UNITED STATES OF AMERICA
	FOOD AND DRUG ADMINISTRATION
	CENTER FOR DRUG EVALUATION AND RESEARCH
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	ANTIVIRAL DRUG ADVISORY COMMITTEE
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	MEETING
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	TUESDAY,
	FEBRUARY 27, 2001
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		The meeting was held in the Grand Ballroom, Gaithersburg Holiday Inn, 2 Montgomery Village Avenue, Gaithersburg, Maryland, Roger J. Pomerantz, M.D., Chairman, presiding.

PRESENT:
	ROGER J. POMERANTZ, M.D., Chairman
	TARA P. TURNER, Pharm.D., Executive Secretary
	PRINCY N. KUMAR, M.D., Member
	WM. CHRISTOPHER MATHEWS, M.D., Member
	RAM YOGEV, M.D., Member
	BRIAN WONG, M.D., Member

PRESENT (Continued):

	COURTNEY V. FLETCHER, Pharm.D., Consumer
	Representative

	JOSEPH S. BERNITO, JR., Pharm.D., Consultant
	(Voting)

	NEIL BRESSLER, M.D., Consultant (Voting)

	DONALD S. FONG, M.D., M.P.H., Consultant
	(Voting)

	SADEER HANNUSH, M.D., Consultant (Voting)

	JOEL MINDEL, M.D., Ph.D., Consultant (Voting)

	JOSE PULIDO, M.D., Consultant (Voting)

	KEITH RODVOLD, Pharm.D., Consultant (Voting)

NON-VOTING MEMBERS PRESENT:

	DAVID CRITTENDEN, D.M.D., Patient Representative

	EUGENE SUN, M.D., Industry Representative

	CHI-CHAO CHAN, M.D.

	STEPHEN C. PISCITELLI, Pharm.D.

	WILLIAM BOYD, M.D., FDA

	ROBERT KUMI, Ph.D., FDA

	KELLIE REYNOLDS, Pharm.D., FDA

	JOSEPH TOERNER, M.D., FDA

	THERESE CVETKOVICH, M.D., FDA

	DEBRA BIRNKRANT, M.D., FDA

ALSO PRESENT:

	MARY JEAN STEMPIEN, M.D., M.S.

	DR. DANIEL MARTIN
		
	DR. PANAYIOTIS GEORGIOU, Ph.D.

	NOEL ROBERTS, Ph.D.

	MICHAEL MARCO

	C-O-N-T-E-N-T-S
	PAGE
Introductions 	5
Conflict of Interest Statement 	8
Introduction by FDA, Debra Birnkrant, M.D. 	10
Review of Approved Products for Treatment of CMV
Retinitis, William Boyd, M.D. 	15

Sponsor Presentation:

	Introduction, Mary Jean Stempien, M.D.,
	M.S. 	19

	Clinical Background, Daniel F. Martin,
	M.D. 	20

	Study Results, Mary Jean Stempien, M.D.,
	M.S. 	27

FDA Presentation:

