percent risk of congestive heart failure with 780 milligrams per meter squared.  With doxorubicin, it's estimated to occur at 400 milligrams per meter squared.
In conclusion, data from two randomized, well-controlled clinical trials reproducibly demonstrate that D‑99 compared with the same dosing schedule of doxorubicin affords a significant reduction in cardiac toxicity as defined by functional criteria using MUGA scans, incidence of congestive heart failure, or by myocardial biopsy scoring.
Thank you for your attention.
Before I turn it over to Dr. Lee, I'd just like to take a moment.  As a clinical cardiologist who interfaces with many of the patients who are at risk for cardiotoxicity or who develop it, the prospects of having a drug that will limit the cardiotoxicity is very exciting, undoubtedly resulting in a significant decrease in the medical burden to the patients, with less cardiac medications, less need to interface with cardiologists, reduced need for hospitalizations, and a significant reduction in the morbidity associated with this disease.
DR. LEE:  I will now present the results for the antitumor efficacy of TLC D-99.

All three phase III studies were designed as a non-inferiority study for the efficacy endpoints.  Since we're comparing a test drug to standard known therapies, the primary goal is to ensure that there is no loss in antitumor efficacy.  The protocol-defined primary efficacy endpoint is response rate, and the protocol-defined test of non-inferiority is a one-sided test to rule out a difference of 15 percent with a type 1 error of 0.05.  This specification of the primary endpoint and the analysis criterion was agreed with the FDA at the end of phase II meeting and was specified in the protocol.
In my presentation, I will also present the more stringent criteria of the two-sided 95 percent confidence interval for the difference in response rates.  The data will show that the response rates in all three studies met the criterion of 15 percent delta and also the more stringent criterion of 10 percent delta.  The FDA analysis that you will see for the response rate is based on relative risk.

Other protocol-specified secondary endpoints include duration of response, time to progression, time to treatment failure, and overall survival.  To evaluate non-inferiority, the lower one-sided 95 percent confidence limit of the hazards ratios for these parameters should be greater than .75 if significant reduction in cardiotoxicity is demonstrated, as in studies 1 and 2, and should be greater than .80 if there is no difference in cardiotoxicity, as in study 3.  In my presentation, I will once again present the more stringent two-sided 95 percent confidence limits.
Study 1 compares the combination treatment of D-99 plus cyclophosphamide to equivalent doses to doxorubicin and cyclophosphamide.  The objective response rates in disease progression results presented here are based on the treatment blinded assessment by Dr. Joyce O'Shaughnessy.  Objective response is defined by the WHO criteria lasting at least 6 weeks.  Disease progression is defined as an increase of 25 percent in any lesion or the appearance of new lesions.  Time to progression is defined as the documented disease progression, as defined here, or death within 6 months of last dose.  This criterion and this definition of time to progression was agreed upon with the FDA review team.

Patients were well balanced with respect to baseline characteristics.  10 percent of the patients in each treatment group had received prior adjuvant doxorubicin.  The objective response rates were 44 percent versus 43 percent.  The p value to rule out the 15 percent delta was highly statistically significant and the results also fulfilled the criteria of no more than 10 percent delta as evidenced by the two-sided 95 percent confidence limit.  There was no difference in duration of response.
There was also no difference between the two treatment groups in time to progression.  The hazards ratio that is presented here, as well as in all of the subsequent presentations, are expressed with D-99 as the denominator.  A hazards ratio of 1 indicates that there is no difference between the two treatment groups and a hazard ratio of greater than 1 favors D-99.  The hazards ratio shown here is 1.07.  As you can see, the lower limit of the one-sided as well as the two-sided 95 percent confidence limit fulfilled the criteria for non-inferiority.

Time to treatment failure is a composite endpoint considering both the efficacy and the safety component of treatment.  Treatment failure is defined as the first onset of progression, cardiotoxicity, or off study due to adverse events.  As can be seen in this analysis, D-99 is associated with significantly longer time to progression.  The p value is 0.04, and the hazards ratio is 1.32.
There was no difference between the two treatment groups in overall survival.  Overall survival was 19 months for the D-99 treated patients versus 16 months for the doxorubicin treated patients.  The hazards ratio is 1.04 and the lower limit of the one-sided confidence interval was .80.
Just as a note of information, the numbers that you will see in the survival analysis in the list of questions that were handed out by the FDA will be slightly different from the ones that you will see presented by me.  The difference is because the FDA numbers were based on a previous older data set.  All of the other parameters that you will see from both sides are based on the updated latest data sets which were submitted to the agency in April of this year.

Quality of life is always important to patients, particularly for women who have metastatic breast cancer.  Quality of life information was collected in this study using two instruments.  The patient's self-assessment of symptoms based on a 10 centimeter visual analog scale where patients were asked to rate the cancer related pain as well as the other kinds of related symptoms.  Additionally, an EORTC quality of life questionnaire consisting of 30 questions was also administered.
There were no major differences emerging from the EORTC questionnaire, but there were some very interesting and consistent findings observed from the patients' self-assessment.  There was pain reduction for both treatment groups during the course of treatment as evidenced during the first 5 cycles where more than 50 percent of the patients were still on study.  The difference between D-99 and doxorubicin was statistically significant at cycle 3 and 4 in favor of the D-99 treated patients.  Furthermore, D-99 patients also reported significantly less other cancer related symptoms at cycles 2, 3, and 4.

A summary of the efficacy results for this pivotal trial is presented here.  D-99 fulfilled the protocol-defined criteria of demonstrating non-inferiority, as well as the more stringent criteria of the two-sided tests.  Importantly, it is interesting to note that all the hazards ratios for the time to event parameters were greater than 1 in favor of D-99 and there was a statistically significant difference in time to treatment failure in favor of D-99, a reflection of the comparable antitumor efficacy and improved safety profile for TLC D‑99.
In summary, this pivotal trial demonstrates that the antitumor efficacy of D-99 plus cyclophosphamide is comparable to that of doxorubicin plus cyclophosphamide.
Study 2 compared single-agent treatment of D-99 to doxorubicin.  The efficacy endpoints and defined analyses in this study are identical to that of the pivotal study 1.  Objective response in disease progression were assessed on a treatment blinded basis by Dr. Joyce O'Shaughnessy.
The treatment groups were well balanced in baseline characteristics.  The only notable difference is the higher proportion of patients in the D-99 treated group with a negative progesterone receptor status. 
Response rate is identical between the two treatment groups, 26 percent in each arm.  The results fulfilled the protocol-defined test to rule out a 15 percent delta and also the more stringent criteria to rule out a 10 percent delta.  The lower limit of the 95 percent confidence interval was minus 9 percent.  There was no difference between the two treatment groups in duration of response.

I would like to note that in the original protocol, the protocol assumed a response rate of 60 percent, which in retrospect was unrealistic for single agent treatment.  This observed response rate in the 20 percent range was actually more in line with what is recently reported in the publications and in the literature, and the study still fulfilled the protocol-defined criterion of non-inferiority.
There was no difference between the two treatment groups in time to progression.  The hazards ratio is .91 and the lower bound for the 95 percent confidence limit was .70.
There was also no difference in time to treatment failure.  The hazards ratio is 1.21, and the lower limit for the 95 percent confidence was .94.
There was a nonsignificant trend towards the difference between the two treatment groups in overall survival.  The separation of the curves began at around 12 months after the start of treatment.  The hazards ratio is .76, and the one-sided 95 percent confidence limit was .58.

The most appropriate analysis is the protocol-specified, protocol-defined analysis.  We did conduct some exploratory analyses to try to understand the reason for the survival findings.  Exploratory analyses were conducted including stratification factors, center effect, and covariate adjustments with prognostic factors.  The result shows a spectrum of summary statistics with p values ranging from .06 to .19, suggesting that these summary statistics are sensitive to the models and factors included.  We do recognize that these are all post hoc, unplanned analyses and are exploratory in nature.
We do not fully understand the reason for the difference in survival.  However, there are a few important points that I would like to bring to your attention.  There is no difference in survival during the first year between the two treatment groups.  You may recall that the median duration of treatment in the study was 4 cycles, about 3 months of treatment.  The timing at which the separation of the curves began, which is at 12 months after the start of study, approximately 9 months after the patients discontinued from study drugs, calls into question the potential impact of post-study therapy.  Post-study therapy was not controlled by the protocol.  The information was not prospectively collected, and the data was not completely available for all patients. 

It is also important to note that the survival data in this study is not consistent with the efficacy parameters in the entire clinical program.  All the other efficacy parameters, including survival, in the other two randomized studies were very comparable between the two treatment groups.
In summary, the results from this single-agent trial show that D-99 met the criteria for non-inferiority for the primary endpoint of response rates, as well as for duration of response and time to treatment failure.
Next I will present an analysis of the subgroups who were at high risk of cardiac toxicity, as defined by Dr. Alexander.  Dr. Alexander had presented the meta-analyses for study 1 and 2 for this subgroup for the reduction in cardiotoxicity.  For completeness, I'm now presenting for you the efficacy results for this group.
D-99 delivers very comparable antitumor efficacy for this group of patients who are at high risk of cardiac toxicity.  The hazards ratios are either very close to 1 or greater than 1, favoring D-99.

Now let's move on to study 3, the confirmatory trial for antitumor efficacy in combination regimen.  Study 3 compares D-99 plus cyclophosphamide to equal doses of epirubicin plus cyclophosphamide.  A question has been raised by the FDA regarding the dose of epirubicin, so I will take a few minutes to address this issue. 
Epirubicin is a widely accepted anthracycline in Europe and in Canada for the treatment of advanced and metastatic breast cancer.  In a combination regimen, epirubicin was approved at doses ranging from 30 to 75 milligrams per meter squared.  Therefore, the dose of 75 milligrams per meter squared in combination with cyclophosphamide that is used in study 3 is actually at the high end of the approved dosing in Europe where this study was conducted.
On an equal milligram basis, epirubicin and doxorubicin were shown to be equivalent in antitumor efficacy.  Randomized controlled trials were conducted using combination therapies including epirubicin and doxorubicin at equal doses. 
The Italian trial was the largest of these studies, and as you can see there was no difference in response rates and no difference in survival at equal doses of epirubicin and doxorubicin.  
Similar findings were observed in the other three independent studies.  There was no difference in response rates and no difference in survival.

Similarly, there was some single-agent studies that were conducted at equal doses of epirubicin to doxorubicin, and the findings were similar to the ones presented here.  At equal doses, there were no differences in response rates or median survival.
The Ontario Cancer Care Guidelines recently published their assessments on the issue of dose comparability in patients with advanced breast cancer.  A thorough literature review was conducted and a meta-analysis of six trials was performed totaling 983 patients being included.  The results show that the hazards ratio for the efficacy parameters was very, very close to 1 and the Ontario group concluded that epirubicin and doxorubicin are equally efficacious in advanced or metastatic breast cancer.

Epirubicin was reviewed at the last June ODAC meeting and the application for the metastatic breast cancer was rejected and was not recommended for approval by ODAC.  It is important to note that none of those studies submitted in that NDA compared epirubicin to doxorubicin.  However, this issue of comparability of epirubicin to doxorubicin was discussed by the FDA.  Upon reviewing a meta-analysis that was submitted to the sponsor, the FDA concluded that the two treatment groups are comparable in the first-line therapy of metastatic breast cancer.
There were a number of studies conducted comparing escalating doses of epirubicin.  Three studies compared doses of epirubicin at 50 to 100 milligrams.  This study here was actually the study that was reviewed at the June ODAC meeting.  While the results show that 100 milligrams per meter squared of epirubicin produced high response rates, there were no differences in survival with the higher doses. 
This study here evaluated escalating doses of single agent epirubicin.  The results show that there was a dose response up to 90 milligrams of epirubicin as a single agent, but there was no additional benefit beyond 90 milligrams per meter squared.  
There was one study that was presented at this year's ASCO that compared 75 to 100 milligrams of epirubicin which showed that there was no additional benefit with 100 milligrams per meter squared.
Furthermore, there were also no studies comparing equal doses of epirubicin to doxorubicin where doxorubicin was shown to be superior.  

Therefore, we are confident that the 75 milligrams per meter squared of epirubicin is an appropriate dose for comparison in study 3.
As mentioned earlier, the trial was terminated at 160 patients due to resource and administrative considerations.  The responsibility for the clinical development program for D-99 was under the Pfizer Corporation until July of 1997.  When The Liposome Company assumed the responsibility for TLC D-99 in 1997, this study was stopped due to resource considerations. 
At the time of termination, there was absolutely no knowledge of the study results.  The early termination reduced the sample size and resulted in a larger variance of the estimates, which actually makes it more difficult to meet the predefined criteria.  As you will see later on, despite the reduced sample size, D-99 fulfilled the predefined criteria of non-inferiority in this study.
Now let's move on to the results from this trial.  The endpoints in this study were identical to that in study 1, and the objective response and disease progression were assessed on a treatment-blinded basis by Dr. Noza Azarnia.  

Patient characteristics were well balanced between the two treatment groups and objective response rate was 46 percent versus 39 percent, fulfilling the criteria of ruling out the 15 percent delta as well as the more stringent criteria of ruling out a 10 percent delta.
The median duration of response was 10 months for the D-99 treated group versus 7.8 months for the epirubicin group.  This difference was statistically significant at a p value of 0.03.
Time to progression was 7.7 months for the D-99 patients versus 6.3 months for epirubicin.  The hazards ratio was 1.45 and the lower bound for the 95 percent limit was 1.03.
There was a statistically significantly longer time to treatment failure for the D-99 treated patients.  The median was 6.8 months versus 4.4 months.  The p value was 0.03, and the hazards ratio was 1.50.
There was no difference between the two treatment groups in overall survival.  The median survival for D-99 was 18 months versus 16 months for the epirubicin treated patients.  The hazards ratio was 1.15 and the lower bound for the 95 percent limit was .82.

