U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

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	PUBLIC HEALTH SERVICE

	FOOD AND DRUG ADMINISTRATION

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	CENTER FOR DRUG EVALUATION AND RESEARCH

	ONCOLOGIC DRUGS ADVISORY COMMITTEE

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	62ND MEETING

	TUESDAY,
	JUNE 8,  1999

		The meeting took place in the Maryland Ballroom, Town Center Hotel, 6727 Colesville Road, Silver Spring, MD at 8:00 a.m., Janice Dutcher, M.D.,  Chair, presiding.

Present:

Janice Dutcher, M.D., Chair
Karen M. Templeton-Somers, Ph.D., Executive Secretary
James E. Krook, M.D., Member
Kim A. Margolin, M.D., Member
Stacy R. Nerenstone, M.D., Member
Robert Ozols, M.D., Ph.D., Member
Victor M. Santana, M.D., Member
Richard L. Schilsky, M.D., Member
Richard M. Simon, D.Sc., Member
George W. Sledge, Jr., M.D., Member
E. Carolyn Beaman, M.H.S., Consumer Representative
Martha Solonche, Patient Representative
Glenn Gruett, Patient Representative
Andrew Harwood, M.D., Consultant
Scott Lippman, M.D., Consultant
Isagani Chico, M.D., FDA Representative

Present: (cont.)

Clara Chu Ph.D., FDA Representative
Gregory Frykman, M.D., FDA Representative
Robert Justice, M.D., FDA Representative
Grant Williams, M.D., FDA Representative

Public Comment:

Gail Hayward (letter)
Susie Bendel
Philip J. LoPresti
Gail S. Broder

Edward Schnipper, M.D., Sponsor Representative
Maurie Markman, M.D., Sponsor Representative
Frank Martin, Ph.D., Sponsor Representative
Ken Cunningham, M.D., Sponsor Representative
Wolfgang Oster, M.D., Sponsor Representative
David Grdina, Ph.D., Sponsor Representative
David Brizel, M.D., Sponsor Representative
John Mackowiak, Ph.D., Sponsor Representative
Gary Koch, Ph.D., Sponsor Representative
Lesley Russell, M.D., Sponsor Representative
Walter Curran, M.D., Sponsor Representative
Randy Allred, Dr.PH., Sponsor Representative
Alan Gordon, M.D., Sponsor Representative
William McGuire, M.D., Sponsor Representative
Franco Muggia, M.D., Sponsor Representative
Todd Wasserman, M.D., Sponsor Representative

Also Present:

Gang Chen, Ph.D.

	A-G-E-N-D-A

Call to Order and Opening Remarks,
Janice Dutcher, M.D., Chair, ODAC	6

Introduction of Committee	6

Conflict of Interest Statement,
Karen M. Templeton-Somers, Ph.D.
Executive Secretary, ODAC	7

Open Public Hearing	9

	Letter by Gail Hayward, National Ovarian 
	Cancer Coalition	10

Sponsor Presentation, ALZA Corporation

	Introduction, Edward Schnipper, M.D.	13
	
	Unmet Medical Need in Advanced Metastatic 	Ovarian Cancer, Maurie Markman, M.D.	15

	Doxil Efficacy in Advanced Metastatic
	Ovarian Cancer, Edward Schnipper, M.D.	31

	Doxil Safety Review, Ken Cunningham, M.D.	40

	Concluding Remarks, Edward Schnipper, M.D.	49

	Questions from the Committee	50

FDA Presentation, Gregory Frykman, M.D., 
FDA Reviewer	95

Questions from the Committee	105

Open Public Hearing

	Susie Bendel - The Washington Clinic	116

Committee Discussion and Vote	126

  Philip J. LoPresti, Mt. Laurel, N.J. 	 158

	A-G-E-N-D-A

  Gail S. Broder, Cancer Survivorship Alliance
	of South Florida 	 166

NDA 20-221/S-012, Ethyol (amifostine) for injection
U.S. Bioscience, Inc.

Sponsor Presentations
Introduction
  Wolfgang Oster, M.D. 	 171
	Exec. V.P., Worldwide Clinical Research
Amifostine: Mechanism of Action
  David Grdina, Ph.D. 	 175
	University of Chicago

Phase I Trial of Radiation Therapy +/- Amifostine
in Patients with Head and Neck Cancer (WR-38)
  David Brizel, M.D. 	 178
	University of Chicago
Patient Benefit Questionnaire
  John Mackowiak, Ph.D. 	 191
	Center for Outcomes Research
Statistical Evidence of Effectiveness and Preservation
of Antitumor Efficacy
  Gary Koch, Ph.D. 	 203
	Chapel Hill, N.C.

Supportive Studies
  Lesley Russell, M.D. 	 210
	Sr. Director, Clinical Research

Benefits/Risks of Amifostine in Radiotherapy for
Head and Neck Cancer
  Walter Curran, M.D. 	 214
	Thomas Jefferson University

Conclusions 	 219

Questions from the Committee 	 225

	A-G-E-N-D-A

NDA 20-221/S-012, Ethyol (amifostine) for injection
U.S. Bioscience, Inc. (cont.)

FDA Presentation
Isagani Chico, M.D. 	 265
  FDA Reviewer
Clara Chu, Ph.D. 	 276
  FDA Statistician
Questions from the Committee 	283
Committee Discussion and Vote 	 308