	Joseph Toerner, M.D. 	91
	Robert Kumi, Ph.D. 	109

Open Public Committee, Michael Marco 	133

Committee Discussion 	137

	P-R-O-C-E-E-D-I-N-G-S
	(9:00 a.m.)
		CHAIRMAN POMERANTZ:  It's nine o'clock, and I think we should get started.
		I'm Roger Pomerantz.  I'll be your Chairman today as we discuss a very interesting issue of valganciclovir hydrochloride tablets for the treatment of CMV retinitis in the setting of HIV infection.
		What we're going to do is start off with an introduction of everyone around the table.  Please give your name, your association, and your expertise.
		Again, my name is Robert Pomerantz.  I'm the Chief of Infectious Disease at Thomas Jefferson University.  I'm a virologist.
		Can we start at the left-hand all the way down at the end, please?
		DR. PISCITELLI:  Steve Piscitelli from Virco Laboratories.
		DR. SUN:  Eugene Sun from Abbott Laboratories.
		DR. CRITTENDEN:  David Crittenden.  I'm a patient representative.
		DR. WONG:  I'm Brian Wong from the West Haven VA Hospital and Yale University.
		DR. YOGEV:  Ram Yogev, Children's Memorial Hospital, Chicago.
		DR. PULIDO:  Jose Pulido, University of Illinois, Department of Ophthalmology.
		DR. RODVOLD:  Keith Rodvold, Colleges of Pharmacy and Medicine, University of Illinois in Chicago.
		DR. MATHEWS:  Chris Mathews, University of California, San Diego, Department of Medicine.
		DR. MINDEL:  Joel Mindel, neuro-ophthalmologist at Mt. Sinai Medical School, and also a member of the Department of Pharmacology.
		DR. BRESSLER;  Neil Bressler, Johns Hopkins University, and I'm an ophthalmologist specializing in retina there.
		DR. TURNER:  Tara Turner, Executive Secretary for the Committee.
		DR. KUMAR:  Princy Kumar, Chief of Infectious Diseases at Georgetown University Medical Center in Washington.
		DR. FONG:  Donald Fong, and I'm a retina specialist and epidemiologist with Kaiser Permanente in California.
		DR. HANNUSH:  I'm Sadeer Hannush from the Cornea Service at Willis Eye Hospital in Philadelphia.
		DR. FLETCHER:  Courtney Fletcher from the Department of Experimental and Clinical Pharmacology at the University of Minnesota.
		DR. BERTINO:  Joe Bertino.  I'm the Section Chief of Clinical Pharmacology at Bassett Health Care in Cooperstown, New York.
		DR. BOYD:  William Boyd.  I'm a medical officer with the FDA.
		DR. KUMI:  Robert Kumi, pharmacokinetic reviewer, FDA.
		DR. REYNOLDS:  Kellie Reynolds, pharmacokinetics, FDA.
		DR. TOEMER:  Joe Toerner.  I'm a medical officer at FDA.
		DR. CVETKOVICH:  Therese Cvetkovich, medical team leader in the Division of Antiviral Drug Products.
		DR. BIRNKRANT:  Debra Birnkrant, Acting Director, Division of Antiviral Drug Products, FDA.
		CHAIRMAN POMERANTZ:  Thank you.
		As you see by the agenda today, we have a number of things to do this morning, in particular, hearing from the FDA about this drug, as well as the applicant's presentations.
		There are going to be four questions that will be addressed to the Committee, three of which will require an official vote from the voting members later in the afternoon.
		So with no further ado, I want to turn it over to Tara Turner, our Executive Secretary, for a conflict of interest statement.
		DR. TURNER:  Thank you, Dr. Pomerantz.
		The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
		Based on the submitted agenda for the meeting and all financial interests reported by the Committee participants, it has been determined that all interests in firms regulated by the Center for Drug Evaluation and Research present no potential for an appearance of a conflict of interest at this meeting with the following exceptions.
		In accordance with 18 USC 208(b), full waivers have been granted to Dr. Courtney Fletcher, Dr. Roger Pomerantz, Dr. Brian Wong, Dr. Princy Kumar, Dr. Ram Yogev, Dr. William Christopher Mathews, and DR. Chi-Chao Chan.  A copy of the waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, Room 12A-30 of the Parklawn Building.
		In addition, we would like to disclose for the record that Dr. Joseph Bertino, Dr. Princy Kumar, Dr. Keith Rodvold, and Dr. Neil Bressler have interests which do not constitute a financial interest within the meaning of 18 USC 208(a), but which could create the appearance of a conflict.
		The agency has determined, notwithstanding these interests, that the interests of the government in their participation outweighs the concern that the integrity of the agency's programs and operations may be questioned.
		Therefore, Dr. Bertino, Dr. Kumar, Dr. Rodvold, and Dr. Bressler may participate fully in today's discussions.
		With respect to the FDA's invited guests, Dr. Steve Piscitelli and Dr. Eugene Sun have reported interests which we believe should be made public to allow the participants to objectively evaluate their comments.
		Dr. Piscitelli would like to disclose for the record that he is participating in a series of Roche sponsored lectures on therapeutic drug monitoring in HIV.