Results from this study show that D-99 plus cyclophosphamide meets the criteria for non-inferiority compared to epirubicin plus cyclophosphamide at equal doses.  It is important to note, once again, that the hazards ratios were all greater than 1, favoring D-99, and there is a statistically significant difference in duration of response and in time to treatment failure favoring D-99.
In conclusion, the TLC D-99 clinical program provided two independent, well-controlled studies evaluating the antitumor efficacy of D-99 in combination with cyclophosphamide.  Both studies fulfilled the criteria for non-inferiority for all of the efficacy endpoints.  It is also important to note that the results from the D-99 plus cyclophosphamide arm in study 3 were very similar to that observed in the D-99 plus cyclophosphamide arm in study 1, hence providing an independent replication of the results for the antitumor efficacy of D-99 in combination with cyclophosphamide from the pivotal trial.
Dr. Jerry Batist, principal investigator for the pivotal study 1 and single-agent study 2, will now discuss the safety profile.
DR. BATIST:  Thank you very much, Dr. Lee.  Good afternoon, colleagues. 

I've been an investigator with D-99 studies for over 10 years, so I have a large clinical experience with this novel formulation of doxorubicin, and I am pleased to be able to present the safety data to you.
For the most part, I'm going to be talking about one part of the database which is 323 patients, all of whom were in comparative phase III studies, in order to give you the context of a comparative trial with which to compare the toxicities of D-99 as in study 1 to dogs and study 3 to epirubicin.
For some less frequently observed toxicities, I'm going to look at a larger number of patients which, as to these patients, patients who were treated on phase I and phase II studies, and that larger group all were treated at a starting dose of less than 100 milligrams per meter squared every 3 weeks.  It's 542 patients.
Naturally in the development program of D-99, even larger, more intense doses were explored.  Among those patients, there were no new toxicities or any different toxicities that you'll not see described in this discussion today.  It's just that they were more frequent and more intense.  Hence, the decision to focus our development on the 60 to 75 milligrams per meter squared range.

Now, you've heard from Dr. Alexander that D-99 results in significantly less cardiotoxicity than does doxorubicin, and the next few slides will summarize what I'm going to show you in terms of safety data this afternoon.
I'm going to show you that there's no increase in severity or incidence of doxorubicin toxicities and no unexpected toxicities; furthermore, that D-99 is associated with less mucositis and diarrhea than is doxorubicin; and also that D-99 patients presented with no grade 3 palmar-plantar erythrodysesthesia, or hand-foot syndrome as we call it, which would result in dose modifications or reduction in the dose.  In fact, among the very few cases of very low grade hand-foot syndrome, the incidence was 0.3 percent.
Then I'm going to describe the D-99 versus epirubicin study 3 toxicity.  I want to put this in context a little bit.  You've heard from Dr. Lee the published results of a number of studies in which epirubicin and doxorubicin at equivalent doses were compared.  You've also heard that the overall response rates and the survival at equivalent doses were the same.  There was no significant difference. 

In the Pritchard analysis of all of these studies, what was also true was that in the doxorubicin group, there was more significant toxicity, more significant neutropenia, mucositis, fever, nausea and vomiting, and also importantly, more episodes of cardiac toxicity, both congestive heart failure and other indices of cardiac damage.  
What you've heard today is that unlike doxorubicin at equivalent doses compared to epirubicin D-99 has a similar cardiac-sparing effect to that of epirubicin.  On the other hand, like doxorubicin in all of those studies, it is more myelosuppressive and does result in more mucositis.
This is the hematologic toxicities observed in study 1 and study 2 where D-99 is compared to doxorubicin, and they're generally very similar with the notable exception of grade 4 neutropenia, which is more frequent in the doxorubicin treated patients than in those who receive D-99.  This is associated with a smaller number of patients who had this degree of myelosuppression for greater than 7 days.  In study 2, looking at all grades of infection, there were significantly fewer in the D-99 group compared to the dox group.

Nonhematologic toxicities are shown here.  The toxicities that are indicative of mucosal damage -- that is, stomatitis, mucositis, diarrhea -- in all of the cases, the numbers favor D-99 with less toxicity compared to doxorubicin.  They reach statistical significance for stomatitis and mucositis in study 1 and study 2 and for diarrhea in study 2.
The treatment related deaths are shown here.  1 patient in study 1 died of sepsis in the D-99 group that was treatment related, and 1 patient in study 2 died of congestive heart failure in the dox group that was treatment related.  There were no treatment related deaths in study 3.
The hematologic toxicities for study 3 are shown here.  As mentioned there is less myelotoxicity with epirubicin.  There's a statistically significantly lower incidence of grade 4 neutropenia with epirubicin compared to D-99.  There was not a statistical difference in the duration of the grade 4 neutropenia between the two groups and this did not result in any septic deaths.
Nonhematologic toxicities are shown here.  They're generally the same with the exception of stomatitis and mucositis being less frequent with epirubicin compared to D-99.

Then finally I want to refer to that larger number of patients because I want to describe skin toxicities which are infrequent, though clinically very difficult for patients treated with doxorubicin.  These are the patients, all of whom started at less than 100 milligrams per meter squared on a 3 weekly basis, 542 patients.  In that number of patients, we saw only 3 cases of hand-foot syndrome, no grade 3 cases, which is the grade at which we would have to reduce the dose of the drug, 1 grade 2 and 2 grade 1.  There was only 1 case of grade 1 radiation recall in the skin, and as it happened there were 7 patients who had accidental extravasation of D-99.  In none of these cases was there necrosis or ulceration of the skin.
So, in summary, I've shown you that there was significantly less cardiac toxicity of D-99 compared to doxorubicin.  There is less mucositis and diarrhea compared to doxorubicin.  Hand-foot syndrome is extremely rare, and in the few cases where it occurred, it was not severe enough to require dose modification.  Where we saw extravasation, we saw no evidence of necrosis.

Now, I want to just take a second to respond to Mr. Cohen's concerns about safety that came up at the very beginning.  I think we've made the case and our contention is that the dose of D-99 would be equivalent to doxorubicin in the 60 to 75 milligrams per meter squared range, so that there would be no requirement for a change in the practice of physicians, in contradistinction to what happens with Doxil.  Therefore, there wouldn't be a safety issue in that regard.  Where there might be a safety issue is in educating our colleagues that this is not Doxil.
Finally, as a practicing clinician who treats many women with breast cancer, I want to express my personal enthusiasm at the prospect of having this novel drug available.  This provides dramatically reduced cardiac toxicity without bringing along with it any added new toxicities.
Thank you.  Dr. Lee will provide a conclusion.
DR. LEE:  Doxorubicin is one of the important agents for the treatment of breast cancer.  All women receiving doxorubicin as part of their treatment for breast cancer are at risk of the side effect of cardiotoxicity from doxorubicin treatment.  Despite decades of efforts to reduce the cardiotoxicity of doxorubicin, there remains a continued and increasing need for a less cardiotoxic doxorubicin which could deliver a comparable level of antitumor efficacy.

TLC D-99 fulfills the objective of improving upon the therapeutic index of doxorubicin.  On an equal milligram basis, D-99 significantly reduces cardiotoxicity while delivering antitumor efficacy that's comparable to doxorubicin.  Both of these endpoints were demonstrated in the pivotal study 1 and these results were reproducible and independently confirmed in two separate studies.
Reduction of cardiotoxicity compared to doxorubicin is highly significant in both studies comparing D-99 to doxorubicin.  D-99 reduces cardiotoxicity by 75 to 80 percent.  The estimated dose at which a 5 percent risk of developing congestive heart failure was 780 milligrams per meter squared with D-99.  Based on our own database, as well from the literature, the 5 percent risk of congestive heart failure for doxorubicin was 400 to 450 milligrams.  So, compared to doxorubicin, this difference represents an additional 4 to 5 cycles of treatment with D-99 before reaching the same level of risk of CHF.

Preservation of antitumor efficacy is demonstrated in both studies using combination regimens with cyclophosphamide, the indication that we are seeking today.  In both studies 1 and 3, hazards ratios are all greater than 1 in favor of D-99, and all the parameters met the criterion for demonstrating non-inferiority.
D-99 is associated with other safety advantages.  Compared to doxorubicin, D-99 had significantly less mucositis and diarrhea.  The D-99 formulation of liposomal doxorubicin is not associated with increased hand-foot syndrome.  There were no reports of grade 3 or 4 hand-foot syndrome in the entire clinical program.  TLC D-99 is also not associated with severe necrosis or ulceration upon accidental extravasation. 
TLC D-99 provides clinical benefits and offers an important therapeutic option for breast cancer patients.  Compared to doxorubicin, D-99 is a safer formulation while delivering comparable efficacy.  The demonstrated patient benefits support the approval of D-99 for the first-line treatment of metastatic breast cancer in combination with cyclophosphamide.
Thank you very much for your attention, and we are ready to take your questions.
DR. SCHILSKY:  Thank you very much.
Are there questions from the committee?  Dr. Nerenstone?

DR. NERENSTONE:  Correct me if I'm wrong, but I think the way you defined time to treatment failure was a mixture of patients who progressed as well as those who had to drop out due to toxicity.  One of the ways people could stop on the doxorubicin arm was if they reached a value of doxorubicin where the investigator thought that they might have some cardiac toxicity at a certain dose of doxorubicin, even in fact if they had no signs of cardiac toxicity.  It was a nonobjective level, but it was at the investigator's discretion. 
Can you tell me how many patients were actually stopped because of the cumulative dose of doxorubicin they had received and if any of those patients were actually responding at the time they were stopped?
DR. LEE:  Dr. Nerenstone, can I clarify?  You're asking the endpoint for time to progression or time to treatment failure?
DR. NERENSTONE:  I believe it was your time to treatment failure.
DR. LEE:  All right.  May I have the slide?

This is for study 1.  5 percent of the patients versus 10 percent of the patients were stopped due to an ejection fraction drop, a documented cardiotoxicity endpoint.  An additional 1 percent versus 5 percent of the patients were discontinued from treatment because the investigator or the patient was concerned that there may be additional risk of cardiotoxicity and hence the patient was stopped from treatment.
DR. NERENSTONE:  Do we know how many of those patients were actually responding when they were stopped?  Or by virtue of the fact that they were stopped, they had to be responding at that point.  Is that correct?
DR. LEE:  By virtue of the fact that they were stopped due to a toxicity endpoint, they have not progressed.  They could be either responding patients or stable patients.
DR. NERENSTONE:  And I have one other question.  Dexrazoxane was allowed on study, and there's no discussion of how many patients were on it and anything about their response rates as opposed to those patients who were not on it.  Can you give us any more details about that?
DR. LEE:  None of the patients actually was treated with dexrazoxane in this study because the protocol allowed patients to be treated with the amendment at the higher doses.
DR. SCHILSKY:  Dr. Margolin?

DR. MARGOLIN:  I'm going to sort of pursue the same pathway and hopefully break my set of questions down into not too many. 
The first one I guess is the most straightforward one and maybe directed at one of the statisticians, which is, even though what appeared to be your posteriori look-back at the distribution of your identified cardiac factors looked like they were extremely well balanced between groups, at least as I recall in study 1, I'm not certain from a statistical point of view whether that's as good as prestratification which was apparently not done for preexisting cardiac risk factors.  That's question 1.
DR. LEE:  The only stratification factor in the study was prior use of adjuvant doxorubicin.  That is the only stratification factor.  There were no other stratification factors for other cardiac risk factors.
DR. MARGOLIN:  I know that.  That's why I asked the question.
DR. LEE:  Could you please clarify?
DR. MARGOLIN:  Maybe Dr. Lamborn could answer the question.  You understand my question.  Right?
DR. LAMBORN:  As I understand, you're referring to slide 53, study 1, pivotal, cardiac risk factors where they list the balance of the risk factors.

DR. MARGOLIN:  Exactly.
DR. LAMBORN:  And the question was would there have been any additional benefit to doing baseline stratification, and my sense is, as long as you ultimately have balance, which is what you hope for, that that's okay.
DR. LEE:  Thank you very much.
DR. MARGOLIN:  Thank you.
Then I guess the only other related question I'll ask is probably more rhetorical, but I'm also bothered by -- I guess you had probably some very good consulting cardiologists and people who specialize in this area, but it was somewhat bothersome that on slides 54 and 55, which I think are the same slide, you had quite a few patients grouped in the 400 to 499 milligrams per meter squared cumulative dose of dox, and even 7 patients 500 to 599, and 2 600 to 699.  Some of us would probably stop sooner than that or would have added the dexrazoxane even without changes in the MUGA determined LVEF because it gets a little scary up there, and we know those tests are not perfect.
DR. LEE:  I'd like Dr. Winer to address that please.

DR. WINER:  Can you just clarify your question a little bit?  Are you asking about whether those patients should have continued to be treated or --
DR. MARGOLIN:  I guess the comfort level of allowing treatment to such high doses just because there wasn't a change in the LVEF or because the protocol said you didn't you have to or because the dexrazoxane was considered p.r.n.
DR. WINER:  Well, it's a tough issue.  In the course of the study, every attempt was made I believe to try to make sure that patients would be treated as safely as possible in the sense that MUGAs were done every cycle after 500.  They were shipped off to Yale.  There was no treatment decision until the individual institutions and Yale had both read them.  It's still a concern.  