	P-R-O-C-E-E-D-I-N-G-S
	(8:02 a.m.)
		DR. DUTCHER:  All right.  We're going to get started.  This is day two of the 62nd Oncologic Drug Advisory Committee.  Welcome.  Today we are going to be discussing two agents.  One is Doxil and one is Ethyol.  Before we get started I would like to go around the table and introduce people who are sitting at the table.  
		Ms. Beaman.
		MS. BEAMAN:  Good morning.  I'm Carolyn Beaman, Sisters Breast Cancer Network, consumer rep. to the committee.
		DR. SLEDGE:  George Sledge, Medical Oncologist, Indiana University.
		DR. SANTANA:  Victor Santana, St. Jude's Childrens Research Hospital, Pediatric Oncologist.
		DR. NERENSTONE:  Stacy Nerenstone, Medical Oncology, Hartford Hospital, Connecticut. 
		MS. SOLONCHE:  Martha Solonche, SHARE, New York City, Patient Rep.
		DR. SCHILSKY:  Richard Schilsky, Medical Oncologist, University of Chicago.
		DR. MARGOLIN:  Kim Margolin, Medical Oncology and Hematology, City of Hope, Los Angeles, California.
		DR. DUTCHER:  Janice Dutcher, Our Lady of Mercy Cancer Center, New York.
		DR. TEMPLETON-SOMERS:  Karen Somers, Executive Secretary to the Committee of DA.
		DR. KROOK:  Jim Krook, Medical Oncologist, Duluth, Minnesota.
		DR. OZOLS:  Bob Ozols, Medical Oncologist, Fox Chase Cancer Center.
		DR. WILLIAMS:  Frank Williams, Team Leader, FDA.
		DR. FRYKMAN:  Gregory Frykman, FDA Reviewer.
		DR. JUSTICE:  Bob Justice, Acting Division Director.
		DR. DUTCHER:  Thank you.  We are now going to read 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 and information provided by the participants, the agency has determined that all reported interest in firms regulated by the Center for Drug Evaluation and Research present no potential for a conflict of interest at this meeting with the following exceptions.
		In accordance with 18 U.S.C. 208(b) full wavers have been granted to Drs. Kim Margolin and Victor Santana.  Copies of these waver statements may be obtained by submitting a written request to FDA's Freedom of Information Office located in room 12A-30 of the Parklawn Building.  
		In addition, we would like to disclose for the record that Drs. Richard Schilsky and Robert Ozols have interest which do not constitute 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 these interests that the interest of the Government and their participation outweighs the concern that the integrity of the agency 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 the financial interest, the participants are aware that the need to exclude themselves from such involvement in their exclusion will be noted for the record.
		With respect to all other participants we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.  Thank you.
		DR. DUTCHER:  Thank you.  The open public hearing today is going to be in two parts.  We are going to read a letter now and then after the presentations we are going to have a speaker.
		The letter is from Gail Hayward, an ovarian cancer survivor, and president and founder of the National Ovarian Cancer Coalition.
		DR. TEMPLETON-SOMERS:  "I wear two hats when I enter the ovarian cancer world.  One hat is that of president and founder of the National Ovarian Cancer Coalition, NOCC.  The second is that of ovarian cancer survivor since 1989.  I have fought to survive nine and one half years without a remission of the disease. 
		Ovarian cancer is life threatening.  More than 50 percent of the women who have it die within five years of diagnosis.  That is because in at least 70 percent of cases women are not diagnosed until the cancer has reached an advanced stage when it is often too late to cure.  
		In these all too common cases the fatality rate is an alarming 80 percent.  For those of us who live longer, our lives are often a roller coaster of tough chemotherapy treatments, numerous side effects, and a continuing anxiety-filled search for what to do next when the current protocol is no longer effective.
		For me the suffering has brought with it not only physical decline but, even more difficult, post-traumatic stress along with stressful financial difficulties.  The far-reaching tentacles of ovarian cancer deeply affect our family members.
		Despite the continuous onslaught I have developed an insatiable desire to live.  My daughter died of cancer a year ago.  She left two little boys now age 8 and 9.  I have made a decision that I will be there for them as they grow.  They need me and I need them.  I am deeply grateful for every breath I take.
		I founded the NOCC in 1993.  In 1996 we got our not-for-profit status.  The organization started out with a group of 20 women in a support group.  We now have over 11,000 members, 20 state chapters, and we reach literally millions of people each year with awareness and educational programs for ovarian cancer.  
		Busy?  You bet.  But the organization is a gift to me.  It is not an accomplishment that can be done by one.  Dedicated people have come forward and offered their undaunting support of time and effort to dispel myths and misunderstandings about ovarian cancer and they have committed to improve the overall survival and quality of life from ovarian cancer.  NOCC collects the personal letters sent to us by thousands of ovarian cancer survivors and their families.  Above all they want hope.
		Like myself many have been through paclitaxel- and platinum-based chemotherapy regimens as well as topotecan.  Doxil, doxorubicin hydrochloride liposome injection, is an innovative drug in a new wrapping that delivers the drug effectively and without the horrendous side effects usually experienced by most chemotherapies.  It gives hope for extension of life with quality of life.  I have personally met with representatives from ALZA and was educated about Doxil.
		I nor NOCC has any financial obligations to this pharmaceutical company.  I am convinced, however, through my own personal experience of taking Doxil for 10 months along with my knowledge of the drug that Doxil should be made available to women like myself who are refractory to many other agents.  
		I speak not only for myself but also for the 185,000 women alive with ovarian cancer today.  Gail Hayward, ovarian cancer survivor and president and founder of the National Ovarian Cancer Coalition."
		DR. DUTCHER:  Thank you.  We are now going to proceed with the sponsor presentation.  I should forewarn you that we are going to be using a timer today because we have so many speakers.  You do have an hour to complete the presentation and then we'll have questions for the sponsor.
		DR. SCHNIPPER:  Good morning.  On behalf of ALZA Corporation I am Ed Schnipper and I would like to introduce our program this morning.  Doxil is currently approved for use in patients with AIDS-related Kaposi's sarcoma who have relapsed on chemotherapy or who are intolerant to chemotherapy.
		We are here today to present our supplemental NDA for use of Doxil in patients with advanced refractory ovarian carcinoma.  Specially, we are asking for an indication for patients with metastatic carcinoma of the ovary who are refractory to both paclitaxel- and platinum-based chemotherapy regimens and who also may be refractory to topotecan.  Refractory in this setting is defined as a patient who has progressed the disease while on therapy or within six months of therapy.
		The agenda for this morning will begin with a talk from Dr. Maurie Markman on the unmet medical need followed by Frank Martin who will speak about the technology behind Doxil and some of its pharmacology.  I will then speak about the efficacy studies that are in the SNDA, followed by Ken Cunningham who will speak about the safety of Doxil.  I will return to make some concluding remarks and will be happy to take any questions you might have.
		Also with us today are several consultants that will help us answer any questions.  All of these consultants have been participants in our clinical trials.  We have with us today Dr. Alan Gordon of the Sammons Cancer Center in Dallas, Dr. William McGuire of the University of Mississippi, and Dr. Franco Muggia of NYU Medical Center.
		In addition, I have with me several of my colleagues from ALZA who will again help me answer any questions that you might have.  I would now like to introduce Dr. Maurie Markman from the Cleveland Clinic.  
		DR. MARKMAN:  Good morning.  It is a pleasure to speak to you briefly this morning on the topic of the unmet medical needs regarding ovarian cancer.  In hearing the letter from Ms. Hayward, I must acknowledge that it is impossible for me to say more than she said in her letter.  It was obviously truly profound statements.
		Ovarian cancer affects approximately 25,000 women in the United States each year.  Unfortunately, there will also be approximately 14,000 deaths associated with this cancer.
		As you have so eloquently heard, the fundamental problem is it is currently extremely difficult to find the disease in its early stages.  In fact, 70 percent plus of women with this malignancy will present with advanced disease where the standard treatments currently are the platinum agent and paclitaxel.  
		Despite what I certainly would characterize as substantial improvements in the chemotherapy for this malignancy both from the perspective of response rate and survival and, importantly, quality of life, the bottom line is more than 20 percent of women with this malignancy receiving chemotherapy will fail to respond to front line treatment.  
		In the advance disease, particularly suboptimal disease setting, 80 percent of patients will ultimately relapse and be candidates for a second-line treatment approach and just from the perspective of definitions to some that you are going to hear in the next few moments.  
		It has been learned through experience in not only ovarian cancer but other malignancies as well that it is important when you talk about second-line therapy to divide your patient populations up into two relatively broad categories that have very important clinical meanings regarding treatment options.
		The first is so-called sensitive patient population.  That is a population that has a very realistic chance of responding to retreatment with the same or similar drug that you have just given them.  For definitional purposes we will define those individuals who have had a response to therapy and they have been off therapy for at least six months, and that is the population which we are not going to discuss further, certainly because we actually have relatively reasonable treatment options available today in that setting.
		But it is the refractory patient population, those who have progressed while on therapy or never responded to therapy, or progressed within six months of the completion of therapy who are very unlikely to respond to retreatment with the agents they received.  That is going to be the focus of our attention and the truly unmet needs.
		There are actually three drugs that I can mention that are currently approved as second-line treatment of ovarian cancer, paclitaxel, altretamine, and topotecan and just very briefly to show you some of the response rates.  The purpose of my presentation is certainly not to do any comparisons or contrasting or anything of the sort, but just to give you an idea of the kind of objective response rates that have been reported and confirmed in the medical literature.
		The patient populations vary certainly.  This is somewhat of a moving target based on what the current front line therapy is because that becomes then the standard to which you want to compare your second-line treatment strategies to because those are the drugs that the patients will have failed and that's what you are then going to use.
		If you look at topotecan there is data of about a nine to 10 percent response rate in paclitaxel patients.  In those individuals who have received platinum and topotecan, the response rate of paclitaxel is about three percent.  Actually, with altretamine, which is an older drug and, therefore, was not really tested in that era of the platinum paclitaxel topotecans, we really do not know what the objective response rate.
		And to that population that is resistant to platinum, paclitaxel, and topotecan, which is now a relatively common population as these three drugs are widely used, we actually have no objective data, certainly not presented to ODAC, to demonstrate what the anticipated activity is of any drug in this setting.
		Now, very briefly there are several factors that are known to very much influence the chances of a second-line agent working in a refractory setting.  Certainly the worse population from the perspective of coming up with an agent that has activity that's going to have meaning for patients is that patient who is truly progressed on initial platinum-based chemotherapy.  Again, in 1999 that's platinum and paclitaxel.  
		And, of course, a patient who has progressed after multiple regimens, clearly that tumor has demonstrated to have developed a variety of resistance mechanisms and, therefore, the chances that the next drug you're going to try is going to work is, of course, increasingly small.
		However, it is important to point out that ovarian cancer is different than many other malignancies and, therefore, this question of second-line or third-line or fourth-line therapy, whatever you want to call it, is a very meaningful question in this malignancy where it may not be in another malignancy.
		Again, Ms. Hayward's comments, her long survival, her multiple chemotherapeutic regimens is a very poignant example of the reality of treatment of ovarian cancer in 1999.
		Relapse is common as I suggested.  However, prolonged survival is also common and becoming increasingly common.  In fact, most recent projects based upon follow-up on trials in women with advanced ovarian cancer treated with platinum paclitaxel based regimens advanced disease but so-called optimal residual disease.  
		In other words, stage-three disease with a relatively small amount of cancer remaining in the abdominal cavity, 40 percent of that population will be alive 10 years after diagnosis.  Long survival is becoming increasingly what we would anticipate.  However, again, the relapses are common.
		And importantly, particularly when we talk about the issue of is it appropriate to even consider second-line therapy, this patient population very fortunately often has an excellent performance status for a very prolonged period of time and, therefore, they are reasonable candidates to at least consider a second-line treatment option.  In other words, it is important to have those options available for the patients to think about.
		In addition, it is important to point out that even though we do have other agents that have been approved for second-line therapy in the management of ovarian cancer, it is important to argue very strenuously that we need to have options, not just one drug.  The reason for that is very simple.
		Based upon the individual patient characteristics and their prior response and, importantly, prior toxicity to the front line therapy, the choice of a second-line regimen may very well be influenced by those factors.  I just give three very simple examples that all the oncologists on the panel are very aware of.
		An individual who has received prior front line therapy, the platinum paclitaxel, may very have experienced neurotoxicity from the front line regimen and, therefore, that's an individual if you had options available in the second-line setting you would certainly want to stay away from drugs that had neurotoxicity as a potential effect.
		An individual who had excessive bone marrow toxicity with the front line regimen, very much you would want to try to stay away from a regimen that you knew had major toxicity as bone marrow toxicity.  Of course, the obvious problem of somebody with a lot of nausea and vomiting you very much want to stay away from an agent that you knew had a potential toxicity to be significant nausea and vomiting.
		Finally, because this patient population is able to live for so long with overall such good quality of life, it is critical as we think about second-line, third-line agents that we think about those agents that are well tolerated and convenient for patients. 
		The last thing we want to do is take a patient who is doing well but still has active disease and make the quality of life bad.  Clearly all of these agents have toxicities.  They are cytotoxic, the ones we are talking about.  They have the potential of causing harm but we have to do our best to cause the least possible harm so that we can prolong survival and hopefully improve the quality of life.  I thank you for your attention.
		DR. MARTIN:  Good morning.  My name is Frank Martin.  I'm principal scientist at ALZA Corporation.  The key structural feature of all liposomes including the Doxil liposome you'll hear about today is a lipid biolator membrane made out of material such as phosolipids and cholesterol.  
		These membranes when they are exposed to water, or these lipids when they are exposed to water, spontaneously form membranes that wrap around a small portion of the aqueous compartment forming a structure that is much like a small cell, a tiny cell.
		In the case of Doxil there is a single such lipid biolator membrane and the overall dimensions of the particle is about 100 nanometers.  So to give you a point of reference, this is about 1/100th the size of a red blood cell.  These are small particles.
		There are two structural features that differential Doxil from other liposomes.  The first one is the way the drug is loaded.  Doxorubicin hydrochloride is actively pumped into the internal compartment of these liposomes using an ion gradient method.  It's possible to achieve such high concentrations of doxorubicin internally that the drug actually falls out of solution forming a gel like precipitate inside the liposome.
		This is important because it leads to very stable encapsulation of the drug and to a very high amount of drug in each liposome.  Indeed, it is possible to load about 15,000 molecules of doxorubicin in a single liposome of this size.
		It also leads to very robust stability because these particles, as you will see in a moment, to do their job are going to have to circulate in the bloodstream for days so we want to keep the drug in the liposome in order to optimize the amount that's delivered to the target site.
		The other feature is the hallmark of a STEALTH liposome, and that is the polymer layer which is chemically grafted to the surface of the liposome.  The polymer is polyethylene glycol, which is known to be an inert safe polymer, and it forms a very dense hydrophilic layer around the liposome.  
		This layer is designed to do two things; to keep biological proteins and plasma from binding to the liposome and destabilizing it, No. 1, and, No. 2, to reduce the rate at which the reticuloendothelial system recognizes and clears these particles from the bloodstream.  It's intended to make like a tiny formed element in blood.
		Now, by virtue of the way the drug is encapsulated, the small size, and the polymer coating, these liposomes circulate for long periods of time after intravenous administration.  This is illustrated here with the pharmacogenetics of Doxil in cancer patients showing on this axis the concentration of doxorubicin and plasma over a seven day period after administration.
		There are two curves plotted here.  One is the total amount of drug in the bloodstream over this period.  The other is the proportion of that total that is still liposomes.  I would like to draw your attention to two important points here.  The first is virtually all of the drug remains in the particles while they are circulating in the bloodstream.  The other is the clearance is very slow.  
		Indeed, the half-life for Doxil is about two to three days in these cancer patients.  By virtue now of their small size and long circulation time, these particles are able to access sites of disease that have abnormal blood vessels.  In one such site is tumors.  
		It is well known now that tumors have defective capillaries particularly in areas undergoing angiogenesis where these capillaries are sprouting.  They are growing so haphazardly and so quickly that defects and gaps are present in the endothelial walls.  These liposomes are small enough to physically extravasate through these gaps and lodge in the interstitium of tumors.
		Evidence for that is shown here in a preclinical model.  This is a xenograft of a prostate cancer in mice.  In this study what we are doing is looking at the area under the curve in the tumor after a single dose of either Adriamycin or Doxil at time zero.  You can see that the pattern of uptake is quite different for these two drugs.
		In the case of Adriamycin, the uptake is rather rapid and the elimination rate is rather fast.  This is in full agreement with what one would expect from the literature.  The Adriamycin enters the tumor and is cleared within a few hours.
		An identical doze of Doxil has a different pattern.  First of all, it takes several days to reach its peak.  The peak is higher meaning that these liposomes are actually carrying more drug to the tumor.  The residence time in the tumor is very long taking a week in this rodent model for the drug to be eliminated.
		Our interpretation of these data are that, No. 1, it takes a long time for the liposomes to enter and they enter as intact particles.  That is, the drug is still in the particle.  Then over the ensuing time period the liposomes break open, release their drug, the drug becomes bioavailable, is metabolized and eliminated from the tumor.
		This differential uptake pattern is also seen in humans.  In the next slide what I'm going to be showing you is a gamma scintigram of a patient, a completely sarcoma, where we injected not Doxil but the same liposomes containing Indium 111, Indium 111 chelated to EDTA so that we can use gamma scintigraphy to follow both the kinetics and the distribution of the liposomes.
		Importantly this method only tracks or reports the presence of intact liposomes.  If the chelate is released from the liposome, it is immediately eliminated in the urine within just a few minutes.  The radioactivity is reporting the existence and movement of intact particles.
		Shown in the first panel is the gamma scintigram at four hours post injection.  I'm drawing your attention here to this patient's left where there are several Kaposi's sarcoma lesions.  The lesion I would ask you to follow is the lesion that is circled.
		At four hours you can see clearly that the major radioactive distribution is blood pool.  That is, the major vessels in the chest are shown.  You can see some activity in the bladder which represents the Indium EDTA that was not in the liposomes when they were injected so this was immediately eliminated in the bladder.
		You could start to see uptake in the lesion at 24 hours.  It reaches a maximum uptake at 48 hours.  Yet, even at 96 hours all of these lesions in the leg are positive indicating two things.  (1) it takes a while for these lipsomes to get into the lesion, and (2) even at 96, and we even have other time points later at two, three, or four days later the liposomes remain in the lesion as intact particles so they are lingering in the lesion for some period of time.
		The uptake pattern in Kaposi's sarcoma has been verified biochemically as shown here in a group of seven KS patients who were injected with Doxil at time zero and 48 hours later a representative cutaneous lesion was biopsies as was adjacent normal skin beyond the margin of the lesion.  The total drug in these tissues was then measured and you can clearly see that the amount of drug in the lesion is much higher than the amount of drug in adjacent normal skin in all of these patients.
		Differential uptake in Kaposi's sarcoma seen here does provide benefit to Kaposi's sarcoma patients.  Indeed, Doxil was first approved for use in patients with Kaposi's sarcoma that had failed first-line therapy and including a group of patients that had received prior Adriamycin.  Response rates in the original submission are shown here.  
		Since that time randomized trials have been conducted of Doxil as a single agent versus a variety of combinations including ABB, BV, and the Doxil plus BV.  In all of these trials a high response rate in Kaposi's sarcoma has been confirmed and these are all now in the medical literature.
		Of course, we were interested in other histologies beyond Kaposi's sarcoma.  Adriamycin is active in a variety of solid tumors so preclinically we screened a variety of tumor types in xenograft and rodent models.  One model we tested was an ovarian cancer xenograft, the HEY xenograft.  Indeed, we found activity of Doxil in the xenograft as shown here which is a typical tumor growth curve.  
		Here is both sides of the tumor versus time after implantation.  As you can clearly see, Adriamycin is active in this model versus the control group.  Doxil at the same administered dose as superior activity to Adriamycin.
		Based on the preclinical activity that we saw here and based on some work done in a Phase I trial in which a group of heavily pretreated ovarian cancer patients was admitted into a Phase I trial and work done by Franco Muggia, we found clinical activity in a number of these patients including a bona fide partial responder and some miner responses.
		Based on the preclinical activity of Doxil in ovarian cancer and indication of clinical activity really represents the rationale for our looking into the utility of Doxil in ovarian cancer which will be the topic of discussion today.
		I would like to ask Dr. Schnipper to return and to begin the sponsor's clinical presentation.
		DR. SCHNIPPER:  The clinical development of Doxil for ovarian cancer began in 1994 and was designated an orphan designation in 1998.  The supplemental NDA that we're talking about today was filed in December of this past year and granted priority review earlier this year.
		The data that I'm going to discuss today will demonstrate that Doxil is active in these refractory patients, the Doxil is generally well tolerated, and the Doxil is convenient to administer.
		The program consist of four trials, three noncomparative trials and preliminary results from an interim analysis of a randomized Phase III comparative trial comparing Doxil to topotecan.
		The three multicenter noncomparative trials all contained relapsed or refractory patients.  Refractory, as we said, is narrowly defined as patients who have progressed while receiving therapy or within six months of receiving therapy, patients who are defined as platinum and paclitaxel refractory, to fill that definition for both drugs whether they were given individually or in combination.
		Similarly, patients who were additionally refractory topotecan also fill that definition for all three drugs either individually or if the drugs were given in combination.
		The primary endpoints of all these studies were response rate and all responses were based solely on measurable disease.  All responses were confirmed by repeat radiologic scan at least four weeks from the demonstration of response.  All available scans were subjected to independent radiologic review.  Secondary endpoints included time for regression and duration of response.  
		The initial dosing regimen for all three files with the exception of trial 30-22 was 50 milligrams per meter squared every four weeks.  The median dose actually received across all three trials was 50 milligrams per meter squared every four weeks.
		The Phase II trials were conducted at multiple sites.  Two of the studies were done in the U.S. and one in Europe.  The median age is shown here.  The number of patients in each trial that fulfilled a definition of being refractory to platinum and paclitaxel was 28, 49, and 26 respectively.  
		In Study 30-47 there were 33 patients that additionally fulfilled the criteria for being refractory to topotecan and 10 patients in Study 47E.
		It is also important to note that there was quite a short interval between patients having received their prior regimen and progressive disease before entering on the Doxil trials.  In addition, most patients had received two more prior regimens.
		I would like to now turn to the results of these three trials.  Of the 28 patients in Study 30-22 who fulfilled the definition for being refractory to both paclitaxel and platinum.  There were six responders.  One complete and five partial responders for an overall response rate of 21.4 percent.
		In 30-47 there were 49 patients who fulfilled that refractory definition.  There were nine partial responders for a response rate of 18.4 percent.
		If you look at the patients that also fulfilled the definition of being refractory to topotecan, there were 33 patients, six responders, one complete, five partial for a response rate of 18.2 percent.  In Study 47E there were no responses in the patients who fulfilled the definition for refractory.
		Now, we looked at a variety of factors to explain why the results from 30 and 47E were not consistent with the results from the other two trials.  In looking at some of these factors, we noted that there were indeed a couple of differences between the patients in this trial and the patients in the other trials.
		For example, the baseline CA 125 was somewhat larger.  The bulky disease, the sum total of measured disease at baseline was somewhat larger.  Patients spent a shorter amount of time on trial.  Patients who left trial in general left trial for death or progressive disease rather than toxicity.
		So it appears that it is at least possible that the patients on this trial entered at a later stage in their disease and were treated perhaps for shorter periods of time than the patients in the other trials thus making it more difficult for them to respond.  Nonetheless, these patients are included in our overall analysis of response rate.
		Looking at all the responses together across the trials we can see that for the platinum and paclitaxel refractory patients, it was an overall response rate of 14.6 percent.  If we look at those patients that were additionally refractory topotecan, the response rate was 14.0 percent.  Combining all the patients together, the response rate was 14.4 percent.
		As Dr. Markman stated, some of the most difficult patients to treat are those who actually progress while on platinum.  If you look at just those patients, the response rate was 10 percent in those extremely difficult to treat patients.  
		A Kaplan Meier curve of duration of response showed a median duration of response of 39.4 weeks, almost 10 months.  The time to progression across all these trials was 15.9 weeks, almost four months.
		If we also look at performance status of these patients and plot a Kaplan Meier curve of first decline and performance status and put that on the same curve, same chart as the time to progression, we can see the two curves are parallel.  Patients maintain their Karnofsky status until the time of progression.  Patients were generally were able to continue their daily life while on therapy.
		If we turn our attention now to our randomized trial, Study 30-49, this was a study designed for patients who had failed primary therapy with platinum.  The patients were then randomized to receive either Doxil, 50 milligrams meter squared every four weeks, or topotecan, 1.5 milligrams per meter squared daily times five every three weeks.
		Patients were required to have measurable disease.  In this study the primary endpoint was timed to progression with endpoints response rate, duration of response, etcetera, also looked at.
		The study was conducted at 90 sites throughout the United States and Europe and has recently reached its target accrual of 460 patients who have continued to be followed for response.
		What we are showing here is the results of the first planned interim analysis that per protocol was scheduled to be undertaken when 200 evaluable patients were entered.  We are going to talk only about the 237 intent-to-treat patients that were accrued to reach this goal.  
		Those patients would have had to have at least six months of follow-up to be included in this analysis.  We will present the entire population for safety and we will concern ourselves for efficacy with that subset of patients, 81 patients, that met the definition that we have said before, for being refractory to platinum and paclitaxel.
		Of the 44 patients on the Doxil arm who met that definition, there were six responders for a response rate of 13.6 percent, pretty much in line with what we've seen from the Phase II trials.  On the topotecan arm, there were 37 patients, three responders for a response rate of 8.1 percent. 
		We've talked a lot about response rates.  What about the magnitude of these responses?  What we have here is a graphic representation of a table that you all have in your briefing documents that looks at all the patients from all the studies, a total of 27 responders, and looks at the percent reduction in lesions.  As you can see, the majority of the patients had quite large reductions in their lesions from baseline to when it was measured as a responder.  
		In fact, nine patients had complete disappearance of all measurable disease.  Only two of them were considered complete responders because under the strict definition of complete response, some of these patients may have had an ill defined shadow on CAT scan or some unevaluable disease so they were not considered complete responders but, in fact, had disappearance of all measurable disease.
		As you can see, there were very few patients that, in fact, qualified as responders by having only relatively small differences from baseline in their measurement of disease.
		I would like to just briefly summarize the Phase II efficacy data that we've discussed by saying that across all studies we had a response rate of 14.4 percent in these highly refractory patients.   The duration of response was almost 10 months with a time to progression of almost four months thereby demonstrating activity of Doxil in these highly refractory patients.
		I would now like to introduce Dr. Ken Cunningham to talk a little bit about the safety of Doxil.
		DR. CUNNINGHAM:  Good morning.  My name is Ken Cunningham.  I would like to present to you the safety profile of Doxil.  The experience comes from five ovarian studies totally 408 patients.  It is this population which I intend focusing on this morning. We have a further 772 patients in the total solid tumor population, and in the Kaposi's sarcoma clinical experience we have 1,721 patients.  This additional experience is consistent with the ovarian experience.
		Turning first to drug exposure, the median cycle dose was 50 milligrams per meter squared.  The median cycle length, 29.5 days.  The cumulative dose was approximately 150 milligrams per meter squared, some patients receiving a lot more.
		This graph shows the dosing tensity by cycle.  Now, some 42 percent of patients actually dose modified.  That is, they had a dose reduction or a dose delay.  But you can see that a high dosing tensity was sustained throughout.  Indeed, at the 6th cycle 11.2 milligrams per meter squared was the mean dosing tensity which is 90 percent of the intended.
		Turning to adverse events, you can see that from this chart that the patients who experienced adverse events, the majority had grade I or grade II, 60 percent had grade III, and a substantially fewer number had grade IV.  There were four deaths on study.  One of these deaths was considered to be drug related and that was a patient with neutropenic sepsis who had been heavily pretreated.
		I should point out that the numbers on this chart are 396.  That's the total number of patients on whom we received adverse event report forms.
		Palmar-plantar erythrodysthesia, or PPE, sometimes known as hand-foot syndrome is the commonest side effect with Doxil.  You can see that the majority of patients have mild to moderate events but some 17 percent have grade III.  Two patients in the ovarian population were categorized as having grade IV.
		Stomatitis is the second commonest.  but, again, the majority of patients have mild to moderate events.  You can see a similar pattern as we move down the other adverse events, the majority mild to moderate events.
		Alopecia occurred in 16 percent of patients.  This was mainly minor hair thinning although .7 percent of patients had some more extensive hair loss.
		Looking at the hematologic laboratory data and focusing on the severe grade III/grade IV events, neutropenia occurred at grade IV in 8.6 percent of patients.  That is, a neutrophil count of less than 500.  Relatively few patients had growth factor, 4.1 percent.  Only one patient was reported as having neutropenic sepsis.
		Slightly more patients had anemia.  16.4 percent had grade IV anemia with hemoglobin of less than 6.5 grams.  Consistent with this figure, 14 percent had blood transfusions.
		Thrombocytopenia was less frequent.  1.2 percent of patients had a platelet count of less than 25,000 and very few patients had platelet transfusions.
		Eleven percent of patients withdrew due to adverse events and the commonest reason was Palmar-plantar erythrodysthesia, 3.5 percent.  The other events can be seen here and all account for 1 percent or less of withdrawals.
		I would like to say a few words on the management of PPE.  Looking first the grading system, PPE affects the palms of the hands, the soles of the feet.  In its mildest form is erythema that the patient may not even be aware of.  Sometimes it's associated with tingling.  
		As we move through to grade II there is erythema in association with sometimes edema and sometimes desquamation.  Grade III, some blistering.  grade IV is obviously a more diffuse problem.
		With grade I we suggest redosing.  Obviously there are other recommendations to the patients.  The patients are advised to wear loose fitting clothing, they shouldn't wear shoes which are too tight, or indulge in any activities which would tend to rub or abrade the skin.
		At grade II a delay of one to two weeks should be instituted.  At grade III and IV a similar delay but this time when the patient is redosed they should be redosed at 75 percent of the original dose.
		We propose that we put this in our PI.  We also believe that with good education and following this plan we can minimize the effect of PPE.
		When considering an anthracycline, clearly cardiac toxicity should be considered.  In our total solid tumor database of 772 patients -- we're now talking beyond the ovarian population -- we had six patients who withdrew due to cardiac toxicity.  Five had asymptomatic left ventricular ejection fraction declines.  One patient had congestive heart failure.  That patient had, in fact, had 22 cycles and a cumulative dose of 944 milligrams per meter squared.
		Five additional drug related cardiac events were reported, all grade I.  Doxil pharmacokinetics mimics the pharmacokinetics of continuous infusion doxorubicin and it has been well established that continuous infusion doxorubicin is associated with less cardiac toxicity.
		We've also done some animal work, preclinical animal models including the rabbit have been studied and shown that milligram for milligram doxorubicin causes more cardiac toxicity than Doxil.
		A limited amount of biopsy data has been performed.  As you are aware, biopsy data is probably the most sensitive way of looking at anthracycline and toxicity.
		In one study with 10 KS patients, patients received between 469 and 860 milligrams cumulative dose of Doxil.  They showed minimal cardiac toxicity based on the Billingham score.  A Billingham score of 1 is the first point on the three point scale that indicates or denotes cardiac toxicity.
		We've also looked at four solid tumor patients and their doses range from 675 right up to 1,680 milligrams.  In two cases these patients had prior Adriamycin of at least 300 milligrams.  You can see again that the Billingham score runs from nought to 1.5 so minimal cardiac toxicity, although far more data is needed to generate sufficient information on this subject.  
		As Dr. Schnipper has already mentioned, we are currently conducting a large randomized comparative study in ovarian cancer, Doxil versus topotecan.
		So far in this study we have recruited 135 Doxil patients and 132 topotecan patients.  This interim safety analysis has about four months of safety update reviews to the FDA.
		You can see from this that between 40 and 45 percent of patients are still on study.  Terminations are slightly higher in the topotecan arm.  So too are delays, interruptions, and dose reductions, 65 percent for topotecan and 44 percent for Doxil.
		Here we see the percentage of patients with adverse events by severity.  The yellow bar shows Doxil and the pink bar shows topotecan.  You can see that for both groups the majority of patients get mild to moderate events.  Doxil is associated with slightly fewer events at grade III but significantly fewer, less than .001, for grade IV. 
		To illustrate the comparative safety a little bit further, what we've taken here are Doxil's five most frequent adverse events and compared them with topotecan.  What you can see is that, of course, PPE is the commonest event for Doxil, the majority getting mild to moderate.  Eighteen percent here get grade III.  One patient is reported as having grade IV.  Stomatitis the second commonest.  Again, mainly mild to moderate.
		But for the remaining three events, there are more topotecan patients who experience these particular events.  In particular, I draw your attention to anemia where many more experience grade III and IV anemia.
		Here we have done the reverse.  We're look at topotecan and the top five topotecan adverse events.  The striking thing is that these are mainly hematological as one might predict and that there are fewer grade III, IV events denoted with the dark and mustard color for Doxil or the darker red color for topotecan.  There are many fewer grade III, grade IV events for Doxil versus topotecan.
		Focusing on neutropenia for a minute, in the neutropenia here there were 13 neutropenic cases reported with topotecan versus none reported with Doxil.  Also, there were two deaths associated with neutropenic sepsis in the topotecan arm, and no drug related deaths with Doxil.
		Looking at alopecia 56 percent of patients had hair loss with topotecan.  Seven percent had total hair loss.  12.5 percent had hair thinning with Doxil.  There were no cases of total hair loss.
		In summary, we would summit that Doxil is generally well tolerated.  It is associated with relatively mild myelosuppression and minimal alopecia.  PPE is the most common adverse event that is manageable and that is evidenced by the relatively low number of patients who actually withdraw as a result, 3.5 percent.
		The adverse event profile is predictable.  That's based on the similarity in adverse events in the total solid tumor patient population, the Kaposi's sarcoma population, and also the three years marketing experience that we now have.  
		Thank you very much.  I would now like to hand the podium back to Ed Schnipper who is going to make some concluding remarks.
		DR. SCHNIPPER:  So what is the value of Doxil in this patient population?  First, Doxil meets an unmet medical need for patients for whom there is no approved therapy.  It has an objective response rate of 14.4 percent in these highly refractory patients the duration of response being almost 10 months.  It's generally well tolerated and has convenient monthly dosing.  Doxil is dosed with a one hour infusion once a month through a peripheral vein since stop was vesicant.  It's less intrusive than many other therapies in patients' lives.
		In conclusion, Doxil is active in patients with ovarian cancer who are refractory to platinum and paclitaxel and who also may be refractory to topotecan.  Doxil represents a valuable addition to the treatment options for these patients.  
		Thank you and we'll be happy to take your questions.
		DR. DUTCHER:  Thank you for a very concise and ahead-of-time presentation.  
		Are there questions from members of the committee?  Dr. Ozols.
		DR. OZOLS:  The committee is going to have to try to answer the question of whether Doxil has really a meaningful therapeutic benefit in this group of patients.  You're talking about a drug that produces a response rate of about 10, 12, 14 percent with as many patients dropping out because of toxicity as well.  
		You've got to face a situation where patients, as Maurie pointed out, are living longer.  You have many patients who don't have symptoms who do have active disease and does a partial response really make much difference to them?
		It's doubtful that you're going to impact on survival with that kind of a response rate in that group of patients.  When we look at therapeutic benefit, we have to ask several questions like who really is going to benefit.  I think it's not the challenge of saying whether this drug is active or not.  This drug definitely has some activity.  I think we are seeing objective responses.  There are some issues of trying to figure out where best to use this drug.
		One of the things is when you talk about refractory, you have a 10 percent response rate in patients who actually progress on disease and that's the worst group of patients.  Do you have any responses in patients who progress on their initial treatment with paclitaxel and platinum?  
		I mean, we talk about progressing on disease.  That could be progressing on second-line treatment of platinum or paclitaxel.  But do you have any patients in that 20 percent or more you pointed out who don't respond to initial treatment?  Do they respond?
		DR. SCHNIPPER:  We haven't specifically broken the data down that way.  We have responses on patients who have progressed on their last platinum, on the platinum they had just before they took Doxil.
		DR. OZOLS:  And that's a different group of patients.
		DR. SCHNIPPER:  Right.
		DR. OZOLS:  Because the worst group is still the patients who get their initial paclitaxel, carbo-platinum, whatever, and then progress on that disease.  In that treatment do they respond at all?  Because I'm trying to figure out who shouldn't get the drug.  I think because of the toxicity that we're seeing and the limited activity, certainly I think we need to give some guidance to the clinicians about where to use it and where not to use it.
		DR. SCHNIPPER:  I don't have specific information on that particular group of patients.  We have patients who have progressed while on platinum after as many as five different regimens.  We also have patients who --
		DR. OZOLS:  That's a touchy issue about patients who have had lots of regimens.  Patients who have had many regimens and continue to be treated with multiple regimens, you are selecting out a group of patients who actually have a better overall prognosis.  When you say it's the worst group of patients because they've had more than three or four treatments, in fact, you may be selecting out patients who have a long natural history and, therefore, do reasonably well.	It's's really the ones who are going right through treatment are the ones that were --
		DR. SCHNIPPER:  Yes.  You are absolutely right.  We were obviously very concerned about that.  One of the things we looked at is we looked at the patients who had a longer time to regression on Doxil than their prior regimen.  There were actually 23 patients who had more than 90 days longer time to progression on Doxil than their prior regimen indicating that they were not patients who necessarily would have long times to progression on any regimen that they have.
		DR. OZOLS:  Another questions.  Again, trying to figure out who should get it and who shouldn't.  Did you really see any therapeutic benefit in the sense of symptom relief?  I mean, the patients you're talking about who had symptoms from their disease with a 10 percent response rate, were those symptomatic benefits?
		DR. SCHNIPPER:  The majority of the patients who entered these trials entered with a very high performance status, as Dr. Markman said.  The case support forms on these trials asked for the investigator to evaluate evaluable disease as well as measurable disease.  
		Of the responders in the phase through trials, there were five patients who entered with ascites.  At the time that they demonstrated response, five out of five had improvement in their ascites.  In fact, there was some evidence that patients were feeling better and doing better. 
		The majority of the patients felt reasonable well when they started so we looked at things like pain medication and other sorts of things.  Most of them weren't on pain medication to begin with.
		DR. OZOLS:  I mean, in ascites you can have a little bit of ascites picked up on CT scan that goes away or you can have massive ascites that goes away.  I mean, the symptomatic benefit is still something that still really bothers me a little bit.
		The other thing that I'm very concerned about the European study.  I mean, that's a group of investigators who are very good investigators who were able to get together to do this study and they had no responses.  
		Now, you can say maybe that's because the worst group of patients but, again, that concerns me because in a community you may actually be giving this drug to a worse group of patients than you actually saw in your trials so the community practice maybe reflects more the European practice and then you maybe have no responses.  I'm very concerned about a large trial with zero out of 36.  That's very concerning that there is no activity in that group of patients.  And to say it's because they have worse disease again may be --
		DR. OZOLS:  We were obviously concerned as well, but we were very much encouraged by the fact that our randomized Phase III trial had results that were very consistent with our overall Phase II results.
		DR. SCHNIPPER:  But can you again tell in patients if you say that the European data had no responses because they were a worse group of patients, again can we hone in on who shouldn't get the drug?  Do patients with bulky disease not respond then?  I mean, should you try to --