		Dr. Sun would like to disclose for the record that he is employed full time with Abbott Laboratories.  
		In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the record.
		With respect to all other participants, we ask in the interest of fairness that they address any current or previously financial involvement with any firm whose products they may wish to comment upon.
		Thank you.
		CHAIRMAN POMERANTZ:  Thanks, Tara.
		And let's get right into it then.  We're going to start with Debra Birnkrant from the FDA, Acting Director, Division of Antiviral Drug Products, introduction and opening remarks.
		Debra.
		DR. BIRNKRANT:  Thank you very much, and good morning.
		I can use an antiviral myself.
		(Laughter.)
		DR. BIRNKRANT:  I'd like to welcome members of the Division of Antiviral Drug Products Advisory Committee, members of the Ophthalmic Subcommittee of the Dermatologic and Ophthalmic Drugs Advisory Committee, guests, and representatives from Roche.
		Today we will be discussing NDA 21304, valganciclovir for the treatment of CMV retinitis.  Following my brief opening remarks, Dr. William Boyd of the Division of Anti-Inflammatory Analgesic and Ophthalmic Drug Products will present a regulatory perspective with regard to approvals of CMV treatment.
		Then we will proceed with the applicant's presentation.  This will be followed by a brief period of questions for clarification purposes, and the FDA will present their regulatory perspective on the safety and efficacy data supported in this application, as well as pharmacokinetic data to support maintenance therapy.
		This will also be followed by a brief period for questions for clarification purposes.
		In the afternoon, we will have an open public hearing and questions for the Committee to discuss.
		Next slide.
		To set the stage for today's meeting, I'd like to make a few comments with regard to the regulatory background of this NDA under discussion today.  The development of valganciclovir coincided with the development of highly active anti-retroviral therapy for the treatment of HIV infected subjects.
		With the implementation of HAART, we saw a decline in the incidence of CMV retinitis.  This had a major impact on Roche's development plan for CMV retinitis for valganciclovir, and in their background document that they supplied to the Committee, they stated that in the early '90s for a clinical trial for CMV retinitis of 160 patients, it would take approximately 15 months at approximately 15 sites, but for that same size trial in the late 1990s, it would take twice as long, and it would have to be conducted at least at twice as many sites.
		So because of the impact of the decline of CMV retinitis in the setting of HAART, Roche postponed their plans for development of valganciclovir in 1997.  However, the Division of Antiviral Drug Products asked Roche to continue development because of the medical need for an oral drug with greater bioavailability than what was currently on the market or just greater bioavailability for CMV treatment.
		Roche then expanded their Phase 2 study of CMV retinitis and agreed to supply additional data to support a CMV retinitis indication, as well as they agreed to supply data from a solid organ transplant study, as well.
		So in the end, agreement was reached that Roche would continue the development of valganciclovir both for CMV retinitis and for prevention of CMV disease in solid organ transplant therapy.
		Next slide.
		I'd like to represent my previous comments graphically.  This graph is taken from an article in the New England Journal of Medicine that appeared in 1998 looking at the declining morbidity and mortality of CMV retinitis in the setting of HAART.
		The lead author is Palella in this study.
		What you can see is a graph of three major opportunistic infections, CMV, MAC, and PCP.  The incidence between the years 1994 and 1997.
		Next, next.
		With the initiation of HAART following approvals of indinovir, sequinovir, and ritanovir, you can see in red in the next representation a decline in the incidence of CMV retinitis between the years '94 and '97, from 17 per 100 person-years down to less than three per 100 person-years in 1997.
		Next slide.
		So not only did the implementation and initiation of HAART impact the development plan for valganciclovir, it also had an impact on the primary endpoint in a clinical trial designed to study CMV retinitis with valganciclovir, and that is historically the primary endpoint for CMV retinitis treatment was time to progression, but in the era of HAART this had to change.
		It had to change because of the impact of a new HAART regimen on disease progression itself.  So Roche sought consultation with outside ophthalmic or ophthalmologic experts, and they proposed an endpoint of the proportion of patients with disease progression at week four, and FDA accepted this endpoint.
		Next slide.
		With regard to the medical need for another anti-CMV treatment, on this slide you can see that there are six currently available, approved drugs to treat CMV retinitis.  We start with ganciclovir intravenous, which was approved in 1989.  There are two other intravenous products, foscarnet and cidofovir.