I think that in every situation, it's a matter of weighing the risks and benefits of continued treatment.  I can tell you personally, having taken care of many of these patients, with each and every patient we debated whether it made sense to go on.  There were patients who pushed to go on where I said, no, I really want to stop.  Undoubtedly there were patients who came off the trial.  I know for sure there were because I took some off because of cumulative dose.  I think it's worth mentioning that those were patients who were not considered treatment failures.  They were censored in that analysis because, in fact, it wasn't a treatment failure.  They came off.
DR. SCHILSKY:  Dr. Kelsen?
DR. KELSEN:  Can I ask a follow-up to that?  It's a question for your position and then a question about the survival curves.
What is your position on the addition of Zinecard to this agent should it reach approval?  Are you going to recommend that it be used at a certain dose, or do you feel so strongly that cardiotoxicity is so unlikely that you believe there is no need for a cardioprotective agent?
DR. LEE:  I would like to call upon Dr. Speyer who has a lot of experience with Zinecard to address this.
DR. SPEYER:  Zinecard is a very interesting drug.
DR. SCHILSKY:  For the record, could you identify yourself and state your affiliation?
DR. SPEYER:  I'm Dr. James Speyer.

Zinecard is a very interesting drug.  As you know, Zinecard is only approved for use after cumulative dose of doxorubicin at 300 milligrams per meter squared.  It is an additional drug that has to be added, and therefore there is possible additional myelosuppression. 
The possibility of interference with the antitumor efficacy was debated at this committee a number of years ago.  It certainly led to the recommendation for waiting until patients had gotten 300 milligrams per meter squared.  It also has led in the community to some reluctance to use it. 
This trial simply didn't test that.  What D-99 provides is an opportunity to use an anthracycline from the start with significantly less cardiotoxicity with doxorubicin.
DR. KELSEN:  I do appreciate the answer but if I could just ask this again.  Is your position that the cardiotoxicity risk is so small -- I believe I heard 1.5 percent on one of those slides -- that you believe another advantage of this is that you do not need, at any dose, to use a cardioprotective?
DR. SPEYER:  My own personal view is that that's the case, and the only way I would think about doing that is if I were really seeing benefit and I were seeing a fall in ejection fraction and we weighed the risks versus benefits in that particular case.

DR. KELSEN:  Then a second question.  We're going to hear from the review board I believe a significant concern about survival in study 2, and I just want to make sure I understood the point that you were making.  If I understood what you were saying correctly, the curves overlap during the period of time that patients in study 2 were receiving the study compound or the conventional control arm.  The curves diverge in favor of the conventional arm after the median was well past, but you don't have data to address the issue as to whether salvage was different between the two arms.  Is that correct?
DR. LEE:  That is correct.  One more point of clarification.  Actually the curves overlap for the first 12 months.  In that study, actually the median duration of treatment was 3 months.  So, actually the curves overlap for an additional 9 months after the end of treatment for a majority of the patients.
DR. SCHILSKY:  Dr. Raghavan?

DR. RAGHAVAN:  A follow-up question to Dr. Kelsen's because I guess I missed the point of the answer.  This is study 2, you slide 86.  So, the curves are very nicely together for the first 12 months, but then at 18 months, there's a 15 percent difference in survival.  At 24 months, there's a 15 percent difference in survival.  The curves come back together again and then they diverge, although by then the power of the study is weak because there are 3 and 8 cases, although you could ask the question does that mean that there just weren't enough patients alive of the ones who were further out in the D-99 arm.  
So, I always get very uneasy if I see a survival curve that starts to drop away.  You've kind of dismissed it and I kind of want to bring you back to it.  So, can you talk a little more about the one test of head-to-head efficacy of new drug versus old drug?  Talk a bit more and let's forget about the first 12 months.  Let's talk about longer-term survival.  What's the deal there?
DR. LEE:  First of all, given the totality of the information, we really do not believe that this divergence in the curve is a reflection of treatment differences.
I'd like to call upon Dr. Eric Winer, who is principal investigator for this study, to give some clinical perspective.

DR. WINER:  The data are the data, and in study 2 there is a trend towards a lower survival in patients who were treated on the D-99 arm.  It's something that the sponsor has been very concerned about.  It's something that I think all of the consultants have paid a great deal of attention to.  I certainly have.  I was involved in that study.
I think for a number of reasons I'm quite convinced that this is not a result of the inferiority of D-99, and I think there are a few issues to bring up.
One is that in that study the response rates are absolutely identical in the two arms.  There are few treatments, unfortunately, that clearly have been demonstrated to change survival in metastatic breast cancer, and in almost all cases where that has occurred to my knowledge, it does not occur in the absence of a difference in response.  So, it certainly doesn't go along with the other parameters in the study.
Second, in the two other studies that have been presented, no difference in any efficacy parameter.

And third -- and I think this is the weakest of the points but I think it's worth noting -- the survival curves do stay together for those 12 months and separate after that.  At least in my mind, it at least raises the question of the extent to which post-study treatment is playing a role.  Post-study treatment was not controlled for at all, and even retrospectively going back and looking at it, the sponsor really was not able to sort that out. 
So, I think for all of those reasons, I don't believe that the survival curves indicate that it's a less efficacious drug.  But it's an issue.
DR. SCHILSKY:  Other questions?  Dr. Nerenstone?
DR. NERENSTONE:  This is going to brought up I know by the FDA reviewers, but for your third study you make the argument that epirubicin is equal to doxorubicin on a milligram-per-milligram basis.  However, when you look at the toxicity profile, in particular on your slides 117 and 118, clearly the D-99 is more toxic with ANC less than 500, with a p value that's significant compared to the epirubicin combination arm, likewise the stomatitis, mucositis, and greater than grade 3 side effects.  Overall, there's also nonsignificantly nausea and vomiting -- you can argue that's pretty close -- but infection and neutropenic infection, although those are not statistically significant.

This is a reversal of the toxicity profile that we saw in studies 1 and 2.  How do you interpret those dissimilar results if you assume that epirubicin is equal to doxorubicin?
DR. LEE:  I'd like to call upon Dr. Jerry Batist to discuss this.
DR. BATIST:  Thank you.
You've heard reference to one of two meta-analyses that were performed to look at the question of what is the right dose of epirubicin relative to doxorubicin.  The one that you heard most about was the one that gathered a group of eminent medical oncologists who practice principally in the treatment of breast cancer, chaired by Kathy Pritchard.  They were charged with establishing practice guidelines for the use of epirubicin.  Their conclusion was that it was absolutely equivalent in antitumor efficacy, and their recommendation, moreover, was in this dose range, 60 to 75 milligrams per meter squared.

Now, you're absolutely correct that we saw enhanced toxicity in some parameters.  As I pointed out, and was observed in that meta-analysis as well, at equivalent doses of doxorubicin and epirubicin, that's exactly what is seen as well:  equivalent overall response, equivalent overall survival, increased nausea/vomiting, increased neutropenia, increased mucositis, but also importantly increased cardiac toxicity.  That was observed even in a number of very small series of patients.  And that's where there's a dramatic distinction. 
So, this is equivalent to doxorubicin we can say, as it performs on a milligram-per-milligram basis in comparison to epirubicin, enhancement in some of these toxicities, some, but not all, but it's very different from doxorubicin because it preserves the cardioprotection that we see with epirubicin.
DR. LEE:  If I may, I would also like to call upon Dr. Bob Leonard who is one of our investigators from study 3 and has a lot of experience using epirubicin in Europe.  Maybe he can shed some light on the equal dose issue.
DR. LEONARD:  Yes.  I'm Bob Leonard, medical oncologist in Edinburgh, Scottland.
As you're probably aware, we have an enormous experience of using epirubicin in Europe as a standard drug in the treatment of advanced breast cancer and increasingly recently used in the adjuvant setting as well.

Now, the data you've heard in the comparative analyses simply speaks to the experience that we've had using the drug in combination where we regard it as an equivalent drug to doxorubicin with probably a better safety profile in terms of the clinical toxicity and probably in terms of the cardiac toxicity as well.  None of the data we've heard in the studies today would contradict that routine clinical experience that we have.  It's very hard to use doses of epirubicin above the equivalent of 25 milligrams per meter squared weekly even as a single agent in advanced breast cancer because of clinical toxicities.  So, it's a standard dose of a standard drug used very widely and in fact in Europe at a much higher level of patient exposure than even doxorubicin is these days.
I don't know if that answers all of your questions, but I think it answers some of them.
DR. SCHILSKY:  Thank you.
Dr. Johnson.
DR. DAVID JOHNSON:  I want to also come back to Dr. Kelsen and Dr. Raghavan's point because, as I've listened to the presentation and read through the material provided by the sponsor, I'm reasonably persuaded that there's less cardiac toxicity.  I'm not persuaded that there's equal efficacy to doxorubicin.

What you've given us are three studies, none of which was powered or designed to really look at survival endpoints.  They looked at response endpoints.
DR. LEE:  That's true.
DR. DAVID JOHNSON:  Actually you gave us data about epirubicin where you can change response but you didn't change survival.  In your own data, you showed us that.
The third study you showed us was actually an aborted study.  So, I'm having a hard time even figuring out how to use those data.
So, I'm equally concerned with this difference in survival, and I think it would be surprising to me, frankly, if you did not have information about second-line treatment or the subsequent treatment for these patients and at least some differences that might have emerged that could have explained or given some possible explanation for the difference in survival beyond the fact that this drug is less efficacious than doxorubicin.
So, for example, if you could show me that the doxorubicin arm all received a taxane or 50 percent of them did or so and no one on the D-99 arm did, I would be much more comfortable with your conclusions about the comparability of the efficacy of the two agents.

DR. LEE:  Dr. Johnson, I'd like to respond to the issue about the lack of information on post-study therapy, and then I'd like to call upon Dr. Steve Piantadosi to talk about the validity and integrity of study 3 being a terminated trial.
First of all, the post-study therapy information was really incomplete for us to make any kind of inference or conclusion on.  We simply didn't have information on 20 percent of the patients.  Bear in mind that this study actually started in 1992, quite a while back, and we actually retrospectively tried, as hard as we can, to collect complete information on post-study treatment, but the information was simply not available for 20 percent of the patients, and even in the remaining 80 percent of the patients, there were a lot of patients that clearly had missing data.  As you might imagine, patients move around.  They move to other sites.  They may have died some years ago, and it's very difficult to go back and collect information to the extent that we can address this post-study therapy issue.
Then I'd like Dr. Piantadosi to maybe address the study 3 early termination.
DR. WILLIAMS:  Could I address the point you just mentioned before we go on?

From our review of your data, we saw that 69 percent in each arm, at least, had been documented to get a taxane.  Now, there may have been, in that other 31 percent in each arm, others, but at least from the data you submitted, 69 percent in each arm had a taxane.
DR. LEE:  Yes, that is true, and actually we interpret that as sort of an indication of the lack of information also because during this period of time almost all metastatic breast cancer patients who had already been treated with a doxorubicin-based treatment would have received taxanes, and close to 30-40 percent of them, according to the records, didn't receive taxanes.  So, we really do not believe that we have adequate information to draw any conclusions from this.
Dr. Piantadosi?
DR. PIANTADOSI:  Thank you.  I'm Steve Piantadosi from the Johns Hopkins Oncology Center, a consultant to the company.  I'm sure the committee thought they had seen the last of me this morning, but I'm back.
(Laughter.)
DR. PIANTADOSI:  I may be here tomorrow too, weather permitting.

I share the concern over study 3 and the illustration of an unfortunate consequence of having to do clinical trials in the real world, and that is resource limitations.  
The essential question, as far as I'm concerned, is whether or not you believe that the study represents an unbiased estimate of the treatment effect.  The only way that the study could be biased is if a decision about termination were made with knowledge of the results, barring some other disaster with disclosed randomizations or something like that.  But we're very confident in the methodology of the study.  The only issue is whether or not it was terminated with knowledge of the results, and in fact that was not the case.

Now, as such, one could then imagine that the study had been designed with this particular sample size that is not an aborted study at all.  Consider, for example, if the study had gone to twice its sample size rather than half its sample size.  Would anybody then speculate, well, we should throw out half the data because the investigators didn't follow the original plan to conduct the study?  And I think the answer is no.  So, as long as you have confidence that the study is showing you an unbiased estimate of the treatment effect, it should be considered for the strength of evidence as it stands.
As such, it represents a higher hurdle for the treatment to overcome because the imprecision that results from the smaller sample size widens the confidence intervals on all of the outcome measures, primary and secondary, and as you saw from the results, even so, this study meets the prespecified hurdles.
DR. LEE:  I just want to add and assure you that we had absolutely no knowledge of the study results when we terminated the trial.
DR. DAVID JOHNSON:  I believe you.
(Laughter.)
DR. DAVID JOHNSON:  I actually have another question, and that has to do with your proposed indication.  Why are you specifically asking to do this in combination with cyclophosphamide?
DR. LEE:  We have two independent randomized trials conducted in combination regimens that show very comparable and replicated, reproducible antitumor efficacy, and on that basis, we are recommending the indication for combination treatment.

DR. DAVID JOHNSON:  Yes, that's true, but you could also make the argument that "comparability" then is on the basis of the cyclophosphamide.
DR. LEE:  I'd like Dr. Eric Winer to address this, please.
DR. WINER:  You could make that argument.  Cyclophosphamide was there.  The question is in those studies is cyclophosphamide masking any inferiority of D-99 versus doxorubicin.  Obviously, there's no experiment that can provide an answer to that.  Cyclophosphamide is an active drug.  It's a less active drug, I think we all believe, than doxorubicin.  I personally think that it's unlikely that it would be masking an effect, and in other trials that have included cyclophosphamide where other agents have been compared, there have been differences seen despite the presence of cyclophosphamide.
If I can just, for a second, come back to your question about the survival issue because it's clearly a very, very important issue, and I realize I already addressed this, so bear with me for a second.