		DR. OZOLS:  I can show you some of the parameters of responders versus nonresponders and show you that there is quite a lot of overlap in terms of responders versus nonresponders in terms of these issues of bulky disease based on characteristics, etcetera. 
		If I can have the slide on, please.  You can see from here if you compare the responders to the nonresponders in terms of the 21 responders in the Phase III trials and the nonresponders, you see they compare pretty favorably in terms of a number of regimens.  If you look at drug-free interval, they are fairly close.  In terms of platinum-free interval also fairly close because, remember, these studies started in 1994 so some of these patients got platinum in sequence, then Doxil and then topopecan.
		The sum of legions was slightly higher in the nonresponders but look at the ranges which overlap quite a bit, as well as the CA-125.  I think it would be very difficult for a practicing physician to actually predict from these typical prognosticators who would respond and who would not respond because of the overlap in the ranges here.
		DR. OZOLS:  And your progression when you patients progress, that was a radiologic progression or physical progression?  It wasn't a CA-125 progression?
		DR. SCHNIPPER:  In the vast majority of the patients there were a few exceptions but the vast majority was radiologic progression, yes.  I'm sorry, they were all radiologic progressions.
		DR. DUTCHER:  Dr. Margolin.
		DR. MARGOLIN:  I've got a couple of questions.  In study 30-49 it looks like, if I got the numbers right, you have about 80 patients that you're looking at that have the double refractoriness and there were about 400 so far in your interim analysis.  Is that correct?
		DR. SCHNIPPER:  No.  There's 237.
		DR. MARGOLIN:  Okay.  So there's about 40 percent of the total that are analyzable for fulfilling the refractory criteria.
		DR. SCHNIPPER:  Correct.
		DR. MARGOLIN:  The question I have since this is an interim study and you have only partial accrual, are attempts being made -- is the statistical design of that study intended to allow a completely separate statistical analysis of patients who fulfilled the refractoriness criteria so that at the end you'll be able to look at those patients separately with a robust statistical analysis and compare the activity of the topotecan and the Doxil?
		DR. SCHNIPPER:  Yes.  The patients who were stratified for level of refractoriness at the beginning of the trial so they are priorly set up for that.
		DR. MARGOLIN:  That's not the same question.  Well, we talked about that yesterday.  Prestratification for balanced factors between your groups is fine if you're going to look at the data all together at the end.  But designing the study II contained purposely enough patients so that at the end you can break out those patients and look at them separately requires more patients than the prestratification.   
		DR. OZOLS:  I'll ask Dr. Allred from our statistical group to answer that specifically.
		DR. DUTCHER:  Please state your name for the record.
		DR. ALLRED:  My name is Randy Allred.  Yes.  This was a planned interim analysis as specified in the protocol.  These patients were a subset of the 200 evaluable patients that were stated in the protocol.  
		The other thing to keep in mind is that all patients are accrued now so accrual is closed.  We're just waiting for follow-up time to complete.  The study was not powered to show differences in this subset of patients.
		DR. MARGOLIN:  Thank you.  If I could please have one more.  This would be more theoretical
or future studies.  I think Dr. Markman and others in this field have shown us that the patients who in general do the worst are those with measurable disease.  That large group of patients who don't have easily followable disease and you can decide what you want to do with the marker are actually more favorable.  
		If one were to agree based on some of the things we talked about yesterday, that in certain populations of patients it is appropriate to look at time to progression as an appropriate endpoint as a surrogate for clinical benefit, would that not answer a need that might actually show greater activity for this and other new drugs in ovarian cancer?  Are any attempts being made to address that group?
		DR. SCHNIPPER:  I'm trying to specifically understand your question.  Are you asking if we are exploring time to progression as a means of looking at only the measurable disease population?
		DR. MARGOLIN:  No.  Are you doing any studies in nonmeasurable evaluable patients carefully selected ?
		DR. SCHNIPPER:  No.  The entry criteria for all our studies are measurable disease.
		DR. DUTCHER:  Dr. Nerenstone.
		DR. NERENSTONE:  Yes.  I share some of Dr. Ozols concerns about the toxicity of this drug.  I just had a few questions for the sponsor as well.  Dosing - this is a pharmacokinetically different drug than we're used to.  I want to know did they dose according to ideal body weight or actual weight?  Especially since in the community the patients are going to get this drug are going to have a lot of ascites.  They could have pleural effusions and even obesity is sometimes a problem.  How are these patients dosed?
		DR. CUNNINGHAM:  Hello.  My name is Ken Cunningham.  The patients were dosed according to their actual body weight in fact.
		DR. NERENSTONE:  One of my other concerns that may relate to that is that even in the Phase III of 44 percent delay or reduction in subsequent doses of the Doxil, having treated some patients and seen PPE, I can't minimize the effect of patients of this side effect.  
		Do you think that maybe you're at too high a dose?  That 50 per meter squared is the first dose might be beneficial but 44 percent dose reduction for other doses leads me to think that perhaps a smaller dose in subsequent because this can be cumulative might be really clinically more tolerable.  Has any thought been given to that?
		DR. CUNNINGHAM:  Well, our plan, of course, is to at the very first signs of grade II PPE 2 dose reduce.  If doctors take note and make that first dose reduction early then, in fact, PPE is well minimized.  Our particular stance at the moment is to start with 50 but accept that many patients will actually be reducing their dose once they get the first signs of grade II PPE.
		What may be of some help is we have done a study where we started a lot higher and we had to dose de-escalate and I would be happy to show the results and how we actually came down and the reduction in PPE with you.  Would that help in answering your question? 
		DR. NERENSTONE:  No.  I'm just talking from a clinical perspective that as this drug is going to go on market at the appropriate dose, I'm just concerned that the indication is a 50 per meter squared for each dose and that may just be really too high.  When you require 44 percent of patients to dose reduce in a well controlled trial of people who are used to giving this drug, it makes me a little concerned that when it goes out to market where clinicians are not as familiar with the side effects, that you might actually be overdosing these patients.
		DR. CUNNINGHAM:  I think the one thing that I would like to comment on is, as I showed you in the presentation, the majority of patients even at cycle VI were receiving 90 percent of their intended dose intensity.  A lot of patients might actually have a dose modification but it's actually relatively small and doesn't impact enormously on the absolute dose.
		The other thing to say is that 44 percent aren't dose modifying for PPE.  It's probably about 20 percent of patients who get PPE dose modified.  There are other reasons for dose modification.
		DR. NERENSTONE:  And one other clinical question.  Because this is looked at as really almost a continuous infusion of Doxil, if patients require neupagen or support of their white count, when do you give it and are you going to have any guidelines to help the clinicians with that?
		DR. CUNNINGHAM:  Well, you saw from my slides that only four percent of patients actually had growth factors.  Clearly you're right in alluding to the longer half-life and there being a rationale for delaying the introduction of growth factor. 
		At this juncture we cannot give precise information in the PI as to when that should be but we would certainly be suggesting probably out at four days or four days plus.
		DR. DUTCHER:  Dr. Santana.
		DR. SANTANA:  I have two questions.  One hopefully will be simple and the other one you can give me more data.  And that is trying to address this issue that Stacy was presenting which is what is the true equivalency of this product to doxorubicin in terms of milligram per milligram?  
		Obviously you are putting in more molecules of doxorubicin in the liposome than you are with free doxorubicin.  I ask that because one of the slides that you showed us, which was a xenograft model in which you did a study of saline versus Doxil versus Adriamycin.  
		The dose of the product was the same as Adriamycin, 6 milligrams per kilo and that is very misleading because in essence you ought to be giving more molecules of doxorubicin and the Doxil than you are with free doxorubicin.  If you could address that issue of equivalency of doxorubicin units.  
		Then a follow-up question regarding toxicity is that I've heard comments that patients with this disease can have long periods with disease with relatively good survival.  In the patients who had a response, do you have any chronic toxicity data?  That is, in those patients who responded that you followed for long periods of time, are there any issues of chronic toxicity, particular cardiac?
		DR. SCHNIPPER:  I'm going to start with the second question first if I may.  I'm going to ask Dr. Franco Muggia to make some comments on that since he has some of the longest experience following some of these patients.
		DR. MUGGIA:  I'm hearing some misconceptions about the toxicity that one observes with this agent.  For one, when you see the degree of neutropenia and anemia you have to consider the baseline characteristics of these patients.  These are heavily pretreated patients.  In fact, out of 52 patients that we treated at the University of Southern California we analyzed the data and anemia is a prognostic factor for survival.  So a lot of the patients come to this trial anemic.  The anemia that you see there reflects disease more than it reflects the effect of the drug.  I think the toxicity of the drug as you saw was PPE and mucositis
		In our experience grade IV neutropenia was not present in the overall experience as you saw that grade IV neutropenias are very few and far between and probably reflect a lot of prior treatment.  When you see this topopecan versus Doxil trial, then you see the events of grade IV neutropenia as few.
		The issue of GCSF is really not strictly relevant to this drug and it is not something I had to use in my experience of three consecutive trials of Doxil.
		Now, when it comes to the cardiac toxicity, I think I can expand on that a bit as well.  We have looked at 21 patients that received in our Phase I to III trials.  These are not all ovarians.  They include all diagnoses.  We've looked at 21 patients that have exceeded 500 milligrams per meter squared, 500 or greater.  
		Our of those they have received a median of 770 milligrams per meter squared of Doxil.  We have looked at the serial ejection fractions.  In fact, there were only three that have ejection fractions that dropped more than 15 percent.  Two of them had received prior free doxorubicin and one's ejection fraction was actually measured in another facility.  
		We have no incidence of congestive heart failure except that one patient that was shown in one of the slides.  One patient that received 990 plus milligrams per meter squared was a patient that had renal disease and hypertension and was on beta blockers.  Not a picture of cardiomyopathy.  She developed probably in-stage renal disease which was a complication of her preceding cisplatin therapy.
		So I think there is a misconception that patients are dropping off because of toxicity.  They are not.  They are dropping off because of progressive disease.  The patients are entered with a variety of treatments up front so they are a heterogenous group.  Some can withstand all kinds of treatment.  Others are much more frail but it is progressive disease that really leads to the drop off.
		The PPE is a problem of the first two or three cycles.  Once you make the dose adjustment, the PPE is not a cause for drop off.  In fact, it was very rare that a patient was not continued.  I can site you anecdotes of two grade III or IV toxicities that went on to receive the drug for two years.  They have PPE on the second cycle and then they went on and got two years of treatment.  
		It's a problem that probably there is a learning curve.  I think with a lot of education when one starts with 50 and then looks at the next dosing, whether it is safe to give the next dose at 50 or dose reduce I think it is something that is strictly manageable.		
		In terms of clinical benefit, I think these are difficult issues, but I can site you a number of patients where the interval to some disease related event which required treatment or surgical intervention was short.  Then they went on Doxil and stayed on Doxil for a longer period of time than the two or three events before.  There are several patients like that and to me it reflects clinical benefit.
		DR. OZOLS:  We need to clarify that about patients dropping out because of adverse events.  I mean, the sponsor just said that patients are dropping out at about a 20 percent rate because of adverse effects.  You're telling us that people weren't dropping out because of adverse effects.
		DR. CUNNINGHAM:  The overall withdrawal due to adverse events was, in fact, 11 percent and 3.5 percent was accounted for by PPE.
		Slide on, please.
		You can see from this slide here which I showed in the main presentation that is the situation.  The denominator when I was talking about patients who actually had PPE, this denominator here reflects the 396 overall ovarian patient population denominator, hence the discrepancy.  But 3.5 percent of patients out of all those ovarian patients actually withdrew as a result of PPE.
		DR. SANTANA:  Answer the equivalency question.
		DR. SCHNIPPER:  Yes.  I meant to get back to that question.  I'm going to ask Dr. Frank Martin to address that.
		DR. MARTIN:  Just to clarify, in all of the preclinical models when we talked about milligrams of doxorubicin injected, they were equivalent.  That is, doxorubicin is equivalent.  In comparison, for example, 8 milligrams per kilogram, that was an absolute number of doxorubicin administered to the animal.  Those were identical injected doses.  
		Now, if you're interested in knowing what the activity of Doxil is relative to Adriamycin, in a way to sort of define the therapeutically equivalent dose, I do have information on that in one animal model if you would like to see that.
		Slide on, please.
		This is a Lewis lung tumor model.  Again, a typical growth curve, tumor size versus time after implantation.  What we did here was we dosed the animals with the maximum tolerated dose of Adriamycin.  In other words, at any higher doses of Adriamycin these animals would experience toxicity that was unacceptable.  You can see there is activity.  Adriamycin at its MTD is better than the saline control.  
		We then took Doxil from the same administered dose, 9 milligrams per kilogram, and diluted it down, titrated it down to 5 milligrams per kilogram, and tried to arrive at the dose that showed approximate equivalence.  As you can see in this model, one milligram per kilograms of Doxil provided about as much antitumor response as 9 milligrams per kilogram of free doxorubicin.
		Now, this was not the case in all models but of all solid tumors we tested in this manner, the improvement in terms of antitumor activity ran from about 2.5 fold up to 9 fold.
		DR. DUTCHER:  I have a question.  Just in looking through some of the data, it looks to me that the median number of treatments in the Phase II studies were really two and the median duration of cycles was either two or three.  In the European study it was essentially one.  So the evaluation of disease was at four weeks, single evaluation?  Did the stable patients also come off at four weeks?
		DR. SCHNIPPER:  The evaluations were every other cycle if the patient stayed on.  For patients that had an event, they were documented at that time.  If somebody had some clinical event, they would have been documented for that clinical event.
		DR. DUTCHER:  So it does come back to Dr. Ozols' question of who shouldn't get this drug.
		DR. SCHNIPPER:  I think since we're talking a lot about clinical benefits, it is probably important to hear some more from a clinician.  I'm going to ask Dr. McGuire to make some comments on that and then we'll come back to the actual data.
		DR. MCGUIRE:  I'll try to be brief.  Having used a fair amount of this drug in my own patient population, I think a couple of points need to be made.  First, one can't really look at performance status in an ovarian cancer patient like you can in other cancer patients because often times performance status may go from 80 plus to 40 plus.  These patients, to put it mildly, go to hell in a handbag very quickly with valve obstruction, ureteral obstruction, etcetera.
		In terms of dropout rate having treated a number of patients on the trial, it's an 11 percent dropout rate and only 3 percent for PPE.  But we all know that when we have a patient on a study there are multiple factors that lead the clinician in conjunction with the patient to decide to continue the drug or not to continue the drug.  
		In a patient that has some skin toxicity, maybe even a grade II PPE who has not met the criteria of a partial response who has stable disease, the investigator may, in fact, take the patient off the study.  They can't take the patient off the study because of progressive disease because the patient has not met the criteria for progressive disease so the patient is taken off study for an adverse event. Whereas that same patient, were that patient to have a near partial or partial response, that patient would have been left on the study.  
		I do think the 11 percent is an excessive or somewhat of an overestimate of true toxicity of this drug.  I think Franco even has more experience and those of us that have used a lot of this drug know in the patient that is benefitting from the drug in terms of symptom relief, in terms of some tumor response, that the patient will, in fact, implore the doctor to continue the drug even with some skin toxicity.
		DR. DUTCHER:  Dr. Krook, you have a comment?
		DR. KROOK:  Going to the Phase II studies which you based with the refractory patients, I recall a time to progression of 15.9 weeks.  Can you give us a feeling of the overall survival of these people a la the discussion yesterday and the fact that these are people who are heavily pretreated?
		DR. SCHNIPPER:  Yes.  I can.
		DR. KROOK:  In both the responders and the nonresponders.
		DR. SCHNIPPER:  Let me start off by showing you the overall.  If I could have the slide on, please.  
		You can see here that if you look in the various populations, the overall survival -- if I could have the next slide, please -- of just the ovarian patients that were refractory.  Can I have the slide on, please?
		If you look at the refractory platinum and paclitaxel patients, you see the survival there listed as 34 weeks and the triple refractory 38 weeks.  Overall for all patients on all intent-to-treat was 38 weeks.
		DR. KROOK:  In those people who responded, in other words, the time to progression is in the responders, do we lengthen the survivorship significantly compared to the overall?
		DR. SCHNIPPER:  The answer to that is yes.  There is quite a longer time to progression in the responders compared to the nonresponders.  We obviously have statistical concerns about looking at respondents versus nonresponders.  But if you want to see that curve, we can show that to you.  
		With apologies to Dr. Simon, we can put that curve up.  If Dr. Simon would just like to turn away for a moment.  Since you asked, we'll show that curve.  This is the Kaplan Meier curve of responders versus nonresponders with apologies again to Dr. Simon.
		DR. DUTCHER:  Ms. Solonche, do you have comments or questions?
		MS. SOLONCHE:  Yes.  I do have a couple of questions and comments.  These are from the person who has survived ovarian cancer for four years.  But these comments are also from the thousands of women who have died from ovarian cancer in that four years.
		Regarding the dosing question, I know that science likes to start with the most someone can take and go downward.  But from the patient point of view in regard to this particular drug, and probably many others, has anyone considered starting at a lower dose, say 35 milligrams, making life perhaps a little easier on the patient and then increase the dose if things are going well.  Or is the concern that at that level of drug the response would be even lower than it is with the 50 or 40 milligram dose?
		DR. SCHNIPPER:  Well, you've correctly stated the problem.  But the answer to your question is, yes, we are studying lower doses.  We don't know what the efficacy is of lower doses before we recommend such a thing but we certainly are studying lower doses.
		I would like to ask Dr. Gordon to comment on that because he has a lot of experience with some of these trials.
		DR. GORDON:  We found at this dose it was generally fairly well tolerated as you've heard.  My experience with treating a lot of our patients was we began to be more adept at picking up the PPE and making adjustments when necessary.
		As you've heard, and we've seen with our patient population, too, most of the PPE if you picked it up early and could take care of it, patients did very well.  In fact, in most of our patients it was almost a difficult problem because it occurred later on in the course as a cumulative dose in patients who are responding.  
		Our patient population if we tried to dose reduce them, they were actually fairly concerned about the fact that we might be decreasing efficacy in a responding patient.  We often had to talk the patients into a dose reduction at the later cycles.
		MS. SOLONCHE:  Well, my problem with that is that, you know, you can say that, okay, only 3 percent had a PPE reaction and only 4 percent had another toxicity reaction.  If a woman is taking this treatment and she has maybe stage I reactions in five different areas rather than stage II reaction to two areas, you know, whatever combination, that woman is going to have a more difficult time.  Is there a way that you have sorted this out individually and then cumulatively to see the patient reaction?
		DR. DUTCHER:  Well, most of the studies do have dose reduction schedules for that.  I think that you can --
		MS. SOLONCHE:  Right, but --
		DR. DUTCHER:  Everyone got the first three doses.
		MS. SOLONCHE:  Right.  But if you have a mild reaction in one area and you have a mild reaction in another area, you put those all together and you feel less than good.
		DR. DUTCHER:  I don't mean to argue with you but I think many of the toxicity grades that we use in judging drugs are purely laboratory abnormalities or other things that are not likely to be associated with symptoms.  I think the safety of this drug would suggest that a patient who has four grade I's is unlikely to feel bad or to be as ill as a patient who has one grade IV.
		MS. SOLONCHE:  I don't mean to make this very personal but have you ever had chemotherapy?
		DR. DUTCHER:  No.  But these are the kinds of things that you learn to deal with as a physician.  They can certainly give you a schedule in the package insert that would tell what dose reductions might be appropriate.  As you probably know, there's a learning curve.  They have gone up and down the dose range with this drug and I think have a lot of information in well over 2,000 patients of varying illnesses who have taken this drug.
		DR. GORDON:  Most of the dose reductions that were done were done because of the patient's toxicity much more so than laboratory toxicity in the study.  The neutrophil counts was a minor issue.  It really was the PPE and stomatitis were major causes of the dose reductions.  When these interfered with the patient's capabilities to continue, then dose reductions were performed to make it easier for the patients to tolerate.
		MS. SOLONCHE:  I also want to go back to something that was mentioned yesterday ad nauseam.  The idea that time to progression is the indication that you look at, whereas from the patient perspective we are looking at survival and I don't think we have enough data on that at the moment to see this as a drug that is going to advance treatment in a great way.
		DR. SCHNIPPER:  I'd like to finish answering your other question first.  That is, in terms of the side effect profile of Doxil, I think it's important to keep in mind that these trials were started in 1994.  This represents the sum total of all our experience included our early experience.  This represents probably the worse case scenario before our learning curve.
		If you look at the incidents of some of these side effects now versus 1994 at most of the sites, and I think any one of my colleagues here would agree, it's significantly less.  
		Let me address your other concern about the time to progression versus survival as an endpoint.  I think it is important to keep in mind that we are here to talk about accelerated approval for Doxil.  Accelerated approval means that we will come back later with survival data from randomized trials.  
		In fact, we are ahead of the curve in some extent because I have already given you a peak of what is to come from the randomized Phase III trial indicating activity in that trial.  The whole idea of the accelerated approval process, at least as I understand it, is to bring drugs forward with reasonable likelihood that they would benefit patients with subsequent proof to come.
		DR. DUTCHER:  Dr. Schilsky.
		DR. SCHILSKY:  I'm curious to know, you've shown us some data on estimates of tumor bulk and responders and nonresponders.  Can you tell us how those data were derived?  How was tumor bulk estimated in the patients in this study?
		DR. SCHNIPPER:  This was a measurement on CAT scan of the total area of measurable lesions.
		DR. SCHILSKY:  And was that done by investigators at the site or was it done by the independent review panel?
		DR. SCHNIPPER:  It was done by the investigators at the sites and then reviewed by the independent panel.
		DR. SCHILSKY:  And I'll tell you in a minute why I'm pursuing this.  Do you have a sense of what the level of concordance was between the site reviews and the independent reviews?
		DR. SCHNIPPER:  Yes.  I do.  The level of concordance was quite high.  It was also interesting to note that they were responders that were picked up by the independent radiologic review that were not picked up by the investigators in both ways.
		Of the patients that were available for review -- and if I could have the slide on, please -- the level of concordance was quite high.  The overall response rate by the investigator was 21.3 percent and was 17.3 percent after independent radiologic review of available CAT scans.  We felt quite validated.  And keeping in mind that it went both ways.  We feel that the data is quite solid.
		DR. SCHILSKY:  So it would be reasonable to conclude then that an investigator at a site or the radiologist at that site would be able to estimate the tumor with a reasonable degree of accuracy within the difficulties inherent in doing that, I guess.  What I'm trying to get at is the question that Bob Ozols started the session with, which is it seems pretty clear that there is activity of this drug.  
		The question is is there any way of defining which patients are most likely to benefit from it because it does seem to have activity but it only seems to have activity in a small percentage of all of the patients who were exposed to it.  Ovarian cancer is one of the few solid tumors in which we've traditionally given some credence to the ability to estimate tumor bulk.  
		One of the things that you showed us in showing us the characteristics of responders versus nonresponders is that while there is some overlap, there were, for example, no responses in any patient who had a tumor bulk estimated greater than about 100 or 105.  
		One of the things I'm wondering about would be if it is possible to reasonably and reliably estimate tumor bulk, and recognizing this is still a small sample size, even if one, you know, sort of doubled that upper limit, could one reasonably say that a patient has a tumor bulk in excess of some number, that the probability of that patient responding would be exceptionally small and, therefore, perhaps provide some guidance to clinicians in who is most likely to benefit or who is least likely to benefit.
		DR. SCHNIPPER:  I'm going to ask Dr. McGuire to make some comments.  Before I do, I think it's clear to say that with tumor bulk as a prognosticator, that would probably be true of any drug.
		DR. WILLIAMS:  I'd like to make a comment also.  I'm a little concerned about the quality of the data for this analysis because I do know that back and forth on this issue that the number of lesions versa the number of measured lesions used for determining a response might not be the same.  It may just be just a coincidence or a random matter how many lesions were actually measured leading to what we're calling tumor bulk.  I agree that if perspectively determined it might be an interesting question.
		DR. MCGUIRE:  Well, I wish it were that simple in ovarian cancer.  I think what we all know is that what you see on the CT scan is the tip of an iceberg.  Some of these patients that have bowel dysfunction that get explored for bypass of bowel obstruction, there's almost always a lot more tumor than meets the radiologist's or the clinician's eye.
		What we really have to make judgment on is really patient symptoms.  I think that often, although we can't prove it, that the low response rate in the European study that was done was maybe due to the fact that in contradistinction to this country, often time treatment is withheld until the patient actually has significantly symptomatic recurrence of ovarian cancer.
		Often times, as I've already alluded to, these patients bowel obstruct fairly quickly.  This is not a drug that works in one week or two weeks.  If you wait too long to initiate therapy, I agree with you that you are less likely to respond.  I'm not sure that one can prospectively pick up that patient population based on sum of lesions.
		For example, a patient may, in fact, have a huge pelvic mass that meets the criteria of greater than 100 square centimeters and be asymptomatic from it and would take that patient unperturbed weeks to months to actually develop a bowel obstruction.  
		There may also be a similar patient you has eight or 10 one centimeter lesions that are conveniently placed in cirrhosal surfaces on the small bowel that is under 100 centimeters and that patient may bowel obstruct within one month of that first evidence of CT progression.  
		I think it would be nice, but I think it's true with all of the second-line and third-line drugs that we use whether it's topotecan, or I guess I should have mentioned other drugs since they are not FDA approved but which we clinicians use.  It will is hunt and peck on the typewriter in terms of taking a patient.  
		The only ones we tend not to use are oral agents and patients that have significant bowel dysfunction because of concern that they are not getting the drug into the systemic circuit.  I don't know but Maurie has a lot of experience and may also want to add to that.
		DR. MARKMAN:  Thank you.  I really feel that it's important to comment on a very important issue in the clinical trials arena.  That's not the discussion today but one of the problems is there's a serious dislink between how we objectively measure response from something that we can measure on a CT scan, particularly in ovarian cancer.  
		I would agree with Bill that this is a very difficult disease to do that because of the abdominal cavity.  That population that we can actually enter in one of these trials may very well be the population we cannot ask the question that Bob asked which is clinical benefit.
		Just because that patient has that mass that we can measure, they may not have any symptoms.  I would submit we are actually looking at a very small part of the population when we do the typical clinical trials we do for drug approval.  
		A typical patient with ovarian cancer we see later in their course is that patient who has a variety of vague but important symptoms, clearly has disease, has an elevated CA-125, that's a patient you would like to measure clinical benefit but would never be on one of these trials because they don't have that measurable disease category or they don't meet some of the other criteria because they've had too much therapy.
		That is really where you can get at this true question of clinical benefit which I agree 100 percent with Bob is the question we want in which the cancer patient population wants to know about.
		I personally believe we should expand the trials and include that population but that's not the population you are discussing today.  It's hard to say where is the evidence of clinical benefit when, in fact, the people you put on the trial were just there because they happened to have measurable disease.
		I'll go further than that to say that I think that's a very important population than what I'm talking about.  I have actually used this drug in that population in my own trials that would never meet the criteria of the FDA because they are based on other criteria.  It is an active drug that does have patient benefit associated with it.  Patients do feel better and it's a tolerable drug.
		But I think it's very hard when you ask that question in a population of patients on these trials that very well don't have those kinds of symptoms where you can really directly address the question because that's not the question.  It's you got a mass and does it shrink.  I think it's very hard to put those two together and it's, therefore, very, very difficult to ask that question of clinical benefit in this setting unless you go beyond the trials that are designed the way they are.
		DR. DUTCHER:  Dr. Simon.
		DR. SIMON:  I mean, I think that's right but I think sort of the presentation has it exactly wrong then because the FDA is not biased to wanting measurable disease.  The FDA wants to see clinical benefit.  We haven't really had any presentation of any kind of clinical benefit.  There's been no evidence of symptom relief.  It's hard to see how the 15 percent response rate translates into changing the course of disease in any of these patients.  
		I guess my specific question is we're being asked for a recommendation with regard to accelerated approval which I guess the basis -- that is, do we believe this 15 percent response rate is a reasonable basis for expecting that will translate into clinical benefit on other trials that the sponsor will do.
		I personally question whether a 15 percent response rate is likely to translate into a survival benefit.  What trials is the sponsor going to do if they are granted accelerated approval?  What trials are in process that will demonstrate clinical benefit and what will be the logic?
		If you're talking about your current randomized trial against topotecan, I can see two problems with that.  One is you are probably only going to have 80 patients who are doubly resistant to platinum and, I guess, taxel.  That's going to be a fairly limited number.  
		Secondly, what is the logic going to be?  Are you going to show better survival than topotecan?  If you show equivalent survival to topotecan, are we then supposed to believe that topotecan has a survival benefit in that set of patients?  What are the trials that you are going to do and what is the logic that you are going to demonstrate clinical benefit?
		DR. SCHNIPPER:  I'd just like to make a few comments and then I'll ask Dr. Cunningham to make some additional comments.  
		The first comment, of course, is that these trials were discussed with the agency obviously before I initiated them so there was some concurrence there about measures.
		Secondly, the number of patients on the total population that are refractory in the Phase III trial would probably be more like double or a little bit more than what you've seen there because this is only half of the population that has been accrued so it would be a much larger group.
		DR. SIMON:  I meant 80 per arm which is double what you have now which would still probably not be sufficient.
		DR. SCHNIPPER:  And, of course, there are additional measures in those trials that were pilot in Phase II but not reported on because they were just pilot in terms of quality of life measures, etcetera, that are built into the Phase III trials that were not built into the Phase II trials.
		DR. WILLIAMS:  I'd like to also comment, Dr. Simon, that we certainly had at times entertained the Phase IV trial being in a setting similar to but not identical to the setting for the accelerated approval.  It's quite possible we would consider a significant clinical benefit in the setting of second-line.  We might consider that to be adequate for meeting the purposes of fulfilling the Phase IV requirement for this indication.
		DR. SIMON:  What would have to be shown in second-line?
		DR. WILLIAMS:  Basically clinical benefit by whatever means the sponsor fulfills that requirement.  Certainly survival.  But I --
		DR. SIMON:  Superior to topotecan or equivalent to topotecan?
		DR. WILLIAMS:  I'm not talking a specific trial at this point in time.  If one could show equivalents to topotecan for clinical benefit and show that the increment of clinical benefit had not been lost in that equivalence comparison, that would be theoretically possible.  But certainly superiority would be a much more practical consideration.
		DR. CUNNINGHAM:  If I may just give you some details on the current study.  It's a 460 patient study in over 100 centers.  The study stratifies for refractory patients versus nonrefractory patients.  The primary endpoint is tied to progression.  Of course, we also monitor response rate and survival.  
		The study has, as I said, been completed but we are now going through the process of analysis and that will be sometime before that full analysis has taken place.  We estimate that the number of refractory patients should approximate half the patient population.
		DR. DUTCHER:  One left.
		DR. OZOLS:  Maybe during a break you can come up with this number, but I still think it's important to know again who we can use in what objective manner and one is how patients have responded.  I think you talk about a 10 percent response rate of patients who had progressed their disease while on treatment.  I suspect most of those patients are patients who progressed on second-line treatment.
		The real question then is how many patients who never responded to any other treatment responded to this?  Do you have patients who have -- you know, if I give a patient taxel-carbo and they progress, what is the response rate in that group?  If I give them taxel-carbo and they progress, they get topopecan and progress.  I suspect it's less than 10 percent.  Are there any responses in patients who never respond to anything else?
		DR. SCHNIPPER:  I don't have that information.  I'll try to get that for you.
		DR. DUTCHER:  Thank you.  I think we better take a break.  Come back at 10:05.
		(Whereupon, at 9:44 a.m. a recess until 10:06 a.m.)
		DR. DUTCHER:  We're going to proceed with the FDA presentation.  Dr. Frykman.
		DR. FRYKMAN:  Dr. Dutcher, members of the committee, FDA colleagues, ladies and gentlemen, it is my pleasure on behalf of the FDA to present the agency's highlights of the review of SNDA 50-718.  Like any worthwhile undertaking, there are a number of talented individuals whose talents combined to produce a very good review.  
		Two people I would like to acknowledge in particular are Grant Williams for his leadership and Alvis Dunson.  I think the company would join me in acknowledging Alvis' effort in keeping the entire review project coordinated.
		The specific proposed indication, as you've heard, is that Doxil is indicated for the treatment of patients with metastatic carcinoma of the ovary who are refractory to both paclitaxel- and platinum-based chemotherapy regiments and who may also be refractory to topotecan.  
		In this case, refractory is defined as patients having progressive disease while on treatment or within six months of completing treatment with the two above regimens.  The agency has determined that the text in brackets is probably -- the number of patients to base that indication on is probably too small and, therefore, will not be further considered.
		Under the federal regulations outlining the accelerated rate approval mechanism, there are two requirements that must be met.  The first, that treatment provides benefit over "available therapies."
		The exact definition for this application is that there are either drugs labeled for or with a large body of literature supportive of efficacy for ovarian cancer refractory to platinum and paclitaxel.  In this case the FDA has determined that there are no available therapies.  Further information about this will be forthcoming in a guidance document soon.
		The second requirement is that approval be based upon a surrogate endpoint that is reasonably likely to predict clinical benefit.  In this case, that surrogate would be objective tumor response.  Therefore, the committee has quickly come to the conclusion that the question that is going to be asked is whether the data presented by both the sponsor and the agency on objective response indicate that Doxil is reasonably likely to be associated with clinical benefit in this population.
		In order to begin to answer that question, from the agency's perspective let me just briefly outline again the four trials that you've heard already presented from the sponsor.  Three of the four studies were Phase II, the single Phase III study, and the last in chronological order, the last Phase II study are currently close to accrual but are still maturing the data.  
		The schedules that were used in the four trials were different.  Three of the trials, the last three, had a four-week schedule.  The first trial was an every three-week schedule.
		Two of the studies were completed completely in the United States.  One is being done both in the United States and Europe.  The single study that we've heard about, study 47E, is being conducted and was conducted solely in Europe.
		To begin with, the efficacy review.  I won't point out too much on this slide except for the fact that this was the every three-week schedule.  A total of 35 patients were accrued to this study and the population targeted for enrollment was platinum and paclitaxel failures.
		The agency's methodology in review was to use the primary electronic data presented by the sponsor.  In this case each patient's case was reviewed to determine its platinum and paclitaxel refractiveness.  Of the 35 patients enrolled, 27 were found to meet the above criteria.
		The serial tumor measurements then that were listed for each patient were reviewed looking for confirmed responses.  That is, responses that were noted to have occurred at a time point and then four weeks later.  Of those, six of the 27 patients were found to be meeting the criteria for a response rate of 22 percent.  The confidence intervals shown here range from 9 percent to 42 percent at the upper 95 percent bound.
		The next study, 30-47, again you've already heard about that so I'll make these comments brief.  This was on a four-week schedule.  A total of 89 patients were enrolled into the study and of those 89 82 were found to be both platinum and paclitaxel refractory.
		The serial tumor measurements were again reviewed as in the prior study.  Of those 82 patients that were platinum and paclitaxel refractory, 14 were found to have been meeting the criteria for response for a response rate of 17.1 percent, 95 percent CI ranging from 10 to approximately 27 percent.
		The third study that was reviewed only in brief by the agency was that of 30-47E.  The study was conducted only in Europe.  Again, it was a Phase II single arm open label study.  The schedule used was every four weeks for six cycles.  At the time of data submission 52 patients had been enrolled into the trial.  Of the 52 patients that had been enrolled, the sponsor determined that 36 of the 52 had met the criteria for platinum and paclitaxel resistance.
		The FDA accepted the sponsor's results without detailed review stating that zero of 36 patients were responding to Doxil under the schedule.  95 percent CI ranges from zero percent to 10 percent in this viewgraph.
		The last study I would like to review is study 30-49.  This was their only Phase III randomized trial.  The study population was slightly different as opposed to the Phase II trials in that it was just platinum based chemotherapy for which the patients had to be refractory to.  Targeted therapy was for one year and the primary endpoints were timed to progression and response rate.
		At the time of data submission or at time of data cutoff for submission of this application, 241 patients had been enrolled of which 237 had actually received treatment.  This was perfectly balanced between the two arms.  Of the 237 patients receiving treatment, 81 or approximately 1/3 were found to be both platinum and paclitaxel resistant.
		Of those 81 patients 44 were in the Doxil arm and 37 in the topotecan arm.  Of the 37 in the topotecan arm, three responded for a response rate of 8.1 percent.  In the Doxil arm of the 44 patients refractory to both drugs, six responded for a response rate of 13.6 percent.  
		In this case we have chosen just the Doxil arm as this was not intended to be a comparative study at the time of interim analysis.  The 95 percent CI ranges from approximately 5 to 27 percent.
		Combining then all of the Phase II studies plus the Doxil arm of the Phase III study, we derived a response rate of 13.8 percent with 95 percent CI ranging from 9.2 percent to 19 percent for Doxil.
		In terms of the safety review, this slide and those following it will focus on the organ system that was affected by Doxil therapy.  In this case the manifestations of the cutaneous toxicity of Doxil are grouped cutaneously.  
		Specifically you've heard previously about the Palmar-plantar erythrodysthesia that under the three week schedule was in excess of 80 percent.  That had been reduced down to approximately 40 percent in the three four-week schedules; that is, 30-47, 30-47E, and 30-49 Doxil arm.  Other manifestations of the cutaneous effects of Doxil include rash, exfoliative dermatitis, vesiculobullous rash.  
		This graph shows essentially the same data but for the mucous membranes manifesting itself as mucositis and stomatitis.  Asthenia didn't fit well into any of the categories.
		The third grouping of toxicities was that of mild suppression.  Neutropenia was found to be present in approximately 50 percent of incidents in the three week schedule that had been reduced somewhat down to 37 percent in the four week schedule.  The same for leukopenia, anemia, and thrombocytopenia.
		In study 30-47 there were patients that required both red cell and platelet transfusions, although there were no significant hemorrhagic consequences of the thrombocytopenia.
		Lastly, this graph illustrates the gastrointestinal adverse effects of Doxil; nausea, vomiting, anorexia, and diarrhea.  The sponsor states in their study report that with current 5HT3 antagonism that nausea and vomiting should be completely medicable.
		This last graph demonstrates the adverse events under the four-week schedule using study 30-47 that was reviewed carefully by the Food and Drug Administration.  In this instance, the six most common adverse effects which corresponds to that in the questions to the committee are Palmar-plantar erythrodysthesia, astenia, anemia, nausea, neutropenia, and stomatitis.
		In blue is shown the relative frequency of each of these adverse events.  In red is the frequency of serious adverse events.  Serious adverse events in this case were defined as grade IV hematologic toxicity and grade III and IV nonhemotologic toxicity.
		Note that the serious incidents of PPE is significantly less, although it is still approximately 20 percent and can be anticipated to be so under the proposed schedule.
		In terms of summary, the sponsor has submitted three Phase II trials, one Phase III trial.  The one Phase III trial has again close to accrual but is still maturing.  In one of the Phase II trials they are still maturing as well.  A 13.8 percent response rate was determined by the agency combining the Doxil arms of the four submitted studies.  There was one Phase II trial that revealed no responses.
		In terms of the safety summary, clearly the four-week schedule is less toxic than the three week schedule.  The adverse events can be grouped in terms of cutaneous and mucocutaneous events, hemocological, and gastrointestinal toxicities.  Asthenia was frequent as well.  Some of these adverse advents, while not necessarily highly frequent, are quite serious. 
		So we return then to the question that we started with.  Does the committee feel that the objective response determined from these trials indicate that Doxil is reasonably lucky to be associated with clinical benefit in this population.
		DR. DUTCHER:  Are there questions from the committee?  Dr. Ozols.
		DR. OZOLS:  On your review of the response and efficacy, do you have any impression or analysis of who you think may benefit and who we should or shouldn't treat?