		Then we have the ganciclovir implant, and an intraocular injectable.
		The medical need relies on the issue related to a formulation of a drug that would not require an invasive procedure or maintaining an indwelling catheter for patients to receive a particular product, and with the development of valganciclovir, you have an orally bioavailable product that's has tenfold greater bioavailability than the currently approved ganciclovir capsules.
		And with that, I'd like to say that the division is looking forward to the deliberations this afternoon and the discussion throughout the day of our Advisory Committee assembled here, and I would now like to introduce Dr. William Boyd, our ophthalmology consultant at the FDA, who will present a regulatory overview of approvals for CMV treatment.
		Thank you.
		DR. BOYD:  Good morning.  This will just be a brief presentation on approved products for the treatment of CMV retinitis in immunocompromised patients.
		We've already gone through the list of approved products, which are Cytovene IV, Foscavir injection, Cytovene capsules, the Vitrasert implant, Vistide injection, and Vitravene IV injection.
		Cytovene IV, which is ganciclovir, was approved on June 23rd, 1989.  Two of the clinical data sources for approval were a randomized controlled trial studying immediate versus delayed treatment in 42 subjects, and a non-randomized retrospective immediate versus delayed treatment study in 41 subjects.
		Let me just take a moment to explain what we mean by immediate versus delayed treatment.  After randomization, if you were randomized to delayed treatment, you did not receive treatment right away.  You were monitored on a weekly basis, and at the first sign of advancement of disease, treatment was initiated.
		Next slide.
		The primary endpoints for these studies were time to progression of CMV retinitis.  The primary endpoint analysis in study number one, and this relied on mask photographic evaluation, was the median time to progression of 50 days for immediate treatment and 14 days for delayed treatment.
		In study number two, there was a median time to progression of 71 days for immediate treatment versus 29 days for delayed.
		Foscavir injection was approved on September 27th, 1991.  Among the clinical data sources for approval was a randomized, open label, controlled trial studying immediate versus delayed treatment in 24 subjects.
		The primary endpoint was a time to progression of CMV retinitis.  In the primary endpoint analysis, there was a median time to progression of 93 days for immediate treatment versus 22 days for delayed treatment, and again, this was based on a mask photographic analysis.
		Cytovene capsules were approved on December 22nd, 1994.  It's not approved for induction therapy due to poor bioavailability.  It's only five percent available.  The study design for the maintenance indication relied on three randomized open label trials with Cytovene IV as a comparator for a total of 505 subjects.
		The Vitrasert implant was approved on March 4th, 1996.  Among the clinical data sources for approval were a randomized, parallel, ganciclovir implant versus ganciclovir IV trial in 188 subjects, and the primary endpoint was a time to progression of CMV retinitis.
		The primary endpoint analysis demonstrated a median time to progression of 210 days for the implant versus 120 days for IV ganciclovir, and this was based on mask photographic analysis.
		Vistide injection was approved on June 26th, 1996.  Among the clinical data sources relied upon for approval was a randomized, open label, controlled trial studying immediate versus delayed treatment in 48 subjects.  The primary endpoint, again, was time to progression of CMV retinitis.
		The primary endpoint analysis demonstrated a median time to progression of 120 days for immediate treatment versus 22 days for delayed treatment, and again, this relied on mask photographic analysis.
		Vitravene IV injection was approved on August 26th, 1998, and among the clinical data sources utilized for approval were limited open label, controlled clinical studies studying immediate versus delayed treatment and ADIs.  The primary endpoint, again, was time to progression of CMV retinitis.
		The primary endpoint analysis demonstrated a median time to progression of 80 days for immediate treatment versus 14 days for delayed treatment, and again, this relied on mask photographic analysis.
		Just, again, a brief summary of the approved products:  Cytovene IV, Foscavir injection, Cytovene capsules, Vitrasert implant, Vistide injection, Vitravene IV injection.
		It's been mentioned before that there's not an oral agent available for both induction and maintenance therapy.  There is morbidity associated with catheter use for the IVs, as well as the need for a surgical procedure for the Vitrasert implant.