But in the absence of seeing a difference in response in the two arms in study 2 or a difference in response duration or a difference in time to progression, it's very hard for me to attribute a difference in survival that's occurring many months out to the two treatments in question.  I'm left, although it is less than a fully satisfying answer, recognizing that metastatic breast cancer is an incredibly heterogeneous illness and that there are differences in patients and that some of that can happen in studies that are of reasonable size but not huge.
DR. DAVID JOHNSON:  In response to that, Eric, let me say that treatment for some other solid tumors -- and I'll use an example, say lung cancer, non-small cell.  Treatment is brief and oftentimes the curves will follow along precisely the same for several weeks, to even months, after treatment is completed, then separate out well beyond the time of treatment administration.  So, I don't know that this is necessarily unusual or unique to this particular study.  This may be something we've seen in solid tumors.  So, I don't know that, just because it doesn't follow the trend of the other two studies, we should throw these data out.  
I'm very concerned about these data actually.  As I said, it troubles me about whether this is in fact comparable and efficacious.  I suspect it is, but that's not what we're asked here.  We're not asked to guess what we think.  We're asked to render an opinion on what the data show.

DR. SCHILSKY:  Let me ask one question since it hasn't come out yet and this has sort of been disturbing me, as I've been sitting here listening to the data.  I'd appreciate any comments from FDA as well.  It has to do with the choice of response rate as the primary efficacy parameter. 
Typically the committee usually considers response rate as at best a surrogate estimate for efficacy.  Here a decision was made to develop the entire clinical program based on a response rate as the primary efficacy parameter.  I'm puzzled by how that decision was reached.  I'm actually quite surprised that that was the agreed upon efficacy parameter.  Perhaps we could have some discussion, and I'll ask you first, Dr. Lee, if you could just describe to us how the decision was reached to use response rate as the efficacy parameter.
DR. LEE:  Okay, and then perhaps Dr. Williams can add to that.

During the discussion of the protocol design, response rate was chosen as the primary endpoint at least in part because of the fact that we built in three interim analyses.  In order for the three interim analyses to really be realistic so that, as you accrue the patients, you have sufficient information to act upon it, the information or the endpoints that you have to act upon should be rather readily available rather than having to wait for a long time. 
However, in discussions with the FDA review team, they also said that you can use response rate as a primary efficacy endpoint but we need to make the commitment to follow up and collect sufficient information for time to progression.  Hence, as you can see, in all of the three trials, we did follow up patients to provide sufficient information on time to disease progression.  In fact, if you had chosen time to progression as the endpoint, we would have met the criteria for study 1 and 3, and for study 2, we just missed because of the duration in that study.
Dr. Williams?
DR. WILLIAMS:  Rich, I was involved with these decisions, so I know what we were thinking because I was thinking them.
(Laughter.)
DR. SCHILSKY:  Maybe you could share that with the rest of us.

DR. WILLIAMS:  You're correct.  This was novel.  We had not done it before.  The thinking behind it was that this was doxorubicin, and if you could ever believe a surrogate that tumor response was going to reflect a benefit you're going to see, that it would likely be in this surrogate.
I think we really stretched because we thought this was an important trial to do, and it was basically impossible to do an equivalence trial I think sized for survival equivalence, the number of years you have to go in breast cancer to see a death and then to do equivalence.  So, because there was the hope that there was going to be a decrease in cardiac toxicity, we said we would take one-sided.  We said we would take a ratio of response rates of .75, not the 15 percent absolute amount that was quoted earlier.  And I think we really stretched.  My feeling is that's as far as we should stretch to try to bring a drug with a decreased cardiotoxicity into the marketplace.
We had seen with dexrazoxane the actual decrease in response rate in the largest trial of that submission.  So, we had seen this occur.

It's still debatable whether that was the right decision, but that's the decision we made and that's why I don't feel very flexible about stretching those boundaries any further.
DR. SCHILSKY:  Yes.  I was just curious about the thinking because this morning we saw a drug which essentially is fluorouracil, and yet the studies were required to be powered around a survival endpoint and result in much bigger trials.  So, I think it's important for the committee to understand sometimes the thinking behind --
DR. WILLIAMS:  Of course, the response rate is higher in breast cancer.  Maybe the response rate is a little more respected in breast cancer as a manifestation of effect, but I still think it is debatable.
DR. SCHILSKY:  Other questions for the sponsor?  Dr. Lippman?
DR. LIPPMAN:  I'd just like to ask, I guess, Dr. Piantadosi about this.  I don't imagine it would have an effect, but in study 2, which is the one that is raising the concern, in the design there were three planned interim analyses, but because of rapid accrual, I guess one or two of them weren't done.  Does that affect the statistical power?  Does that change anything?

And then I guess the other comment that I have would relate to slides 87 and 90, this issue of looking at efficacy just in the patients at high risk for cardiotoxicity.  But initially the interim analysis question.
DR. PIANTADOSI:  Yes, thank you.  My opinion regarding the interim analysis question is that having missed an interim analysis carries no impact or importance on the final outcome of the study.  The study could easily have been designed without interim analyses and we'd be looking at the same data.
DR. LIPPMAN:  I guess I was just wondering if it actually strengthened some of the findings because we know the more interim analyses you do, that you have to adjust for that I guess.
DR. PIANTADOSI:  Well, you adjust typically the type 1 error level.  No, I don't think it strengthens any of the findings.
DR. WILLIAMS:  We didn't adjust for the one interim analysis that was done.  Right?  Wasn't there one interim analysis performed?
DR. LEE:  For study 2 now, right?  The second interim analysis and third interim analysis were performed and the boundaries were adjusted way ahead of time.  We stuck to those boundaries.

DR. WILLIAMS:  And the final overall alpha is ‑‑ what is that that's presented?  95 percent or 90 something else?
DR. LEE:  The overall type 1 error is still .05.
DR. WILLIAMS:  And did you use 95 percent confidence intervals, though, at the end or adjust --
DR. LEE:  Yes.
DR. PIANTADOSI:  The interim analyses were conducted using very conservative O'Brien-Fleming kind of rules.  So, the final analysis is probably so close to .05 it's not worth arguing about.
DR. SCHILSKY:  Dr. Lamborn?
DR. LAMBORN:  I'm just curious.  Did you in fact look to see whether in study 2, using response as a time-dependent variable, you saw any relationship of response to survival?
DR. LEE:  No, we did not specifically look at that.  If I understand your question correctly, your question is whether responders have longer duration of survival?
DR. LAMBORN:  With the appropriate analysis.

DR. LEE:  No.  Having read a lot of the recent publications saying that that is not appropriate, we did not do that analysis.
DR. SCHILSKY:  We'll have Dr. Raghavan ask the last question.
DR. RAGHAVAN:  I'd like to ask Dr. Winer.  I'd be concerned to do down a good drug that's less cardiotoxic, but to come back to the issue of study 2, when I look at the company's submission, table 13, page 39, you made the point that you thought that because response and time to progression and everything were identical, that therefore it implied that the change we were seeing in survival had to do with post hoc effects.  And I don't want to make too much of this because the company has done under-powered trial. 

But you've got 0 versus 2 percent CRs.  You've got 32 percent immediate progression versus 27 percent progression.  You've got 34 percent versus 39 percent stable.  I don't know that that's inconsistent with a difference in survival based on worse efficacy.  I really do understand that the numbers are small, but you seem very sure that all the other indices didn't fit with it.  Can you just expand on that based on the data that the company has put in?  Because it seems to me consistent with a survival deficit.  It's really only the 26 percent partial response versus 24 percent that's the same.
DR. WINER:  I think if we applied any statistical test to these numbers, they would all be very comparable.  These are all extremely small differences. 
Again, just to come back for a second to this survival difference, I don't want to mislead anyone.  I remain concerned about this.  I think it's the single most important issue here.  Because of the benefits of the drug, I feel that that outweighs this particular concern.
But just in terms of survival in metastatic breast cancer, it was just a few years ago that all of us would stand up and give talks and say that there was no evidence that anything we did affected survival in patients with metastatic breast cancer.  Now, we all believed there was some impact, but it was impossible to show it in trials.

I know of three trials recently either published or presented that show survival differences:  the Herceptin trials where there were clearly differences in all efficacy parameters; the docetaxel versus mitomycin, vinblastine trial published in the JCO this year as second-line therapy where there was a very dramatic difference in both response and survival; and finally, there was an Australian trial comparing CMFP versus Taxol where in fact there was no difference in response but there was a difference in survival.  But in that trial, patients who received CMFP never received Taxol.  So, the Taxol patients were receiving an extra treatment.
So, again I don't want to mislead.  I can't be certain that there is no difference, but given all of this information and the other studies, that's why I have arrived to the view that I have.  I think these are all very good questions.
DR. SCHILSKY:  Thank you very much.
DR. LEE:  Dr. Schilsky?
DR. SCHILSKY:  Yes.
DR. LEE:  If I may because just now there was a discussion about the use of relative risk, and we would be --
DR. SCHILSKY:  If you can be very brief.

DR. LEE:  Yes.  I'd like to call upon Dr. Gary Koch to perhaps give some statistical perspective on the interpretation of the two statistical approaches:  one that's based on absolute difference in response rates versus the relative risk approach, particularly for study 2.
DR. KOCH:  Gary Koch, a statistical consultant to The Liposome Company, and I'm with the University of North Carolina.
What has been emphasized in this discussion is excluding originally a 15 percent difference in response rate, but the studies actually showed with 95 percent confidence intervals that you could exclude a 10 percent difference.  Now, it was mentioned a few minutes ago that one could look at relative risk and that one would like the ratio of rates to be at least .75 or to exclude a 25 percent difference in whatever the response rate is.
Now, the response rate in study 2 was 25 percent, and 25 percent of 25 percent is 6 and a quarter percent.  So, if you were designing the study to demonstrate exclusion of a 25 percent difference when the response rate was 25 percent, you would need a sample size of over 500 patients per group.

Now, you would be actually running 500 patients per group in a situation where you've already seen what the differences are in cardiotoxicity.  You'd be producing p values that would have eight or nine 0's in front of a 1 for cardiotoxicity in order to have just a bit more comfort level with relative risk for a response rate that's down around 25 percent.
Now, usually when you're dealing with proportions that vary between 25 percent and 75 percent, almost always statisticians emphasize the response difference, and a response difference of less than 10 percent is very compelling.  Relative risk is appealing when you're talking about rates of 2 percent or 5 percent and you talk about doubling the rate, but the risk ratio is really not a very sound measure when you're talking about rates that are anywhere from 25 percent to 75 percent.
DR. WILLIAMS:  Could I ask Dr. Koch a question?  If what we're really interested in is preserving the antitumor efficacy of a drug in whatever way it's going to be used, is it not reasonable to consider what percentage of that efficacy one might lose?  Certainly that was our thinking.  And one must realize that in the combination studies, we're not looking at all doxorubicin efficacy.  So, what you're saying is if 10 is okay with a response rate of 25, then 40 percent loss of the doxorubicin efficacy is not of concern.

DR. KOCH:  Well, what I'm saying is that if you're going to talk about the difference in efficacy, it should be in terms of a straight percent.  If you're looking at Kaplan-Meier curves, you should say the Kaplan-Meier curves never get farther apart than 10 percent in a confidence interval.  If you're looking at response rates, then you're saying that they never get farther than 10 percent.
Now, if you're talking about death rates from treating patients with myocardial infarction and the control treatment has a rate of 9 percent and the test treatment can reduce that by half to 4 and a half percent, then it's useful to talk about risk ratios for that.  But when you're talking about rates that are between 25 percent and 80 percent, you should simply say how close do you want them to be.  Do you want them to be within 5 percent, in which case you'll need sample sizes of over 500 per group, or are you satisfied that they're within 10 percent?
DR. WILLIAMS:  I would agree with you except that we're using this as a surrogate for survival, and in that case we're talking about the percentage of efficacy that one might think is retained and thinking what that might do in a large survival study.

DR. KOCH:  Well, I understand that, but then if you basically say that the sponsor not only has to provide a comfort level on response rate, they need to also provide a comfort level on time to progression and on overall survival.  When you put forward a criterion on hazard ratio that you would like the lower limit of the confidence interval for the hazard ratio to be above a number, like .75, if the hazard ratio is above .75, the Kaplan-Meier curves never get farther apart than 10 percent. 
So, you're basically requiring sponsors to get multiple wins.  If a sponsor in study 1 and study 3 provide compelling results with respect to response rate, time to progression, and overall survival, that should be fairly reassuring.  If in study 2 they do it for response rate and time to progression, the sponsor is demonstrating effect 8 out of 9 times.  Even for overall survival they do it for the first year, and it's not until you're dealing with time after virtually all patients have had a progression -- that's one of the things you need to remember in study 2.  Virtually all the patients have a progression by 1 year.  So, what happens to them after 1 year is related to those treatments that they're getting after they've had a progression. 

So, the sponsor has assured you with respect to antitumor efficacy that they fulfilled the criterion 8 times out of 9, and on the 9th one, they're not that far away except for the phenomenon that happens after 1 year for unexplainable reasons.
DR. WILLIAMS:  But the criteria that they fulfilled are their criteria, not the ones that the FDA specified in 1994.
DR. SCHILSKY:  Well, I'm sure we'll have additional discussion about this.  So, why don't we take a brief break and reconvene at 3:45.
(Recess.)
DR. SCHILSKY:  Dr. Cortazar will give the FDA presentation.
DR. CORTAZAR:  Thank you, Dr. Schilsky, members of the advisory committee, colleagues, ladies and gentlemen.  I'm going to present the FDA analysis of TLC D‑99.  The indication under consideration is for first-line treatment of metastatic breast cancer.
I would first like to acknowledge all the members of the TLC review team.
I do not want to repeat things that you have already heard.  I will try to emphasize the FDA's perspective in areas where there may be differences.