		DR. FRYKMAN:  Yes.  We had done a significantly expanded analysis over that of the sponsor.  It is clear that there are anecdotes of patients that actually have large bulk disease.  Again, these are spotty anecdotes where there was actually a significant response seen.  Not necessarily a CR but an occasional PR were noted.
		Otherwise, it appears from what the sponsor presented and in the briefing document that, again, patients with apparently more aggressive disease, i.e., younger, perhaps those with a higher CA-125, were associated with a poor response rate.
		Perhaps in terms of advanced histologic rate or more poorly differentiated histologic rate, tumor bulk, perhaps younger age, and perhaps even a significant degree of prior treatment, I would think those factors would be taken into consideration.  But the strength of the association I would not be able to comment on.
		DR. OZOLS:  The other question is, you know, the years -- I mean, I certainly haven't seen many presentations here where you had clinical trials presented by a sponsor which from different groups or different agents or different parts of the country or the world which I'm sure has different results.  
		I'm still concerned that we've got one large trial from Europe which is failing to show any possible reasonable clinical benefit when they have zero out of 36 and they are still going on with more patients.  Do you have any sense of -- two things.  Have you ever seen this kind of thing before or do you have any sense why this particular study is negative?
		DR. FRYKMAN:  As far as experience goes, my experience is quite limited.  I probably wouldn't be able to comment too intelligently on that.  I would make somewhat of a statistical comment.  I'm sure Dr. Simon will have more to say than I.  
		If you look at the 95 percent confidence interval, and if you assume it to be the fact that if this trial were repeated 100 times, 95 percent of the time the results would be within that 95 percent CI, that in fact, albeit unusual, the response rate noted in study 30-47E which was zero, although the CI ranged from zero to 9.7, in study 47, which ranged from something like 30 percent down to 9.7, that those 97 percent CI's actually do overlap.  While it would be an unusual occurrence, within our understanding of statistics, it is actually a possibility.  That is, they do return something close to the same response rate.
		DR. DUTCHER:  Dr. Margolin.
		DR. MARGOLIN:  Given the bias issues that we discussed yesterday and the well recognized difficulty of measuring ovarian cancer, are you quite confident that in terms of the actual data everything is clean and the responses were real responses and there were no issues there?
		DR. FRYKMAN:  Yes.  Well, here's how I can answer this question.  We were not presented with the primary radiographic data so we relied on the sponsors primary electronic data of tumor measurement dimensions.  That is, there may have been one, two, or three lesions each with these dimensions and from that table we could confirm the responses that we showed up here.
		The translation going from the radiographic data to the autronic data, there is always some question about it.  Now, to the sponsor's credit they also underwent an independent radiological review.  For the most part those were confirmed.  Not in every case but for the most part those were confirmed.  That gave us actually reasonably good confidence that an independent body of a radiologist and a gynecological oncologist actually did come to quite close conclusions.
		DR. DUTCHER:  Dr. Nerenstone.
		DR. NERENSTONE:  I just had a question about the first study.  Only three cycles were to be given and that would be even with delays 12 weeks.  The median time to response was really in most of the groups beyond that.  Were there people who were stable at the end of those three weeks who then went on to respond and were they counted in the numerator of responses or was it only at the time after those three cycles that you got the responses?
		DR. FRYKMAN:  During the review of both 30-22 and 30-47 the response was counted at the time the response occurred.  If it was confirmed, then we had data within four weeks or so.  
		If a response occurred and we didn't see a subsequent response or the response maintained and we didn't count that, what I can say is in the cases of a response in 30-22 even thought the duration of therapy was relatively short compared to the other studies, if a response was confirmed within the time period that the data was sent to us by the company, then that was counted.
		DR. DUTCHER:  Dr. Schilsky.
		DR. SCHILSKY:  Greg, I wanted to just come back to a question that I think Bob Ozols raised earlier.  I'm still a little bit confused in terms of how the definition of refractoriness was applied.  There was a grand total of 26 responders across all of these studies.  I guess the question would be of those 26 individuals who responded, do you have a sense of how many of them had been shown to be refractory to a platinum paclitaxel combination as opposed to be refractory to a platinum-based regimen followed by a paclitaxel-based regimen?
		DR. FRYKMAN:  Yes.  So in studies 30-22 the eligibility criteria for the refractoriness was exactly as suggested.  In other words, they could be in sequence or together.  When the study was done, paclitaxel was not on the market yet and so this came on subsequently.
		In terms of 30-47 I believe that also had the same criteria although you could see the change in the standard of care over the time period of study 30-22 to 30-47.  In fact, this is speaking off the top of my head, I would say the majority of the responses or of the patients that were considered eligible in 30-47 had actually been concomitantly treated with both paclitaxel and either carbo or cisplatin.  
		Not necessarily six cycles in a row but these patients may have been treated with platinum up front and then got hexomethomellomin and then gotten something else, PP16, they still recurred, and then they got combination platinum and paclitaxel.
		DR. SCHILSKY:  What I'm trying to get at is, you know, if this drug is on the market and with contemporary management of ovarian cancer usually beginning with a platinum paclitaxel combination, for women whose disease is clearly refractory to that combination.  What is the likelihood that if those women were treated with Doxil that they would respond?  Is there any way we have of estimating that?
		DR. OZOLS:  That's what I asked them, to see if they could get that information; did you ever have a response to somebody who did not respond to something else in the past.
		DR. SCHNIPPER:  I can show you if you would like.
		DR. DUTCHER:  Go ahead.
		DR. SCHNIPPER:  If I could have the slide on, please.  As was correctly stated, in 30-22 many of the patients were treated in sequence because of the treatment guidelines at that time.  By the time the trials evolved, most of the patients were, in fact, treated with platinum and paclitaxel in combination.  Of the 146 patients on the overall refractory database, 115 were treated in combination of which 19 responded.  
		The response rate in patients who received platinum and paclitaxel in combination was 16.5 percent compared to its sequential, keeping in mind that the sequential population may have had up to five regimens prior to having Doxil.
		DR. OZOLS:  Right, but those who received the combination could have responded initially then progressed and then gotten Doxil.  The question is those who received the combination up front and did not respond.
		DR. SCHNIPPER:  We were looking at that over the break and there were at least four patients of the responders who had primary refractoriness to their initial combination.
		DR. OZOLS:  Okay.
		DR. DUTCHER:  Other questions for FDA?  Dr. Santana.
		DR. SANTANA:  When you reviewed the data set, did you get an idea of these patients that developed PPE how severe this was in relation to having to add concomitant meds to control the symptoms?
		DR. FRYKMAN:  Um, yeah.  The study 30-47 again should be reviewed in detail.  Also included with it is a health care quality of life questionnaire which was piloted by the company and was not intended for efficacy or safety purposes.  In fact, it was quite illustrative.  During the review of the case report forms, this data had not necessarily made it into an easily readable form in the electronic data so, in fact, I had the luxury of having each CRF and could go through and look at both what the patient should do as well as what the patient's own feeling about her disease was at the time of being seen.  Some of these patients were being seen every four weeks and we had health care quality of life data on them.
		To a certain extent ut was like actually having the patient in the examining room where you could ask them questions.  "How are you feeling?  How are you walking around?"  Sort of what's up.  The dose reductions that were carried out by the physician clearly correlated with the woman saying, "Gee, it hurts a lot to walk on my feet.  They are blistered."  Or, "Gee, I'm feeling fine.  I'm on my night cycle of Doxil and I have very few complaints."
		I would say that actually the health care quality of life was very illustrative for me and for probably other people that have looked at the data.  We didn't do any statistical correlations but it was clearly correlated.
		DR. SANTANA:  My question was more simple.  How many of these patients required aggressive narcotics use, aggressive analgesic use, etcetera?
		DR. FRYKMAN:  I can't tell you that specifically with respect to PPE.  We did obviously have all the concomitant medications.  It would have required us to correlate each date of the medication given with what was the symptom at the time.
		The first attempt was to obviously delay therapy.  If that wasn't helpful, then the patients had their dose of Doxil reduced.  To what extent they got concomitant medications for the PPE, I guess, I wouldn't be able to comment on direction.
		DR. DUTCHER:  Does the sponsor have any information on that?
		DR. GORDON:  I can't give you exact numbers in terms of --
		DR. DUTCHER:  Would you state your name?
		DR. GORDON:  I'm sorry.  I'm Alan Gordon with the Sammons Cancer Center.  We treated a vast majority of the patients on the 47 trial and for the most part most of the patients required no concomitant medication.  It was just a matter of watchful waiting and it would gradually resolve.  There were occasional instances of maybe some mild analgesics being administered but never any narcotics were required.
		DR. DUTCHER:  What was the time table for the resolution of the symptoms?  How long did you wait between cycles?
		DR. GORDON:  Most of the waits were at most a one-week delay.  There was a rare patient that may have gone beyond one week.  I can't recall anybody specifically going beyond a one-week delay in recovery.
		DR. DUTCHER:  Any other questions for FDA?  Thank you very much.  Before we go onto the discussion we do have one person for the open public hearing.  Is Susie Bendel here?  Just state your name and your affiliation and whether there is any financial support for your appearance.
		MS. BENDEL:  My name is Susie Bendel.  I work for a private physician at the Washington Clinic.  I have no financial to ALZA or anybody else.
		I originally started with Doxil on the breast study.  It was a taxene resistant study.  We used a smaller 30 milligram per meter squared dose.  Our side effects -- what I really want to point out to the FDA that the side effects are really manageable as long as the nurses and the physicians are aware of them.
		As far as the infusion reactions, those are very well managed by stopping the infusion and rechallenging.  There's not a problem with that.  The patients usually become very flushed first so you immediately can stop it before shortness of breath or the patient becomes anxious.
		I'm sure the reason some of the patients went off trial is because they got the shortness of breath and they didn't want any further treatments.  If you see the redness in the flushing of the face, you know automatically to stop the treatment and just flush and then rechallenge them and they do find.
		As far as the Palmar-planter, we had only one and that was after the patient had received almost 12 months of treatment.  As I said, that was at 30 milligrams per meter squared.  It was very mild.  It was in the winter time actually and the patient had gone outside without wearing gloves and she did get very cold.  We encourage our patients to avoid any frictions and things like that and to avoid hot or cold.
		If the patients are acknowledged and the staff is acknowledged, there shouldn't be a problem with any of the reactions you guys have discussed today.
		DR. DUTCHER:  Thank you.
		MS. BENDEL:  Thank you.
		DR. DUTCHER:  Any initial discussion?
		DR. SLEDGE:  Actually, could I ask a question of Bob?  If we compared Doxil to doxorubicin in this setting, what would you expect to see with doxorubicin in a refractory setting like this?
		DR. OZOLS:  Baseline of probably just essentially noise.  I don't think you would see any activity.  You would probably see an occasional response, I think.  We did some studies years ago with doxorubicin as a second-line treatment in just melphalan resistant patients and we saw no responses. 
		There have been several other studies which have shown some responses but there have been no studies.  This was before the day of taxene so we have no data at all about Adriamycin and taxene in refractory patients.  I suspect it would be very, very low.
		DR. SLEDGE:  At least from a response standpoint this sounds like --
		DR. OZOLS:  This sounds higher than I certainly would have expected to see with doxorubicin.
		DR. DUTCHER:  Okay.  Can we turn to the questions.  This application seeks accelerated approval of Doxil for the following indication.  The treatment of patients with metastatic carcinoma of the ovary who are refractory to both paclitaxel- and platinum-based chemotherapy regimens.  Refractory is defined as a patient having progressive disease while on treatment or within six months of completing treatment.
		Under accelerated approval regulations for indications where the new drug appears to provide benefit over available therapies, accelerated approval may be granted on the basis of a surrogate endpoint that is reasonably likely to predict clinical benefit.
		After approval the sponsor is required to perform a Phase IV study to demonstrate the treatment with the drug is indeed associated with clinical benefit.  
		For this application the surrogate endpoint is objective response rate.  The agency has determined that from a regulatory standpoint there is no available therapy for the proposed indication.  
		The central question before ODAC is whether the findings presented in this application are reasonably likely to predict clinical benefit.  The FDA analyses of response rates from three Phase II trials and the interim findings from the Phase III trial are presented in the table.  The summary is as presented by Dr. Frykman of 13.8 percent response rate.
		Dr. Schilsky.
		DR. SCHILSKY:  A question to the FDA.  Do you want us to answer this question independent of whether there are any ongoing or planned trials that might be appropriate to provide the confirmatory data?
		DR. WILLIAMS:  Yes.  We would certainly be open to your guidance if you were to decide to approve this on the basis of accelerated approval.  Guidance on what sort of follow-up trial would be needed.  That would be a good question to answer.  Does that answer your question?
		DR. SCHILSKY:  Yes.  It's not clear that the Phase III trial that's recently completed accrual would be able to provide the confirmatory data for full approval.  I want to be sure that if we answer this question in the affirmative, that it will be clear that there will need to be additional studies beyond the Phase III trial that are appropriately designed to provide the confirmatory endpoint.
		DR. WILLIAMS:  It is certainly our responsibility to make sure before an approval that such a trial is planned and committed to and we would welcome your input on what sort of trial would be necessary.
		DR. OZOLS:  I mean, the problem with this question about available treatments and what is community practice, I think what we would really like to see whether there is a clinical benefit of this agent.  In the real world there are many other drugs that are being used.  I mean, the FDA decided that available is indicative of FDA approval but that is certainly not what's out there and what people use.  Drugs like gypcytamene BP16 and even taxene.  A lot of people are using drugs that do have some activity in this disease.
		In one sense the real measure would be to see what Doxil does against the community standard and that would be Doxil versus you decide.  You pick.  I don't know if the agency would like that kind of a trial or would accept that kind of a trial but that's the real world.
		DR. WILLIAMS:  I feel sure we would accept that sort of a trial.  There was a great deal of debate on this particular application within the agency about the meaning of available therapy, whether it should be just anything in the literature or should just be what's in the label.  I think we came to sort of a compromise that will be published in the form of a guidance soon.  In general it's what's in the label unless there is basically a great deal of data supporting efficacy in the literature.
		I think one of the reasons is I believe if you look in the literature, you will see response rates.  I don't believe that this 13.8 percent response rate would be in the literature as a 13.8 percent response rate.  You would never see the trial with the zero percent response rate and the others would be inflated relative to what we see.  There is some lack of fairness to say here is the FDA response rate versus what's in the literature.  I think that is some of the thinking behind.
		The other point is that we would like to encourage drug companies to update their label so that we have a real effective label that does include all the indications that should be in it.  If the drug companies have no incentive for updating their label, then they may not.  That's the thinking behind our stance.  We're not asking you to make a comparison to what's out there.  We're asking you to say is there or is there not reasonable likelihood that this response rate represents clinical benefit.
		DR. DUTCHER:  Dr. Nerenstone.
		DR. NERENSTONE:  I think that the sponsor has to be commended for looking at this patient population which notoriously has been under represented in clinical trials in terms of drug development.  I think that, you know, we look at this 13 percent response rate and sort of shutter and say it's very low but they have carefully defined the population that they are looking at.  I think that for that carefully defined population, a 13 percent response rate is meaningful.
		In terms of clinical benefit, I mean, I think we would all like to have heard more that patients who were enrolled on study and who got a response did have some meaningful changes in their life in terms of benefit of the drug.  As Dr. Markman pointed out, those are often not the patients who can be put on these kinds of studies.
		Anecdotally he says that he has some patients.  Quite honestly as a community oncologist I also have had a patient who has responded significantly to this medication.  I do think in the patient population we're looking at there is going to be clinical benefit.
		I am still concerned about the toxicity and about the learning curve which the sponsor has admitted there is in terms of treatment using this drug.  I am concerned because most clinical oncologists or Gyn oncologists are not going to have 20 patients to learn on.  You want that first and second patient as well cared for as the number 20th.  I'm still very concerned about their doses.  50 per meter squared is probably fine to start with.  I'm concerned that 50 per meter squared four weeks later is not too high.
		DR. DUTCHER:  Dr. Ozols.
		DR. OZOLS:  Yes.  I mean, there are a lot of issues about clinical benefit.  I'm not going to rehash those.  I would feel much more comfortable about voting yes on the first one if I didn't have that European trial.  Rich Simon did some back of the napkin here calculations.  There is something worrisome about that trial of zero to 36 responses.  That would not have been expected with a response rate of 15 percent by any stretch of the imagination.
		Plus, if that does represent a worse group of patients we've seen, and it's quite common that the drug gets out into the community, that the response rate may drop because we will be treating more and more patients who are sick or have more disease.
		The true benefit needs to be studied and it needs to be addressed in a post-marketing very carefully designed study for symptomatic improvement as well.  I think it should be approved at this point or accelerated but I would feel a lot more comfortable and I would be doing it with less trepidation if we didn't have that European trial.
		DR. DUTCHER:  Dr. Margolin.  
		DR. MARGOLIN:  I was just going to say hopefully that what we would see would be perhaps a little bit of the opposite which is if an attempt can be made to study the drug in patients who have less volume of disease, the nonmeasurable patients with a carefully designed trial, we may actually see greater benefit than what we're seeing now.
		DR. DUTCHER:  Any other comments?  All right.  So question No. 1:  Do the data on objective response indicate that Doxil is reasonably likely to be associated with clinical benefit in this population?  All those who would vote yes?  One, two, three, four, five, six, seven, eight, nine yes.
		All those who would vote no?  Two.  You want to make a comment?
		DR. SIMON:  I think there was no symptomatology data presented.  I think a 15 percent response rate at that stage of disease, unless there was symptomatology data, I don't think it's likely to be associated with a survival benefit.
		DR. DUTCHER:  More toxicity was noted with every three-week schedule and with every four-week schedule.  Consequently, only the latter schedule is proposed for approval.  Toxicity attributed to Doxil in study 30-47, the largest study where Doxil was given by the every four-week schedule is outlined in the following table from the application.  
		Considering the efficacy discussed in question No. 1 and the toxicity described above, do you recommend that Doxil 50 milligrams per meter squared administered intravenously every four weeks be granted accelerated approval for the treatment of patients with metastatic carcinoma of the ovary who are refractory to both paclitaxel- and platinum-based chemotherapy regimens?
		Any more discussion about dose?  Dr. Nerenstone.
		DR. NERENSTONE:  What kind of package insert can the FDA recommend in terms of the PPE toxicity in dose reductions for those physicians who are not savvy?
		DR. WILLIAMS:  I take it that you want us to be as careful as possible on the package insert.  We will do that.  It would be nice to be able to say, well, start at 40 and go up.  I think we would have a hard time doing that without at least some data with efficacy by that method.  We will be very attentive to maximum precautions on the label.
		DR. DUTCHER:  Do the current guidelines, the current package insert, do you have any feel for 
-- it's a much lower dose so this part of it is not in there.  What about infusion reaction that was described that isn't even in the list here?
		DR. WILLIAMS:  We haven't attended too carefully to the labeling.  We generally wait to see if we need to.  We certainly will and we will take all of your comments into consideration.
		DR. DUTCHER:  Yes.
		DR. OZOLS:  Have you started discussions about what will be the appropriate post-marketing trial for looking at clinical benefit?  I think this is an opportunity to try to design something that really looks again, as we talked yesterday, about trying to get a better idea what clinical benefit is all about.  
		I think it's going to be difficult in this disease with all the problems that we've talked about to really show clinical benefit.  That doesn't mean we shouldn't try and I think it's going to be somewhat of a difficult study just comparing it against topotecan.  I'm not sure that will establish clinical benefit.
		DR. WILLIAMS:  You haven't voted yet on whether to approve it but if you do, I would suggest you follow it with a discussion of the trial design recommendation.
		DR. DUTCHER:  All right.  So we'll finish.  We'll go through the votes and then we'll have a discussion because I think that clearly there is a certain level of trepidation.  Although people have some comfort that there is some benefit here, I think they really want to see some more documentation of such.  
		We'll vote on question No. 2.  Should Doxil be granted accelerated approval for treatment of metastatic carcinoma of the ovary refractory to both paclitaxel- and platinum-based chemotherapy regimens.  All those who would vote yes?  One, two, three, four, five, six, seven, eight, nine yes.  All those who would vote no?  Two.
		All right.  For the reasons stated -- and we appreciate the honesty of our committee in terms of their votes -- what would clinicians, investigators, patients feel is sufficient evidence for clinical benefit in either refractory ovarian or perhaps a slightly less refractory group of patients?  What do you want to see?  Dr. Ozols.
		DR. OZOLS:  Well, there is no question we would like to see some impact on survival but with the response rates that we're seeing in second-line treatment, it's unlikely that we're going to see any major impact on survival, particularly when all we're seeing is partial responses.  Again, that's not indictment against Doxil.  That's just indictment against the drugs that we do have available in that situation.  We just don't see enough good responses and complete responses to second-line treatment.
		Survival is something that we all aim for but the only chance we're really going to have an impact on survival is realistically what we do up front with out initial chemotherapy.  I think Doxil needs to be tested up front but that's separate from the indication that we're looking at.
		I think the major impact we'll be looking at of a drug like this is really in the second-line situation the realistic benefit would be symptom control and improvement of symptoms, improvement of quality of life for all the reasons we're talked about in the past though they are more difficult but I think they need to be done.  
		I think a comparison of Doxil versus best available treatment with regard to including symptomatic patients would be the way to go and then give a good quality of life as best that we can and see if they are the real clinical benefit for that group of patients.
		DR. DUTCHER:  Can you get at that if you took patients with only one prior therapy?  One prior taxel-carbo regimen or paclitaxel platinum regimen?
		DR. OZOLS:  I'm not sure I'd worry so much about how much prior treatment they had.  I think I would really worry about the fact that they had measurable and primarily symptomatic disease and see if they got better.
		DR. DUTCHER:  Dr. Williams.
		DR. WILLIAMS:  There was some comment about a lot of patients not being included because of the lack of measurable disease.  Do you think there's a role for patients who are symptomatic and have elevated CA-125 and then have response of both of those?  We've not accepted CA-125 alone at this point but that have simultaneous, a considerable CA-125 decrease plus a decrease in their symptoms. 
		DR. OZOLS:  I think there is enough literature data to support the use of that group of patients for exactly that kind of a trial.
		DR. DUTCHER:  Dr. Margolin.
		DR. MARGOLIN:  Well, I think we also -- I'm not nearly as much the expert in ovarian cancer that Dr. Ozols is but I think that there's a great problem with symptomatic patients in ovarian cancer which is that many of those patients require some kind of mechanical intervention to relieve their symptoms and their symptoms tend to behave in a sudden somewhat unpredictable but rapidly progressive fashion.  
		It's hard to make them go away with chemotherapy and we often don't try to treat them with chemotherapy.  I would move this drug up to earlier use in a minimally symptomatic group of patients and try to include those patients who don't have measurable disease and try to find a way that everybody could agree to use the CA-125 and some careful definition of time to progression as the surrogate for clinical benefit in those patients.  Also build in quality of life both for purposes of disease control as well as because of the very different spectrum of toxicities of the two drugs compared with topotecan.
		DR. WILLIAMS:  Are you suggesting there's a different standard for the use of time to progression in this disease than breast cancer?  You're even going another step further in considering CA-125.
		DR. MARGOLIN:  Yes, because I think the great majority of patients with this disease, those patients whom we can impact on the most are those that are the least likely to have disease you can measure.  Then you end up with just that one dividable endpoint of survival that we talked about yesterday and it's probably not enough.  
		DR. KROOK:  Having been here now for about 20 ODAC meetings I recall that there was a drug that came through for pancreas cancer that basically got approval based on a clinical benefit scale.  I have not seen other sponsors use that but certainly we're in the same type of disease as difficult to measure, difficult to whatever.  There are a few biomarkers which are available for that disease.  
		My suggestion would be that they develop some simple scale to do this, toxicity versus quality of life.  We have looked at, as was discussed yesterday, lots of quality of life scales.  It needs to be simple, easy, and to the point.  I go back to that presentation, although other members may remember that at least that was convincing enough to get full approval, what they did in pancreas cancer.
		Again, response rates were, if I remember right, like 7 percent versus 1 percent.  Yet, somehow we as a group obtained the feeling that there was a benefit to the patient.  That's three years ago but it was here.
		DR. DUTCHER:  Dr. Ozols.
		DR. OZOLS:  As Gail Hayward said in her letter, and this is right and this is the most latest statistics, that 50 percent of ovarian cancer patients now are living five years.  That's at all stages.  If you look back in the 1960's it was 30 percent.  This is a disease that is becoming more of a chronic disease.  Patients are living longer and longer.  I think that's where it becomes incumbent on oncologists to be able to use your treatments judiciously.  
		You certainly can't keep everybody on treatment over five years.  That is why I think the use of CA-125 only is wrong.  Sometimes you want to follow somebody who has minimal disease and no symptoms because you want to have these patients live longer and longer with good quality of life so it's going to be more difficult.
		DR. DUTCHER:  Dr. Sledge.
		DR. SLEDGE:  Actually, having heard Kim, I'm wondering.  It sounds like we're talking about two kinds of separate issues again here which is the quality of life issue versus the overall survival issue.  I guess my question, Bob, would be can we define a quality of life type study or symptomatic type study in patients who have relatively good performance status?  Is that conceivably possible in this disease?
		DR. OZOLS:  Yes.  I think it is conceivably possible.  It's going to have to be a randomized trial and obviously you're going to have to get some very careful selection criteria but I think it can be done and I think it's very important to be able to do that.  More and more of us are doing that in clinical practice here.  You are using your treatments more judiciously.  People are living longer and longer with this and you have to know when to treat and when not to treat.
		DR. SLEDGE:  The post-marketing study that I guess would be required to support this indication will probably not be the sort of trial that Kim is discussing, albeit that is a very important trial.
		DR. OZOLS:  The comparison against topotecan?  Yeah.  I don't have all the details of that study but just at the end of the day you're going to have two drugs that have about the same response rate and you're going to have different toxicities.  I'm not sure what you're going to be able to say other than that.
		DR. DUTCHER:  Dr. Schilsky.  
		DR. SCHILSKY:  I guess I'm still a little concerned about the ability to do a definitive trial with anything other than a survival endpoint.  My concerns relate to the fact that the patients who are most in need of clinical benefit are the patients who are least likely to respond to the therapy. 
		As Dr. Margolin pointed out, often times when they have the symptomatic need, the appropriate therapy is not actually chemotherapy intervention.  It's a different type of intervention.  It's really tough to pick out the patient population in whom you will be able to actually demonstrate clinical benefit in this particular disease.
		I don't know what the other panel members think about the potential of survival as an endpoint.  I never would have believed a drug that shows a 14 percent response rate could impact positively on survival until erindotecan came long.  Obviously a different disease.  Same level of activity that we saw with that drug and subsequently followed up by two randomized trials that each showed a survival benefit in an advanced disease population.
		You could argue that colon cancer and ovarian cancer are two different diseases and you might not be able to anticipate demonstrating a survival benefit in ovarian cancer, although I never would have believed you could see it in colon cancer either until those two Phase III trials were conducted.  
		I'm wondering if, in fact, it would be possible to define a patient population.  Maybe patients who have progressed after front-line standard combination chemotherapy.  I'm not sure what are the appropriate comparators.  Maybe you could remind us what the label says for topotecan.  What group of patients is topotecan currently indicated for?
		DR. WILLIAMS:  Platinum resistant, I think.
		DR. SCHILSKY:  Platinum resistant.  Okay.  So, I mean, the likelihood is that the group it is used in are the patients who are platinum paclitaxel resistant.  It would seem that during a Phase III study compared to topotecan following progression or relapse after platinum paclitaxel with a survival endpoint might be possible.  Where it would actually show that Doxil would win I don't know.  It seems like it would at least be possible to do that trial.
		DR. DUTCHER:  Ms. Solonche.
		MS. SOLONCHE:  Dr. Ozols has mentioned whether it would be possible to do a trial that would show clinical benefit and quality of life and other issues.  He answered the question saying, well, yes, we could do it.  But more than that, I think we must do it.  If we aren't measuring things like quality of life or survival, then what are we doing this for?
		DR. OZOLS:  Yes.  You know, I think you can do studies where patients which you are talking about waiting too late and then came as well and remaining through surgery.  There are a group of patients who are asymptomatic but who have rapidly growing disease or progressing disease.  Then you're not going to wait on that group of patients or they become symptomatic.  
		There are a lot of judicious patient selection that goes into it.  By using CA-125 coupled with radiographic evidence of disease, if somebody who has grown in two months off treatment and you know things aren't -- that would be a patient, for example, you would treat.  You wouldn't wait until something happened.
		What you want to avoid is sometimes a patient with a rising CA-125 only for a year or two years.  You're just wasting your chemotherapy there.  Or who's got a small lesion that doesn't affect the quality of life and doesn't really grow much over a period of time.  By selecting the right patients and you know when to treat them, you could do a clinical benefit analysis in that group of patients quite easily.  It can be done.
		DR. SCHILSKY:  You think you could not do a survival endpoint in that group?
		DR. OZOLS:  With available drugs we have we're still talking about response rates that are going to be in the 20 or 25 percent range at best and with clinical complete responses have that or a third of that.  We saw today only one or two percent clinical complete remissions.  I think clinical complete responders are going to be the only ones that will really impact upon survival.  I think the quality of life and the time to progression are important endpoints in that situation.
		DR. SCHILSKY:  I mean, I must say given the difficulties of actually measuring lesions in ovarian cancer that we discussed already this morning, I'm even more skeptical about trying to use a time to progression endpoint.  I'm not sure how you access progression.
		I mean, there are going to be times when it may be obvious but there are going to be many times when it's going to be impossible.  I'm real skeptical.
		DR. OZOLS:  Actually, with CA-125 data, again, that situation coupled with other things, that could be an indicator of progression.  You could use that.  Again, I'm not saying you use that to dictate your change in treatment or start a new treatment but an indicator to stop treatment.
		DR. DUTCHER:  Ms. Solonche.
		MS. SOLONCHE:  But what about patients whose CA-125 is useless?  There is a large percentage of patients whose CA-125 stays the same.
		DR. OZOLS:  That's true.  I mean, there's a subset of patients where I think the trial design can be done but it's going to be difficult.  You certainly have to include that group of patients as well, but then you would have to use other measures of disease which aren't as objective.
		DR. DUTCHER:  Dr. Nerenstone.
		DR. NERENSTONE:  I think the bottom line is that this drug is going to have an impact on survival.  As Bob Ozols has pointed out, it's going to have to be used somehow in the front-line treatment because we know that's probably the only way you are going to impact on survival.  All these 10 percent, 15 percent drugs in the second- and third- and fourth-line settings, we're not going to be able to show that they impact on survival in a large patient group.
		DR. DUTCHER:  Well, that was the argument for the discussion yesterday and we disagreed.  We asked for that so I think we should ask for that.
		DR. NERENSTONE:  I think you have to decide on -- I think it may be disease specific.  In breast cancer it may be different than in ovarian cancer.
		DR. DUTCHER:  I understand that but I'm still thinking that we're talking about what means that something is a step forward and how do you define that.
		Dr. Margolin.
		DR. MARGOLIN:  I think if we truly don't think that this drug for this indication is going to translate into some kind of clinical benefit whether that is survival.  We shouldn't be voting for it because the confirmation of this will still be in the same indication.
		DR. NERENSTONE:  No.  I think there is clinical benefit.  I've seen clinical benefit from this drug.  If you can actually prove that it's going to improve survival, I think that is the study that is going to be hard to prove.  I think that the study suggesting looking at people who have some symptoms and seeing if there is clinical benefit to any individual patient is doable and probably worthwhile doing.
		I think proving that as second-line or third-line treatment you are prolonging life when you only have a 10 percent response rate is going to be very difficult.
		DR. DUTCHER:  Dr. Sledge.
		DR. SLEDGE:  If I could ask the FDA panel members, if three years, four years from now we come back and we have a front line study that shows no survival advantage over topotecan and a second-line study that shows no quality of life advantage, then what happens?
		DR. JUSTICE:  We bring it back to the committee for consideration to be taken off the market for that indication.
		DR. NERENSTONE:  Do you really have to show advantage or can you show equality?  Because quite honestly using topo and using Doxil, Doxil has a far preferable toxicity profile.  You know, if you show that they are equal, I'm not sure then you would throw out Doxil and say it's no good.  Do you really have to show superiority?
		DR. JUSTICE:  Well, too bad Bob Temple is not here because he would love to talk about the problems of the equivalence trials but it would take a huge trial and would be very difficult to do that.  I think you would have to show that you are better than the controlled therapy.
		DR. DUTCHER:  Ms. Solonche.
		MS. SOLONCHE:  My concern here is also that by giving approval and an accelerated track to this, are we setting a bad precedent in that we are accepting trials that do not show enough response rate ad are we aiming too low?
		DR. OZOLS:  Well, my reading of the regulations is that accelerated approval is really raises a bar for the company now to come back and show us that, in fact, it does make a difference.
		MS. SOLONCHE:  Yes, but I think one problem is that the public will see this approval and maybe some clinicians as well and will think, oh, well, let's concentrate more on this drug.  This is approved.  It must be better than the ones that have not been approved that are used in a similar situation like gemcytabine or etopacide.
		DR. WILLIAMS:  Well, this company chose to proceed with this application and was the first to get accelerated approval.  Perhaps it will encourage other companies to update their label.  They were the first one to demonstrate it and we don't really know if these these other companies could demonstrate it.  We just know that this one did.  This indication is no longer available for the accelerated approval type of approval.  Anybody else could come in and show clinical benefit and get the same indication.
		DR. DUTCHER:  I think what we have to remember is that this is a very selected population, very small numbers of patients.  We often learn more about an agent once it's available for further study than we would from the initial approval trial.  For example, we don't know what happened to the people that were on these trials that were not in the refractory group.  They may have had a different response.  I understand your concerns and we have those concerns but we don't have a lot of options right now.  At least we're talking about one agent that has been demonstrated in a fairly cautious way.
		MS. SOLONCHE:  Right, but this drug, even if it were not approved is still available to the clinicians who want to use it for their patients.  Are we by approving it saying to people this one is better than the other ones rather than what the truth may be, that they were the first.  You see my point?
		DR. MARGOLIN:  Well, for good or for bad we can't legislate the use of the drugs after they are out on the market.  All you can do that for is safety so once it was out on the market for Kaposi's sarcoma, it was available from that time on.  This is a vote to recognize that certain criteria have been met that will have to be followed by more rigorous data.  
		For safety purposes, it's out there and you know that doctors will use it.  There's no choice over that and that's true for many.  In fact, the use of those other drugs that may be better, may be worse, has come from the same thing.  Gemcytabine came out for pancreas and then it started to be used in others.  You can't do anything about that. 
		MS. SOLONCHE:  Well, perhaps it's time to look at the statutes and perhaps change that.  Not of course at this moment.
		DR. DUTCHER:  Dr. Simon.
		DR. SIMON:  I think there is a lot of truth to what you say.  I think when drugs are available, it's harder to do clinical trials of those drugs as well as other drugs.  I think it was a much better situation with CPT-11 when the company came to us with the randomized trials in second-line colon cancer with essentially palliative treatment control groups in one of the trials and showed the survival comparison.  
		I think it's not a good situation to my mind where we approve a drug based on response rate without trials in place or clear indications of what those trials will be to demonstrate whether that drug really does provide any meaningful benefit to women.
		DR. SCHILSKY:  My only point in bringing up the CPT-11, you know, I think we'll all remember that when that drug first came to the committee the rate of grade III and IV toxicity that was reported at that time was approximately twice the response rate that was reported.  Nevertheless, the drug was given accelerated approval.  I think most of us probably were skeptical at that point that it would be possible to demonstrate a survival advantage, and yet it turned out that it was possible.  So I only bring that up as an example of a situation where a drug with a similar level of activity, albeit in a different disease, ultimately was able to demonstrate a survival advantage in randomized trials.
		DR. DUTCHER:  Dr. Simon.
		DR. SIMON:  My only, I guess, issue here is I would hope that the FDA before giving the drug accelerated approval that they have negotiated clinical trials that they believe will be the basis for approval and what those trials will have to show.
		DR. WILLIAMS:  Our approval letter generally states such an agreement with specific trial.  We generally try to include an advisory committee member in the negotiations.
		DR. DUTCHER:  Dr. Krook.
		DR. KROOK:  Simply a comment to my colleague over here.  I'll use the same as Rich did with CPT-11.  When CPT did 11 and once accelerated approval happened, there was a detail man at my shop fairly quickly and allowed the company to advertise.  What I was going to say is the same as Dr. Simon did is that I think we need to set this up.  
		It also does what you say.  It does get in the press.  Having been here again for a period of time, it has taken me more than one year to understand accelerated approval.  I'm not sure I do yet.  It is a different set and it does put the drug out there for people hopefully to reasonably use it.  
		Those of us in clinical practice like every "business," we know colleagues who don't know how to use drugs and do.  As has been mentioned here, we are hopeful that people use it appropriately.  I think that's what you're saying, inappropriate use.
		The other thing it does by an accelerated approval, it solves some of the reimbursement problems.  That did not used to be a problem for me and I suppose not to be talked about here, but it solved some of the reimbursement problems that each of us have to deal with as we go through clinical practice at least for the time being.
		As was mentioned earlier by Dr. Williams, I don't think there has ever been a drug that has been withdrawn but that possibility exist in this approval.  It's not a full approval so that possibility exist.
		DR. SCHILSKY:  Jim you know, you bring up an interesting point and I wonder if the FDA has thought about this.  That is the ability of practitioners to actually distinguish the differences between accelerated approval and full approval.  Whether, in fact, drug companies are required in their advertising and in their discussions with physicians to indicate whether something has been given accelerated approval or full approval.  I think it's a difficult concept.  And the fact that it may well be understood in many cases to be that the drug is so good that it was given accelerated approval.
		DR. KROOK:  Right.  That's true.  That's true.
		DR. SCHILSKY:  When, in fact, I think one has to be appropriately skeptical about the value of the drug when it has been given accelerated approval.  Maybe you could all comment just to inform us a little bit about what kind of instructions do you give to companies about the parameters that they have to apply in discussing agents after they have been given accelerated approval.
		DR. JUSTICE:  Well, they can discuss what is on the labeling.  One thing that we have been trying to do recently is to make it clear that the approval is based on objective response rate only and the labeling, of course, states the objective response and is not based on demonstration of clinical benefit.
		Of course, the company has to advertise according to the approval labeling.  That might not get to all the issues but at least it's a start.
		DR. OZOLS:  One of the things you point out about the other drugs being available is that's what we started with.  There are other drugs available.  I agree with you that no drug should have the imprimatur that this is the drug of choice out there for second-line treatment because obviously the companies when have FDA approval, it will be something that will come out in marketing.
		Having said that, I think it is incumbent on industry and the pharmaceutical industry to get SNDA's out as quick as they can.  The agency wants to approve and make sure that the package insert tells where the drug can and can't be used.  Drugs like BP-16 and gemcytabine should be coming up here.  On the other hand, the agency should make it easier for SNDA's to be done as well, I guess.  It's something that in the real world should get out there quicker so that the physicians know that other drugs have activity.  In the SNDA's you don't have to worry about all the toxicity because you've gone over that in detail on your prior submissions.  I would like to see a lot more SNDA's out there.
		DR. DUTCHER:  Excellent discussion.  Excellent discussion.  I think a lot of food for thought for the negotiations regarding this agent.
		We are ahead of schedule so we're going to start ahead of schedule.  We're going to start back here at 12:30 p.m.
		(Whereupon, the meeting was recessed at 11:17 a.m. to reconvene at 12:30 p.m. this same day.)