		That concludes my brief presentation.  I did have one other slide.  This was a previous version of my presentation for today, and there's a second version you should have on the disk.  If we don't, that's okay.  I think it's coming.
		Okay.  All right.  Thank you.
		CHAIRMAN POMERANTZ:  Thank you.
		We're remarkably ahead of schedule.  We'll see if that continues.
		The sponsor will now start.  Mary Jean Stempien will give the introduction from Roche, Director of Medical Research.
		DR. STEMPIEN:  Good morning.  I'm Dr. Mary Jean Stempien.  I'm one of the physicians on the valganciclovir project team, and I'm very pleased to start off Roche's presentation this morning.
		Could I have the projector on, please?  Okay.  Thank you.
		Roche comes before this Committee today seeking a recommendation for approval of valganciclovir, valganciclovir to be indicated for the treatment of CMV retinitis in patients with AIDS.
		Following my brief introduction, Dr. Dan Martin will come up and give the clinical background.  Dr. Martin is an ophthalmologist at Emory, and he was the lead principal investigator on our primary efficacy and safety study in our package, and then I will return and discuss the development program for valganciclovir and the study results.
		We also have with us two outside experts, Dr. Gary Koch, who is a professor of biostatistics at Chapel Hill, and Dr. Nancy Sambol from UCSF, who's an expert in population PK.  They're not presenting, but they're here in case questions come up during Q and A that are relevant, and they would be happy to participate in that.
		I'd now like to introduce Dr. Dan Martin.
		DR. MARTIN:  Good morning.  In the next few minutes I'll cover the clinical features of CMV retinitis, the impact that highly active anti-retroviral therapy has had on this disease, and the treatment options currently available for patients who present with CMV retinitis.
		This is a photograph of what you see when you look in the back of the eye.  This is a photograph of a normal retina.  It's the right eye.  Here's the optic nerve, and here is the fovea.  These two structures are the most important structures in the back of the eye.
		The fovea is the only portion of the retina that is able to resolve visual acuity of 20-20.
		Throughout this presentation you will hear us refer to zones of retinal involvement by CMV.  When CMV retinitis threatens the optic nerve or the macula, specifically, when it extends to within 1,500 microns from the optic nerve or 3,000 microns from the fovea, we designate that as Zone 1 disease.
		If CMV retinitis involves the retina outside this area to this circle, defined by the ampule of the vortex veins seen here and here, that's designated as Zone 2, and then the more peripheral retina is Zone 3.
		This patient has active CMV retinitis that involves peripheral Zone 2 and Zone 3.
		This is a photograph of the left eye of a patient with active CMV retinitis located in Zone 1 threatening the optic nerve and the fovea.  The clinical appearance here is fairly typical.  CMV infection of the retina causes a full thickness, white, opaque retinal necrosis with some scattered intraretinal hemorrhage.  The area involved by CMV, the vision in this area is permanently lost.
		The CMV can establish itself anywhere in the retina, and once it does, it typically spreads slowly across the back of the eye.  People liken it to a brush fire, leaving in its wake atrophic, necrotic retina that is devoid of visual function.
		If CMV retinitis is allowed to continue across the eye, it will progress to slowly involve all of the retina, leading to complete loss of vision in the eye.
		The goal of therapy then is to prevent or to stop this progression of retinitis and to render this active, white, necrotic lesion completely inactive.
		Prior to the development of or the advent of HAART, approximately 30 percent of patients with a CD4 count less than 50 could be expected to develop CMV retinitis.  In 1996, with the introduction of sequinovir, ritanovir, and indinovir, we had for the first time the opportunity to profoundly suppress HIV viral load.
		Concomitant with that suppression, there can be a rise in the CD4 count, and when that occurred in a large number of patients, it reduced the number of patients at risk for CMV disease, and as a result, there has been a substantial decline in the incidence of CMV retinitis.
		Now, with all of the success that we've had with HAART, one may ask why do we need a new treatment for CMV retinitis, and the answer is as follows.
		Despite the success, we continue to see new cases of CMV disease, and this incidence may increase as patients fail their anti-retroviral therapy.
		For patients who are on HAART, the development of CMV retinitis represents a failure of their HIV therapy, and those patients require anti-CMV therapy usually consisting of an induction followed by some period of maintenance.