This slide outlines the critical times of interaction between the applicant and the FDA.  I'm going to start with the end of phase II meeting.
Ddoxorubicin-based chemotherapy, which is considered the gold standard for the first-line treatment of metastatic breast cancer, is believed to convey a survival benefit of approximately 6 months.  For the application of new drugs for this indication, FDA requests information about survival.  
However, TLC, which is a liposomal doxorubicin, is a special case.  It has the same active molecule as doxorubicin.  In this case, FDA indicated that response rate would be an appropriate endpoint to demonstrate effectiveness when comparing TLC and doxorubicin.
The sponsor planned to power the studies to detect an absolute 15 percent increment in response rate and estimated the overall response rate would be 60 percent.  The agency noted that the sponsor's plan would not be appropriate because if the response rate for the doxorubicin-containing arm was substantially lower than 60 percent, the study would be under-powered.  For example, if the actual response rate was 26 percent, as noted in study 2, this absolute increment of 15 percent will represent well over half of the doxorubicin response rate.

Also, FDA stated that the sponsor would need to demonstrate that the response rate of TLC is at least 75 percent of the response rate of doxorubicin by using a one-sided confidence interval.
These standards are less stringent than often required in equivalence trials but are appropriate because TLC was supposed to be less cardiotoxic than doxorubicin.
So, in summary, the agency would consider non-inferiority to be proven satisfactorily if in both trials the lower bound of the one-sided 95 percent confidence interval excludes 0.75 where R equals the ratio of the TLC response rate to the doxorubicin response rate.

During the June 30th meeting, the sponsor proposed to formally close the single agent trial after enrolling 224 patients.  They stated that the accrual was very slow and that the results, after the third interim analysis, showed the study met the efficacy and safety endpoints.  FDA agreed they had documented less cardiotoxicity with TLC D-99 but did not agree with their claim of comparable efficacy.  The FDA expressed concern about the survival curves for the single agent study which appeared consistently better for doxorubicin and the difference approached statistical significance.  FDA recommended a confirmatory trial since the single agent trial appeared to show that TLC D-99 may be inferior to doxorubicin in its antitumor effect, especially survival, and wasn't likely to show non-inferiority.
The sponsor suggested as a supportive trial a randomized study of TLC D-99 versus epirubicin 75 milligrams per meter squared in combination with cyclophosphamide.  The FDA questioned the epirubicin dose in the control arm as being too low and suggested that a dose of 100 to 120 milligrams per meter squared might be more appropriate.  The FDA expressed the concern that comparison to epirubicin at this dose would not be interpretable in a regulatory context unless one could establish that epirubicin and doxorubicin are equivalent on a milligram-per-milligram basis.
On December 14, 1998, the NDA was submitted.
Again, I will not repeat what you have already heard from the applicant's presentation, just to remind you study 1 is a combination study, study 2 is the single agent study, and study 3 is the combination trial versus epirubicin.

These trials shared the following design features.  They were phase III, multi-center, randomized, parallel, open-label trials.  All of them enrolled metastatic breast cancer patients with no prior chemotherapy for metastatic disease, and patients had measurable or evaluable disease.
I would like to point out the differences in the trial design.  Studies 1 and 3 are combination trials.  Study 2 is a single agent trial.  Study 3 was stopped prematurely after enrolling 160 patients.  
Doses of TLC D-99 are lower on study 1, 60 milligrams per meter squared.  They are higher in study 2 and study 3, 75 milligrams per meter squared.  Only study 2 allowed dose escalations of TLC D-99 and doxorubicin.
Response rate was the protocol-specified primary endpoint for the three trials, while cardiotoxicity was not an endpoint for study 3.  
Study 3 was not conducted under the U.S. IND, so the plans for statistical analysis were not reviewed with FDA.  This was a European trial submitted to the FDA as a supportive trial for the NDA.

We believe the dose of epirubicin used in study 3 has not been established as equivalent to doxorubicin for the following reasons.  Doses of epirubicin of 100 to 120 milligrams per meter squared have been used in combination therapy and were more effective than the lower doses.  The trials that supported the approval of epirubicin for adjuvant breast cancer compared doses of 50 versus 100 in combination therapy, and the epirubicin doses of 100 were associated with statistically significant improvement in both disease-free survival and overall survival.
In addition, trials in metastatic breast cancer comparing epirubicin doses of 50 versus 100 in combination therapy have shown a statistically significant improvement in response rate and time to progression and a nonstatistically significantly longer survival for the higher dose.
Epirubicin at 75 milligrams per meter squared has not been proven a standard treatment for first-line metastatic breast cancer.  A recent ODAC considered an application for epirubicin as first-line treatment for metastatic breast cancer and even at higher doses of epirubicin, 100 milligrams per meter squared, there wasn't sufficient evidence for approval.

We believe epirubicin has not been demonstrated to be equivalent to doxorubicin on a milligram-per- milligram basis.  The MTD of doxorubicin is about 90 milligrams per meter squared while the MTD of epirubicin is in the range of 150 to 180 milligrams per meter squared.  Also, the cumulative recommended doxorubicin dose is lower than the cumulative epirubicin dose, 450 to 500 milligrams per meter squared for doxorubicin and 900 milligrams per meter squared for epirubicin.  
Therefore, we believe epirubicin at 75 milligrams per meter squared in combination with cyclophosphamide is not the best comparator to TLC D-99 75 milligrams per meter squared with cyclophosphamide because this dose of epirubicin may be suboptimal.
Of the two large studies comparing epirubicin to doxorubicin in combination, each at 50 milligrams per meter squared, a significant difference in survival was noted in one, the French multi-center trial.  This survival curve from their report in JCO suggests there is a sustained difference in the survival curves.  After covariate adjustments, the author stated that this difference was no longer statistically significant, but none of the details of the adjustment analysis were provided.  This finding adds to the doubts we have that epirubicin and doxorubicin are equivalent on a milligram-per-milligram basis.

We do not believe the applicant has adequately established the non-inferiority of TLC to doxorubicin.  Although the applicant's studies were powered assuming a response rate of 60 percent, the response rates observed for studies 1 and 2 were well under the expected 60 percent.  
Although the agency stated it would use an odds ratio for the efficacy comparisons, we are presenting the relative risk, which is the ratio of the two response rates.  This concept is easier to understand and is slightly less conservative than the odds ratio.
Using the ratio of response rates approach, only the combination trial demonstrates marginal equivalence, with a lower bound of the confidence interval of 0.78.  The study comparing single drugs fails with the lower bound of the confidence interval of 0.62.  The one-sided 95 percent confidence interval could not exclude in study 2 that the TLC arm was proportionally 38 percent worse than doxorubicin.

This slide summarizes the overall survival for studies 1 and 2.  Survival was the secondary endpoint in both trials.  You may note some subtle differences between the FDA and the applicant's survival analysis.  The applicant submitted an updated survival analysis post-NDA submission.  This update was not planned in the original protocol, and for this reason FDA decided to use the original submission data.  The results of the applicant's updated analysis were similar to the original submission.
The differences of the median survival in study 1 are not reflective of the whole curve.  As you will see in the next slide, the curves cross.  The hazard ratio was 1, indicative of similar overall survival.  The 95 percent confidence interval lower bound for the hazard ratio was 0.71.  However, demonstration of non-inferiority for survival was not explicitly discussed with the agency.
The median survival in study 2 was 5.5 months longer for the doxorubicin arm, with a p value of 0.07, and the 95 percent confidence interval lower bound for the hazard ratio of 0.54.
This slide shows the survival curves for the two treatment arms in study 1.  Again, these curves cross at about 15 months.  The hazard ratio is 1 and indicates no difference in overall survival.

This slide shows the survival curves for study 2.  This near significant survival trend in favor of the doxorubicin arm is very concerning.  The applicant argues that this trend might be due to an imbalance in baseline prognostic factors at the largest study center.  The applicant excluded that center and reanalyzed the survival.  FDA believes this approach is totally unjustified because the randomization was done centrally and there's no evidence of an imbalance for these prognostic factors for the whole patient population.
FDA selected prognostic factors based on a literature review and performed a multivariate analysis to correct for imbalances in important prognostic factors.  This slide shows the results of the multivariate analysis.  You can see it did not correct the adverse trend in survival and in fact the finding became more convincing with a p value of 0.03 in favor of the doxorubicin arm. 
FDA then also included progesterone and estrogen receptors, the two covariates that the applicant used to show the imbalance, and the analysis is still marginally significant in favor of the doxorubicin arm, with a p value of 0.05.
In evaluation of the case report forms and electronic data of tumor measurements, FDA detected a number of progression events in the applicant's original analysis from patients who died many months or years after the last formal evaluation for progression.  

Therefore, FDA requested the applicant to reanalyze TTP.  The purpose of this analysis was to exclude inappropriate late events that have had inadequate follow-up and to include legitimate early events.  This slide shows the results of their reanalysis.  The studies were not designed to show formal equivalence.  The 95 percent confidence interval lower bound was 0.81 for study 1 and 0.66 for study 2.
I want to remind you study 3 is a combination trial comparing TLC to epirubicin, each at 75 milligrams per meter squared.  This trial was submitted as a second trial to demonstrate the efficacy of TLC D-99 in combination with cyclophosphamide.  The trial was performed in Europe, outside of the U.S. IND, was stopped prematurely, and accrued 160 patients out of the 280 patients planned.
The overall response rates were 46 percent in the TLC arm and 39 percent in the epirubicin arm.  The two rates were not statistically different with a p value of 0.4.  The ratio of response rates is 1.19.  The associated one-sided 95 percent confidence interval is 0.81. 

Because this study was stopped prematurely, estimates of efficacy and confidence intervals must be viewed with skepticism.  Moreover, unless one accepts epirubicin at this dose to be an established first-line treatment of metastatic breast cancer, these results are uninterpretable.  The issue with this trial is not the results but the adequacy of the comparator arm.
The median survival was 18.5 months for TLC and 16 months for the control arm, with a log rank test p value of 0.35.  The two-sided lower bound for the hazard ratio was 0.79.
As requested by FDA, the applicant reanalyzed TTP.  TLC showed a trend toward a longer time to progression compared to the epirubicin arm.

In summary, study 3 showed similar response rates and a similar survival and a trend toward longer time to progression for TLC D-99 compared to epirubicin.  However, problems with this study include a relative low dose of epirubicin was used, 75 milligrams per meter squared, instead of 100 to 120 milligrams per meter squared.  This study does not test efficacy of TLC D-99 in combination against a proven dose of epirubicin and, therefore, does not independently substantiate the results of study 1.  Furthermore, the statistical findings may be viewed with skepticism since this was a small study performed outside of the IND and was stopped prematurely.  The results of this trial are not bad.  However, FDA has doubts that the dose of epirubicin used in this trial can be used as a surrogate for the same dose of doxorubicin.
Cardiotoxicity was the primary safety endpoint for studies 1 and 2.  It was evaluated with serial month dated measurements of left ventricular ejection fraction by MUGA scans and by the clinical evaluation of congestive heart failure.  As you can see, TLC is statistically significantly less cardiotoxic than doxorubicin as measured by protocol-defined cardiac events:  6 percent for TLC, 21 percent for doxorubicin in study 1; 17 percent for TLC, 36 percent for doxorubicin in the single agent trial.
Also, there were more congestive heart failure events in the doxorubicin arm for both studies, and the median time to cardiac event was significantly higher for TLC in both studies.
This is a very busy slide.  I don't expect you to see all the details.  This slide summarizes the toxicities observed in the three trials. 

Neutropenic fever was similar between treatment arms on both studies 1 and 2.  On study 3, neutropenic fever was higher in the TLC arm than the epirubicin arm with a difference that was near significance.  
Significantly more thrombocytopenia for the TLC arm than epirubicin on study 3.  
Stomatitis was significantly higher in the doxorubicin arm in studies 1 and 2.  Again, significantly higher for the TLC arm than the epirubicin arm in study 3.
Diarrhea was higher in the doxorubicin arm in study 1, with a significant incidence in study 2.
FDA and the applicant agreed on the reported values for the cardiac toxicity primary endpoint.  Non-inferiority in response rate of TLC compared to doxorubicin has not been established.  Response rate estimates were similar but because of the study size, the confidence interval of the ratio of response rates included a lower bound well under 0.75 in study 2.  Using the ratio of response rates approach, only the combination trial demonstrates non-inferiority with a lower bound confidence interval of 0.78.

Overall survival was similar for the combination study with a p value greater than 0.9, hazard ratio of 1, and a 95 percent lower bound confidence interval of 0.71.  The median survival on study 2 was 5.5 months longer for the doxorubicin arm, with a p value of 0.07.  The applicant suggests the survival benefit in the doxorubicin arm is attributable to an imbalance in prognostic factors favoring doxorubicin.  However, the FDA performed a multivariate analysis adjusting for prognostic factors, and instead of correcting the adverse trend, the adverse findings were strengthened, with a p value of 0.03.
The comparator arm on study 3 is not adequate because the epirubicin dose was suboptimal.  Epirubicin at 75 milligrams per meter squared has not been established as first-line treatment in metastatic breast cancer.

The cardiotoxicity data looks very promising, and it is very disappointing that the studies are too small and did not have the power to show equivalence in antitumor efficacy.  However, the FDA review team believes there is insufficient evidence to support TLC D-99 for first-line treatment of metastatic breast cancer.  Using the ratio of response rates approach, only the combination trial, study 1, demonstrates non-inferiority to doxorubicin with a lower bound confidence interval of 0.78.  Even though comparison with standard therapy in study 1 is marginally persuasive, the findings are not replicated in study 2 with a negative survival trend, and study 3 cannot be interpreted in this context.  The applicant has demonstrated that TLC D-99 is less cardiotoxic than doxorubicin, but this endpoint alone does not support the proposed indication.
DR. SCHILSKY:  Thank you very much.
Are there questions for FDA?  
Let me start off with a question while people are getting their thoughts together.  One of the important issues I think is the whole issue of the epirubicin dose in study 3.  Somehow, as you were going through your discussion of epirubicin, I had the sense that you were looking at the same literature as the sponsor but coming up with totally different results.  You showed us a survival curve of what I thought you said was the French randomized study comparing FAC and FEC, and you indicated that there was a survival advantage I think you said for the FAC in that study.  I believe that's the same study that was included on one of the sponsor's slides, and at least on that slide, the median survival results are said to be not significantly different in the two arms of the study.