	A-F-T-E-R-N-O-O-N  S-E-S-S-I-O-N
	(12:28 p.m.)
		CHAIRPERSON DUTCHER:  Good afternoon.  We are going to resume the last afternoon of this meeting.  We have some new people at the table, so I want to go around once more and just have people briefly introduce themselves.  Ms. Beaman?
		MS. BEAMAN:  Carolyn Beaman, Sisters Breast Cancer Network, Consumer Rep. to the Committee.
		DR. SLEDGE:  George Sledge, Medical Oncologist, Indiana University.
		DR. SANTANA:  Victor Santana, Pediatric Oncologist, St. Judes Children's Research Hospital.
		DR. NERENSTONE:  Stacy Nerenstone, Medical Oncology, Hartford Hospital, Connecticut.
		DR. LIPPMAN:  Scott Lippman, Medical Oncology, M.D. Anderson Cancer Center.
		DR. SCHILSKY:  Richard Schilsky, Medical Oncologist, University of Chicago.
		MR. GRUETT:  I'm Glenn Gruett, Patient Advisor.
		DR MARGOLIN:  Kim Margolin, Medical Oncology and  Hematology, City of Hope, Los Angeles, California.
		CHAIRPERSON DUTCHER:  Janice Dutcher, Our Lady of Mercy Cancer Center, New York.
		DR. TEMPLETON-SOMERS:  Karen Somers, Executive Secretary to the Committee, FDA.
		DR KROOK:  Jim Krook, Principal Investigator, Duluth CCOP, Duluth.
		DR. HARWOOD:  Andrew Harwood, Radiation Oncologist with a special interest in head and neck cancer from Louisiana.
		DR. SIMON:  Richard Simon, Biostatistician, National Cancer Institute.
		DR. OZOLS:  Bob Ozols, Medical Oncologist, Fox Chase Cancer Center.
		DR. WILLIAMS:  Grant Williams, Team Leader, FDA.
		DR. CHICO:  Isagani Chico, Medical Reviewer, FDA.
		DR. CHU:  Clara Chu, Statistics Reviewer, FDA.
		DR. TEMPLE:  Bob Justice, Acting Division Director.
		CHAIRPERSON DUTCHER:  We have a conflict of interest statement to be read, please?
		DR. TEMPLETON-SOMERS:  This one is brief.  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 and information provided by the participants, the Agency has determined that all reported interest in firms regulated by the Center for Drug Evaluation and Research present no potential for a conflict of interest at this meeting.  In the even 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 of fairness that they address any current or previous financial involvement with any firm whose product they may wish to comment upon.  Thanks.
		CHAIRPERSON DUTCHER:  We have two speakers for the open public hearing.  We would like you to please identify yourself, any affiliation with the sponsor, or any financial support.  First is Philip J. LoPresti. Please come to the microphone or the podium, either one.
		DR. LOPRESTI:  Good afternoon, everyone.  Madam Chairperson, members of the committee, and representatives of the Food and Drug Administration.  I am Philip LoPresti, a retired dermatologist and a survivor of head and neck cancer.  
		I served my residency at the Hospital University of Pennsylvania, 1963 to 1966, and I taught in the clinic for ten years after, doing various drug studies at the time.  I am Chief of Dermatology at Our Lady of Lourdes Hospital in Southern New Jersey, which is a Level 4 hospital, and I was president of the Philadelphia Dermatologic Society, which meets monthly from October to June at the five medical schools in Philadelphia, often presenting rare cases treated with medications on study programs such as the one I participated in on amifostine.  
		Therefore, I understand the position you are in today in evaluating amifostine as a possible help for patients with head and neck cancer.  I would like to preempt my remarks by stating I am not associated at all with U.S. Bioscience.  No one has paid me to appear before the committee today.  And as a matter of fact, I drove down to Maryland today from my home in New Jersey in my personal car at my own expense.
		I feel I am more familiar than most physicians with patients who suffer from xerostomia, since dermatologists are often consulted for various complications of this disorder such as secondary mammalian infections, bacterial infections, ulcerations and viral infections.  However, despite 32 years of practice, I never really appreciated the difficulties from a patient's viewpoint until I became a patient.  
		My history briefly is I was diagnosed to have squamous cell cancer of the left tonsil.  I underwent a modified radical neck dissection on May 9, 1997.  This was done at the Hospital of University of Pennsylvania, and I received my radiation therapy there as well.  I volunteered to participate in the amifostine study, and I was fortunate to be enrolled by a random selection pick.  I was the first patient placed on the study at the University, and because of the random pick and the fact that patients 2, 3 and 4 were not picked and several patients did not care to volunteer, I was six weeks ahead of the second patient in the study.  I bring this out because I feel that no other patient on the drug compared -- I had any reason to compare to, and therefore contribute to placebo effect.  However, I could compare my progress with radiation patients that were going through the same treatments that I were, but were not on the amifostine.  I received a total of 6300 Gray over a 7-week period.  
		I would like to share with you my experiences during and after radiation.  During radiation, the first thing that happens, of course, is that you lose the ability to taste.  I always describe this as eating wallpaper with the paste on it and no taste.  Then as the salivary glands become affected, you can hardly speak above a whisper, and one really dreads the nights.  You can only sleep for approximately one hour, and then you must lubricate.  And after about the third hour, you are awake and you can't return to sleep.  And after three hours of staying awake, you are exhausted.  In the early morning, you finally fall asleep and then after sleeping for three hours, you awake with your tongue attached to the roof of your mouth and you are prying your lips from your teeth.  The first swallow in the morning is extremely painful.  It takes about 45 minutes to eat a bowl of dilute cereal, despite the use of oral demerol.  And at that time, I could only eat soups.  I lost 35 pounds in 7 weeks and despite high calorie liquid fluid supplements.  I had no side effects from the amifostine.  No nausea, vomiting, or dizziness.
		Now despite all these personal experiences during the therapy, my side effects from radiation, although similar to non-treated patients, were to a much lesser extent.  As I sat in the radiation waiting room, I spoke to many of the patients.  I got to know these patients because they were considering going on the study and either were not chose in a random pick or they had questions about the PIC line that I had to have in or the side effects of the drug.  
		Of course, many of us compared our side effects during our daily meetings in the waiting room.  In my discussion with my fellow patients, all had oral ulcerations.  I had none.  The mucositis I experienced, which I measured by the serous exudate, was markedly less.  I was able to eat and speak better than every head and neck patient I spoke with at the center, and some of my fellow patients who did not receive amifostine had to be fed with G-tubes because of their inability to swallow.  More importantly, and I think this is the most important point, in addition to the milder side effects I experienced compared to my fellow patients during radiation, the long-term results in my opinion are even more dramatic.  And in a patient's viewpoint, rather spectacular.
		I am now 22 months post-radiation.  I sleep throughout the night.  I eat all foods except for jalapena peppers.  One example I would bring to your attention is that for a person with xerostomia to eat bread is like just about impossible.  If you try to eat a piece of bread or a bagel, the little saliva you have in your mouth just absorbs it so quickly, even if you take a drink of water it is so difficult to swallow.  It doesn't give you the smoothness that saliva does.  Well, I can eat bread.  I just had a sandwich for lunch with very little help of water to drink.  
		I recently had breakfast with two patients who were not treated with amifostine.  And I invited them to have breakfast with me.  I couldn't believe how astonished they were that I could eat a bagel for breakfast and they couldn't even think of ordering that.  
		Teeth are often carious as a side effect of the pH changes resulting in a high bacteria count.  It is recommended the use of fluoride in a mouth piece daily.  In July, I elected to have dental braces put on because I was having difficulty with my bite.  I had prophylactic removal of the molars during my surgical bout, and my teeth drifted.  While I had braces on, I was not permitted to use fluoride, and this was a period of 7 months.  I did not have any caries during that 7 months, or to this day, which is nearly 10 months later.  I attribute this to the fact that my rebound of my salivary glands due to the use of amifostine.  I consider my speech to be 80 percent of normal.  During radiation, I was using salivary topical sprays, a 70 gram Salivart can, 12 cans every 10 days.  Now I use 12 cans over an 8-week period.
		When I was going through radiation, I was told that 2 months post-radiation I would be much improved, but only to expect 20 percent improvement from there on.  I have improved immensely in the past 22 months, and the improvement has been most dramatic in the past 6 months. I do not have to walk through life with a bottle in my hand with limited speech, and I can enjoy the ability to eat all foods. I can sleep through the night.
		In conclusion, I would urge the committee to consider this new use of amifostine from the patient's perspective. I feel I am here on behalf of many patients who cannot speak above a whisper with a terrible quality of life.  Surely our goal is to survive.  I am grateful that I am in a remission.  It is one thing to know that you have a life-threatening cancer, but to compound this with the radiation therapy that will cause tremendous changes in your life via speech, eating, sleeping and tooth decay is staggering to the patient.  As we were taught in our early training in medical school, first do no harm.  I would urge you to help relieve the patient of these harmful side effects of radiation therapy.  Also, I realize one patient's response to therapy does not prove definite efficacy of any medication.  Amifostine in my case has cut down on radiation's terrible side effects dramatically.  I hope you will not dismiss the improvements in quality of life as trivial.  They are important to the patient.  I know.  I have experienced both ends of the spectrum. I would like to thank you for allowing me to discuss my history before your distinguished committee.  I will be happy to provide the committee any first-hand experiences on the course of treatment should you have any questions about this form of therapy during your deliberations.  Thank you.
		CHAIRPERSON DUTCHER:  Thank you very much.  The next speaker is Gail Broder, Cancer Survivorship Alliance of South Florida.
		MS. BRODER:  Thank you for the opportunity to speak on behalf of patients who can be helped by  amifostine.  My name is Gail Broder.  I am the founder and President Emeritus of the Cancer Survivorship Alliance of South Florida and a six-year cancer survivor.  I have no financial interest in the outcome of the ethyol application, and I am here as a volunteer without compensation or reimbursement of expenses.
		Among other things, I serve as the patient representative on the Radio and Chemo Protectants Guidelines Development Panel of the American Society of Clinical Oncology, ASCO.  Through my participation on the panel, I have become aware of the potential benefit of amifostine for cancer patients receiving radiation treatment to the head and neck. I have not personally been treated in this way and have no first-hand experience of xerostomia.  
		Once I became aware of xerostomia as a discrete clinical issue, I realized that I have two friends that suffer from this disorder.  Neither of them has ever complained.  They accept the problem as a price to be paid for successful cancer treatment.  However, it is apparent to me that they experience significant problems with such ordinary activities as eating and speaking.  
		My friend, Barbara, is 39 years old, and four years ago she was treated for lymphoma, including radiation to the head and neck.  She and I spend a lot of time together.  She frequently mentions that her mouth is dry, and it is apparent to me that he has difficulty speaking. Even though she continuously drinks water, she seems never to be able to get her mouth sufficiently moist to be comfortable.  She has told me that during her treatment the production of saliva all but stopped.  I confess, I didn't fully appreciate the effect of her dry mouth problem until she started talking to me about her dental problems. In the months following her treatment, she developed four cavities.  Before that, she had excellent dental health.  
		My friend, Mort, is in his late 70's.  Over 25 years ago, he was twice treated with radiation for head and neck cancer at the University of Pittsburgh.  Since then, he too has had difficulty with a dry mouth, and that is over 25 years.  He has told me that his mouth is always dry and that he has to continually lubricate it in order to speak comfortable.  A humble man, when we eat out, he apologizes for eating so slowly.  Because his mouth is dry, it takes him a long time to chew and swallow food.  It is difficult for him to carry on a conversation while taking a meal.  Mort told me that in the aftermath of his cancer treatment, he required extensive dental treatment.  
		Since I don't have xerostomia, it would be easy for me to minimize its effect on my friends.  It is only because I have spent so much time with both Barbara and Mort that I have come to understand what it means to have this disorder.  I now realize that the morbidity associated with xerostomia can be quite significant for patients with acute and long-term consequences.  
		The introduction of amifostine into the pharmacy to decrease the incidence and severity of radiation-induced xerostomia is a small, but meaningful advance.  As a member of the ASCO Guidelines Development Panel, I reviewed along with the medical experts the available relevant scientific reports and listened carefully to the discussions.  I leave it to the medical experts to report the scientific bases for the approval of ethyol.  As a cancer patient representative, however, I can say that the panel developed a treatment guideline recommending that amifostine be considered for reduction of incidence and severity of xerostomia in patients receiving radiation treatment for head and neck cancer.  
		The guideline is based primarily on a large Phase III randomized controlled clinical trial together with numerous Phase I and a randomized Phase II trial.  The panel rated the level of this evidence as 2 on a scale of 1 to 5.  Based on this level of evidence, the panel graded the recommendation a B on a scale of A, B, C, D, E and no grade.  From a patient's viewpoint, the 2B grade means the evidence is reliable.  In making this guideline, the panel found that patients who received amifostine in the randomized clinical trials had significant reductions in incidence and severity of xerostomia.  That the drug was generally well tolerated with transient side effects, and that in the randomized clinical trials, there was no evidence in the overall response rates or in overall survival -- there was no difference in the overall response rates or in overall survivor between the group that received amifostine and the one that did not.  Importantly, the panel also concluded that there was no evidence from the available clinical data that amifostine leads to the protection of tumor.  
		I have permission from ASCO to share this information.  The guidelines have been formally adopted and will be published I am told in the next few months.  I understand that amifostine is continuing to be studied to further substantiate the panels findings, and I encourage the sponsor and its partners to press on.  Thank you.
		CHAIRPERSON DUTCHER:  Thank you very much.  Okay, we are going to then proceed with the sponsors presentation.  We have a lot of speakers, so just to warn you, we are putting on a clock.  You have your full hour plus 5 minutes.
		DR. OSTER:  Okay.  We tried.  
		CHAIRPERSON DUTCHER:  Okay.
		DR. OSTER:  Dr. Dutcher, members of the committee, Dr. Justice, representatives from the FDA's Oncology Division and guests, I am Dr. Oster, Executive Vice President at U.S. Bioscience.  On behalf of U.S. Bioscience, I want to express our appreciation for having the opportunity to present here today to you the supplemental NDA for the use of amifostine in radiotherapy.  
		Amifostine is currently approved in the United States to reduce the cumulative renal toxicity associated with repeated administrations of cisplatin in patients with advanced ovarian cancer and non-small cell lung cancer.  It is approved for similar or extended indications in approximately 50 other countries world-wide, including the European community.  In the European community, an approval was recently unanimously issued for the use of amifostine in radiotherapy, the indication which we are going to discuss here today.  
		Post-marketing experience is now available from approximately 250,000 treatment cycles from an estimated 83,000 patients treated world-wide.  The emerging safety profile from this observation is consistent with the safety described in the package insert.  
		The proposed new indication which we present here today is for the use of amifostine to reduce the incidence of moderate to severe radiation-induced xerostomia.  This indication has received orphan drug designation by the FDA.  According to the FDA's guidance for the industry of standards for the prompt review of efficacy supplements, a priority review can be assigned if the product would be a significant improvement for treatment or prevention of disease.  
		We submitted this supplemental application in December of 1998, and based on the unmet medical need in this indication, the FDA granted a priority review for amifostine in this new indication in February of this year.  We would like to thank the FDA for their prompt review of our application and for working with us throughout this process.  The indication which we present to you here today is indeed an unmet medical need.  The reduction of severity of radiation-induced xerostomia may be of significant benefit to patients who undergo radiotherapy.
		Let me begin by discussing xerostomia.  As you know, salivary glands are particularly sensitive to radiation modalities, and radiation therapy is a fundamental treatment modality for head and neck cancer, and it is the underlying cause of xerostomia.  Xerostomia is a very frequent complication of radiotherapy in the head and neck region, and once it occurs, it is typically permanent.  Xerostomia is a severe medical condition which has a long-term effect on a patient's capacity to eat, to communicate, and to feel comfortable.  Frequently, patients are cured from the head and neck cancer but suffer from xerostomia, which they find quite distressing, as you have heard.  It really interferes with a patient's daily living.
		The data presented for you here today will show that amifostine has demonstrated a clinically meaningful effect on an irreversible morbidity, xerostomia.  We show you data from a large, multi-center study using multiple, independent but logically linked endpoints.  The findings from this study are statistically persuasive and medically meaningful. Our package also contains a number of supportive studies which we will partly review here, showing the results from efficacy and safety which are consistent with the results from the pivotal study.
		I now would like to introduce our scientific team, which has worked together to come to this event today.  On the left side, you see the presenters, which are also indicated in your agenda.  And on the right side, you see those individuals who have collaborated with us to present to you the data in a scientific and statistical way as they will come to you today.  I would like to point out two individuals who were instrumental in initiating these programs, and these are Dr. Todd Wasserman and Dr. Capizzi.  Without these two, we probably couldn't be here.
		The next speaker I would like to introduce is Dr. David Grdina, who will present to you data on amifostine's mechanism of action. Dr. Grdina is professor of radiation and cellular oncology at the University of Chicago.  Dr. Grdina?
		DR. GRDINA:  Thank you, Dr. Oster.  Amifostine was the premier radioprotector developed by the anti-radiation drug development program that was conducted by the U.S. Army from 1957 to 1973.  In this program, DNA was identified as the critical target for protection from radiation-induced damage.  Amifostine, by virtue of its positively charged amine groups, can localize and concentrate in the microenvironment of the negatively charged DNA.  
		However, amifostine is also a pro-drug that must first be dephosphorylated by membrane-bound alkaline phosphatase to its active free thiol and disulfide forms.  Now these metabolites are extremely important because they are very effective in scavaging damage-producing free radicals.  Now this is important because 80 percent of the damage by radiation to the DNA is induced through the indirect effect, and that is through the formation of water-based free radicals. So DNA damage by radiation induces free radicals, and it is a very rapid process that is essentially completed within 10-3 seconds.  Thus, the radioprotector must be present at the time of irradiation.  The close association of the active forms of amifostine with DNA allows amifostine to protect against both radiation-induced free radicals and chemotherapeutic drug-generated reactive damaging species.  
		The magnitude of radial protection is dependant upon the intracellular concentration of amifostine at the time of irradiation.  This is best demonstrated by analyzing normal and tumor tissues in a mouse model and contrasting the levels of C-14 labeled metabolites of amifostine that accumulate in them as a function of treatment time.  Accumulation varies for normal tissues with salivary gland being among the most effective in taking up the drug.  In contrast, no accumulation above background blood levels is observed in the tumor.
		So a number of factors can therefore account for the selective protection of normal tissues.  First, deactivation of amifostine is required by membrane-bound alkaline phosphatase, which is highly present in normal vascular endothelium.  Secondly, drug delivery to normal tissues is much more efficient by virtue of their more effective functional vasculature as compared to the poor vasculature which is characteristic of solid tumors.  Third, this allows for a significant enhancement in concentrations of amifostine to be achieved in normal tissues as compared to tumors.  And fourth, since the magnitude of radial protection achieved is dependant upon the intracellular concentration of amifostine at the time of irradiation, the high drug concentrations in normal tissues gives rise to their selective protection.
		Finally, in summary, amifostine was designed for and acts as a potent radioprotector.  it binds electrostatically to and shields DNA from radiation-induced free radical damage.  With respect to salivary glands, it is highly concentrated in this tissue, and this is accompanied by very high levels of protection to this tissue.  And finally, the protective effects of amifostine are concentration-dependent and are selective for normal tissues.  At this time, I would like to introduce Dr. Brizel from Duke University and the PI of WR-38, who will speak on the head and neck clinical study with amifostine.
		DR. BRIZEL:  Dr. Dutcher, members of the advisory committee, Dr. Justice, members of the FDA, and members of the public, I would like to thank you for the opportunity to be here this afternoon to share with you the results of the WR-38 randomized trial of radiation therapy with and without amifostine in head and neck cancer.
		I would like to begin by telling you that I am a practicing radiation oncologist, and that the vast majority of my clinical practice is in the care of patients with carcinoma of the head and neck.  Radiation therapy, as you have heard, is a primary treatment modality for this group of patients, either as definitive, curative-intent, stand-alone treatment or as post-operative adjuvant therapy.  Depending upon the disease stage and location at the time of presentation, anywhere from 30 to 80 percent of patients who have this disease are potentially curable of their illness.
		Necessarily, technical aspects of the delivery of radiation therapy lead to the parotid glands being within the treatment fields.  And as we have heard, the parotid glands are very sensitive to the effects of radiation therapy and consequentially, patients do develop xerostomia.
		As we have already heard very eloquently from Dr. LoPresti, xerostomia very significantly adversely influences the normal daily lives of patients who have received head and neck radiation therapy.  This is the face of xerostomia, and I think we don't even need to be physicians to appreciate that this tongue does not look normal.  The mucosa no longer has its glistening moist appearance.  We see many cracks and fissures within the tongue.  
		You have heard from the patient's standpoint what this means.  Let me add my perspective to the picture.  And that is, when I examine these patients, it is necessary to use a tongue blade to retract the tongue.  And when I am finished and remove the tongue blade, the tongue wants to come with the tongue blade.  That is a serious problem in my opinion.
		I would like to get a little ahead of myself and take some data from the trial and show you that this is a longstanding problem for these patients.  These 64 patients, irrespective of which treatment arm they were in in this trial, had late xerostomia Grade 2, which I will define shortly, at the 12-month interval.  Now, of those 64 patients who had late xerostomia 12 months after completing radiotherapy, 63 of the 64 patients still had late xerostomia at the later time point.  Once you've got it, you've got it.  This is a problem that persists for these patients.
		The WR-38 trial had four primary endpoints defined.  Number one was the incidence of acute Grade 2 or higher acute xerostomia based on radiation therapy oncology group guidelines.  The incidence of acute Grade 2 or higher late xerostomia was the second endpoint, again as defined by RTOG criteria.  Acute Grade 2 mucositis or higher, which is confluent mucositis, was the third endpoint.  And finally, the fourth protocol defined primary endpoint of this trial was the preservation of anti-tumor efficacy, which was defined as the local regional control rates at 12 months after the completion of radiotherapy.
		Secondary endpoints which were designed to support and reinforce the primary endpoints included the actual time to the development of acute Grade 2 xerostomia, the objective quantification of whole saliva production, patient assessment of their activities of daily living through a repetitive administration of a patient benefit questionnaire, disease-free survival, and finally overall survival.
		I think it is worth defining who we are talking about here.  The RTOG scale defines Grade 2 xerostomia as moderate to complete dryness of the mouth. So we are looking at this group of patients and worse, and I think it is also worth noting that within the RTOG scale, there is no Grade 3 xerostomia.  
		Patients with newly diagnosed squamous cell carcinoma of the head and neck were eligible to be enrolled on this trial, and it was necessary that at least 75 percent of both parotid glands be included within the treatment portals.  Also, patients were not allowed to receive prophylactic administration of pilocarpine, also known as salogen.
		From October 1995 through October 1997, 315 patients were enrolled in this trial, of whom 303 actually received treatment and they were evenly balanced between the two treatment arms.  Through current follow-up, the median follow-up is 26 months, greater than 2 years.  Patients were randomized via a dynamic allocation process, but prior to randomization they were stratified according to the following parameters, the first of these being the treatment center, and there were 40 centers that participated and enrolled patients on this trial.  They were also stratified by site of disease, presence or absence of nodal disease, Karnofsky performance status, and the type of radiation therapy that they were to receive.  Specifically what that means is either definitive curative-intent treatment, as I mentioned at the outset or post-operative irradiation, where they were further classified as being at either high risk of recurrence or at low risk of recurrence.  Again, they were subsequently randomized at that point, either to amifostine plus radiotherapy or radiation therapy alone.  Amifostine was given at a dose of 200 mg per m2 intravenously, 15 to 30 minutes before each fraction of radiotherapy.  Radiotherapy was given via conventional once-daily fractionation at 1.8 to 2 Gray per dose, to a total dose of 50 to 70 Gray.  The total doses of radiotherapy as well as the technical aspects of the treatment were the same in both treatment arms.
		Patient enrollment was well-balanced with respect to age, gender, primary tumor site, T stage, end stage and the type of radiation therapy.  On the next two slides, I will go into more depth and detail regarding the balancing of the radiation therapy dose received by the two groups of patients on this trial.  Total treatment time is a very important component of the delivery of radiotherapy in clinical care, and we can see that both groups of patients received their total treatment in the same amount of time.  There were no unusual prolongations in the total treatment time.  Similarly, we see that the median number of radiotherapy fractions delivered to the two groups of patients was the same.  
		This is a dose frequency histogram of the radiation therapy which was delivered.  And I would like to work with you on this for a brief period of time, because I think that it really demonstrates the equivalence of the dose delivered to the two groups of patients.  On the Y axis, we have the percentage of patients receiving a given dose, which would be defined on the X axis.  If we go to 90 percent and then work our way across and then down, we see that both groups of patients, 90 percent of them received at least 60 Gray.  Let me repeat, in both groups of patients, 90 percent received at least 60 Gray.  
		Now we see that the median, 50 percent of the patients, the median dose was 64 Gray in the amifostine plus radiation group and 66 Gray in the radiotherapy alone group, and although this median is higher than this median, that is not a clinically meaningful issue.  The real issue is the 60 Gray.  Because at a dose of 60 Gray to the parotid gland, we can expect that all other things being equal, xerostomia should probably be complete and long-term.  The parotid glands cannot tolerate that sort of dose.  And we see that 90 percent of the patients in both groups received at least 60 Gray.  
		Turning our attention now to the first primary endpoint, acute xerostomia, we see 51 percent of the patients who received amifostine plus radiation reached this endpoint, whereas 78 percent of the patients, a significantly higher proportion of patients who received radiation therapy alone had acute xerostomia.  Moreover, what we see is that the dose of radiotherapy that is required to cause this side effect is significantly lower for the patients who received radiation therapy alone.  At a dose of 42 Gray, 50 percent of the patients receiving radiation alone already had Grade 3 xerostomia, whereas it was not until a dose of 60 Gray that we saw 50 percent of the patients developing acute xerostomia.
		Going back to our frequency histogram, I think we can again see what we are talking about here.  At a dose of 40 Gray or 42 Gray rather, 50 percent of the patients with radiation alone are already developing acute xerostomia, whereas it is not until we get to the dose of 60 Gray that we see this same incidence in the patients receiving amifostine plus radiation.
		If we try to breakdown the incidence of acute xerostomia by dose of radiation therapy, I think we again take away from this that the vast majority of patients received greater than 60 Gray.  And for the smaller group as well, we see that with amifostine plus radiation, there is a lower incidence -- a significantly lower incidence of acute xerostomia than in those patients who received radiation therapy alone.  
		Moving from acute xerostomia to late xerostomia, we see a couple of things.  First of all, as highlighted in yellow, the amifostine plus radiotherapy group had an incidence of 34 percent at one year versus 57 percent for those patients who received radiation therapy alone, and this is statistically significant.  I think it is also fairly clear that our denominator is no longer the 303 patients who were enrolled and who received treatment.  We have gotten smaller.  And that is a function of the fact that patients do relapse and die of their disease, and so they are not available, many of them, for follow-up at the one-year point.
		However, what we did to try to look at this issue in more depth was evaluate late xerostomia at different time points.  And once again we see that irrespective of the time point after treatment, we have a lower incidence of late xerostomia in the patients who received amifostine plus radiation therapy than in the patients who received radiation therapy alone.
		A more conservative way of addressing this issue, however, would be to go back and include the entire denominator of 303 patients and then see what the incidence of late xerostomia was.  And once again, we still see that there is a significant difference in favor of the patients who received amifostine with their radiation as opposed to those patients who received radiation alone, 22 percent versus 39 percent.
		If we try to breakdown late xerostomia by radiotherapy dose, we see the same picture again, just from a slightly different perspective.  The vast majority of patients who were alive at this time point received doses greater than 60 Gray, and there was a significantly lower incidence of xerostomia for those patients who received amifostine.
		Whole saliva production at one year was a protocol defined endpoint as an independent measure of late xerostomia.  And I think the picture becomes clearer here today that the volume of saliva is what ultimately determines patients' symptoms and plays a very important role in their sense of well-being.
		The median quantity of saliva that patients could produce at one year if they received amifostine with radiation therapy was 0.26 grams.  More than 2.5 times greater than 0.1 gram, the median quantity which was produced by those patients who received radiation therapy alone.
		The FDA dental reviewer, based on the pilocarpine precedent, has stated that a quantity of 0.1 grams would be an acceptable indicator of clinical efficacy.  Now this was not a prospectively defined protocol endpoint, but it was identified as being clinically meaningful prior to the analysis of any data from the protocol.  And with that in mind, we looked at how many patients were able to exceed this clinically significant threshold.  The amifostine plus radiation therapy group, 72 percent of the patients exceeded the clinically significant threshold of saliva production, whereas a significantly lower percentage of patients, 49 percent, who received radiation therapy alone were able to exceed this threshold.  So a significantly larger proportion of patients treated with amifostine plus radiation therapy were able to produce a clinically significant volume of saliva after their treatment.
		It has been proposed that another way to analyze the volume of saliva would be to look at the change from baseline.  And I would like to state that I think that this is a potentially complicated way of looking at the problem.  And there are some potential opportunities here to get confused in our conclusions.  Because the results, if we are looking at changes from baseline, are driven by the variation in the pretreatment volume. And I will show you some examples in a moment to drive that point, if I may.  Furthermore, the change from baseline does not reflect the end of treatment volume.  And I don't think it is so important where you start.  I think what really matters is where you finish.  
		Now let's go to our examples.  The first patient -- and these are from the WR-38 trial -- the first patient started with 6.5 grams at baseline and finished with just over one gram baseline.  Now the change looks fairly dramatic, a negative 5.5 gram reduction.  Patient number two started lower at 2.1 grams and finished with nothing at all.  The change was -2.1.  If we just look at the change from baseline, well this patient has a lower change from baseline, but this is the one who is still making saliva.  And I think just looking at change from baseline, we might reach an incorrect conclusion.  
		I would now like to turn the podium over to Dr. John Mackowiak from the Center for Outcomes Research in Chapel Hill, North Carolina, to discuss with you the patient benefit questionnaire. 
		DR. MACKOWIAK:  Thank you, Dr. Brizel.  As a secondary endpoint to corroborate the evidence, the primary efficacy endpoint in this study, a patient benefit questionnaire was included.  The questionnaire included eight items, two of which to assess -- I am sorry, three to assess symptoms, three to assess the activities of daily living that were discussed earlier, and two more to assess fluid intake.  
		The instrument was also validated and I want to share with you the results I reached when I did that validation.  One, the instrument has high reliability as assessed by test/retest and also internal consistency.  And two, when we do the factor analysis, we found that there was a positive correlation between all eight items.  All of them described a single factor.  There were not independent factors within that instrument.  Therefore, subscales may be helpful to understand what is going on with the patient, but not absolutely necessary for analysis.  The instrument was administered weekly during the time when the clinical benefit was changing most often, and then at months 1, 3, 5, 7, 9 and 11.  And in the second year of the study, it was only administered at months 17 and 23 following end of radiation.  
		These are the mean PVQ scores for the two groups graphed on this graph.  What we see is, as was described here, the rapid decline in PVQ scores during radiation, the recovery initially after radiation stopped, and then where you see the persistence of the condition.  By looking at the mean scores, you see the separation of the two groups, amifostine and the control group.  
		At FDA's request and with agreement from the sponsor, a longitudinal analysis was conducted. This was to focus on the multiple comparisons issues as well as to address the issue of non-completers.  What I want to do is show you the results of that.  The model that was selected also showed that same rapid decline, and then at the end of radiation, the recovery and again the separation.  The two lines have a statistically significant difference as judged by the overall comparison.  We also saw statistically significant differences at time points at end of treatment, at end of RT, and also at the end of the follow-up period.
		In this graph, what I do is I show you the one-year data and the reason for that as opposed to extending out beyond that.  It was the data that was available when the data set was closed in October of last year.  Data after that was extremely thin, with only at the 11-month point.  And also from what we learned earlier within this clinical trial, the conditions are extremely persistent after that -- extending from the first year onto the second year.
		I also wanted to share with you results of one of the other items.  This is the general dryness question or the general condition subscale that was presented in the FDA analysis.  This is again using the same Laird/Were model, mixed effect model, for that dryness question.  We see that same drop during radiation, separation, and then in this case a recovery within the amifostine group.  The overall -- there is an overall difference between the two lines, and with this question we do see significant difference at all the time points.  All the other items when looked at separately or when collapsed into subscales show a separation.  However, the overall significance is not reached.  So what we are able to see is directionality within the other items of the subscales, but not a statistical significance when taken one at a time.  
		This is the same -- the curve lines are the same lines that you saw in the other graph.  I superimposed onto that the mean scores taken at each time point.  And I show this so you can examine the goodness of fit that is so important when modeling off of mean data.  And in this case, the data points do not lie more than a quarter point or a half point away from the curve line.  That goodness of fit is a prerequisite to make any statistical conclusions based on that model.  
		I have shown you a number of -- the PVQ model and this one, and usually the difference or the gap is one point or slightly less than one point.  But I haven't yet said what one point on the PVQ actually means.  What is the clinical relevance of that one point?  In the next slide, we found consecutive visits within the clinical trial where there was a one grade worsening in the RTOG xerostomia scale.  On those exact same consecutive visits, the patients reported approximately a one point decrease in their PVQ score, 0.96, and it was significant.  On those consecutive visits when there was one grade level improvement in the RTOG xerostomia scale, the patients reported again approximately a one point improvement in their PVQ.  And on those consecutive visits, all the other visits, where there was no change in the RTOG scale, the change in the PVQ score was not significantly different from zero.  
		With that, I would like to conclude and refer to the fact that as we mentioned before, the PVQ scores we feel are very consistent with the other finding, xerostomia, and based on the data presented here and based on the per-protocol endpoint of mean PVQ score and the analysis plan, we feel that the PVQ does strongly support this application.  With that, I would like to refer back to Dr. Brizel to conclude the efficacy portion.
		DR. BRIZEL:  Grade 2 xerostomia was the primary endpoint.  Saliva production, PVQ scores, those were secondary supportive endpoints.  So let us ask the question, how do those correlate with one another?  We see -- I really am over 18.  For late Grade 2 xerostomia, we see that this correlated in a highly significant fashion with saliva production, PVQ score, and the oral dryness question.  Moreover, the PVQ score was highly correlated with saliva production, and reassuring to me as a clinician, oral dryness was highly correlated with saliva production as well.
		Now we will turn our attention to the last primary endpoint, preservation of anti-tumor efficacy.  As defined in the protocol, the local regional control rates at 12 months were the measure of this endpoint, and we see for amifostine plus radiation therapy, 72 percent local regional control, 71 percent for radiation therapy alone.  And we see that the lower limit of the one-sided and two-sided 95 percent confidence intervals was greater than 0.8.  We will hear about this in more depth and detail a little bit later from  Dr. Koch.
		At 18 months, local regional control 61 percent for amifostine plus radiation therapy, 64 percent for radiation therapy alone.  And again, we see the lower limits of the 95 percent confidence intervals around 0.8.
		I like to look at pictures better, and maybe that is just because I am a clinician.  But if we look at the Kaplan Meier plots, which show what is happening over time for local regional control, we see that there is no difference between the two treatment arms.  These are superimposable upon one another.  As a radiation oncologist, I would like to digress for a moment and explain why local regional control is so important.  Number one,  radiation therapy is a local regional form of treatment.  So its efficacy is to be evaluated within what is within the treatment field.  And secondly, and reinforcing this, is the fact that the vast majority of patients with cancer of the head and neck fail in a local regional fashion for their initial failure.  And we will see that in the next two slides.  But here we have the number of failures, local regional failures, and there is no difference between the two groups of patients.  So from a local regional standpoint, there is no evidence of compromise of anti-tumor efficacy.  
		Disease-free survival, which does incorporate non-local failures and deaths from other causes, we again see that the number of events is not different between the two treatment arms.  And the two Kaplan Meier plots are superimposable upon one another.  So again, with respect to disease-free survival, there is no evidence of compromise of anti-tumor efficacy.
		Finally, the ultimate endpoint, survival.   Once again, if anything we see more events occurring in the patients who received radiation therapy alone relative to the patients who received amifostine plus radiation therapy.  The fact that the amifostine plus radiation curve is above the radiation alone curve is not statistically significant, but once again I really think the important point here is that efficacy has been preserved.  There is not a hint of tumor protection if we look at the survival curves.
		For a trial of this type, preservation of anti-tumor efficacy is actually a form of safety.  Now the more conventional form of safety that we are used to thinking about is side effects related to the drug itself.  As we know, nausea and vomiting are two of the well recognized side effects of amifostine.  In this trial, nausea and vomiting was usually mild to moderate in severity, and only 8 percent of the patients had any episodes of grade 3 nausea or vomiting.  The really interesting thing to me is this line or this bullet right here.  There were over 4,000 administrations of this drug during the course of the trial.  Fewer than 1 percent of the infusions of drug were associated with grade 3 nausea or vomiting.  5HT3 antagonists such as zofran were the most commonly used anti-emetics for patients who were on this trial.
		Weight loss during treatment is an indirect way of also looking at the nausea and vomiting issue.  And if someone were to have persistent, ongoing problems throughout a six-week course of radiation therapy, one might expect to see a greater level of weight loss in that group of patients.  In fact, what we see is that the amifostine plus radiation group of patients lost less weight than the patients who received radiation therapy alone.
		Hypotension is the other well-recognized side effect of this drug, and with that awareness, patients received PO or IV hydration 30 minutes prior to the administration of the drug.  Overall, 15 percent of the patients had an episode of hypotension.  But again, only 1 percent of the infusions were actually associated with any hypotensive episodes.  Hypotension, if it was moderate, was only seen in 3 percent of the patients, and this was defined as a drop in systolic pressure greater than 20 mm of mercury.  It was transient.  There were no long-term sequelae, and once again fewer than 1 percent of the 4,000-plus infusions of the drug were associated with moderate hypotension.
		Other grade 3/4 adverse effects which occurred with a frequency greater than 1 percent were skin reactions in three percent of the patients and febrile reactions in 2 percent of the patients.  But once again, fewer than 1 percent of the administrations of the infusions of the drug.  And as we would expect, these were not seen in the radiation group.