		I want to emphasize that point because I think a lot of people have mistaken ideas about how HAART has impacted this disease.  Yes, HAART has reduced the risk for CMV disease, reduced the incidence for it, and, yes, HAART impacts potentially the duration of maintenance therapy that may be required in a patient, but for the individual who presents with newly diagnosed CMV retinitis, if they are on HAART, it's almost irrelevant.  That patient has failed immunologically to allow this infection to occur.
		You may be able to adjust one's HAART regimen and hopefully result in improvement of their CD4 count, but that event is something that takes place down the road, and at least for three, six months, and sometimes indefinitely, those patients will require anti-CMV therapy.  Simply manipulating one's HAART regimen, no one uses that as a primary treatment for CMV retinitis.
		Now, you've already heard the available treatment options, and they are presented here.  All of them are effective to differing degrees, but none of them are ideal for differing reasons.
		Intravenous ganciclovir, followed by intravenous ganciclovir maintenance requires an indwelling catheter which is associated with a negative impact on quality of life and a substantial risk for sepsis.
		Oral ganciclovir has limited bioavailability, cannot be used as induction therapy, requires t.i.d. dosing, and has a relatively high daily pill burden.
		The ganciclovir implant and usually used in conjunction with oral ganciclovir is quite effective, but is a surgical procedure, and there are risks, as is true with any surgical procedure.
		Intravenous foscarnet has some of the same issues as intravenous ganciclovir in that it requires a catheter, long infusion times, risk of sepsis, a negative impact on quality of life, and there's also the issue of renal toxicity.
		Cidofovir, while not requiring daily intravenous infusions, has a substantial risk for renal and, at least in my hands, ocular toxicity, and approximately 50 percent of patients will develop an allergy to probenecid, a medicine that is required to be given concomitant with cidofovir.
		Therefore, the development of an oral agent that is effective for both induction and maintenance treatment that has no intravenous catheter requirement, a convenient dosing regimen, and an acceptable safety profile represents a major unmet medical need in the treatment of this disease.
		As an investigator in the primary efficacy trial, which Dr. Stempien will be presenting in just a few minutes, I've had the opportunity to treat a number of CMV retinitis patients with valganciclovir.
		This is the first patient actually who was enrolled in this study and the first patient ever treated with valganciclovir for CMV retinitis.  He had failed all anti-retroviral therapy presented with a small patch of newly diagnosed CMV retinitis located in Zone 2.  You can also see the edge of it here, was randomly assigned to valganciclovir induction, began taking two 450 milligram tablets twice daily; and at two weeks, there was still some retinal opacification, as is typical in most induction scenarios, but by four weeks the lesion was essentially and completely inactive, and by eight weeks there's no sign of active infection.
		We were quite excited by this.  This was the first time that a patient with newly diagnosed CMV retinitis had had his or her disease rendered inactive by administration of an orally administered compound.
		This is another present who presented with newly diagnosed CMV retinitis located in his nasal peripheral retina; was randomly assigned to valganciclovir induction; and at two weeks, as you can see, the border, which is seen here, is now for the most part inactive.  There's still some opacification of the retina within the lesion, and by four weeks the entire lesion has cleared.  There has been no progression of disease, and now there's a scar in the area of previous infection.
		I'll ask Dr. Stempien to return to continue our presentation.
		DR. STEMPIEN:  Thank you, Dr. Martin.
		IV ganciclovir is a first line treatment for CMV retinitis.  It has been approved in the U.S. since 1989.  It's currently indicated for the treatment of retinitis in immunocompromised patients and for the prevention of CMV disease in transplant patients at risk, and it has a very well described efficacy and safety profile that has accumulated over 12 years of clinical use.
		Oral ganciclovir has been available in the U.S. since 1994.  It is indicated for maintenance treatment only of CMV retinitis in immunocompromised patients and for the prevention of CMV disease in solid organ transplant patients and in HIV patients at risk.
		And as you have heard, it has been limited by its bioavailability and the fact that it needs to be part of a t.i.d. dosing regimen.
		Ganciclovir is preferentially phosphorylated in CMV infected cells via a viral protein kinase, UL-97, and after three phosphorylations it becomes ganciclovir triphosphate, which is the active moiety.  And, again, ganciclovir triphosphate inhibits viral DNA polymerase, and the active moiety has an intracellular half-life of approximately 18 hours.