You then I think said that there were a number of other studies, looking at various different doses of epirubicin in combination, which appeared to show some sort of a dose-response relationship, with higher doses producing better outcomes.  Yet, when I go back to the sponsor's slide in which they summarized a number of studies looking at different doses of epirubicin in combination, they did show the higher epirubicin doses associated with higher response rates, but none of those studies showed an advantage in survival for the higher epirubicin dose.
So, maybe you could just clarify again how it is that you've come to the conclusion that epirubicin at the doses used is not an effective therapy.
DR. WILLIAMS:  I probably did the more recent review of epirubicin, as I was involved in the recent approval -- or recent evaluation.  I've reviewed these literature in detail, especially after a recent interaction with the sponsor.  
Now, remember, it's not our responsibility to show that they're not equivalent.  It is the sponsor's responsibility to show us they are equivalent.  We have shown a lot of data that there appears to be a different antitumor effect between 0 and 100.  If we don't have studies large enough to show a survival effect, that isn't our responsibility.

I was shocked when I found this survival curve within the article in JCO for 1988 because the abstract says it was not significant, but the actual text says it was significant.  But we noticed the difference in number of sites and we adjusted and it's no longer significant.  No p values are given before or after adjustment.  It's amazing to me.  So, that's where that comes from, and that's one of the two large studies comparing the 50 milligrams per meter squared dose in combination.
Again, that's not as good a test, I think, of equivalence if it had been 75 milligrams per meter squared because the more efficacy there is, the easier it is to show a difference.
Now, you talk about the dose-response trial that the sponsor cited.  Again, it's under-powered so you can't say anything definitely, but in the point values for the tumor effects, both response and time to progression, you see a change between 60 and 90.  Now, again, I don't know if 75 is above or below the plateau or if there is a plateau, but that isn't our responsibility.  If we're going to use something as a surrogate for equivalence, then it needs to be proven to us, and it apparently wasn't proven to the sponsor of epirubicin well enough that they thought they could submit it to us and get an approval on that basis.

DR. SCHILSKY:  I'm not trying to get to the issue of whose responsibility it is to prove what.  I'm just trying to understand why it appears that we have the two groups referring to the same literature and showing us apparently opposite results.  I guess part of it is selective reading of certain parts of the literature.
Questions from other committee members?  Dr. Krook?
DR. KROOK:  I go back to the administrative history here.  There was a meeting on June 30th, 1998.  Study 2 was closed.  It seems that most of us are looking at this and there was obviously a decision made, in combination with the FDA, to close the study early.  Now we're looking at survival differences or whatever.  I'm wondering if we could go back to there and why was the decision made at that point to close this.  I suspect that might have affected the survival, less patients, and the numbers.
DR. WILLIAMS:  Again, it might be appropriate if I answer since I was involved in those decisions.

Both from the minutes and from my recollection, we never advised to close the study.  The company wanted to close the study.  It seemed like the main reason was they were having accrual problems.  We were concerned.  So, we said you could add Zinecard to the other arm of the study if you're concerned that investigators don't think it's ethical to continue.  But we never advised them to stop.  We stated if you want this to stop, that is your decision, but we're concerned about these values.  So, I don't think there's any disagreement.
DR. KROOK:  Again, I'm not a statistician.  If we had the full complement of the study, would we do better statistically since that's where we seem to look at things?  I think the answer is yes, but maybe Dr. Lamborn can comment.  We obviously didn't go to the planned study accrual.  Therefore, the statistical reasons change and the confidence intervals change, if I'm right.
DR. LAMBORN:  As I understand your question, obviously if you have a larger pool of information, your confidence intervals are going to be narrow.  Whether or not this would have affected the direction, for example, of the survival, there's no way of knowing.  There's no reason to believe, as Dr. Piantadosi mentioned before, that an early stop that was not a basis by looking at something is going to affect that.  But you definitely narrow your confidence intervals.

DR. SCHILSKY:  Dr. Kelsen.
DR. KELSEN:  Could you put back up the survival curve of FAC versus FEC?  When you looked at this curve, it sort of looks a little bit like the curve from the second study that we're concerned about because it looks like the survivals are absolutely overlapping for the first 200 days.  I guess that's in days.  So, that's about two-thirds of a year.  And then they diverge and they don't come back together again, although they don't reach statistical significance.  That looks an awful lot like the curve that you showed us or that we've seen from the sponsor for the phase II.  Is your interpretation saying there's a salvage therapy difference?  Is there any data in that paper as to a salvage therapy difference?
DR. WILLIAMS:  There's a paucity of data to totally understand the study, and that's why I don't trust these results one way or the other.  I think they raise doubt.

But you're not going to see a difference in curves unless you have deaths, and the fact is with breast cancer, it takes a longer time than it does with colon cancer or lung cancer.  If you look how far you've come down on the survival curve before you see a difference, it looks like to me it may be 75 percent.
DR. KELSEN:  I was struck.  We had this real long discussion before as to whether or not there was a difference in efficacy of the liposomal preparation and the parent analog.  Well, for the first 3 to 6 months or a year maybe, they're identical.  But I'm struck that it almost looks like the same -- 
DR. WILLIAMS:  But this is always going to occur with first-line breast cancer treatment.
DR. KELSEN:  Yes.
DR. WILLIAMS:  And you're always going to have a later part in the curve.  So, if you ever have an effect on the curve, it's going to be sometime after you stopped your first treatment.
DR. SCHILSKY:  Dr. Lippman?

DR. LIPPMAN:  To clarify, I think, Grant, you were the one that mentioned this.  Initially we got into this discussion with Dr. Koch about absolute versus relative changes in response rate and there's no way to win type of situation.  But I think you were the one who said this, that initially when you target a 60 percent response rate, then a 10 percent absolute difference means something different entirely than if, unfortunately, your response rates are lower at 20 percent.  So, obviously, the absolute difference means different things based on the overall response rate I guess is the point.
DR. WILLIAMS:  You've got to remember that we were doing something different and using response rate for first-line approval of breast cancer here.  This response rate is because we have the same drug, same molecule, and we're using it as a surrogate of what we think that effect is going to have on ultimate survival years down the line.
In that circumstance, we're interested in how much of the antitumor or of the beneficial effect imparted by doxorubicin are we losing, and I don't believe we ever conceived of using a response rate down in the 20's range to demonstrate equivalence for that effect.  It was theorized that the response rate would be higher.  As mentioned earlier, if it was going to be lower, it wouldn't have been practical to say that a ratio of .75 would be your goal.  If you thought it was that low, then you probably should have designed the endpoint to be survival, but with the combination arm, the response rate turned out to be up in a higher range where it was reasonable to do equivalence trials. 

So, what really happened was the response rate was much lower than planned.  The study was much under-powered for this outcome, and we don't have the study showing equivalence that we wanted.
DR. SCHILSKY:  Grant, the issue of using response rate as a surrogate to predict survival years down the road -- I guess one of my concerns about that is that, if we are willing to accept some reduction in response rate for this agent in exchange for the benefits with respect to cardiac toxicity, can we assume that reduction in response rate actually will translate into some decrement in survival down the road, and is it a one-to-one relationship?  I'm not comfortable with accepting that as ‑‑ you may say the response rate is a surrogate for benefit, but I'm not sure in my own mind that one can accept the notion that some change in response rate is a reliable predictor of a similar change in survival.
DR. WILLIAMS:  Right, and that's why we asked for a demonstration of non-inferiority.  If you're going to start extrapolating and say, well, I think maybe we've got 5 percent difference in response, then that translates.  No, I don't think anybody could do that.

The responsibility of the new drug is to show that you have efficacy, and in this setting a non-inferiority design was chosen to show that you have the same efficacy as doxorubicin and response rate was chosen as a surrogate.  I do believe that's debatable, but that's the agreement.
DR. SCHILSKY:  Let me ask one other question to the committee.  It has to do with the level of concern about the survival data in study 2 in the context of the proposed indication of using this drug in combination with cyclophosphamide because what we seem to have is study 1 which there seems to be a reasonable level of comfort with the notion that that may demonstrate equivalence in combination with cyclophosphamide.  We have study 2 where there's concern about inferior survival in a single agent comparison.  We have study 3, which at best may be difficult to interpret, and we have a proposed indication not to use the drug as a single agent, but to use it together with cyclophosphamide. 
I guess I'm just wondering if those people on the committee who have been concerned about the potential survival decrement in study 2 are equally concerned in the context of the proposed indication.
Dr. Raghavan.

DR. RAGHAVAN:  I think that what this illustrates is that there are no shortcut paths to drug development, and if you have under-powered studies, you get to the FDA and you get into trouble.
Now, as was expressed by Dr. Williams, the third study, while it is sort of comforting in a general sense, in reality isn't comforting at all for all the reasons that were enunciated.  It's almost valueless data to us because of the lack of controls and the early stopping and sort of breaking all the rules of good trial design. 
So, that then leaves us with two trials, one of which, any way you cut it or slice it, gives the drug what appears to me to be the potential for inferior anticancer effect.  That then leaves you with one study, which isn't a very big study, which leaves you with a comfortable feeling that this is a much less cardiotoxic drug with equivalent activity.

The problem is what do you do with that.  I'm persuaded by investigators that I really respect representing the company that this is a less cardiotoxic drug and they would like to use it regularly, single agent or whatever.  Yet, I look at the data and I'm very troubled by study 2.  Dr. Koch's statistical discussion, while I accept his points about the 75 percent lower limit, the rest of it I really found didn't address the issue very well.
So, I think we're left with a situation of almost equipoise.  How much concern do we have that Adriamycin in an unrestrained environment will poison hearts?  I was struck by the lady who spoke about here difficulties with cardiac toxicities right at the beginning, and I'm very sympathetic to that.  On the other hand, I was also struck by the fact that she said, but I'm happy to be here.  
So, I think when people look at us, if we're being harsh on this drug, I don't think we're being bureaucrats and being persnickety about trials.  I think we're actually looking at a drug and saying is there evidence that to cut down toxicity, which can be avoided other ways, we're not sacrificing cure rates or response rates.  And we know that this will get translated down the line into the adjuvant setting.
So, I think we have the problem of just not enough information to be really comfortable.
DR. SCHILSKY:  Dr. Margolin?

DR. MARGOLIN:  I'd like to echo that and just sort of add a corollary which is that even though, according to data we were given today and what we all sort of know from being in the clinics, that the most popular combination with doxorubicin and its buddies is with cyclophosphamide.  Things are changing fast in breast cancer.  We're learning about how one can combine with various drugs.  New drugs are coming up all the time.  And if we have something for which we can only feel comfortable with the preservation of activity in this very strict setting of co-administration of these drugs, I think we're going to be stuck with more of a problem than a solution.
DR. SCHILSKY:  Ms. Zook-Fischler?
MS. ZOOK-FISCHLER:  Well, as a patient, I'm coming from a somewhat different perspective, and I'm a patient in treatment at the moment.  My first concern for myself and other women dealing with breast cancer is always survival as the bottom line. 

Nevertheless, it seems to me, for those particular patients for whom cardiotoxicity would be a problem, it becomes a moot point because if you can't give them the full dose of doxorubicin, it would be good for the physician and the patient to have an option because they may not be able to get the survival advantage that you're speaking about with the doxorubicin.  So, I personally from a patient's point of view, even though I'm most concerned about survival, I would like the option to be available to patients for whom the other drug is not really the best choice.
DR. SCHILSKY:  Dr. Lamborn.
DR. LAMBORN:  I'd just like to make a comment about study 3 from a statistical standpoint.  I understand the issue of whether the epirubicin is a reasonable control, and I don't want to address that because I think that could stop the thing right there.
But if the issue is the fact that the study was stopped early, I do want to reiterate that the early stopping, if it was not done because of the effect, does not preclude looking at those confidence intervals and deciding if they are useful.  So, just to make sure that we're making the decision on the right pieces of information.
DR. WILLIAMS:  As a regulatory comment, as a reviewer I'm not sure that I can ever with certainty say why a study was stopped.

DR. SCHILSKY:  Let me just bring us back to are there any other questions to be directed to FDA, because otherwise we're drifting into discussion again.  Dr. Lippman.
DR. LIPPMAN:  I just wondered if the FDA had looked at this type of subset analysis that was presented by the sponsor in slide 90 on the subset of women that were at high risk for cardiotoxicity, because the issue was just raised about women that are at high risk and this would be a good option.  In this one, both studies 1 and 2 were lumped together and the survivals are equivalent.  Has study 2 been looked at in this group?
DR. WILLIAMS:  Well, I'll make a couple comments.  First, I want to remind Ms. Fischler that there is a drug which is approved, which is Zinecard, which is available to be given after 300 per meter squared, which is the dose after which most people get congestive heart failure and cardiac toxicity.  It is available.  So, I can't see that this would be that helpful in terms of fulfilling a need after 300 per meter squared.
Regarding the post hoc analysis of patients at high risk, I really don't think that is quite the issue.  First of all, I believe the data is under-powered for equivalence overall.  It's certainly going to be under-powered for equivalence in any subset.