		29 patients did discontinue their amifostine during the course of this protocol, the predominant reason being nausea and vomiting. I would like to emphasize a most important point, however, which is that 28 of those 29 patients did go on and complete their full course of radiation therapy.  Again, we need to keep sight of the fact that the objective is to give these patients optimal anti-cancer treatment.  So even though 29 patients discontinued amifostine, 28 went on to receive their full cancer treatment.
		There were 50 hospitalizations in the amifostine plus radiation group and 31 in the radiation therapy alone group.  Of note, however, only six of those hospitalizations were attributable to the drug itself.  
		To conclude the safety aspects of this presentation, at a dose of 200 mg per m2, amifostine was well tolerated.  There were no new or cumulative toxicities that were identified during the course of this trial.  And nausea, vomiting and hypotension do remain as the most common adverse side effects attributable to the drug.
		To wrap this all up, we found in the WR-38 trial that amifostine significantly reduced the incidence of greater than or equal to acute xerostomia and late, long-term xerostomia. Saliva flow was preserved to a significantly larger extent in those patients who received amifostine with their radiation therapy.  Patient assessment via the patient benefit questionnaire also indicated clinical benefit to the patients.  Amifostine did not reduce the anti-tumor efficacy, irrespective of whether we looked at local regional control, disease-free survival, or overall survival, and amifostine is safe at the recommended dose.
		I would now like to turn the podium over to Dr. Gary Koch from the University of North Carolina at Chapel Hill, who will provide additional analysis and insight into the statistical aspects of this trial.
		DR. KOCH:  Thank you very much.  Not very often you have faculty from Duke and North Carolina working together.  But it can happen and often does happen and happens quite successfully.  I have assisted U.S. Bioscience as an independent statistical reviewer for the findings of WR-38.  Since the statistical results for xerostomia, as presented by Dr. Brizel, were clearly convincing, I have given primary attention to anti-tumor outcome.
		Showing non-inferiority of amifostine for anti-tumor efficacy was a primary objective of WR-38.  And accordingly, it had well-planned analyses.  I requested some additional assessments to confirm the robustness of findings for non-inferiority from the planned analyses.  These assessments were based on the Kaplan Meier survival curves which were included in the WR-38 study report, the briefing book, and Dr. Brizel's presentation.  They are not new, but they enhance understanding for what you have already seen.
		Their purpose was to clarify how the overlapping or better nature of the Kaplan Meier curves for amifostine than for RT alone convincingly supported the non-inferiority of amifostine for anti-tumor outcome.  Let us now briefly review the statistical results for anti-tumor outcome.
		The analysis plan for WR-38 prespecified the ratio of local regional control proportions at 12 months as the primary criterion.  And these are the proportions that are shown here.  The lower one-sided 95 percent confidence limit for this criterion exceeded the prespecified threshold in the protocol of .70 for non-inferiority, and that is demonstrated here and here for a one-sided confidence interval and here and here for a two-sided confidence interval.  Moreover, these lower limits exceeded .80 as opposed to the specified criterion of .70.  And we can see this for the rates at 18 months as well as those at 12 months.  
		Now these analyses at 12 or 18 months included 127 or 126 of the amifostine patients, and they included 135 or 133 of the control patients.  Thus, losses to follow-up or censoring are relatively small.  That is, there are about 41 or 44 patients or 15 percent of the original 303 patients in the combined groups, rather than being high as possibly suggested in the FDA review.  There were not that many patients lost to follow-up during the 18-month follow-up period shown here.  So censoring tends to be low as censoring is usually understood to be.  Also, over 50 percent of the patients, 77 in the amifostine group and 85 patients in the RT alone group, completed 18 months of follow-up with LRC maintained, and they should not be regarded as having censored time to event data, since they had the most favorable outcome of maintaining LRC for this entire follow-up period.  Also, my understanding is that LRC rates tend to decrease slowly after 12 to 18 months, that is, most failures occur before 18 months.  And so 12 to 18 months is a reasonably mature follow-up period for its evaluation.  As stated previously, censoring for this mature follow-up period was relatively low, less than 15 percent.  And so lack of maturity for follow-up data and excessive censoring are not limitations of this information.
		Now a very important point in the FDA review was that evaluation of anti-tumor efficacy should account for all time to event data for all patients.  And this is best done with the Kaplan Meier curves for the two groups, and they can be seen on the next display as clearly overlapping.  And so these overlapping Kaplan Meier curves provide very clear evidence of what the similarity of maintaining local regional control is for the two groups.  Now the FDA review has expressed some concern that the hazard ratio, as shown here, has a lower confidence limit of .64.  But a hazard ratio is a very difficult concept to interpret in terms of similarity of survival curves like Kaplan Meier curves.  The hazard function can be thought of as the negative slope of the logarithm of the survival curve.  So a hazard function is a negative of the slope of the log of a survivorship function.  That is a hard concept to understand, and the hazard ratio is actually the ratio of two such things.  It is much more informative to understand non-inferiority in terms of what the Kaplan Meier estimates are doing.  So we can look at the ratio of Kaplan Meier estimates at 12 months or 18 months, and note that their lower confidence limit exceeds .89 here or .81 here.  And this is a much clearer way to understand the non-inferiority or the similarity of patterns of survival over the full time course.  It is also compatible with what the confidence interval on the hazard ratio indicated.   And if you are interested in further understanding a hazard ratio, I have a display on a transparency that I could give comments about on that later.  But I would rather you focus on the similarity of the Kaplan Meier curves, as I will proceed in the remainder of this discussion.
		So in the next display, we have the Kaplan Meier curves for disease-free survival.  Again, we note that their lower confidence limits are again above .90 over here for the ratio of the 12-month values, above .80 for the ratio of the 18-month values, and then on the next display for overall survival, we see the overall survival is clearly better for the amifostine group.  And again, the lower confidence limits are in the vicinity of .99 at 12 months, .98 at 18 months.  Very convincing information for non-inferiority of amifostine relative to the control group.  
		And now if we proceed to the next display, ratios of even Kaplan Meier rates are a hard concept to understand.  A usual way to proceed is to focus on the difference in success rates.  So what we proceeded to do was to produce confidence intervals for the difference in the control rates as originally obtained in the analysis plan, and their lower confidence limit is -10 percent here and in the vicinity of -15 percent.  And so we know that the difference in control is no greater than 10 percent based on 12 months and no greater than 15 percent based on 18 months.  
		Now we can help to understand these quantities by recalling guidelines that apply to anti-infective drugs.  For anti-infective drugs, non-inferiority is established if the difference in success rates does not exceed 10 percent when the better of the two treatments has a 90 percent success rate.  Here we have the 10 percent difference achieved by rates that are in the vicinity of 71 percent.  Also, if it turns out that the better of the two treatments has a rate between 80 and 90 percent, then the confidence bound decreases to -15 percent, which is satisfied here by rates in the 60 percent range.  And if the better of the two treatments has a success rate lower than 80 percent, then the guideline for anti-infectives allows a non-inferiority margin of 20 percent.  And so what you see here is these rates which are below 80 percent actually satisfy criteria that are substantially stronger for non-inferiority than the guidelines that are usually emphasized for anti-infective drugs.  
		Now if we proceed to the next display, again we see for LRC rates from the Kaplan Meier curves a lower confidence limit of -10 percent and -15 percent, and on the next display for disease-free survival, a lower bound of -6 percent or -10 percent.  These are very convincing for non-inferiority.  And on the next display for overall survival, we see lower bounds of -1 percent.  We almost start to see a pattern where there is almost superiority in overall survival.  Very clearly there is non-inferiority for overall survival.  And so in the final display, we note that lower limits of one and two-sided, 95 percent confidence intervals are indeed sufficiently high to clearly assure non-inferiority of the amifostine group for anti-tumor efficacy.  Thank you.  I would now like to introduce Dr. Russell, Senior Director of Clinical Research at U.S. Bioscience.
		DR. RUSSELL:  I would briefly like to present some data which supports the ability of amifostine to reduce the radiation-induced xerostomia and in addition summarize the results of two Phase III studies which support the conclusion that amifostine does not compromise the anti-tumor efficacy of the co-administered cytotoxic therapy.
		As you can see on this slide here, this slide illustrates the number of studies that have been undertaken with amifostine where the incidence of xerostomia or reduction in salivary gland function has been looked at as an endpoint.  These studies have been undertaken in an total of 554 patients.  Dr. Brizel has outlined the details of study WR-38 in some detail, and for the purposes of time, I will only concentrate on the study undertaken by Dr. Antonadou.
		This slide outlines the treatment schedule of the study that she undertook. All patients received radiation at standard fractions of 2 Gray a day, to a total dose of 60 to 74 Gray.  Patients received weekly carboplatin at a dose of 90 mg per m2 per week.  Patients were randomized to receive this regimen alone or this regimen preceded by a daily infusion of amifostine administered at a dose of 300 mg per m2 prior to each fraction of radiation or the carboplatin respectively.
		The patient demographics are outlined in your briefing book. But suffice to say that there was no statistical differences in the treatment arms for age, gender, tumor site, tumor state, or nodal status.
		Here are the results of late xerostomia documented at 3 months following treatment.  As you can see, those patients who received amifostine, there was a significant reduction in the incidence of Grade 2 or higher late xerostomia, falling from 83 percent in the control arm to 27 percent in the amifostine arm.  And this result is highly significant.
		We have recently received some updated information from Dr. Antonadou at 9 months and at 12 months for this endpoint.  As you can see, the results that she reported at three months are preserved at these later time points, with reductions from 72 percent to 17 percent at 9 months and 56 percent to 8.3 percent at 12 months, both of these results attaining statistical significance.  
		She also assessed anti-tumor efficacy. And as you can see, using this regimen, all patients sustained a response to treatment.  There were 20 out of 22 complete responses in those patients who received amifostine and 18 out of 23 patients in those patients who received radio-chemo alone.  Local regional control at 18 months has been preserved with local control of 83 percent in the patients who received amifostine and 76 percent in the patients who were in the control arm.
		The safety outline in the study showed that one percent of patients who received amifostine suffered from some nausea and vomiting, and all patients in this study received a 5HT3 antagonist prior to treatment.  Transient hypotension was recorded in 3 percent of patients, but in no patient did they suffer any long-term sequela.  
		So in conclusion, for this study there was significant reduction in Grade 2 or higher late xerostomia, preservation of anti-tumor efficacy, and amifostine was well-tolerated.  And so this small study does support the findings that Dr. Brizel outlined earlier for study WR-38.
		I would now like to move on to the supporter studies for anti-tumor activity.  The first study was undertaken in patients with rectal cancer by Liu, et al.  All patients in this study received whole pelvic radiation plus or minus amifostine at a dose of 340 mg per m2 administered prior to each fraction of radiation, which was 2.25 Gray per day.  All of these patients had metastatic unresectable cancer.  
		As you can see here, there is complete response rate to treatment, with 16 percent in those patients who received amifostine and 10 percent of those patients who received radiation alone.  Median survival for this patient population was 15 months for those patients who received amifostine and 12.6 months for those patients who received radiation alone, and these results are represented on the Kaplan Meier curve here.
		The last study I would like to present is the ovarian cancer study that formed the basis of the previous approval. In this study, all patients received cisplatin and cyclophosphamide plus or minus amifostine administered at a high dose of 9 to 10 mg per m2 prior to each dose of cisplatin. As you can see, with a median follow-up of 41 months, the survival curves are completely superimposable.  
		So we have demonstrated in three randomized, well-controlled, Phase III studies that amifostine does not compromise the anti-tumor efficacy of the co-administered treatment.  I would now like to hand over to Dr. Walter Curran, whose is Professor and Chairman of Radiation Oncology at the Kimmel Cancer Center, and in addition Chairman of the Radiation Therapy Oncology Group.
		DR. CURRAN:  Members of the committee and the FDA, I just want to make a few brief comments related to my observations regarding the ability of this agent, amifostine, to protect against the subsequent development of radiation-related xerostomia in head and neck cancer patients.
		If you can have the slide off, I just have a couple of slides I will present later in my comments.  I am a practicing radiation oncologist whose practice includes head and neck cancer patients, and I also serve, as Dr. Russell mentioned, as the Group Chairman of the RTOG.  This is a cooperative group that seeks to improve outcome among patients afflicted with six major diseases among adult cancers, and some of our studies include ways to reduce or modify treatment-related toxicity.  
		I just want to say a couple of additional comments regarding xerostomia.  The minimum radiation dose used to treat head and neck cancers is 50 Gray.  And if salivary gland is included within the radiation field, that dose is largely lethal to salivary gland function.  Since the majority of head and neck cancer patients receive radiotherapy as part of their management, most head and neck cancer patients are at risk for xerostomia.  
		Xerostomia, as you have already heard, can be both permanent as well as devastating, causing problems with fissures in the lips and mucosa, difficulty with swallowing, the need for oral comfort agents, and really a need to change the lifestyle of patients afflicted with this.  There is no approved therapy to reduce the risk of radiation-related xerostomia.  There is one approved therapy for the management of xerostomia once it is established.  However, that therapy requires frequent dosing and in most cases patients still need to take large quantities of liquids without really a satisfying effect.
		It is clear that all of us who treat such patients need some other effective approach to reduce xerostomia.  Now if you look at WR-38 as presented by Dr. Brizel, it is my view that it presents convincing data that Grade 2 or worse xerostomia is reduced by the application of this agent during radiotherapy.  Many of us who followed this study and did not participate in it had hoped for such an effect, but I was personally surprised at the magnitude of effect of the agent in this study.  Many of you are familiar with the difficulty in reducing or modifying cancer therapy-related toxicity, and it was certainly gratifying to see such a positive result in this study.  And this data, along with the data presented by Dr. Russell, certainly provides a strong core of evidence to support this agent's use in reducing xerostomia risk.
		I want to spend a couple of minutes just discussing the issue of local/regional control, which was presented by Dr. Koch and Dr. Brizel as well.  Clearly we see that there was an equivalent local/regional tumor control rate between the amifostine-containing arm and the control arm.  But to further establish the fact that anti-tumor effect was not compromised by amifostine -- if I could have the first slide, please.  Tom Pajak, the chief biostatistician at the RTOG did an analysis of over 500 patients who were entered into RTOG trials in the past.  These patients had similar pre-treatment characteristics as patients entered into WR-38.  And what is shown on this figure is the local regional tumor control rates with the yellow figure showing the RTOG data base with the one-year local/regional control rate of 68 percent, 62 percent at two years.  The yellow numbers down here are the numbers from the WR-38 study, in which one-year and two-year local regional control rates were nearly identical at 71 and 61 percent respectively.
		Now the other issue that I think is relevant is whether adequate follow-up of the WR-38 patients has been done in order to assure ourselves that we have seen the patients that are at risk for local/regional failure.  This is from the same RTOG data base of over 500 patients analyzed by Dr. Pajak.  And it looks at at what time point patients suffered local/regional tumor failure.  Out of all those patients who suffered a failure, 78 percent in this cohort of over 500 patients suffered it during the first year and over 90 percent during the first two years.  And when you consider that in WR-38 the median follow-up time available is 26 months, the minimum follow-up time 18 months, clearly we have those patients at an adequate time point to see what their risk for failure was.
		So in summary, it is my view and the colleagues involved with head and neck radiotherapy that I have spoken to that the data regarding protection from xerostomia is convincing from WR-38.  It is also a -- there is also a safety profile of the amifostine, which appears manageable from our point of view.  Keep in mind that the doses of amifostine necessary to reduce the risk of xerostomia are less than the doses required to reduce the risk of cisplatin-related nephrotoxicity.  And the RTOG has found the profile emerging on amifostine sufficiently interesting that it is currently testing this agent to reduce toxicity in two other disease sites.
		DR. OSTER:  I would now like to conclude our presentations, and I promise I will be very brief. The supplemental NDA for amifostine which we presented to you today represents a new indication for a drug which is already approved in cancer.  Amifostine gives the opportunity to reduce the incidence of a severe, irreversible morbidity, xerostomia.  Our pivotal trial, WR-38, plus the supportive body of evidence contained in this SNDA confirms the efficacy of amifostine against the toxicity of xerostomia.  All studies consistently report positive xerostomia results with amifostine.
		In study WR-38, we showed with several different endpoints statistically highly significant results for acute xerostomia, late xerostomia, saliva production, and the patient benefit questionnaire instrument.  These independent endpoints showed a strong correlation amongst each other.  We believe that these findings are clinically meaningful and provide the patients with a true clinical benefit.  
		The studies contained in this SNDA also provide reassuring evidence of safety in our radiation program.  Indeed, the toxicities with amifostine we observed at the dose used in radiation were substantially less in incidence and severity than for the higher doses typically used in our labeled indication in chemotherapy.  
		Two randomized studies with 100 patients and 242 patients were available for the initial approval showing no evidence of tumor protection.  The relevant follow-up endpoints chosen in these two studies were survival.  WR-38 is the third well-controlled clinical trial, comprising more than 300 patients.  Tumor outcome measures included local/regional control rates, local/regional control over time, disease-free survival and overall survival, all of which show no evidence, not even a hint, of reduced anti-tumor activity.  We believe the clinical data presented today are reassuring that amifostine indeed preserves anti-tumor activity.
		Amifostine was designed by the Walter Reed Institute here in Bethesda as a radioprotective agent.  It took this product and the investigators involved in the radiotherapy program with amifostine a long journey to arrive before this committee.  We believe that this SNDA shows that amifostine is safe and effective in the following radioprotective indication.  To reduce the incidence of moderate to severe radiation-induced xerostomia.  I thank you very much for your attention, and we are now prepared to entertain your questions.  
		CHAIRPERSON DUTCHER:  Thank you very much.  We appreciate your keeping up with the time.  You did a very good job.
		DR. OSTER:  Thank you.
		CHAIRPERSON DUTCHER:  Questions for the sponsor?  Yes, sir?  Dr. Harwood?
		DR. HARWOOD:  I would like to ask the radiation oncologists who have presented why there is such a small number of definitive radiotherapy patients in this trial?  As you will observe, two-thirds of the patients entered into the trial were post-operative patients.  Only one-third of them were definitive radiotherapy patients.  And there were only five patients with cancer of the nasopharynx -- I think 11 patients with cancer of the nasopharynx, which would be the group that I would have thought would have benefitted perhaps the most.  And also, I would like to ask why it has had such relatively poor support amongst the head and neck radiation oncologists in this country?
		DR. OSTER:  I would like to call upon Dr. David Brizel to respond to these questions.
		DR. BRIZEL:  You may have to help me remember everything, but I will do my best here.  I don't know if they will be in the order in which you asked, but I think that a large component of the answer to your question relates to the fact that for patients who are resected, post-operative radiotherapy is fairly standardized and it is fairly standard to give once daily radiation therapy.  Now when we switch gears and go to the group of patients who are receiving definitive radiotherapy, as a head and neck radiation oncologist I am sure you are aware of the fact that there are a lot more competing entities out there.  For early stage disease, once daily treatment is still fairly standard.  However, when we get into the realm of more advanced stage disease, T2 disease and on up, then we start getting into competition for modalities such as hyperfractionation or accelerated fractionation or radiation with concurrent chemotherapy. And depending upon institutional policies and biases, there is direct competition for what actually compared to other cancers is a relatively small subset of patients. I mean, there are only 40,000 head and neck cases in the United States each year, of whom roughly only 10 to 15 percent actually are enrolled on clinical trials.  So I think that is why we see more post-op patients than we see definitive curative-intent patients.
		Now the other question I believe that you asked related to nasopharynx cancer.  And certainly with those big large fields that we put on for those patients with the whole parotid gland, including the patients in the next room sometimes, yes, that is a real problem.  However, again, we are into the issue of competing protocols.  And again, this trial ran from 1995 through 1997, at which time people were becoming aware, especially through the intergroup randomized trial, that there was a very definite clinical benefit associated with the use of radiation and concurrent chemotherapy, and that would have immediately and automatically excluded patients from  participation in this trial.
		As far as the last question that you asked me, I believe that was why was this trial so poorly supported.  I don't know.  Maybe I have my blinders on.  We were very enthusiastic supporters of it, and I can only speak to my institution.
		DR. HARWOOD:  Yes, there is a lot of -- there is a lot of patients been entered from overseas.  Let me just follow-up with -- it seems to me that the main worry about this drug is this issue of tumor protection.  And I am not sure that you are going to be able to determine the issue of tumor protection on patients that have had the gross bulk of their disease resected and are being given postoperative radiation.  So it seems to me that that issue has to be addressed in the patients who have not had their disease resected who are being treated with definitive radiotherapy, who would have a cure range in the range of 50 percent.  And it would be that group that I would be worried about the potential for tumor protection.  And I would also be worried about that spreading of the survival curves occurring after 18 months. You know, we only have 18-month follow-up here.  I know in post-operative patients, that may be adequate.  But would you be comfortable taking a  T2N0 tonsil cancer with a 50 to 75 percent chance of cure whose salivary glands are going to be radiated and give them amifostine?
		DR. OSTER:  Dr. Curran?
		DR. CURRAN:  Yes, Dr. Harwood, with respect to the first concern you had that there was a large proportion of patients who were pot-resection receiving radiotherapy.  The RTOG data base of over 500 patients that I showed on those two slides matched patients according to whether they were definitively irradiated or received post-op treatment.  The two RTOG studies that we derived that data from, one was a post-operative study looking a RT plus or minus chemo, and the other was a definitive study.  So when we looked at the local/regional control rates, and I showed you the one/two-year local/control tumor rates, those were based on a match of the proportionate post-operative versus definitive cases.  So that even when we match with a much larger data base of American and Canadian treated patients, the local/regional control rates are basically superimposable.
		And the other issue is when you talked about the issue of the bulk of tumor being removed, those times to local failure that I showed you in the pie graph also include a majority of patients receiving postoperative radiotherapy.  So still over 90 percent of the tumor failures occur within the first two years, even when a majority of patients are receiving postoperative radiation.
		Now as far as the question about a T2 tonsil patient, again there is no suggestion in WR-38 that I am aware of that would suggest that there is a compromise of that definitive radiotherapy for that patient, and there is no suggestion that there is going to be some difficulty in getting treatment delivered over the tight time frame that you are going to want to deliver the treatment for that kind of patient.
		DR. HARWOOD:  One last question.  I noticed that Dr. Antonadou's name comes up, and I noticed that she was given reference #5, and the reference #5 is anonymous.  I wonder if you could share with us where Dr. Antonadou comes from and why she isn't here and where that data has been published?
		DR. OSTER:  The data were actually reported at the previous ASCO meeting and we, U.S. Bioscience, obtained data printout and we also received the protocol and we wrote up a report, and this is the basis of our presentation here.  Dr. Lesley Russell has analyzed the data, and she may be able to extend on this if you have any further questions.
		DR. HARWOOD:  Where is Dr. Antonadou?
		DR. OSTER:  Dr. Antonadou was trained in Paris in Guildruff, and is currently practicing in Athens.  
		DR. HARWOOD:  Thank you very much.
		DR. LIPPMAN:  I wonder if you could comment on what I think is one of the major challenges in the conduct and interpretation of studies like this that the primary endpoint is obviously a subjective one and the study is unblinded.  And so -- and further, since the RTOG scale is certainly well accepted in this country, I am not sure how well accepted or what kind of experience centers, for instance, in Germany, who contribute a large number of patients, have with this.  And since the data are very compelling with the issue of folks in a Grade 2 and on the face of it, Grade 1 being mild and Grade 2 being moderate, there seems like there is a lot of potential for subjectivity and potential bias unintentional.  So the question is what sort of measures were taken to make sure that there was consistency in the measuring of this primary endpoint?
		DR. OSTER:  David?
		DR. BRIZEL:  I think that is a really important question, and it was a question that I asked as well as I initially became involved in this trial.  At each institution at the on-study visit, if you will, each of the investigators at that institution received instruction and review as to what the RTOG scale is so that people were familiar with it.  The fact that it was unblinded is actually an interesting one.  Speaking as an investigator who put patients on the trial, when patients came back for their follow-up during the treatment, just being in a busy practice I tended not to look at what they had. And when I saw the study nurse in the room, I knew they had been on the study.  But if I guessed as to which treatment patients had received or not, I was wrong as often as I was right.  
		The other issues, though, that I think really bear on this are the fact that all of the supportive endpoints all go and point in the same direction.  We saw the slide that showed the high level of correlation between late xerostomia and saliva production, late xerostomia and patient benefit questionnaire score.  All of those -- I would be a lot more concerned about this if we saw xerostomia getting better and saliva getting worse or things going off in different directions.  But they were all consistent.  And again, the last point that I would make is that the large number of institutions that participated is actually beneficial in this respect.
		CHAIRPERSON DUTCHER:  Dr. Schilsky?
		DR. SCHILSKY:  I just want to follow-up on Dr. Lippman's question, since I am not a radiation oncologist and I have never had the opportunity to use the RTOG scale.  So maybe you could explain a little bit further.  Grade 1 is -- we are talking about acute xerostomia.  So Grade 1 is mild mouth dryness and Grade 2 is moderate mouth dryness.  What is the difference?
		DR. BRIZEL:  A great question.  And it is a semi-quantitative system and it is not a perfect system.  The Grade 2 is moderate to severe dryness.  Mild dryness, if you look in a patient's -- first of all, the patient tells you.  So there is that aspect of subjectivity to it.  But with mild dryness, when you look in the mouth the saliva may be a little thick.  Moderate to severe dryness -- I mean, if you can find it at all -- first of all, we saw the tongue where there is nothing and the tongue blade sticks to the tongue.  But if they do have any saliva, quite often it is like a rope.  It is real ropey.  
		DR. SCHILSKY:  So is this -- is this a grading scale that is determined by the examiner, by the patient, by the interaction between the two?  And can you tell us, has it ever been looked at with respect to intraobserver variability?  If you sent two different people or two different examiners in to examine the same patient, how consistent would the grading scale be between the two examiners?
		DR. BRIZEL:  Actually, I would like you to -- that is intriguing.  But could you please ask the first part of the question one more time?  Is it related to the -- who determines the scoring, is that it?
		DR. SCHILSKY:  Yes.  How is the scoring actually done?
		DR. BRIZEL:  It is the physician who actually assigns the score, but it is based on an interaction between the physician and the patient, consisting of both historical information from the patient and the physical findings.  
		DR. SCHILSKY:  And with respect to whether it has ever been validated across observers?
		DR. OSTER:  We have some experts who really -- we have some experts here with us, Dr. Kent and Dr. Le Veque, whoever wants to comment further on this.  They really have expertise in this area and I think they are able to respond to this question in further detail.
		DR. SCHILSKY:  I would like to hear it.
		DR. OSTER:  Dr. Kent?
		CHAIRPERSON DUTCHER:  Please for the recorder state your name and affiliation.
		DR. KENT:  I am Kenneth Kent.  I am a maxillofacial prosthodontist heading the Maxillofacial Reconstruction Center at the University of Pennsylvania Medical Center.  Xerostomia is a very subjective entity.  There have been numerous attempts in the literature to more accurately define objective criteria.  However, for the very dry patient, there is almost no saliva to measure.  When you are looking at mild versus moderate to severe, there is relative ease in determining differences between the two.  I could not testify to literature citations on this.  However, having spent more than 20 years educating clinicians, both medical clinicians as well as dentists in the evaluation and management of xerostomia, it is relatively easy to train someone in a standard fashion.
		DR. SCHILSKY:  Could I just ask one follow-up question with respect to the criteria for late xerostomia?  Because looking at the criteria again, it seems to me that the grading is sort of a two-parter.  Because the grading says -- for example, Grade 1 is slight dryness of mouth/good response on stimulation.  And Grade 2 is moderate dryness of mouth/poor response on stimulation.  So is that an either/or or is that an and represented by that slash?
		DR. OSTER:  Dr. Le Veque?
		DR. LE VEQUE:  Could you rephrase that or repeat that for me, please?
		DR. SCHILSKY:  Yes. Well, I am just reading the criteria.  So for late xerostomia, Grade 1, it is slight dryness of the mouth/good response on stimulation.  And Grade 2 is moderate dryness of the mouth/poor response on stimulation.  So since those are two different things, the question is to be Grade 2, for example, is moderate dryness of the mouth sufficient to be Grade 2, or do you have to have moderate mouth dryness and a poor response on stimulation?
		DR. LE VEQUE:  Well, I think that in looking at the RTOG late criteria, the inference is that in Grade 1, patients can be stimulated via gustatory stimulation or neurotransmitted stimulations, so on and so forth.  Whereas in Grade 2, those attempts at coercing saliva would likely not work.  Again, as Dr. Brizel pointed out, this is a semi-quantitative scale.  And as Dr. Kent also pointed out, understanding the scale is in large part being able to make the assessment visually.  Because there is no attempt to actually quantify the saliva.
		CHAIRPERSON DUTCHER:  Excuse me, could  you just give your name and affiliation for the reporter?
		DR. LE VEQUE:  I am sorry.  I am Francis Le Veque. I am a clinical associate professor of oncology at Carmenos Cancer Institute in Detroit.
		DR. SCHILSKY:  This is part of my concern with respect to these data sets.  This is the primary endpoint.  About two-thirds of the patients were enrolled outside the U.S.  I don't know how experienced those investigators were with applying the  RTOG criteria.  And at the great majority of centers that did participate in the study, most of the centers enrolled fewer than 10 patients on the study.  And again, of course they may treat many other patients with head and neck cancer and use the RTOG criteria routinely.  I just don't know and I am trying to get a sense of -- since this is really the primary efficacy endpoint, I am trying to get a sense as to how reproducible it is and how easy it is to apply it and how likely it is that different investigators will apply it in the same way and so on.  
		DR. CURRAN:  One comment I could make, Dr. Schilsky, is that even though on this slide of the Atlantic we call these the RTOG late toxicity scoring scale, on the other side of the Atlantic, they are called the EORTC scoring scale. So it is not unlike the performance status criteria which are sometimes called ZERBRA and sometimes ECOG and sometimes COBG.  I don't know details about the German investigators, but it is my understanding they are experienced head and neck radiation oncologists.  But I think that this is admittedly a semi-quantitative/semi-qualitative assessment.  But even if we all sat in the room and designed the study impeccably today, we would be left with the same semi-quantitative data.  And when you have -- you know, as a non-participant, when you see such a consistent difference in observation, that is convincing to me because I don't think interobserved variation is as substantial as we suspect.  Because in reality in the clinics, patients are dry or they are not dry.  And the distinction is not as hard as one may think.
		CHAIRPERSON DUTCHER:  Dr. Margolin?
		DR MARGOLIN:  Along the same lines as -- not so much the quantification, which of course I share the same concerns about and also would wonder about what happened to the stimulated saliva production if it is used as part of the definition.  But more importantly, on page 19 -- I don't know the slide number, but it is on the left side -- in which the .1 gram threshold was being looked at as representing a worthwhile threshold from the dental consultant, of the approximately two-thirds of patients in each randomization arm that started in the study and got to the one-year mark by the previous slides, only two-thirds of those in the amifostine arm and less than half of those in the non-amifostine arm had measurements of the unstimulated saliva production.  And even though the numbers look nice, I would be concerned about their incompleteness.  I don't know -- I assume the FDA reviewer is going to do that, but I would like to know what the sponsor has to say about that.
		DR. OSTER:  Yes.  It is a very important question and we obviously asked ourselves this question as well, and Dr. Lesley Russell has some information in this regard.
		DR. RUSSELL:  We obviously looked at the reasons for data being missing at this time point.  And if I could have slide 130, please.  As you can see, of the patients in both groups, the reasons for missing data in both treatment groups was either that the patients had died or had had progressive disease and had gone on to receive probably some further treatment and thereby were not participating in this actual assessment.  The other reasons for incompleteness of data are relatively well balanced between the two treatment groups.  And as patients in any trial, some are lost to follow-up.  And then were just unable to perform this test.
		CHAIRPERSON DUTCHER:  Dr. Santana?
		DR. SANTANA:  My question was already answered -- asked.
		CHAIRPERSON DUTCHER:  Ms. Beaman?
		MS. BEAMAN:  Yes. In reference to one of the trials, I noticed that over half of the patients dropped out.  You noted that 1 percent suffered from nausea and vomiting and then 3 percent hypertension.  But would that be enough to account for over half of the dropouts in one of the trials you noted?
		DR. OSTER:  I am sorry, can you repeat your question, please?
		MS. BEAMAN:  Yes.  Page number -- I'll find it.  Go right ahead.  I'll come back to that.
		CHAIRPERSON DUTCHER:  Dr. Lippman?
		DR. LIPPMAN:  I would just like to come back for a moment to the primary endpoint and the scale.  Although Dr. Curran has sort of put this into a two point system, you are either dry or you are not dry, the system clearly states Grade 1 as being mild and Grade 2 as being moderate.  The question I guess I have is was there an investigator meeting or with the research nurses or the physicians from the different countries just with pictures like Dr. Brizel showed or some sort of sense of we know it is qualitative and we know it is not perfect, but these are -- just so we are all on the same page, these are the criteria we are using?
		DR. OSTER:  A very good question.  Dr. Russell?
		DR. RUSSELL:  There was one -- there was certainly one major investigator meeting held before the start of the study for the European sites.  And then prior to trial initiation at each of the sites, an initiation visit was done where the scale was gone over in great detail with both the investigators and the study coordinators.
		DR. LIPPMAN:  And then just a follow-up, I guess the reason why that is so important is I gather the analysis -- the FDA analysis looking at all xerostomia versus none was not as convincing as the Grade 2 or greater.  So that distinction between mild and moderate becomes very important. So it is nice to know that you had that meeting.
		CHAIRPERSON DUTCHER:  Dr. Ozols?
		DR. OZOLS:  Dr. Curran, you said that the RTOG is doing some more studies with WR amifostine looking at other protective effects.  If we approve it today, what will that do to those studies?  Do you think they will decrease and could you tell us what those trials are?
		DR. CURRAN:  Yes, Dr. Ozols.  The current Phase III trial within RTOG is looking at amifostine as a potential protectant against combined modality esophagitis and pneumonitis in patients with locally advanced non-small cell lung cancer.  Since there is no data -- and it is a randomized study with or without amifostine.  Since there is no data in this study related to that question, it is my hope that action today would actually help that study rather than hinder it.  We have pilot data from two institutions on it, but no convincing data that makes me think we don't need a randomized study in that area.  The other area which is under investigation is to reduce radiation related proctitis and cystitis in men receiving radiation for prostate cancer.  Again, data is only preliminary and at single institutions.  So I think more work needs to be done in that area as well.
		CHAIRPERSON DUTCHER:  Dr. Sledge?
		DR. SLEDGE:  I have a number of toxicity questions.  I guess the first relates to the PVQ scale.  Does the PVQ scale summate benefit and toxicity or is it just benefit?
		DR. OSTER:  Dr. Mackowiak?
		DR. MACKOWIAK:  There are eight different items, as you know.  Three of them were symptom questions.  So to the extent they measure the patient's perception of their toxicities.  And also, the other three activities of daily living and the need to use external fluid are probably the best measure of benefit.  The two happen, of course, as we assessed in factor analysis, in a highly correlated way.
		DR. SLEDGE:  I may not have made myself clear.  Do they -- are all of the factors that are being measured in essence related to head and neck type symptoms or do they include things such as the nausea and vomiting, the hypotension -- how patients experienced those?
		DR. MACKOWIAK:  You are right on the first part.  They are all assessed -- the head and neck symptoms related to radiation toxicities.
		DR. SLEDGE:  Okay.  I guess the second question, the nausea and vomiting that was seen in this trial, is this -- I saw 15 patients discontinued therapy due to nausea and vomiting.  Is this sort of nausea and vomiting that could be controlled with standard anti-emetics?  And if so, was that allowed in the course of the study?  To what degree were anti-emetics allowed?
		DR. RUSSELL:  We actually formally recommended that anti-emetics be administered to all patients on the amifostine group.  This was not done in 31 patients, and we know that 31 patients actually received no anti-emetics.  And of those 31 patients, actually 25 reported no nausea and vomiting.  If we look at patients who did receive anti-emetics -- and if I could have slide 175, please -- we can see -- and I don't know if this includes the 15 patients or not, but probably not.  We can see that for those patients who received 5HT3 antagonist, they clearly did have some amelioration of nausea and vomiting.  The 61 percent of those patients who received a 5HT3 antagonist as a single agent reporting no further nausea or vomiting.
		DR. SLEDGE:  And a third question related to toxicity.  Comparing the amifostine and the control group, there is a difference of 19 patients in terms of number of patients hospitalized.  But the slide said that only 6 of these were attributable to the amifostine.  If that is so, what are the other 13 attributable to?
		DR. RUSSELL:  The hospitalizations occurring in both treatment groups were largely related to a side effect of radiation.  So if they had oral mucositis or oral pharyngitis and perhaps required some feeding supplementation.  And then there were other admissions for other co-morbid conditions related neither to radiation or to amifostine.  And in some of these patients, they were related to their underlying tumor.
		DR. SLEDGE:  Help me out a little bit here.  This seems to be a fairly major difference.  And you are saying that amifostine markedly reduces acute oral pharyngeal toxicity.  So --
		DR. RUSSELL:  No.  Our data actually show that the incidence of both oral mucositis and pharyngitis is actually largely comparable between the two treatment groups.
		DR. SLEDGE:  Again, I guess I am still confused.  Why the major difference then in hospitalization?  I mean, it is a pretty marked difference.
		DR. RUSSELL:  I am at a loss to explain the difference at this point in time.  What we do know is that the incidence of Grade 3 mucositis and pharyngitis was the same between the two treatment groups.  And if you look at the index of weight loss that we observed, one would suggest that both nausea and vomiting and pharyngitis or mucositis wasn't having that major an impact on the patients who received amifostine, because actually they suffered less weight loss.  So like you, I am a little -- I can't explain the difference in the hospitalizations.
		DR. OSTER:  If I can just add to this.  Obviously I think you are referring to probably the medical reviewers assessments and our assessment?
		DR. SLEDGE:  I am referring to your slide on page 30.  It says 50 versus 31 in terms of hospitalizations.
		DR. OSTER:  Can we see slide 50 again?  But again, I think the important point to make is obviously the amifostine-related.  And we went through these case record forms page by page to verify that only six patients were hospitalized because of amifostine-related toxicities.
		DR KROOK:  But the issue is why -- why?  Was it because of drug, nausea, vomiting?  
		DR. RUSSELL:  Sorry, are you wanting to know the reason for the six amifostine-related --
		DR KROOK:  I guess I would like to know to follow-up on Dr. Sledge, why six in that arm?
		DR. RUSSELL:  Who were amifostine-related?
		DR KROOK:  Right. But was it nausea/vomiting?  Was it leukopenia?
		DR. RUSSELL:  No, I can tell you those.
		DR KROOK:  Okay.
		DR. RUSSELL:  Two of those six patients, actually right at the end of their treatment or two or three days following their treatment, so they were still considered related toxicities, experienced a skin type reaction.  One of the patients had an erythema multiform, but was also receiving carbomazepine.  So the investigator was actually unable to say which definitely caused this reaction.  The other four admissions, two were related to some nausea and vomiting and other general conditions.  It wasn't necessarily an amifostine-related nausea.  And the other two were an irradiation type reaction.  Whereas you know, when you assess these patients you have a possibly/probably/definitely related problem to take, and they took the possibly related problem because they were unable to rule out the contributory effect.
		DR. SLEDGE:  Is this a statistically significant difference in hospitalization rates?
		DR. RUSSELL:  I am unable to say.  I didn't run a P value beside this.
		CHAIRPERSON DUTCHER:  Dr. Nerenstone?
		DR. NERENSTONE:  Continuing on about the safety questions, hypotension was noted to occur in 15 percent of patients despite being prehydrated.  Can you tell us what hydration they received, how long, and what the overall additional time patients needed to be in the clinic to get their hydration, their anti-nausea medicine and the amifostine before their radiation therapy?
		DR. BRIZEL:  Typically the patients received 500 cc of hydration either orally or intravenously -- orally water and intravenously saline.  And this was given rapidly.  As the slides in my presentation showed, 15 to 30 minutes prior to the administration of the drug.  Since the drug was given 15 to 30 minutes prior to the administration of radiation, altogether we would be looking at a period of an extra 45 to 60 minutes.
		DR. NERENSTONE:  With mucositis being such a problem in a lot of these patients, were a lot of these patients able to tolerate oral hydration?
That is a lot of water.
		DR. BRIZEL:  That is something that can evolve over time.  All of these patients did have PIC lines. I cannot comment on the actual hard numbers, but what one might expect is that towards the initiation of therapy, usually with once a day radiation it takes around two weeks or so for serious mucositis to start to become manifest. And so towards the later phases of treatment, since many of these patients had their PIC lines anyway, you would be giving it IV usually.
		CHAIRPERSON DUTCHER:  Dr. Krook?
		DR KROOK:  Actually you answered part of my question that they all had PIC lines in.  But going back to Mrs. Beaman's question about withdrawal, certainly those of us who have put VADs in people, we certainly have problems with PIC lines and VADs.  And certainly some of the withdrawals might have been related to just this extra hour and excuse my midwestern fussing around with the extra hour or two that it takes, having met the radiation beam myself, getting through their quick was one of the nice things to do.  And certainly if I were on a treatment arm that was an hour or two before, that certainly would add to my feelings.  There must have been a few withdrawals just because of that extra inconvenience.  But again, I am looking at table 18 in the book that says the withdrawals are only 27.
		CHAIRPERSON DUTCHER:  Mr. Gruett?
		MR. GRUETT:  You brought up a study of 4,000 people on vomiting.  You passed that by quite rapidly.  Were there other studies being done on these 4,000 people and are there other studies that you have done that have shown negative information?  I have had a very difficult time following all of the charts and the information because it varies so rapidly.
		DR. BRIZEL:  First of all, I apologize if I did not make that as clear as I should have. It was actually what I said was that within the context of this trial, there were over 4,000 administrations, doses of the drug, that were delivered to the patient, not actually that there were over 4,000 patients on the study.
		MR. GRUETT:  You brought that up in the vomiting discussion when you were given your presentation.
		DR. BRIZEL:  In the toxicity.
		MR. GRUETT:  So do you have follow-up on that 4,000 and the statistical data mentioning what the limit of vomiting was?
		DR. OSTER:  Limit of vomiting?  Sorry.
		MR. GRUETT:  Yes, when you brought up the 4,000 patients, you were bringing up also -- you were discussing the vomiting in this discussion.  And I was wondering if you have more information or statistics confirming this.
		DR. OSTER:  I think Dr. Brizel only wanted to say that whereas when you look at the percentage by patient, it may occur -- you know, the percentage as it is given to you, which I think is in the range of what was it again?  Nausea and vomiting?
		DR. RUSSELL:  It was 8 percent.
		DR. OSTER:  8 percent Grade 3.  But when you then look at the incidence by infusion, you find that it is less than 1 percent.  In other words, those patients who have experienced nausea and vomiting in one course, may have taken the next time a 5HT3 receptor antagonist and were then doing well and didn't have a reoccurrence of their nausea and vomiting.  That is also an experience which we have from our post-marketing experience and from other trials in chemotherapy.
		MR. GRUETT:  Another thing that I was trying to find out in your statistics is actually what is the percentage of people that are affected by your drug.  I interpolated it to be 23 percent, but I could be wrong on my understanding there.
		DR. OSTER:  I think the Grade 3 nausea and vomiting, as we presented, was 8 percent, right?  8 percent.
		MR. GRUETT:  No, in the curing of the drug -- the stopping of the dryness.  Those who were successfully affected by using the drug.
		DR. OSTER:  Okay.  Roughly you can say you have 30 percent of patients less with acute, severe xerostomia and 30 percent less with late xerostomia.  So the treatment affect is roughly in this range.  30 percent less of patients have this toxicity.
		CHAIRPERSON DUTCHER:  Dr. Schilsky?
		DR. SCHILSKY:  Just a question to clarify a little bit about the PVQ.  And again, I think part of what I am grappling with and I suspect others are is the fact that this was an unblinded study and we have very subjective endpoints.  Therefore, it is really difficult to determine what is an actual effect of treatment and so on.  So the PVQ, as best as I can see from the briefing document, is a 10-item scale.  And a high number is good.  That means if you are a 10, you are not having any problems.  And so as I look at some of the charts that were shown, first of all the mean values rarely go below 5.  And in most cases, they don't go below 6.  So that would tell me that the average patient is actually not reporting much in the way of discomfort, side effect and so on, because they are at the high end of the scale.  
		Second of all, the difference between the curves tends to be about one unit.  So I wonder if there is a way you could help us interpret the clinical significance of saying that you are having a six-day versus a seven-day.
		DR. OSTER:  Before I ask Dr. Mackowiak to respond to this, let me remind you, if I may, that we obviously were aware of the fact that some of the assessments may be criticized to be subjective, and that is one reason why we have in this study not only assessed xerostomia with various modalities, three, but we also assessed basically two different events, acute xerostomia and late xerostomia, at a number of defined endpoints. And I think we can say here, based on the consistency which we have through our time points and on the consistency which we have throughout measurements, and based on the correlation which we have between the measurements, that this is a set of robust data.
		DR. SCHILSKY:  Although it could just be a systematic bias that all goes in the same direction.
		DR. OSTER:  In terms of when you have a triple or when you have a P value on acute xerostomia which is below 0001 and a P value for late which is below 001, I think it is probably unlikely that you find this just by bias.  But I would like to ask really John to comment on the question which you posed. 
		DR. MACKOWIAK:  On the bias question, in a short-term pain study if there was a one-day duration maybe I could see that happening very quickly.  But you have to remember these patients received amifostine over a six-week period of time and then we are asking them 12 months or 11 months after treatment ended are you different.  And as you can imagine, I don't think that a placebo effect can act that long.  As far as -- are there others who -- because I will put the chart up if you would like.
		DR. SCHILSKY:  I think that is a valuable point you made.  My other question is what -- just in general, could you give us a way of interpreting the clinical significance of a one point change in the scale?  Because whatever scale you used, there rarely seems to be more than about a one point difference.  So what is the clinical significance of a 7 versus a 6 or an 8 versus a 7?
		DR. MACKOWIAK:  I am going to put up slide 45 to show the -- the slide one before this one first, and then we can go back to that.  What we saw first was patients started -- the range was 10 to zero.  I didn't show the bottom end of this scale.  But patients even prior to radiation reported on average 9. Again, these are averages.  Right as you would expect, we see a 3-point drop in the scores for the amifostine treated group and a 4 point drop for the control group.  The clinical significance of that after radiation, that one point difference that we showed is roughly one grade level.  So that change from mild to moderate.  When I looked at the scores, the actual patient scores, the standard deviations around these are quite wide.  And that is part of the reason why the statistical significance is affected.  Because patients are affected very, very differently from patient to patient.  Is there anything else I can add to that?
		DR. SCHILSKY:  Go to your next slide.
		DR. MACKOWIAK:  Oh the next slide, exactly.  Thank you.  Thank you for reminding me.  This is the RTOG xerostomia toxicity grades.  Again, we look for consecutive visits where a clinician observed a change.  And I don't know which one validates which, but my version of it, since I usually live in a PVQ world, I think they both validate each other.  You can't have both of them accidentally coming to the same conclusion all the time.  We saw one grade level worse or a one point decrease.  One grade level improvement or one point increase.
		DR. SCHILSKY:  I think all you can really say from that is that they seemed to go in the same direction.  I wouldn't stress the one to one because you are dealing with two very different scales.
		DR. MACKOWIAK:  They are very different scales.
		DR. SCHILSKY:  It is basically a 3-point scale versus a 10-point scale.  So I might say that if somebody had a one grade level worse on the RTOG scale, I might have expected that they might have had much greater than just a .96 fall in the PVQ scale.  That doesn't strike me as being much of a change at all.  Whereas going from a grade 1 to a grade 2 on the RTOG scale would presumably be a much bigger change.
		CHAIRPERSON DUTCHER:  Dr. Simon?
		DR. SIMON:  I had a couple of questions.  One, what did the protocol say in terms of when the final analysis would take place in terms of the anti-tumor effect?  Did it name a number of events, as protocols frequently do?  Number of recurrences?  What did it specify?
		DR. RUSSELL:  The primary protocol-defined endpoint was the incidence of local/regional control at one year.  There was no predefined number of events.
		DR. SIMON:  And when would that final analysis take place? Did the protocol specify when the final analysis would take place?  Would it take place when all patients had been followed for one year or two years?
		DR. RUSSELL:  When all patients had been followed for two years.
		DR. SIMON:  But that has not happened yet, is that right?
		DR. OSTER:  Well, what we have done is obviously we have analyzed the information for one year and for 18 months, and to corroborate the meaningfulness of this observation, we have looked into the RTOG data base, which we have shown to you, which basically says two observations.  Number one, 75 or 78 percent of all of the events in this patient group have been in the first year. So there is not much action in the curve after one year.  Less than that happened after 18 months. And when you then compare the curve which Dr. Curran showed matched with a matching population from the RTOG experience to our patient population, it is superimposable.
		DR. SIMON:  But this is before the time of the protocol-specified time of final analysis.  My second question -- 
		DR. OSTER:  If I can just add one thing.  The primary endpoint for preservation -- for assessing preservation of anti-tumor activity was local/regional control as assessed at 12 months.
		DR. SIMON:  But the time of the final analysis was to be when all patients have been -- two years after the last patient entered the study, is that right?
		DR. OSTER:  It wasn't specified as the final analysis. We had further follow-up because --
		DR. SIMON:  The definitive analysis.  Usually a protocol -- I would say almost every NCI-sponsored protocol would have a time of definitive analysis, either expressed in time after the last patient is randomized or expressed when a specified number of events had occurred.  Did this -- okay.  My second question is in your analysis of local/regional control, how are withdrawals handled?  Patients who left the study for whatever reason or patients who had a distant recurrence, or patients who went off study because of toxicity or whatever.  How were they handled in that analysis?
		DR. RUSSELL:  This analysis was taken purely on an intent to treat.  So that for all patients who actually discontinued study for whatever reason, we specifically asked the investigators to continue to follow-up these patients for local control.
		DR. SIMON:  But I notice in your curves you show a whole bunch of censored points in the drug-treated group, very early like about two months.  There is a cluster of about 6 or 7 censored observations in the drug-treated arm that are censored at about two months.  I was wondering why that is.
		DR. OSTER:  I am sorry, which curve is this in?  Is it in the local/regional control curve?
		DR. SIMON:  Yes.  Okay, so it looks to me like you have censored patients.  It looks like you have censored some patients when they went off study perhaps for toxicity or whatever.
		DR. OSTER:  No, not because of toxicity.
		DR. RUSSELL:  No.  I mean, some of these patients are lost to follow-up and we realize that.  The loss to follow-up obviously does occur in this  patient population.  And if a patient chooses not to come back to the clinic, we have to then censor those persons.
		DR. SIMON:  But I don't understand why that cluster would be in the drug-treated arm and not equally distributed.  
		DR. OSTER:  Dr. Koch?
		DR. KOCH:  I am not sure whether this will address your question, but you might put up slide 216.
		DR. SIMON:  I was looking at figure 7 in the executive summary from the sponsor.
		DR. KOCH:  Yes, I know that that is the figure you are looking at.  This is an attempt to provide disposition of the people that were lost.  So basically in the two groups in terms of through 18 months, these are the reasons why various individuals may have been censored.  Now as to which ones were censored at which time, I can't tell you that.  But this is the disposition and set of reasons for the number of people who were censored prior to 18 months in the two groups.  
		DR. SIMON:  Okay.  Well, the censoring I think is of concern, particularly in a therapeutic equivalence question.  My final question was for the postoperative -- the patients who received radiotherapy in the postoperative setting, what sort of increment in local control at 12 months would we believe that radiotherapy gave them?  What would have been the local control rate at 12 months had they gotten surgery alone?
		DR. BRIZEL:  Well, typically for -- I think it is worth at this point defining the post-op population a little bit better, because that puts the answer in its proper perspective.  The post-op patients were defined as either high risk or low risk for their recurrence actually based on criteria from the randomized trial that was conducted at the M.D. Anderson Hospital and that was published about five years ago.  The low-risk patients, which constituted only a small portion of the post-op patients, were those who had negative resection margins at the primary site and/or no evidence of extracapsular nodal spread in the neck dissection specimen if they had that.  The high-risk patients had positive margins and/or extracapsular spread in the neck dissection.  But they constitute the majority of the post-op patients and really drive the issue.  I will confine my answer to that group of patients.
		Patients with high-risk -- patients who were resected and have high risk pathologic characteristics, we would expect a recurrence rate of approximately 70 percent, either at the primary site or in the neck.  So a local/regional control, if you will, of only around 30 percent.  If we give those patients postoperative radiotherapy, we see local/regional control rates in the realm of what was observed for the overall population in this trial.
		CHAIRPERSON DUTCHER:  Last question, Dr. Lippman.
		DR. LIPPMAN:  The proposed indication, of course, is based primarily if not entirely on one large, well-done randomized trial, and I think that is reasonable given the issues with the endpoint.  I guess the question is that the proposed indication just refers to its use in radiation-induced xerostomia.  And as you know, with increasing use of concomitant chemoradiotherapy, this doesn't exclude that population and there are some reasons to think that this may or may not work or it may require a higher dose and other things.  It really seems like a separate question and whether the proposed indication would need to be more specific tailored to the evidence from the trial.
		DR. BRIZEL:  I think the trial can -- the trial addresses the patient population that was studied within the trial.  And within -- as we discussed at the beginning of the Q&A session, there are many different competing approaches for the treatment of patients with more advanced disease, as you indicate, including concurrent chemotherapy and radiotherapy.  We don't know the answer to that.
		DR. LIPPMAN:  I guess my question is would you want to limit the proposed indication to the population you studied?  Because the way it is written now, it is not clear if it includes radiation alone or radiation with chemotherapy.
		CHAIRPERSON DUTCHER:  We will have to talk about that when we talk with the FDA.  
		DR. OSTER:  Okay.
		CHAIRPERSON DUTCHER:  We are going to take a 15-minute break and we are going to be back at 3:05.
		(Whereupon, at 2:47 p.m. off the record until 3:03 p.m.)
		CHAIRPERSON DUTCHER:  All right, we are going to get started. Dr. Chico is going to present the FDA review.    
		DR. CHICO:  Good afternoon, members of the advisory committee and ladies and gentlemen.  I will be presenting the FDA review for the supplemental NDA for ethyol for radiation-induced xerostomia.  Our presentation is divided into two parts.  We recognize that the quality of life endpoints are important, so Dr. Clara Chu, our statistician, will be presenting our methods of review and results on that.
		These are the members of the FDA review team.  I would like to mention special acknowledgements to the Division of Scientific Investigations and the Division of Dental and Dermatologic Drug Products reviewers for their help in our review.
		The application seeks approval for ethyol for the reduction of moderate to severe radiation-induced xerostomia with primary data on a single prospective multi-center randomized Phase III trial comparing standard fractionated radiotherapy with or without ethyol in patients with head and neck cancer.
		As mentioned earlier by the sponsor, the patients were randomized evenly between treatment arms.  Stratification factors identified were sites of disease, clinical stage, nodal status, volume of parotid glands for radiotherapy and type of radiation.  The distribution of patients enrolled according to these stratification factors were balanced.
		Type of radiation was one stratification factor which grouped patients according to the amenability of their tumors to surgery, status of tumor margins after surgery, node positivity and extension of the tumors to the neck.  These factors determined the intended radiation dose.  Inoperable patients received -- were prescribed 66 to 70 Gray.  Postoperative high-risk patients received 60 to 66 Gray.  And postoperative low-risk patients were prescribed 50 to 60.  
		This grouping allowed enrollment of a wide range of therapeutic and prognostic groups of patients with head and neck cancer.  Administration of a wide range of doses of radiotherapy was present in the study, and we have seen this as an important prognostic factor for head and neck cancer as well as an important factor in determining the risk for late xerostomia.  The FDA reviewer grouped patients according to the likelihood of experiencing late xerostomia as in patients who received more than 45 Gray, and the likelihood of experiencing severe late xerostomia as in patients who received more than 65 Gray.  This analysis was done in full recognition that factors other than total doses of radiation affect the incidence and severity of late xerostomia.
		As is shown here, there is significantly more patients who received more than 65 Gray in the RT-alone arm.  The difference between those receiving 45 to 65 Gray was not significant, and the overall difference in the distribution of patients was only marginally significant with a P value of .056.  The effect of this distribution on the primary endpoint of late xerostomia will be shown in a later slide.  
		The primary endpoints related to radiation effect include acute xerostomia, acute mucositis and late xerostomia.  Acute events were defined according to RTOG criteria.  For acute xerostomia, those were Grade 2 or greater within 90 days of start of radiation, as well as for acute mucositis, except that those are more than Grade 3 events.  For late xerostomia, this was also defined using the RTOG criteria except that the time window use is between 9 to 12 months following radiation.  This was the protocol-defined time window.
		These analyses were all prospective and they were all performed in the intend to treat group, and the statistical comparison used was Fisher's exact test.
		The incidence of Grade 2 acute xerostomia was significantly reduced in the patients receiving ethyol.  The FDA reviewer agrees with this assessment.  However, there was no difference between treatment arms in the overall incidence of acute xerostomia, which include Grade 1 and Grade 2 patients.  Therefore, it appears that ethyol prevents moderate or Grade 2 acute xerostomia, but does not prevent its overall incidence.  
		The applicant's analysis of late xerostomia was based on a retrospective definition of events at one year or 365 plus or minus 31 days from the start of treatment.  This analysis, however, showed a significant difference between treatments arms, with an advantage on patients in the ethyol group.  Although this is a close approximation of the protocol definition of 9 to 12 months following treatment, it became apparent during later discussions with the applicant that additional data would have to be submitted to the agency to determine the incidence of late xerostomia that would reflect more accurately the protocol definition.  The results of the updated analysis is presented in the following slide.
		The revised analysis by the FDA as shown in yellow font here were determined by determining Grade 2 or greater late xerostomia documented on visits labeled month 9 or month 11 after treatment.  Our analysis was carried out on all patients treated in the study, showing findings that were similar to that of the applicants.  40 percent of the patients in the RT arm versus 24 percent of the patients in the ethyol arm reported Grade 2 or greater late xerostomia, showing a statistically significant difference in favor of ethyol, with a P value of .0015.  
		Please note, however, that the reminder of the applicant result is a misprint.  These two columns should be interchanged such that for patients in the RT arm, there was 34 percent greater late xerostomia and 57 percent for the amifostine arm.  I am sorry, 34 percent --
		DR. WILLIAMS:  You have changed it on your slide.
		DR. CHICO:  Oh, I am sorry.  This was a last minute correction, I am sorry.  Although patients on the ethyol arm received a higher median dose of radiation compared to patients on the radiation arm, an advantage for ethyol was seen in each group, especially in patients who received between 45 to 65 Grays of radiation.  This difference is also present in the patients who received more than 65 Gray, but it was less impressive.
		Another primary endpoint of the study was acute mucositis, and the analysis of the applicant showed that there was no difference in the incidence of Grade 3 or greater acute mucositis between the treatment arms.  Analysis of events between Grade 1 to Grade 4 also showed no difference.
		In summary, the results of the analysis of the primary efficacy endpoints related to radiation effects by the applicant and the FDA were generally in agreement.  The robustness of a finding of a significant advantage in favor of ethyol regarding the incidence of moderate to severe acute and late xerostomia were clearly demonstrated.  There was a significantly lower incidence of moderate acute xerostomia, a significantly lower incidence of moderate to severe late xerostomia, but no difference in the incidence of acute mucositis.  Since the overall incidence of acute and late xerostomia were similar between treatment arms, the applicant changed the proposed indication to prevention of moderate to severe radiation-induced xerostomia in patients with head and neck cancer.
		The primary efficacy endpoints related to radiotherapy involve assessments by investigators of the degree of xerostomia.  On the other hand, important secondary endpoints also related to the efficacy of ethyol are measurements of saliva production and the patient benefit questionnaire.  These are endpoints which provide objective measurements of xerostomia and should reflect patients' own feedback regarding the effect of xerostomia on their quality of life respectively.
		Evidence of tumor protection is provided by assessment of local/regional tumor control at one year, which was a primary endpoint, and secondary endpoints of disease-free survival and overall survival.  The safety endpoint was described also.
		The applicant's analysis of saliva measurements showed that there was a significant difference favoring ethyol in the unstimulated saliva production at one year using .1 gram saliva production as the cut-off to establish clinically significant saliva production.  A similar analysis of stimulated saliva production at one year showed no difference between the treatment arms. A longitudinal analysis by the FDA reviewer of unstimulated saliva production done in order to establish trends over time did not support the positive findings by the applicant.
		Instead of four post-radiation follow-up time points prospectively defined in the protocol, the applicant retrospectively compared measurements of saliva only at three time points -- at baseline, at first follow-up visit, and at one year following radiation.  Wilcoxon rank sum analyses of saliva collection were planned.  However, details of the analysis were not specifically written in the protocol.  The applicant consulted with the experts and the decision to use categorical assessments of clinically relevant levels of saliva production in the applicants analysis were decided after all the samples have been collected.  
		An exploratory analysis using comparison to baseline measurements was undertaken based on uncertainty from the literature in establishing a normal and abnormal range of saliva production.  Tracking the change in salivary flow over time has been suggested as one method of monitoring the degree of pathology from certain disease states or the degree of damage from certain therapeutic interventions such as radiation.  This analysis shows a trend of less change from baseline stimulated production for patients in the ethyol arm.  For the unstimulated saliva production, there doesn't seem to be any trend of a difference between the treatment arms.  Note, however, that where there was the greatest difference between treatment arms in the stimulated production at month 11, there were only 40 percent of patients and 45 percent of patients in the amifostine arm who submitted samples for analyses.
		The analysis methods and subsequent results by the applicant and the FDA were different.  Analysis of saliva measurements by the applicant showed a significant difference in unstimulated saliva collection at one year, but was not supported by the FDA's longitudinal analysis of unstimulated saliva collections.  Nor their analysis of the stimulated saliva collections at one year.  A comparison of baseline by the FDA showed a trend toward less change for patients in the ethyol arm in the stimulated saliva collections.  
		To address the issue of quality of life, also different methods were once again employed by the FDA, and the difference in the methodology and results of the FDA analysis will be presented by our statistician, Dr. Clara Chu.
		DR. CHU:  Okay.  I am Clara Chu, and I will discuss the analysis of the patient benefit questionnaire data.  I will first describe the reasons why the sponsor and the FDA obtained different results after analyzing these data and then briefly discuss how the FDA analyzed these data, show some results from the analysis, and then summarize these results.
		The first difference is that the sponsor and the FDA used different measures of clinical benefit.  The sponsor used a mean score that was calculated from 8 questions from the questionnaire.  The FDA defined three individual subscales using specific questions from the questionnaire.  
		The first subscale, functional well-being, was defined using two questions.  One pertaining to one's ability to speak due to dryness and the other pertaining to one's ability to eat due to dryness.
		The second subscale, general condition, was defined using the question corresponding to an overall feeling of dryness at rest, that is, while not eating or chewing.  
		Use of external aids was defined using two questions, one corresponding to the frequency of fluid intake for eating, and the other corresponding to the frequency of fluid intake for comfort not associated with eating.  
		The second difference occurred in the number of data points used in the analysis.  The sponsor excluded all the data points beyond the one-year follow-up visit, while the FDA included all these data points.  
		In the FDA analysis of the patient benefit questionnaire data, the FDA employed a pattern mixture model to investigate the impact of missing data in this analysis, that is, to determine whether or not the missing data could be considered ignorable or not treatment-related.  This approach consisted of dividing patients into two groups, dropouts and completers, where dropouts were defined as those patients who dropped out before the beginning of the second year of follow-up, and completers were defined as those who remained on study through the second year of follow-up.  
		The table on this slide shows the number of patients in each treatment group split by their dropout and completers status.  The method used to analyze the data was a longitudinal analysis with GEE quadratic models for each of the PVQ subscales.  
		To give an idea of what results were obtained in this analysis, the mean scores at two-month time intervals were displayed for each treatment group and dropout and completer status group for each of the subscales.  This plot displays the predicted means for each treatment group split by dropout and completer status, and it is clear that within dropouts and completers, the trends are the same between the treatment arms for functional well-being.  And the same holds true for general condition and also for use of external aids.
		Because the trends are about the same for treatment arms within both dropout and completer groups, the individuals were then combined and the longitudinal analysis performed.  This plot shows the predicted mean scores and the observed mean scores for each two-month interval -- oh, I am sorry.  This plot shows the predicted mean scores and the observed mean scores for each two-month interval for the subscale functional well-being.  The predicted means -- actually, the predicted and the observed means for ethyol are shown in red, and the radiation observed and predicted means are shown in yellow.  From this plot, it is not clear whether there is a trend in favor of the ethyol arm for this particular subscale.
		However, for general condition, both predicted means and the observed means do follow a trend in favor of the ethyol arm, and the same can be said of use of external aids.  
		To summarize the results of the PVQ analysis, first it needs to be understood that the results of this analysis should be considered descriptive and exploratory because of the difficulty in interpreting the results due to the subjective nature of the questionnaire.  And also in addition, the open label trial design can result in bias of different types. Also, there is the need for adjustment of multiple comparisons.  
		Second, trends are in favor of the ethyol arm for the subscales general condition and use of external aids.  And lastly, it is not clear whether or not there is a trend in favor of the ethyol arm for functional well-being.  I'll turn this presentation back to Dr. Chico.
		DR. CHICO:  Thank you, Dr. Chu.  The next endpoint would be tumor control.  And according to the sponsor's analysis, there is no difference between the treatment arms with respect to local/regional tumor control at one year, which was again the primary endpoint.  There was also no difference between the treatment arms in the disease-free survival rate and overall survival rate.  Supportive evidence from another randomized study in patients with rectal cancer reported no difference between treatment arms in overall survival rates after radiation.  
		At planning meetings with the applicant, the agency recommended that at least 195 local/regional failure events are needed to yield 80 percent power to exclude a hazard ratio of .7.  For the analysis of local/regional failure at one year, the number of events was approximately half of that recommended.  Aside from the high censoring rate, there was also selection of a liberal lower confidence limit of 70 percent in a non-inferiority test.
		Safety findings were described.  Despite lower daily doses of ethyol, a significantly greater frequency of expected severe adverse events such as nausea, vomiting, fever, allergic reactions, hypotension and dizziness were observed.  There was a 19 percent dropout rate in the ethyol arm.  Such dropout rates raises concerns regarding the effect on efficacy results.  There were more missed radiotherapy doses in the ethyol arm compared to the radiotherapy-alone arm.  There were twice the number of radiation doses missed due to toxicity in the ethyol arm.  However, the differences were not statistically significant.  Adverse events from treatment resulted in 101 hospitalizations in the amifostine arm and 63 in the radiation-alone arm.  
		Regulations require that for a drug to be approved, substantial evidence of effectiveness be demonstrated through adequate and well-controlled trials. There should be substantial evidence of important clinical benefit and a tolerable toxicity profile.  There were significantly more adverse but expected events in patients treated with ethyol.  There were significant numbers of dropouts, hospitalizations and missed doses.  Although these were expected events, these raised concerns regarding one's ability to deliver ethyol in the treatment itself.  On the other hand, one should take caution not to overinterpret toxicities in a no-treatment controlled trial.  Judgment of a tolerable toxicity profile should be taken into consideration with other benefits that may be present with the treatment.
		The analyses results suggesting that ethyol decreases Grade 2 to 4 late xerostomia are robust and are clearly statistically significant.  Results of the analysis of saliva production in patient benefit questionnaire data may be supportive but were less impressive.
		Finally, evidence to support the proposed indication comes from a single, large, adequately controlled randomized Phase III trial.  In most cases, the FDA has required more than a single trial.  However, in other cases, the FDA relied only on a single adequate and well-controlled efficacy study to support approval.  Generally only in cases in which a single multi-center study of excellent design providing highly reliable and statistically strong evidence of an important clinical benefit such as an effect on survival, and that a confirmatory study would have been difficult to conduct on ethical grounds.  
		Whether this single unblinded trial with these efficacy and safety findings is adequate to support approval is not clear, and this very important question seems ideal for consideration by the advisory committee.  Thank you.
		CHAIRPERSON DUTCHER:  Thank you very much.  Okay, questions for FDA from members of the committee?  Dr. Sledge?
		DR. SLEDGE:  There are a couple of questions.  First, getting back to the safety one.  I will ask you the same question I asked the company, which is the difference in terms of hospitalizations.  Is this a statistically significant difference, and do you have any sense of why there are so many more hospitalizations with the drug?
		DR. CHICO:  I think it might have been my mistake not to have labeled it appropriately.  The hospitalizations were based on the number of events, not on the number of patients who were hospitalized.  So maybe that may explain the discrepancy in numbers.  However, we did not perform a statistical analysis on the difference, but the sponsor did and they did not show a statistically significant difference.
		DR. SLEDGE:  Okay.  With regard to the PVQ scales, my understanding from the company presentation was that this was a fairly standard scaling system, is that correct?
		DR. CHICO:  The patient benefit questionnaire was internally validated.  This was a subject of one of our conferences with the sponsor, and they had several experts decide which were clinically significant endpoints to use as questions in the questionnaire.  But it was not validated in another study.
		DR. SLEDGE:  So this is the only study PVQ has ever been used in?
		DR. CHICO:  That is what I am aware of.
		DR. SLEDGE:  That wasn't the impression I had.  
		CHAIRPERSON DUTCHER:  Is that correct?  
		DR. MACKOWIAK:  May I address that?
		CHAIRPERSON DUTCHER:  Yes, please.
		DR. MACKOWIAK:  I'm sorry, I did not mention that the PVQ was developed by the RTOG.  I did notice that an instrument that was very, very similar was used in pilocarpine studies earlier, but I don't know what other studies it had been used in.  I can research that and get back to you on that.
		DR. SLEDGE:  I guess my question related to the PVQ then is we have two different ways of analyzing the same data.  Is there any reason -- I was given no reason to choose one over the other.  
		DR. OSTER:  If I may, can I comment on this?  I think what we tried to show you in our presentation was that it probably boils down to which model you are using.  And the goodness of fit issue is a very important question.  When you look at our model, which was chosen by our experts, you see that basically our model fits very well and is almost superimposable in the distribution of events and measurement points to our primary endpoint, which was defined as mean score.  So I think our model which we have selected indeed shows and exhibits this goodness of fit.  And we were asked by the FDA to add to our initial protocol-stipulated methodology, which was analysis of mean scores, a longitudinal analysis.  We chose this one.  We checked this with the FDA in our statistical analysis plan, and this is how we conducted it.  We also have, if you wish, the goodness of fit presentation of the model which the FDA chose, and we would be happy to share this with you.
		CHAIRPERSON DUTCHER:  I think the issue is whether this scale has been used in other head and neck studies. That is the question you are asking.  
		DR. MACKOWIAK:  It has been used in other head and neck studies.  And your other item -- you haven't been given information regarding which model to select.  And I think that both presentations at the close show the trend favoring the amifostine arm as relates to the issue to be discussed today.  Is the information supportive?  I think that is the important part to remember.  There are differences in the data that are used.  There are differences in the model that are used.  And I don't know if we want to spend the time to go through the detail of those finer differences, but if you want us to go to the bottom line, I think both groups agree that the trend favors the amifostine arm.
		CHAIRPERSON DUTCHER:  Dr. Schilsky?
		DR. SCHILSKY:  A quick question regarding your analysis of the saliva production and your decision to do the analysis based on change from baseline.  So during the sponsors presentation, they essentially offered a rebuttal to your chose method of analysis, and I wonder, having heard their rebuttal, whether you accept it or whether you still feel that the change from baseline is the appropriate analysis.
		DR. CHICO:  I don't think it would be fair to say which one is right and which one is wrong.  The sponsor has adequately presented that certain categorical assessment of clinically significant saliva production is accepted, and it has been accepted by our consultants from the agency.  However, this analysis which I performed which is a change from baseline was based on just literature concerns that you can never establish a normal level of saliva production, and that maybe changes from baseline would be an important endpoint to look at.  I recognize though that both of these analyses only reflect quantitative measurements of saliva.  It doesn't reflect qualitative or functional changes in the patient.  
		DR. SCHILSKY:  One other question about the PVQ analysis that you performed.  So you decided to do an analysis differently from the analysis that the sponsor did.  You decided instead of using the overall scores to break it up into these functional categories.  But you didn't really tell us why you decided to do it that way and how it is that you decided which scales to group together and why you chose to group them in the ways that you did.  
		DR. CHICO:  Dr. Chu and I talked about this when we were doing the review, and I think the reason -- the main difference in the analysis between the sponsors and ours was we made an attempt to group the questions according to specific symptoms, which would probably be reflected more specifically in the label if approved as a significant quality of life change with the treatment, compared to just looking at the overall means of all 8 questions.  This was what we thought to be clearer and clinically significant.
		MR. GRUETT:  Did you do any analysis on tumors that may possibly exist with in the saliva glands?  
		DR. CHICO:  No, we did not.  No.  Maybe --
		DR. BRIZEL:  The tumors -- first of all, patients had to have squamous cell carcinoma, which in and of itself is an exceedingly unusual histology to arise in the saliva gland.  And secondly, because of tumor protection concerns, patients who presented with primary salivary gland tumors were specifically excluded from eligibility in this trial.
		MR. GRUETT:  I have one more question.  The confusion between the analysis of the data, was this called out in the protocol?
		DR. CHICO:  Which analyses?  Would you please specify?
		MR. GRUETT:  What we have been discussing, the difference in your analysis of information and their analysis.  Was there a variation in the protocol?
		DR. CHICO:  I think there is a table -- if you have a copy of my review -- on page 18, which summarizes the analyses that were intended and the analyses that were actually done.  For different endpoints -- endpoints like late xerostomia, acute xerostomia and acute mucositis, the analyses of those were all prospectively defined in the protocol.  It was just in the analyses of the secondary endpoints where there was a little bit of contention between the sponsors and the FDA.
		CHAIRPERSON DUTCHER:  Dr. Ozols?
		DR. OZOLS:  I am most concerned about your conclusion that the secondary endpoint of tumor control is premature to make a conclusion that there is no potential decrease in tumor control.
		DR. CHICO:  We had recommended during our meetings with the sponsor that ideally they should probably have at least 195 events to document adequately the curve of local/regional tumor control.  However, there were only about 100 events reported at one year to document local/regional tumor control.  So that is the reason why we thought this was probably premature.
		CHAIRPERSON DUTCHER:  Dr. Margolin?
		DR MARGOLIN:  Just a clarification to help me understand, Dr. Chu, your analysis.  In these graphs that you showed us, I assume that what you were really doing based on this predicted and observed model is trying to demonstrate that as time goes on the number of dropouts versus completers gives you much more variability and a less tight curve to compare between the groups.  Is that correct?
		DR. CHU:  That is correct.  As time goes by, there are very few events, and that is why those lines are going all over the place.  
		DR MARGOLIN:  Thank you.
		CHAIRPERSON DUTCHER:  Dr. Simon?
		DR. SIMON:  Could you review how many patients had saliva samples available at the 12-month analysis?
		DR. CHICO:  Before I answer that, I would like to just emphasize that the time windows that were used in the collection of saliva had very great variability.  The time labeled as month 1 was collection between month 0 to month 3, month 5 were collections between month 3 to month 6, while month 11 were collections between month 6 to month 15, which is a 9-month time span.  But to answer your question, on the events that were labeled as month 11, for the stimulated -- let me just flash the slide.  If you would just refer to page 17, which is the graph of change from baseline saliva measurements.  At month 11 for the stimulated production between treatment arms, in the amifostine arm, there was only 45 percent of patients who provided samples, while 40 percent of patients provided samples in their radiotherapy arm.
		DR. SIMON:  So it is like 45 percent?
		DR. CHICO:  Over here.  
		DR. SIMON:  Could you focus that?  What about earlier on?  So what about at an earlier time?
		DR. CHICO:  All right.  For month 1 for the stimulated saliva production, there were 65 percent of the patients in the amifostine arm provided samples while there were 71 percent of the patients in the radiation arm that provided samples.
		DR. SIMON:  So is it your impression that there is a large difference between whether you do change from baseline or just absolute value of the --
		DR. CHICO:  It is my impression that between treatment arms in the stimulated collections, there seems to be a lesser degree of change from baseline.  Notice that we did not perform any statistical analysis because we want this to be plainly a description and exploratory.  And because of mainly the concern was the large number of dropouts in month 11, and you have to consider for multiple analysis endpoints if you want to do a -- try to confirm it by doing statistical analyses.
		DR. SIMON:  This was less true for the PVQ issue in terms of missing data?
		DR. CHICO:  There was also a large number of missing data in the patient benefit questionnaire, and I think Dr. Chu can expound on that some more.
		DR. SIMON:  I mean, for example, what percentage of the patients had questionnaires around one year?