Secondly, that isn't the question.  We believe there's a cardiac benefit.  There may be a lot more in these patients, but we're dealing with the fundamental issue of whether we know there's equivalent efficacy.  So, I think in the presence of an approved agent that should prevent or certainly decrease the number of events, if applied after 300 per meter squared, I don't see how that analysis is really relevant beyond the main question you have which is, is the benefit here worth the doubt regarding equivalent efficacy?
DR. SCHILSKY:  Dr. Lamborn?
DR. LAMBORN:  Dr. Williams, I just wanted to check that I had understood something that you said a little while ago.  I thought I heard you say that if in fact you had anticipated a response rate on the order of 25 percent, that you would not have been comfortable with using response as a surrogate for survival in demonstrating equivalence.  Is that what you said?

DR. WILLIAMS:  I don't think it would have been practical, first of all, to power a study.  We were comfortable with the concept that in doing an equivalence or a non-inferiority study, you need to rule out loss of not more than a certain amount of the efficacy of the drug.  In this case, .75 was below the .8 that is often discussed.  Powering a study to demonstrate that with such a low response rate would probably lead you to a similar size study for showing equivalence in more ultimate endpoints such as survival.
DR. SCHILSKY:  Any other questions for the FDA?  Dr. Beitz?
DR. BEITZ:  I just wanted to point out that if the committee does feel the need for additional information, that perhaps in your deliberations you could advise as to the nature of additional studies that could be performed with this compound to establish efficacy in relevant populations.
DR. SCHILSKY:  Dr. Johnson?
DR. DAVID JOHNSON:  Well, actually I want to discuss that too. 

The question I wanted to pose to the FDA is putting myself for the moment into the sponsor's shoes, I'm trying to think of a way that I'm going to prove the comparability of my product, thinking that, as I've been told by my expert colleagues around the country, that it's becoming increasingly difficult to show survival differences based on a single agent because of the availability of other products. 
I do a lot of work, of course, in lung cancer, and I hear this a lot, that the reason there wasn't a survival advantage with drug X over drug Y is because of all the salvage therapy that went on.  Now, that's always humorous to me in lung cancer, but it may be actually relevant in breast cancer.  The only caveat that I would say about that is that a really good drug seems to be able to overcome that particular issue, Herceptin being a recent example of that.
My sense is this is sort of why you chose the response or at least agreed with the sponsor about using response as an endpoint, which I too like Rich was a bit surprised to see that we had thought that was acceptable.  Is that something we need to discuss, or is it only because the product was perceived to be the same thing in just a different package? 
DR. WILLIAMS:  Of course, this was 1994 that this study was designed.  The reason we accepted response was solely because it was two different forms of doxorubicin, and we thought that the antitumor efficacy would hopefully reflect the other.

We've had these discussions.  I think you gave both sides of the argument about follow-up therapy.  A good drug seems to be able to overcome it, and obviously the advisory committee took the position that it still could be shown and the time to progression wasn't sufficient in first-line breast cancer.
DR. SCHILSKY:  If there are no other questions directly for FDA, before we get into our discussion, we do have two additional requests from the public to speak to the committee.  First is Dr. Marissa Weiss representing Living Beyond Breast Cancer.
DR. WEISS:  My name is Dr. Marissa Weiss, and I'm a physician.  I take care of breast cancer patients.  I'm an oncologist.  I'm also President and founder of Living Beyond Breast Cancer, which is a nonprofit educational organization.  And I'm author of the book, Living Beyond Breast Cancer.
I invited myself here.  Liposome did not invite me here.  They do buy a table at our gala each year, as every other pharmaceutical company does do, and they do provide an unrestricted grant for our outreach, but so do other companies.

Living Beyond Breast Cancer's mission is to help women who have been diagnosed with breast cancer live as long as possible with the best quality of life.  I think everyone is here for the same reason, which is that the whole point of finding breast cancer early and treating it effectively is to give life after treatment is finished.  And that's why I'm here because I see Evacet as an opportunity for women who have breast cancer to live beyond their treatment with a good quality of life.  And we're not just talking about quality of life.  For those people here who do treat women with breast cancer with Adriamycin-based regimens, you can die of that complication, the cardiotoxicity.
I chose to speak after the data were presented because I wanted to address some of the issues that were raised.  I think everyone here knows that we want to have better treatment options to present to patients when they have metastatic disease, what that disease progresses, that that's what the purpose of this drug and other advances that have come forth for women with breast cancer.

I have to say that I've been following this discussion all around, and I'm really struck that everyone is taking the survival differences very seriously, which is terrific.  But we are talking about one endpoint in one study that's observed after 1 full year of follow-up that wasn't even statistically significant.  By many other criteria, these drugs did look like they were equally effective.  We're not talking about proving beyond the effectiveness.  We're just talking about equivalence here.
With respect to the comments of if we start using this drug, not just with Cytoxan but then maybe in the adjuvant setting and maybe you're going to start sticking it with Herceptin, that I think is irrelevant to this discussion because that's not what this indication is up for.  We're talking about looking at this drug with Cytoxan as first-line chemotherapy for women with metastatic breast cancer.
I think we have to keep some of this in perspective because Doxil has been approved for use in cancer.  That's ovarian cancer not breast cancer, but it associated with the higher side effects of PPE and this drug is not.  But probably more importantly, epirubicin was approved in the adjuvant breast cancer setting.  However, the bar for efficacy was lower for epirubicin since it was compared to CMF and not to an Adriamycin-based regimen.

Also, if these data showed a trend to improved survival with Evacet over Adriamycin, we wouldn't have a discussion here.  I know that the goal here is to prove at least equivalence.
I think that the data presented to ODAC in the spring on epirubicin was with the doses of 100 to 120 milligrams per meter squared, but this is not the standard dose in Europe nor is it the dose used in patients with metastatic breast cancer.  It was the dose used in the United States for the adjuvant treatment, but you really can't fault this study for using the 75 milligrams per meter squared dose since it was the standard of care in Europe at that time, even though it was not used at that point in the United States. 
So, I just don't want anyone here to lose sight of the fact that as doctors taking care of people, women with breast cancer, that we need better options to treat the women that we have the privilege of taking care of.  When you have a medicine that's working, when you've got somebody in front of you who has got metastatic breast cancer for which an Adriamycin-based regimen is working, you want to keep using the drug that's working.  In this situation, twice the number of women who received the Adriamycin-based regimen had to stop their treatment for fear of the cardiac toxicity relative to Evacet.  

So, the main thing is I see this as a physician, that this gives me a tool sitting across the table from a women in a blue gown who's got metastatic disease, who's trying to find something that she can extend her life with, I can keep going with the medication that she's already responding to.  And I see this drug as giving women an option, and I think it's an important medication that should be approved.
Thank you.
DR. SCHILSKY:  Thank you very much.
(Applause.)
DR. SCHILSKY:  We had a request from Ms. Meeker who we heard from earlier today to address the committee once again.
MS. MEEKER:  Thank you.  I want to repeat that I'm not here subsidized or connected with anybody.  I'm here on my own.  I'm here because this group was addressing the treatment of metastatic breast cancer, not initially diagnosed breast cancer.

In metastatic breast cancer, treatment may produce no response.  The time of a remission is measured in months for all of the metastatic patients.  The time to a second recurrence is measured in months.  Ultimately, we still measure overall survival of metastatic breast cancer patients in months, not years.
I am really astonished and quite emotional I think because I hear a discussion that seems to me to assume that we're going to be alive for years, so it's very important whether the drug being discussed by you according to your rules -- and I won't attempt to have that discussion -- has months of less effectiveness rather than Adriamycin.
In my case, for example, when I developed my first recurrence -- and there's a mistake on the little thing I typed out this morning at home.  I was given CMF because of the metastases to my left brachial plexus.  During that time, I developed a second primary.  I was not a candidate for anymore Adriamycin-based chemotherapy unless there would have been one that hopefully would not have damaged by heart.  There might be one of those in the future. 

I now have metastatic disease.  I'm in not a remission but at least only in a state with bone metastases.  My future is measured, according to the median at least, in months.  I don't believe it and I'm going to fight with all my heart.  But what I want to do now is stay alive and healthy until there is something that will address my breast cancer.
Just as a couple of other people have stated, what we need is tools of choice for physicians to prescribe for their patients so that if one chemotherapy is not available or efficacious, there might be another one.  In my case, the choices are constrained because of my reaction to the Adriamycin.  Unfortunately, I had bad side effects even though I had very positive treatment effects. 
It seems to me that whatever the rules for adoption of the drug, if you are down at the third decimal place to the right of the decimal point in discussing relative efficiency of the drugs, that you're describing a drug that might be useful for me and would be the only one that my body could possibly tolerate.
Thank you.
DR. SCHILSKY:  Thank you.
(Applause.)
DR. SCHILSKY:  I think we can go on to the questions, and I'm sure they will engender some additional discussion.  Yes? 
DR. LEE:  I know I asked for one.  Can I --
DR. SCHILSKY:  No, I'm afraid due to our time constraints, we need to go ahead with the questions.

So, we have a series of questions.  We have a preamble describing the study results.  And I will ask for a formal vote on each of these questions unlike what we did this morning.
Question 1.  Do these studies demonstrate that Evacet is significantly less cardiotoxic than doxorubicin at the doses and schedules studied? 
Does anyone want to take a crack at answering that one?  Dr. Nerenstone?
DR. NERENSTONE:  Yes.  I think that that's the one thing that we could probably all pretty much agree on.
DR. SCHILSKY:  All right.  Well, any further discussion on that? 
(No response.)
DR. SCHILSKY:  Let's see if we do. 
(Laughter.)
DR. SCHILSKY:  All who would vote yes in response to that question, please raise your hand.
(A show of hands.)
DR. SCHILSKY:  11 yes.
All who would vote no?
(No response.)
DR. SCHILSKY:  0 noes.  So, it's unanimous.

Moving on two question 2.  Is study 1 an adequate and well-controlled clinical trial demonstrating the efficacy of Evacet in the first-line treatment of breast cancer?
Comments from anyone?
(No response.)
DR. SCHILSKY:  No comments.  Yes, Ms. Zook-Fischler.
MS. ZOOK-FISCHLER:  I just wondered if a word was omitted.  Was that to be first-line treatment of metastatic breast cancer?
DR. SCHILSKY:  Yes.
Dr. Margolin?
DR. MARGOLIN:  Actually I'd like to ask for another clarification which is, does the FDA intend for us not to have Evacet plus Cytoxan in that line?
DR. WILLIAMS:  That's a point you can discuss.  This was the proposed indication basically and you can make a discussion of that.

DR. SCHILSKY:  Well, the proposed indication from the sponsor was Evacet in combination with cyclophosphamide.  So, we could amend the wording to say is study 1 an adequate and well-controlled clinical trial demonstrating the efficacy of Evacet in combination with cyclophosphamide in the first-line treatment of metastatic breast cancer?
DR. WILLIAMS:  I think that's fine.  That's really more appropriate.  The final vote, if one voted that two of these studies were appropriate, then you could have the discussion whether it should be restricted to cyclophosphamide or not.
DR. SCHILSKY:  So, let me just restate the question again with these modifications.  Is study 1 an adequate and well-controlled clinical trial demonstrating the efficacy of Evacet in combination with cyclophosphamide in the first-line treatment of metastatic breast cancer? 
All who would vote yes, please raise your hand.
(A show of hands.)
DR. SCHILSKY:  9 yes.
All those would vote no?
(A show of hands.)
DR. SCHILSKY:  1 no.
Any abstentions?
(A show of hands.)
DR. SCHILSKY:  1 abstention.
So, it is 9 yes, 1 no, 1 abstention.

Question 3.  Considering the standards of efficacy agreed to by the agency for this situation, is study 2 an adequate and well-controlled clinical trial demonstrating the efficacy of Evacet in the first-line treatment of breast cancer? 
Maybe I could ask for a clarification here just so we're all clear.  Perhaps the agency could restate what were the standards of efficacy the agency agreed to.
DR. WILLIAMS:  That was the response rate, .75.  That was the standard.
DR. SCHILSKY:  So, you're asking us that in considering that standard with respect to response rate as the measure of efficacy, is study an adequate and well-controlled trial demonstrating efficacy for Evacet.
DR. WILLIAMS:  We would expect you to take everything into consideration.  I guess when it was written, some people might not actually buy the concept that the response rate was a surrogate, but taking in consideration the fact that we did commit to that idea, we wanted you to take that into consideration.

DR. SCHILSKY:  So, it might be worthwhile before we vote on this to just refer one last time to the study 2 results that are shown in the table in the questions because this is the single agent study in which the response rates are 26 percent in each arm, the response duration is 7.8 months for Evacet, 6.5 months for doxorubicin.  The overall survival is 14.6 months median for Evacet, 20.1 months median for doxorubicin.  That has a p value of 0.07, and the time to progression was 3.8 months for Evacet and 4.3 months for doxorubicin, also with a nonsignificant p value of 0.58.
Dr. Margolin.
DR. MARGOLIN:  I think in the interest of fairness to the sponsor, since I think Grant is giving us a little bit the option to decide whether we want to stick by the FDA's very strict definition, it would be interesting to have, if somebody has at hand, what the confidence intervals were on those response rates.
DR. WILLIAMS:  I'd like to challenge your statement.  I consider our standards, the fact that we used response rates to start with, to be not at all strict and the .75 is actually lower than .8.  If you use Dr. Koch's approach, they're lenient.
DR. SCHILSKY:  Dr. Kelsen.