		DR. CHU:  We don't have the slide with the actual frequency counts at one year, but I can refer you to my review.  There is a frequency plot in the review.  
		DR. SIMON:  Do you remember just approximately what it was?
		CHAIRPERSON DUTCHER:  Identify yourself.
		DR. CHEN:  This is Gang Chen, Biometrics team leader, FDA.  So the frequency at about 12 months is around 80 percent for both groups.  
		DR. SIMON:  One other question I had was there was this difference in radiation dose delivered.  Was it your impression that that was attributable to missed doses because of toxicity of the drug and dropouts?
		DR. CHICO:  In the first place, the patients were randomized with prescribed doses.  And some of these patients, especially those who were not operable, were prescribed 66 to 70 Grays of radiation when starting treatment.
		DR. SIMON:  But it was balanced with regard to --
		DR. CHICO:  It was.  That is right.  Let me show -- 
		DR. SIMON:  But what they actually received was not very well balanced.  
		DR. CHICO:  That is true.  Let me just --
		DR. HARWOOD:  The difference in dose between the two arms I think was very small and really not expected to have a significant effect.  
		DR. SIMON:  Well, it is 56 percent of the radiation only had over 65 Gray, and it was 43 percent in the drug plus radiation.
		DR. WILLIAMS:  Dr. Simon, the sponsor did a frequency distribution I think on page 13 of their slides, and I think that our analysis may be somewhat an artifact of where we just happened to pick.  We picked it for I think a physiological reason.  But if you look at the frequency distribution, I think we might have just picked a place where it was trending in the other direction.  So I am not sure that one can say that overall it was unbalanced.  It was in that particular analysis.
		DR. CHICO:  And I think that was clearly stated that our overall comparisons did not show a significant difference with a P value of .056.
		DR. SIMON:  Well, okay.  Just for my own knowledge, is this stimulated saliva production more important medically than unstimulated?  
		DR. CHICO:  From -- maybe our experts can answer that.  
		CHAIRPERSON DUTCHER:  Dr. Le Veque, can you identify yourself?
		DR. LE VEQUE:  Thank you.  Let me answer your question first about the stimulated saliva, and maybe I can in one presentation also address the problem of differentiating between baseline and residual saliva.  This study, unlike other studies that have addressed salivary gland dysfunction from radiation therapy, is a preventive study in the sense that -- which in toxicity I believe is a gold standard, to prevent the toxicity rather than to treat the toxicity.  In this instance, as has been pointed out I think very carefully by the sponsor, is that the end of this study, patients who were responders, patients who were in the amifostine arm, had residual saliva.  They would go to bed at night and wake up with it in the morning without stimulation.
		The question of stimulation is an interesting one but not really meaningful in a scientific sense because the instances where you stimulate saliva -- saliva can be stimulated many ways.  In the pilocarpine studies, the whole concept of pilocarpine is one of stimulation.  In the pilocarpine studies, the patients who were on pilocarpine didn't do very well with stimulated saliva because it was already -- the glands were already being stimulated.  In this instance, the type of stimulation that was used in this study I believe was somewhat flawed and I think the sponsor will acknowledge this.  The stimulation collection was done hard on the heels of the unstimulated collection in glands that were pretty beat-up from the standpoint of obvious production of salivary flow.  So right after the unstimulated collection, the stimulated collection occurred, and the methodology used was a parafilm chewing, which is mechanical stimulation, which is the poorest of all stimulatory mechanisms in this mode.
		So I would offer the comment that the baseline issue is, from the prospective of a clinician who works with this patient population, is not meaningful.  What is meaningful is we don't zero out in these patients.  We have something left.  And not only do we have something left, we see a slight improvement over a period of time. 
		DR. SIMON:  Just to clarify.  The FDA's analysis of the unstimulated -- change from baseline in unstimulated saliva showed no difference.  
		DR. CHICO:  The FDA analysis of the unstimulated saliva showed that the trends between treatment arms were similar.  
		DR. SIMON:  Right. 
		DR. WILLIAMS:  I think a good take-home message for future trials is how important it is to be very specific in specifying your analyses.  Because we can never say what is the right thing -- we can say maybe we would prefer one or the other, but we can never be assured that something is not data driven unless we have the analysis prior to the data.  So I think it is very important to specify in advance your planned analysis.  
		CHAIRPERSON DUTCHER:  Dr. Chen?
		DR. CHEN:  I have a few comments regarding the statistical difference or the statistical analyses performed by the sponsor and by the FDA.  The first issue I want to discuss is about Dr. Gary Koch's comments on the higher censoring rate.  Actually, in our review -- in the FDA review, we did mention about the higher censoring rate.  The censoring here we defined it as actually censoring patients consists of those patients who were lost to follow-up and those patients who were not events at the study cut-off date.  So that is why we see the very high censoring rate.  In other words, actually we are talking about the lower event rate.  The second issue regarding the measure -- the health ratio we used for the time to event analyses, I think this is very important and also it is a well-known measure used for time to event analyses.  And I think it is appropriate.  
		The third issue is regarding the different models we used for PVQ analysis.  We had a meeting with the sponsor and we did agree that the longitudinal analysis was a mixed model that the sponsor proposed.  The issue is not what model we should use.  The question is how should we interpret the results for those model-based analyses.  So actually I could let Dr. Chu present our results and the interpretation.  So those are my comments.
		CHAIRPERSON DUTCHER:  Other questions for FDA?  Any other clarifications people need before we discuss?  Dr. Simon?
		DR. SIMON:  Just in terms of -- could you summarize your analysis of the PVQ data?  The conclusions you reached from the PVQ data?  
		DR. CHU:  Well, one, the first bullet in the summary probably being the most important is that the results that we arrived at from the analysis is that they should be looked at as being descriptive and exploratory.  This would be because of like the subjective nature of the questionnaire and also due to the fact that we have an open label trial design in the study and also the fact that we need to adjust for multiple comparisons.  The other bullets are simply basically just saying that the trends are in favor of ethyol simply by eyeballing the plots.
		DR. SIMON:  Is that as strong a statement as you can make is that the trends are in favor of one group?
		DR. CHU:  Yes.  That is about as strong a statement as we can make.
		CHAIRPERSON DUTCHER:  Other questions?  Yes, sir.
		DR. WASSERMAN:  My name is Todd Wasserman.  I was just going to ask Dr. Chico, as I understand it, the change in baseline analysis on the salivary function was just something you decided to use because you had no other defined way of analyzing the data?
		DR. CHICO:  No.  This was something that I used based on literature which stated that that is one possible way of tracking changes in saliva production from disease or from therapy.  It is not my own.
		CHAIRPERSON DUTCHER:  Thank you very much.
We are now going to proceed --
	DR. KENT:  Madam Chairman, if I could just add one other thing?  Kenneth Kent.
		CHAIRPERSON DUTCHER:  Okay.
		DR. KENT:  Relative to the measurements, the whole science of saliva is something which has been blossoming within the last 10 years and there have been major changes in the quantification of the salivary measurements.  There currently are no hard and fast gold standards.  The best gold standards that exist state that any patient that receives radiation therapy to the salivary glands in excess of 45 Gray will have extremely deleterious morbidity.  The major measure is a quality of life issue for these patients.  Quality of life issue measures are very difficult for patients because they can only compare themselves to their existing experience.  Dr. Lo Presti presents a very valid example.  He perceived that he was very dry.  His perception.  However, when he compared himself to his peer group of patients who received radiotherapy without the benefit of medication, he realized that his morbidity was not nearly as great as anyone else.  It is standard that when a patient sits for an interview, they are constantly sipping water.  It is very unusual that a patient can get up and give a 20-minute dissertation after receiving high dose radiotherapy to the salivary glands without having to take a single drink.  I think this testifies very strongly to the quality of life change that can occur with this medication.  
		CHAIRPERSON DUTCHER:  Thank you.  Thank you very much.  Okay.  Does anybody need anything else further clarified?  I would like to just go with the discussion and then if there are issues that need clarification, we will clarify them.  Because it sounds like some of us are confused and we don't want to be confused.  Any comments or questions?  I will proceed.  Ready?
		Okay.  This application seeks approval for ethyol to reduce the incidence of severe radiation-induced xerostomia, severe being defined as greater than or equal to RTOG Grade 2 acute and late xerostomia.  Efficacy data come from a single multi-center randomized Phase III trial in patients with head and neck cancer. It compares ethyol plus standard fractionated radiotherapy with radiotherapy alone in 303 patients.  The patient characteristics were generally well-balanced on the study arms.  
		The primary efficacy endpoints were acute and late xerostomia, Grade 2 or higher, and acute mucositis Grade 3.  There was no difference between the study arms and the incidence of acute Grade 3 mucositis.  However, acute and late xerostomia, Grade 2 or higher, were significantly more common on the radiotherapy alone arm.  And there you have the tables showing acute and late xerostomia.
		Although patients on the RT plus ethyol arm received a higher median dose of radiation therapy than patients on the RT arm, a higher proportion of patients randomized to the RT arm received higher total doses of radiation greater than 6500 Centigray.  When patients were grouped according to radiation dose received, an advantage for ethyol was apparent in each group.  And there is a table showing incidence of late xerostomia by dose.  
		Does the trial provide substantial evidence that ethyol decreases the incidence of moderate to severe xerostomia in patients undergoing radiation treatment for head and neck cancer?
Dr. Simon?
		DR. SIMON:  I just want to make a general comment.  I guess not just specific to this question, but I have a lot of concern about -- I think the whole analysis is data-driven because the sponsor decided to present this at a time prior to the stated time of definitive analysis in the protocol, presumably because of what they believed the study showed, even though it was at a time when according to the curves we see, there are lots of patients who are censored at around 15 months.  And I don't believe that that is the way to analyze clinical trials.  I don't believe it leads to reliable analysis.  
		DR. WILLIAMS:  Rich, I would like to make a comment.  That may be true for tumor data, but I believe for efficacy, when the primary endpoint -- all the data is collected by one year, that these data wouldn't have changed.  
		DR. SIMON:  We are seeing 18-month data here.
		DR. HARWOOD:  As a radiation oncologist, I absolutely agree with that.  You see xerostomia develop in less than six months and then starts improving after that.  So in terms of this drug's ability to protect the salivary glands from the effect of radiation, you will see this at 6 months, 12 months, and probably see even more improvement as the time goes out.  So I think in terms of this drug having an effect, and it certainly seems to me that it is having a beneficial effect on xerostomia and acute mucositis, then I think we will have seen it by the time that these patients have been followed.  As I have indicated earlier, I think there is somewhat of a concern about tumor protection, but I think that that is less of a concern in the patients that are receiving post-operative radiation, as has been demonstrated from the data from the RTOG.  But I have residual concerns about tumor protection in definitive radiotherapy patients.  But I really do think that the evidence that has been presented -- and anybody who has ever done quality of life studies in head and neck cancer know how difficult it is.  I started doing this 20 years ago, and I had difficulty demonstrating differences in quality of life between patients who had had their larynxes preserved by radiation and those that had had laryngectomies, believe it or not.  So quality of life studies are very hard.  
		One might suggest that we should initiate the bagel test.  Because I agree with the patient advocate that this is one of the most significant effects of radiation in the inability to eat dry bread.  This has been amply demonstrated that amifostine in his particular case has improved his quality of life. So forgive me for being a simple man, but I would have understood it better if they had asked the patients randomized into the trial, can you eat a bagel or a piece of toast in the morning or can you not?  And I kind of suspect the evidence would have been strongly in favor of amifostine.
		DR. WILLIAMS:  I'd like to go back to Rich's question, which I believe if we are addressing question number one, as the protocol defined it and as we analyzed it, it was the months 9 through 12 data that we used to determine late xerostomia, and that was the primary endpoint in the protocol.  So for the purposes of that endpoint, additional follow-up would not be helpful.  
		However, I believe there was an amendment to the protocol changing analysis to later and the purpose of that was to collect more tumor data.  But for the purposes of question one, I don't know that that applies.  
		DR. HARWOOD:  I completely agree. You have to look at all the data together.  There is a lot of data been produced on this, including the information. The reason that the salivary gland was chosen was that that was protected the most, I think, in the original U.S. Department of Defense data from 25 years ago, and I am sure that is what has led to this trial being done.
		DR MARGOLIN:  I realize we are not supposed to talk about the package insert before we vote, but I think it is important because the question has been raised by the FDA and by Dr. Harwood and some of us are also concerned about the inability or the underpowered state of the current data to really reassure us that tumor protection is not being afforded.  And if this gets out, obviously with all of the other kinds of things that are being done in head and neck cancer, and the use of platinum which is a drug for which this protector is already approved, one can just imagine all the other situations that it will be used for very different than the patients that were in this study.  So the question is whether that package insert will say something specific about postoperative resected head and neck patients undergoing radiation alone, for example, as opposed to chemoradiotherapy or as opposed to patients with primary definitive therapy being given for an unresectable tumor.
		DR. HARWOOD:  I was actually -- I actually prepared a few comments and you have kind of hit the nail on the head.  I think that this -- it is my opinion that the drug is protecting salivary function.  It is also my opinion that there is enough data in the trial to support its use in patients who are receiving postoperative radiation.  I personally would be hesitant to recommend it at this point in time in definitive radiotherapy patients because I don't think that we have enough patients entered into the trial to permit us to be absolutely confident that there is no tumor protection, even though I think it is very unlikely to be the case.
		One interesting piece of information is that this drug has been approved in renal protection and ovarian cancer for cisplatin, and there is five-year data on that to suggest that there is no tumor protection.  Interestingly in head and neck cancer, increasingly cisplatin plus or minus 5FU is used as a predictor of radiation responsiveness, in that in the VA laryngeal cancer study patients who are given up-front chemo, primarily cisplatin, and if they responded they went on to radiation and had laryngeal preservation, and if they didn't, they went on to surgery.  So I regard the ovarian cancer study as very significant in that we have five-year data to support the fact that amifostine is not protecting and producing a lower responsiveness in the ovarian cancer patients.  But I personally would be hesitant to recommend it right now until more data is accumulated in the definitive radiotherapy patients.
		This drug, I think, also becomes more important because more and more patients are now receiving hyperfractionated radiotherapy and chemotherapy and radiation, which all of us know produces significantly increased mucosal toxicity.  There has been some discussion here about toxicity of amifostine, but the toxicity and morbidity of amifostine is vastly less than what one sees in patients getting simultaneous chemo and radiation for head and neck cancer.  
		I remember an early study in chemo and radiation in head and neck cancer, and one would start off with 150 patients and due to the lifestyle of these patients, of which we are all aware, only 25 completed the study.  So I find it absolutely extraordinary that in fact the sponsor has in fact been able to get as many patients through this study as in fact they have.
		So I also would think that it probably could be approved in the chemoradiation advanced head and neck patients, because those patients get profound mucositis.  And in the two supporting studies, I think they showed a significant reduction in mucositis in them.  So I really am personally in favor of some kind of limited approval, but not blanket approval such as they gave in the United Kingdom.
		DR. WILLIAMS:  It is quite possible to go ahead and answer this question number one just for the efficacy and then have some other answers for others such as tumor control.
		CHAIRPERSON DUTCHER:  I think we have to remember that the question is asking only about xerostomia.  Only about salivary production, not about mucositis.  So does this trial provide substantial evidence that ethyol decreases the incidence of moderate to severe xerostomia in patients undergoing radiation treatment for head and neck cancer, and I guess through endpoints months 9 through 12.  All those who would vote yes?  11 yes.  Voting no?  Okay, one no.  Carolyn Beaman voted no.  So two no.  Okay.
		The next issue is salivary measurements.  Clinically meaningful levels of saliva production in time categories for saliva collection analysis were defined retrospectively.  In the analysis of unstimulated saliva collection, the applicant used greater than .1 gram of saliva as the cutoff for adequate function. They used the time window of one year's follow-up defined as 6 to 15 months after treatment, and noted a significant difference in favor of the ethyol arm.  63 patients with adequate function on the ethyol arm versus 43 patients in the RT arm with a P value of .003.  The analysis of stimulated saliva collections by the applicant and longitudinal analysis of unstimulated saliva collections by the FDA did not show statistically significant differences between study arms.  
		Do the results of the salivary measurements provide supportive evidence that ethyol reduces the incidence and severity of late xerostomia?  Dr. Margolin?
		DR MARGOLIN:  I am sorry, I must either be misinterpreting this slide or these numbers may be wrong.  But on page 19, again these bars suggest that the total number studied was only 63 in the amifostine arm and the number studied was 43 in the RT alone arm, and that these are the percentages of -- 
		CHAIRPERSON DUTCHER:  I think those are the n's.  
		DR MARGOLIN:  Can those be clarified?
		CHAIRPERSON DUTCHER:  Those are the n's, I believe, on the slides, correct?
		DR. WILLIAMS:  I believe you are looking at a different analysis. This was the sponsor's analysis, not the one done by Gani.  
		DR MARGOLIN:  But the numbers were identical.  That is why I was querying that.  
		CHAIRPERSON DUTCHER:  Those are the n's.
		DR MARGOLIN:  So in the question, what do 63 and 43 --
		DR. RUSSELL:  Let her comment on the slide first.
		DR. RUSSELL:  The n's are actually the numbers of patients who had more than .1 gram.  So it is 72 percent of those patients who were actually analyzed for this endpoint and 49 percent of those patients analyzed for this endpoint respectively.
		CHAIRPERSON DUTCHER:  And what are those denominators?
		DR MARGOLIN:  Is 63 the denominator or the numerator?
		DR. RUSSELL:  The numerator.  
		DR MARGOLIN:  So the 22 percent is the previous number that the patients -- the 97 and the 106 is the denominator?
		DR. RUSSELL:  The level -- approximately those numbers.  They are slightly less in both treatment arms.
		CHAIRPERSON DUTCHER:  It says late xerostomia -- on page 15, late xerostomia at one year patients available data, n equals 97 for amifostine and n equals 106 for RT.  And then here we have unstimulated saliva at one year, 63 had the number that was .1 gram or greater.  So that 63 is 72 percent of the 97 roughly speaking.  Close enough.  Is that right?  That is right.  Okay.  So, a comment, Dr. Lippman?
		DR. LIPPMAN:  I do think the salivary measurements are supportive. I was concerned initially when I saw the .1 cutoff and it was defined unfortunately later on.  But I think when -- listening to the presentation and seeing the median saliva levels, it looks as though -- this data looked at from several angles seems to be supportive.  So I do feel that the salivary data is supportive and that there is no accepted standard.  
		DR. SIMON:  Well, I think it is difficult to make a judgment here.  When two different analyses give what appears to be two totally different answers, I think there needs to be some assessment as to why they are giving different answers.  And what it is about the data that is -- does doing things from baseline just add a lot of variability to data?  I think there needs to be a more in-depth analysis myself before I could make a judgment.  I think it is difficult.  There is a lot of missing data, which is very understandable.  But for myself, I think that really when you -- I don't like the use of cutoffs like that.  I would have rather just seen sort of a more straight forward analysis without introducing thresholds, particularly when you haven't defined the thresholds prospectively in the protocol.  So I am just left with concern one way or the other.
		DR. HARWOOD:  I hate to come back to this, but you have to understand the patient population that you are dealing with.  And I think -- and one has to look at the lifestyle of the patients that we are studying.  And this is different.  And it is very difficult, let me tell you, to have the follow-up levels.  As a clinician that has treated hundreds and hundreds of these patients, it is very hard to get these patients to come back for follow-up, and it is very hard to get them to do these various studies of saliva functions.  So I personally think the numbers of patients that they have got to measure the saliva is extraordinarily high given the patient population that you are dealing with.  I really do.
		DR. SIMON:  I meant to imply that.  That it was not a criticism of the study.  That for this patient population, I think that was good.  But still you do not want to be left with doing the analysis two ways and getting two totally different answers.
		DR. LIPPMAN:  But at least in terms of the unstimulated saliva, on page 18, the medians are different as well.  So the cutoff issue I have the same concern, but it does look as though when you look at the data in different ways, at least the unstimulated data seems to be consistently supportive.
		DR. SIMON:  As long as the pre-treatment medians wouldn't be different also.  
		CHAIRPERSON DUTCHER:  Dr. Schilsky? 
		DR. SCHILSKY:  Just one other comment about that.  I mean I guess looking at it from the clinical perspective, there doesn't seem to me to be any particular rationale to have chosen the FDA's analysis method of looking at change from baseline.  I personally actually was quite persuaded by the comments from the sponsor that what is important is where you end up at the end of the treatment.  Because the bottom line is is your mouth wet or dry when you have completed all the treatment.  And who cares how wet it was when you started.  
		DR. HARWOOD:  Exactly right.  And it comes down to can you eat a bagel or can you not.
		CHAIRPERSON DUTCHER:  So the Phase IV study is going to be bagels.  Other comments?  All right.  Do the results of the salivary measurements provide supportive evidence that ethyol reduces the incidence and severity of late xerostomia.  All those who would vote yes?  12 yes and one no.  Carolyn votes no.  Okay.  
		Patient benefit questionnaire.  As described in the presentations, analytical plans for this parameter were submitted retrospectively.  Consequently, the applicant and the agency chose different methods of analysis.  The applicant evaluated the overall mean of the 7 subscales of the PVQ and found a statistically significant difference in favor of ethyol 7 months and one year after completion of therapy.  The longitudinal analyses by the FDA looked at three discrete areas identified by the reviewers as most clinically significant -- functional well-being, global assessment of dryness and use of external aids and found trends in favor of ethyol.
		Do the results of the patient benefit questionnaire provide support to this application?   Dr. Sledge?
		DR. SLEDGE:  This kind of gets back to the methodologic question I was asking earlier.  If this scale has been used previously and has been used in the way that the sponsor used it previously, then I don't see any particular reason why we should take the FDA as opposed to the sponsor way of analyzing this.  If it hasn't, then it is a flip of the coin as to which one to accept.  But my understanding from what I heard was that it has indeed been used before and it has been used in head and neck cancer.
		DR. WILLIAMS:  We certainly had no evidence submitted to us that it had been used in another trial and that it had been connected up to a particular clinical event.  I mean our tendency to frown upon lumping of a bunch of different subscales is we don't know what it means when you get through.  I mean, what does it change on the scale versus a particular subscale may ask a question and you can at least calibrate it to that question.  There is a 2 point change on this question dealing with a specific name.  So that is where our philosophy came from.  But we had nothing submitted to us to indicate it had been used in other trials in support of it.
		CHAIRPERSON DUTCHER:  I want to make one comment from the sponsor.  
		DR. MACKOWIAK:  Sorry, just to clarify.  The instrument had been used in other studies, pilocarpine studies.  However, non-significant findings, of course, are rarely published.  And we talked about the difficulty of finding a difference.  So when we looked to the literature to find publications of instruments, we are not going to see it there.  So it has been used.
		CHAIRPERSON DUTCHER:  Thank you.  Dr. Nerenstone?
		DR. NERENSTONE:  I think even the FDA said that their analysis was trending in favor of it.  It is descriptive. I think that is all you can say.  Does it tend to support the application?  Yes, it does.  In a statistical hard-nosed way, no it doesn't.  Next question.
		CHAIRPERSON DUTCHER:  She has to get out of here.  
		DR. HARWOOD:  Amen to that.
		CHAIRPERSON DUTCHER:  Okay.  We are voting.  Do the results of the patient benefit questionnaire provide support for this application?  Those who would vote yes?  11 yes.  I am abstaining.  And the patient rep voted no.
		Tumor control.  In the evaluation of cytoprotective agents such as ethyol, one must consider the adequacy of evidence demonstrating that the cytoprotective agent is not protecting the tumor from anticancer treatment.  In this case, the FDA determined that relatively large trials in patients with head and neck cancer would be needed to rule out such a tumor protective effect relative to radiation therapy.  The most relevant data submitted is from the randomized control study discussed above.  In this trial, no difference was noted between the arms in time to local/regional recurrence, disease-free survival and overall survival.  The lower bound of the 95 percent confidence intervals cannot exclude the possibility that ethyol is 36 percent, 31 percent, and 13 percent inferior respectively.  
		The sponsor also cites data from a 100 patient randomized study of radiation therapy plus/minus ethyol in rectal cancer, and data from a randomized trial of chemotherapy plus/minus ethyol in ovarian cancer.  
		Is there adequate evidence that ethyol does not protect tumors during treatment of head and neck cancer with radiation therapy?
		DR. HARWOOD:  This is where I have expressed concerns already.  I think that the problem with the trial to some degree was the large number of patients who were postoperative patients who have been resected for cure, albeit though they have a fairly high frequency of recurrence.  And the relatively small number, one-third I think, of definitive radiotherapy patients entered into the trial.  I have already talked about this.  So I believe that there is enough data to say this drug is not tumor protective in the post-operative patients.  But I personally would prefer to see more definitive radiotherapy patients treated and followed for a longer period of time.  Because it is those patients who I think conceivably could be at risk from three to five years out of having a 5 to 10 percent difference in survival.  I don't know that that is the case, and there is no evidence that that will be the case.  But I think that there has just not been enough follow-up on that group of patients for me personally to recommend its use in that area.  
		So I would think that we do have enough information on the postoperative patients, because that is the large group in the trial.  And those patients do, as has been discussed, tend to recur early.  But in the definitive group of patients, I would be somewhat more hesitant because there are just not that many patients that have been entered.  And the supporting studies, the rectal cancer study, I think, is really irrelevant.  These are patients being treated palliatively with radiation for rectal cancer.  There are two other supporting studies which are chemoradiation studies, but the follow-up in those patients is short and the number of events and recurrences are less than 5, I do believe. 
		So I think that we have enough patients followed for long enough who are postoperative, but in the definitive radiotherapy patients, I would personally prefer to see larger numbers of patients followed for longer periods of time to be absolutely certain on that issue.  And I think that is a very important issue.
		CHAIRPERSON DUTCHER:  Dr. Williams?
		DR. WILLIAMS:  Could you clarify what you mean by -- I mean wording you might use in labeling by a postoperative patient?  Which patients who are going to have surgery and radiation do you think this might be indicated for?
		DR. HARWOOD:  These are patients that have had a curative resection and had all gross tumor removed but have positive margins or extracapsular extension and things like that.  The definitive patients are patients who have never had surgery and who are receiving radiation for cure, of course.  So the postoperative patients, both the high and low risk -- and I think they had a good definition of the -- the sponsor had a good definition of this.
		CHAIRPERSON DUTCHER:  Dr. Margolin?
		DR MARGOLIN:  Yes.  I would like to strongly agree with that and support that.  And I think it would be very, very unwise for us to take any -- to put any faith in the data against tumor protection in other histologies for which other treatments are given.  We have many examples in oncology where things that would appear to be interchangeable are not.  
		CHAIRPERSON DUTCHER:  Mr. Gruett?
		MR. GRUETT:  I think the key word here is adequate, and I don't think that has been demonstrated.
		CHAIRPERSON DUTCHER:  Dr. Schilsky?
		DR. SCHILSKY:  I think we all have the same concerns.  And I guess one thing I am unclear about is I suspect that the design of this trial was based upon the total number of patients entered with respect to ability to look at non-inferiority.  So once you start to break-out these subsets, I don't know that we have any sufficient power in any subset to be able to conclude with a reasonable level of confidence that there is not an inferior outcome for the amifostine-treated patients.  Maybe somebody could comment further on that.  But I am just -- I mean I think that the concerns are completely valid about we don't have enough events yet to determine that there is not actual tumor protection.  But I don't know that the solution to that problem is to start to break it out into subsets.  Because I have a feeling then that the patient numbers are going to be too small to be able to draw any conclusion with confidence.
		DR. HARWOOD:  Well, I think that we have 200 patients, I believe, give or take that are the postoperative patients. And as has been discussed and I completely agree with that 90 percent of these recurrences occur within the time frame of these patients that have been followed.  And I think the additional supplemental RTOG data that was presented is very supportive of that.  So I really do think that we have enough patients followed for long enough in that group.  And there is absolutely -- I would add that there is absolutely no hint of tumor protection in any of this data, nor in any of the other data that has been accumulated through the years.  So I kind of have a feeling that my worries about the definitive radiotherapy group are kind of theoretical, and in the fullness of time will not prove to be correct.  But I really think that it will be prudent to do that.  
		But I really strongly believe, as a radiation oncologist treating many head and neck cancer patients, that I would be comfortable treating the postoperative patients with amifostine.
		CHAIRPERSON DUTCHER:  Dr. Lippman?
		DR. LIPPMAN:  I have a real concern similar to Dr. Schilsky about taking out subsets from this trial to make recommendations.  I mean, this was a very well-designed, well-powered large trial for this disease, and I would just be very concerned to make recommendations from subset analyses within this trial.  And that was why I made the comment, because you addressed this earlier about the chemoradiation.  I don't think we can make any comments about that.  I think that needs to be clarified in the recommendation.  But in this case, to subsect based on any of these stratification factors I think is going to be problematic.
		CHAIRPERSON DUTCHER:  Dr. Margolin?
		DR MARGOLIN:  I think you are absolutely right about that.  Because this is -- what we were talking about was actually a subset and not the complete patient population here.  But I think what you end up having to do in the package insert is not to put it in the first sentence of the indication that it is only for post-op NED patients, but rather to go into extensive detail in the package insert that certain populations of patients were not studied in sufficient detail to allow this indication to apply to them or to recommend it, such as chemoradiation or definitive radiation patients.
		CHAIRPERSON DUTCHER:  Dr. Ozols?
		DR. OZOLS:  Dr. Chico, you concluded that it was premature.  But since most of the events have taken place, do you think there will be more data coming from this trial with longer follow-up?
		DR. CHICO:  I would think there would be, although the cutoff point that was determined was up to 18 months, and that was the extent they provided to the agency.
		DR. WILLIAMS:  It sort of depends on what kind of patients were entered and how long -- I am not sure -- maybe the sponsor might have a comment.
		DR. BRIZEL:  Thank you very much.  I think we are getting to the crux of the issue here which is what is the natural history of this disease.  And in other diseases -- prostate cancer and breast cancer, for example -- the natural history of the disease may be 15 or 20 years.  And certainly within that context, absolutely with longer follow-up, you would expect to see more events.  But in head and neck cancer, not just through the RTOG data base, but if you look at the article that I published in the New England Journal.  If you look at articles or institutional experiences and cooperative group experiences just about anywhere, you see that 80 to 90 percent of all of the events that are going to occur do so within this 12 to 18 month framework.  So with all due respect, I think that the likelihood of seeing more events with longer follow-up is probably pretty small.  And again, the events that we have seen have been local/regional events.  And so when I look at this, I see the natural history of the disease again.  The problem with not having "enough events" is that compared with ovarian cancer or the Liu study, which was unresectable rectal cancer, a much greater proportion of these patients are cured of their disease.  So there aren't as many events to occur.  And in order -- I am no statistician and I don't pretend to be, but if we want to look at the number of events that we are talking about to prove non-inferiority, we are looking at a very minimum of doubling the size of the study population, if not a tripling or a quadrupling.  And to put that in the proper perspective for this group of patients, the largest study randomized trial in head and neck cancer was an RTOG forearm randomized trial that accrued 1,100 patients on it.  Only 1,100 and took six years to get there.  The next largest was the British chart study, which again took many, many years and only had 900 patients.  So I think it is very important to keep these issues to frame the context of the discussion.  Thank you.  
		CHAIRPERSON DUTCHER:  Yes, Mr. Gruett?
		MR. GRUETT:  I am a cancer survivor.  I had throat cancer.  My entire throat has been removed.  And I worry about this drug.  My doctor has told me that my chances now -- I am in recovery for two years -- are very good.  I am probably 98 percent cancer free.  But if I was on this drug, I would worry because we don't have information that goes beyond two years, and I am a patient.  And for my own self, the benefits I don't think overcome the gamble that takes place in this unknown period of time between the two and five year period that I was explained that cancer could reoccur.  So my feelings are I am afraid of it.  Because we don't have enough information.  I guess fear is the unknown and we are lying in an unknown area right here.  Because maybe it has suppressed the cancer, but it didn't remove it.  So I don't think there is enough info yet.
		CHAIRPERSON DUTCHER:  Dr. Simon?
		DR. SIMON:  I think the issues are difficult.  Dr. Chico quoted a figure before of 190 or 200 events needed for an equivalence trial, and that is the kind of thing you might calculate ahead of time once you actually have data that power doesn't really become the definitive issue because you have some of the data already.  On the other hand, I personally always like to see two studies, just because one study can and has been sometimes a fluke.  And in this particular case, the study looks pretty convincing.  But in terms of -- I looked at what was shown for the RTOG data and it was not true that 80 or 90 percent of the events occurred by 12 to 15 months.  Once you got to 2 years, yes, the curves plateaued then.  But certainly not at 12 months.  So I think some points are being stretched here.  I think there was sort of a rush to present this at a time when we could have had a little bit more follow-up, although probably not enough to make a difference.
		Personally I am torn between the fact that I really like to see two studies, because I think one can be misleading, and on the other hand I know that studies in this population are very difficult to do and this is a drug that looks like it has some real advantages to offer to the patient.  So I think it is a difficult judgment.  
		I think with regard to the issue that was raised in terms of subset analysis, I don't -- a lot of times we say we want to stay away from subset analysis, and that is in a situation where we see ineffectiveness sort of across the board except possibly for a subset.  And there, I think it is very compelling to sort of stay away from subset analysis and then recommend some approval for some subset which may just be a random finding.  Here I think we have reason to believe that some subset of patients really warrant longer follow-up and that they were not well represented in this trial.  I think the cautious thing -- it may be appropriately cautious to not recommend approval of the drug for that subset.  And also that may lead to then another study in that group of patients, which I think would really be good to me for a drug that really offers something to cancer patients where most drugs don't.  I think it is appalling that we should not be able -- for a common disease, we should not be able to have two good studies.
		CHAIRPERSON DUTCHER:  Dr. Wasserman?
		DR. WASSERMAN:  Yes.  Todd Wasserman, again, radiation oncologist from NSU.  Gail Broder eluded to the fact this morning that there was an ASCO panel which has deliberated over the last roughly year and a half and whose report has gone through the board and is pending publication.  And we wrestled with the issue -- I was on the panel too and we wrestled with the issue of tumor protection.  And one, we recognized that tumor protection was a theoretical risk only.  I mean, there was really never any data to suggest that tumor protection would occur.  There was always a worry that it could occur.  And so you had to prove the null effect essentially, the lack of any effect on the tumor.  And it was concluded that this was something that would just take forever, number one, and has been part of the baggage that this drug has carried around all this time.  So I can tell you that the writing in the ASCO report, for whatever it is worth, is that it is a theoretical risk only.
		DR. LIPPMAN:  I'd just like to address the issue of two studies.  This is the area that I work in and I would like to sort of highlight what Dr. Brizel just said.  In head and neck cancer, this would be considered a very large, well-done definitive trial.  The trials that usually come out are like the ones mentioned with 40 patients randomized and things of this sort.  And the VA cooperative study program larynx preservation trial, which was really a landmark trial, had 330 patients.  So personally I would go with a well-designed large randomized trial as opposed to two or three studies of 50 patients, which is common in the head and neck literature.  It doesn't address the issue we are talking about in terms of tumor control, but in terms of definitive studies in this area.
		CHAIRPERSON DUTCHER:  Okay.  Is there adequate evidence that ethyol does not protect tumors during treatment of head and neck cancer with radiation therapy?
		DR. WILLIAMS:  Janice, do you want to modify the -- yes, that is what I wanted to ask.  There has been some talk about modifying the question.
		CHAIRPERSON DUTCHER:  All right.  Are you ready?  Turn the page.  Is there adequate evidence that ethyol does not protect resected tumors?  I guess it wouldn't.  Would you like to make a stab at this question?
		DR. WILLIAMS:  Dr. Harwood, you are on.
		DR. HARWOOD:  Is there adequate evidence 
-- sorry, just give me the first part and I will go on from there.  
		CHAIRPERSON DUTCHER:  Oh, you don't have the question?
		DR. HARWOOD:  Is there adequate evidence that ethyol does not protect tumors during treatment
-- during postoperative radiation treatment of head and neck cancer with radiation therapy?  Now I am doing a double positive there, but I think that is -- or is there adequate evidence that ethyol does not protect tumor during postoperative radiation treatment of head and neck cancer?
		CHAIRPERSON DUTCHER:  All those who would vote yes?  8 yes. All those who would vote no?  One -- and we have two from the other two members.  Three, no.  Abstain?  Did you vote?  What did you vote?  
		MR. GRUETT:  Yes.
		CHAIRPERSON DUTCHER:  You voted yes.  So then 9 yes.  9 yes and 2 no.  All right.  Now to safety profile.  There were significantly more severe adverse events, more missed radiotherapy sessions, and more hospitalizations in the amifostine plus radiotherapy arm.  Adverse events attributed to ethyol are listed in the following table.  Regulations require that substantial evidence of effectiveness be demonstrated through adequate and well-controlled investigations.  In most cases, the FDA has required more than a single trial.  As noted in the 1998 FDA guidance for industry, providing clinical evidence of effectiveness for human drug and biologic products, in other cases FDA has relied on only a single adequate and well-controlled efficacy study to support approval.  Generally only in cases in which a single multi-center study of excellent design provided highly reliable and statistically strong evidence of an important clinical benefit such as an effect on survival and a confirmatory study would have been difficult to conduct on ethical grounds.
		DR. WILLIAMS:  Janet, I would like to make an additional comment.  The comment here is from a guidance on clinical effectiveness for drugs, and the sponsor was very attentive to this guidance and noted on page 13 that it expands a little bit on the survival and also mentions irreversible morbidity as a suitable endpoint.  So we could add that in there if you wanted.
		CHAIRPERSON DUTCHER:  That's a good term.  So an important clinical benefit such as an effect on irreversible morbidity, et cetera.  Considering the efficacy evidence presented from this single randomized Phase III study, considering the safety data and considering the data on tumor protection, should ethyol be approved to decrease the incidence of moderate to severe xerostomia in patients undergoing radiation treatment for head and neck cancer?  All those --
		DR. WILLIAMS:  You are going to amend the question to be postoperative again, aren't you?
		CHAIRPERSON DUTCHER:  Postoperative.  Undergoing postoperative radiation treatment for head and neck cancer.  Is that what you were -- Dr. Simon, is that what your comment was?  Other comments?  Dr. Lippman?
		DR. LIPPMAN:  Although it is unusual to give simultaneous chemotherapy with postoperative, it is occasionally done and maybe later on in the description, as you pointed out, you could indicate that it is for single modality radiation alone.
		CHAIRPERSON DUTCHER:  I think the FDA pretty much understands that.  Any other comments?  No.  All those who would vote yes on question 5?  9 yes and one qualified yes and one very narrow indication yes.  So that was 11, I think.  Any no?  One no.  And I think the qualified yes, again, is the same issues that came up and the narrow indication seems to be the same issues that related to postoperative.  So 11 yes and one no.  Thank you very much.
		(Whereupon, at 4:38 p.m., the meeting was concluded.)