DR. KELSEN:  If I can pursue that just a little bit.  If I read this question right, the standard of efficacy that you agreed to was that the lower bound on the ratio of response rates, since we're talking about that now, would not drop below .75.  Is it a correct statement that when you say considering the standards of efficacy that you agreed to, that the lower bound of the response rate around this 1.0, .62 is below the .75 that you -- it's the ratio in this case that you required when you made this discussion with the sponsor.
DR. WILLIAMS:  That's what I'm referring to.  The other endpoints, I don't believe they're insignificant, but that was what I was referring to.
DR. SCHILSKY:  So, we have that piece of information, and of course, we've been discussing for the last several hours the concern about the apparent decrement in survival, although it doesn't quite make it as a statistically significant difference.
Dr. Lippman?

DR. LIPPMAN:  Yes, I just wanted to address that because it came up in one of the presentations recently that it wasn't significant, and we lived by the p value of .05.  So, it could be by chance even though we know that there's a biologic continuum.  But the concern I think that was consistent between the FDA and the sponsor was that the p value trended more towards significance after adjustment for covariates and was statistically significant in the agency analysis in the covariate adjustment.
DR. SCHILSKY:  Dr. Kelsen?
DR. KELSEN:  This is sort of a procedure question.  The way that's written, how can one say anything other than no since the way it's written, it says you said that they have to have .75 and it's .62.  So, I'm a little lost as to how one --
DR. WILLIAMS:  We just asked you to consider.  We didn't say you're bound by them.
DR. KELSEN:  Okay, thank you.
DR. SCHILSKY:  So, I think what we're trying to get to the bottom line here is that this study doesn't appear to make it with respect to the response rate rules that had been agreed to previously, and there is a concerning trend in the survival, although not a statistically significant trend.  I just wanted to be sure that everybody remembered the course of the discussion as we go through these questions.
David?

DR. LEE:  I would like to provide the lower bound of the confidence limit that was requested by Dr. Margolin.  For this study, the lower bound is minus 9 percent based on a difference in response rates.
DR. SCHILSKY:  Thank you.
David?
DR. DAVID JOHNSON:  Again, my sense has always been that we're advisory.  We're not policy makers here.  We've heard the fact that the FDA agreed with the sponsor for a particular endpoint doesn't mean we have to agree with that endpoint.  A large part of the discussion that has been ongoing today has dealt with that particular issue.  I think that some of the discussion we've had has at least made fairly clear to me that some of us are uncomfortable with that as an endpoint to declare comparability and efficacy.  I think this is an issue that we're going to be wrestling with not just this time but in the future as well, and I'm not sure there's an easy solution to it.  

Based on the strict definition, if we accept what the FDA has said, then the answer to the first question in my view has to be yes, and the answer to the second question has to be no.  There's not even reason for voting.  I think that we have to remember that we're only advisory.  We're not policy makers here. 
DR. SCHILSKY:  Dr. Raghavan.
DR. RAGHAVAN:  I think the other point that I'd add -- two points.  One is that the assumption was made -- and I think it was a mistake post hoc -- that response was an appropriate surrogate on the assumption that survival would be equivalent or potentially equivalent, and that assumption was not fulfilled.  We can second guess all the reasons for it.  I have yet to hear a compelling explanation that let's me feel that more patients would have been alive in that single-arm study on the new drug than on the old drug, and dead patients don't get side effects. 
The second point I would make is that when we talk about statistical significance, as Scott started to say, driven by a p level, even when we allow for prognostic variable adjustment of a 2 percent chance that we're making a mistake, so I don't know what we're really talking about.  It seems to me fairly clear that in study 2 more patients died on the new drug.
DR. SCHILSKY:  Dr. Lamborn?

DR. LAMBORN:  In a way, I'd like to follow up on the same thing.  I think that whenever you pick your primary efficacy measure, you do it on the assumption that the secondary measures do not have a strict p value criteria, but you expect them to be consistent or you worry.  In this case I think we're in the situation where the primary efficacy was the surrogate to start with, and the secondary measure is certainly worrisome.  So, I think that's the way the p value ought to be looked at, and I think that's what others in the group are saying as well.
DR. SCHILSKY:  Although Dr. Johnson felt that we may not actually need to vote, we'll vote anyway.  So, just to restate the question, considering the standards of efficacy agreed to by the agency for this situation, is study 2 an adequate and well controlled clinical trial demonstrating the efficacy of Evacet in the first-line treatment of breast cancer? 
All who would vote yes, raise your hand.
(No response.)
DR. SCHILSKY:  All who would vote no?
(A show of hands.)
DR. SCHILSKY:  10 no.
Anyone who wishes to abstain?
(A show of hands.)

DR. SCHILSKY:  1 abstention.  It's 0 yes, 10 no, 1 abstention.
Question 4.  In the first-line treatment of breast cancer, can we assume that efficacy of epirubicin, 75 milligrams per meter squared, is equivalent to that of doxorubicin, 75 milligrams per meter squared, when given in combination with cyclophosphamide, 600 milligrams per meter squared?
Comments?
(No response.)
DR. SCHILSKY:  No comments.
Shall we just vote it?  So, can we assume the efficacy of epirubicin at 75 is equivalent to that of doxorubicin at 75 in first-line treatment of metastatic breast cancer?  All who would vote yes?
(No response.)
DR. SCHILSKY:  All who would vote no?
(A show of hands.)
DR. SCHILSKY:  8.
Abstentions?
(A show of hands.)
DR. SCHILSKY:  2 abstentions.
Let me just ask for those who would vote no again, please raise your hand.

(A show of hands.)
DR. SCHILSKY:  8 no.
And abstentions?
(A show of hands.)
DR. SCHILSKY:  3 abstentions.
My right visual field here is obscured by this projector.  It's hard to see. 
Question 5.  Considering the standards of efficacy required by the agency in this situation, is study 3 an adequate and well-controlled clinical trial demonstrating the efficacy of Evacet in the first-line treatment of metastatic breast cancer?
All who would vote yes?
DR. LAMBORN:  Can I ask a question first?
DR. SCHILSKY:  Yes, please.
DR. LAMBORN:  If the statement is that it is not equivalent, demonstration of equivalence has not been made, which was the previous vote, under what guidelines are we then looking at the question of this as -- I'm not sure that question 5 is relevant if the majority vote was that the comparator was not demonstrated equivalent to doxorubicin and the indication is for -- I'd just like a discussion.

DR. DAVID JOHNSON:  Now you're being logical.
(Laughter.)
DR. DAVID JOHNSON:  You can't do that.
DR. SCHILSKY:  Do you feel you need us to vote on that one?
DR. WILLIAMS:  No.
DR. SCHILSKY:  All right.  No vote required.
Question 6.  Do you recommend approval of Evacet in combination with cyclophosphamide for the first-line treatment of metastatic breast cancer?
Discussion on this one?

DR. DAVID JOHNSON:  Yes.  I'd actually like some discussion on this issue because as I recall the standards that we've adhered to in previous discussions, we've looked for a pivotal trial that we felt confident gave us the results we were looking for and then adequate supporting data to really back that up.  Here I think, while I said this quite a long time ago, in my heart I believe -- no pun intended -- that this drug works and potentially has a role, I don't think the data that have been presented to us are convincing of that.  While the first trial the majority felt was adequate and well designed, et cetera, it's hard to imagine that we can vote anything other than no on this in light of the fact that we don't consider the supporting data is sufficient.  Now, again, we're an advisory group.  I guess we can do what we want to do, but it's difficult for me to understand how we would do that candidly.
DR. SCHILSKY:  Other comments?  Dr. Raghavan.
DR. RAGHAVAN:  The other thing that has been kind of troubling -- well, there are two bits to it.  One was that Grant Williams made the point that there actually are alternatives for those who want to continue to use Adriamycin.  But there has been almost a tacit assumption ‑‑ and I'm unaware of data that support this assumption -- that treating forever is a good thing for patients with metastatic disease and that Adriamycin is the only drug out there.  

The reality of the situation is that for the person who's had a major myocardial infarction before she gets her breast cancer and who never has access to Adriamycin, in addition to the fact that there's CMF which sometimes doesn't work, there must be 15 other drugs that can be either approved used or on some form of literature approval used for breast cancer.  So, it's not as if this is the only way that we can get this lifesaving drug for women with breast cancer.  
The reason I make this point is that, therefore, I'm not sure that we should lower the bar by comparison with other drugs that we look at.  The way the rhetoric has gone today, it sounded a little bit like the bad, old committee is keeping a very, very vital drug from people with breast cancer.  I think that the offset of that is that we can make a worse mistake which is to forget that there are good alternatives that are proven and work in second, third, fourth, fifth line and then introduce a drug that may actually have less people alive at a time point, particularly if used as a single agent.  I recognize that the approval indication is for in combination, but therein lies a problem in terms of trying to dissect out the various components of response.  So, I think we just need to keep in mind what we're actually talking about here. 
DR. SCHILSKY:  Ms. Zook-Fischler.

MS. ZOOK-FISCHLER:  I just have to reiterate what I said before.  It seems to me approving this drug doesn't eliminate the physician -- approving this drug would not eliminate the other options.  It would just add to the arsenal of options.  I think that from my experience with the women I've known, breast cancer is such an individual disease and each women's response to it on an emotional level, besides the physical level, is very personal.  I think the more options out there, the better.
DR. SCHILSKY:  Dr. Margolin?
DR. MARGOLIN:  I think I agree much more with Dr. Raghavan, but there's a reason which is that the danger we're trying to avoid is getting a drug out there that hasn't been proven not to be inferior and will be used for the wrong reasons in too many people who will then not have been treated right and will miss their best chance to have their best long-term remission.
DR. SCHILSKY:  Dr. Krook?
DR. KROOK:  A little different opinion.  I listened to Dr. Johnson here.  I think the pivotal study does sway me towards the fact that this would be a drug -- we may argue whether Cytoxan adds something or not.  Most of us perhaps don't use AC in the metastatic situation. 

The other two studies -- and again it was brought up, are they supportive or not supportive.  I think there's enough, at least in my opinion, in the other two studies to perhaps support it.  I can look at the survival and say there's very few people out there that far.  So, I guess I would say the pivotal study at least leans me towards saying that this is an option and would be viable and the others don't totally not unsupport it.
DR. SCHILSKY:  So, you're prepared to?
DR. KROOK:  So, I'm prepared to say that looking at the pivotal study, I see that at least it's similar with efficiency.  I'm willing to say, as we've said, that it improves the lack of cardiotoxicity, and that the other two are somewhat supportive, although I see the survival problem.
DR. SCHILSKY:  So, you'd be prepared to vote in favor of approval on the strength of one pivotal trial for which the primary efficacy endpoint is response rate.
DR. KROOK:  You're going to ask for hands sooner or later.
(Laughter.)
DR. SCHILSKY:  Dr. Lippman.
DR. LIPPMAN:  I think that the concern is that the pivotal trial is in combination.  If the pivotal trial had been single agent, you'd feel comfortable about that drug.  I think Dave Johnson brought that up.  So, that's one of the issues.

Of course, data in other trials could maybe not be supportive, but the fact that they're going in the wrong direction and very close to statistical worrisome levels is part of the issue.  Your comment about the pivotal trial, the concern I have is that it's a combination.
DR. SCHILSKY:  Dr. Nerenstone, a comment?
DR. NERENSTONE:  I was just going to echo really what Dr. Lippman said.  I think as somebody out in the community who is treating these women and you tend to use single agent treatment, the single agent study was not positive and, in fact, survival went in the same direction as the lack of response rate.  That is, it didn't meet its primary goal, but also survival was in the wrong direction.  So, that study is internally consistent, and that's the problem.  So, I have a lot of concerns.
DR. SCHILSKY:  I think we've had a good discussion.  Why don't we go ahead and vote?  I'll restate the question.  Do you recommend approval of Evacet in combination with cyclophosphamide for the first-line treatment of metastatic breast cancer?
All who would vote yes, please raise your hand.
(A show of hands.)
DR. SCHILSKY:  2 yes.
All who would vote no?
(A show of hands.)

DR. SCHILSKY:  9 no.
Okay, that concludes today's session.  Thank you very much.
DR. BEHRMAN:  Dr. Schilsky?
DR. SCHILSKY:  Yes.
DR. BEHRMAN:  I know it's running late, but could we get just a little more guidance on this concept of response rate as the endpoint?  Is this something that the committee was very unhappy about seeing, mixed feelings, something you'd want to discuss at a later date?
DR. WILLIAMS:  Right.  If you have a discussion, it should be specifically about, say, liposomal doxorubicin, not all the different possibilities.
DR. BEHRMAN:  In the setting where the compound -- where it's the same molecular entity.
DR. SCHILSKY:  I think that's an important question.  We can take a few minutes to discuss it.  Well, Dr. Raghavan, do you want to start off?
DR. RAGHAVAN:  I'm very unhappy with that concept.
(Laughter.)
DR. SCHILSKY:  Dr. Johnson, anything to add?

DR. DAVID JOHNSON:  Well, probably for the first and maybe the only time in my life, I agree with Derek.
(Laughter.)
DR. SCHILSKY:  I think I raised the issue earlier today and I'm equally uncomfortable with having selected response rate as the primary efficacy parameter because even though we expect fairly high response rates in breast cancer, particularly with an active drug like doxorubicin, to use that as an attempt at predicting whether or not survival will turn out to be equivalent some years down the road, I'm troubled by that.  I'm not confident that it's that good a predictor, and so I'm also unhappy with that choice of response rate.
Dr. Lippman?
DR. LIPPMAN:  I think it sets maybe a troublesome precedent because we may think that these drugs are similar, but when they're delivered in different ways, they're really different drugs.  What it could raise, as a lot of these new molecular targeting agents come down and we think we know they work by the same mechanism, there really may be a lot of differences.  So, I'd be concerned about establishing a precedent.

DR. SCHILSKY:  Okay.  Thank you.  We will reconvene at 8 o'clock tomorrow morning.
(Whereupon, at 5:15 p.m., the committee was recessed, to reconvene at 8:00 a.m., Friday, September 17, 1999.)