		Valganciclovir is a pro drug of ganciclovir, and it's distinguished from ganciclovir by the presence of this valyl ester group.  Here are the key characteristics of valganciclovir.
		Most importantly, we can achieve ganciclovir exposures measured as systemic area under the curve following a 900 milligram dose of valganciclovir that are similar to the exposures that we can achieve with standard IV ganciclovir dosing given as five milligrams per kilogram.
		The reason we can do this is because of the improved bioavailability.  It is tenfold higher than what we can achieve with our current oral ganciclovir formulation.  So the bioavailability is approximately 60 percent.
		And importantly, just a small amount, less than two percent of the absorbed dose actually appears as parent compound, valganciclovir, in the plasma, and it has a relatively short half-life.
		And we have developed valganciclovir as a 450 milligram tablet.
		The next few slides will show you the comparative PK profiles of our ganciclovir formulations and show you how they compared to valganciclovir.  Here's a typical IV ganciclovir profile.  This is on a semi-log scale, and here is oral ganciclovir, which is dosed three times daily, and as you can see, it has a much lower C-max than IV ganciclovir.
		And here I have superimposed the PK profiles for valganciclovir.  This is the curve for ganciclovir following a valganciclovir dose, and this is a 900 milligram valganciclovir dose.
		Here's the parent compound, valganciclovir, which appears briefly in the plasma and is cleared rather quickly.
		The C-max of valganciclovir actually falls between that of IV ganciclovir and oral ganciclovir.  Likewise, the C-min is bracketed by that for oral and for IV.  And most importantly, the area under the curve for the ganciclovir delivered following a valganciclovir dose is very similar to the area under the curve that we achieve from IV ganciclovir dosing.
		Now, here are the PK parameters that go along with the curves that I've just showed you.  The IV ganciclovir 24-hour AUC is approximately 26 compared to oral ganciclovir, which is about half that, or 13.
		Now, both of these formulations are approved for maintenance therapy, and they are both efficacious, although there is a twofold difference in area under the curve.
		If you look at the difference between C-max though for the two formulations, you see a much bigger difference.  There's a tenfold difference between IV ganciclovir and oral ganciclovir for both C-max and for C-min.
		So based on these PK considerations, it appeared to us that it was most likely that area under the curve was going to be the PK parameter that would best correlate with efficacy.
		And, importantly, following valganciclovir dosing, we do achieve an area under the curve that is very similar to what we achieved following IV ganciclovir dosing, and the C-max following valganciclovir is about 60 percent that of IV ganciclovir.
		In addition, we did do some PK/PD work from another ganciclovir study.  We explored PK/PD in  a study GAN-2226, which was a dose ranging maintenance study that included both IV ganciclovir dosing and three different doses of oral ganciclovir ranging from three grams per day to six grams per day.
		And we utilized a population PK approach, and while that methodology did have some limitations, the conclusion of the result pointed to area under the curve as being the most important PK parameter to correlate with efficacy, and in that study efficacy was measured as time to progression.
		This is completely consistent with our expectations going in simply based on consideration of the PK profiles for oral ganciclovir and IV ganciclovir.
		So based on these considerations, we targeted for valganciclovir an AUC of approximately 26, which corresponds to the median AUC that we achieved with IV ganciclovir dosing, and we found in a dose ranging study that we could achieve that target AUC with a 900 milligram dose of valganciclovir.
		So that during maintenance treatment, looking for that AUC of 26, that would correspond with a 900 milligram dose of valganciclovir, and then during induction dosing, which is typically given twice daily, that would double the AUC and double the dose of valganciclovir to 1,800 milligrams daily.
		Valganciclovir is rapidly hydrolyzed to ganciclovir by intestinal and hepatic esterases, and we have not detected any other metabolite of valganciclovir, other than ganciclovir.
		Therefore, all ganciclovir drug interactions that have been described to date would certainly apply to valganciclovir, and likewise because ganciclovir is predominantly renally cleared, patients with renal impairment would require a dose adjustment if they were using valganciclovir.
		So the PK profile of ganciclovir following valganciclovir dosing provided the potential for a therapeutic alternative to IV ganciclovir treatment of retinitis both for induction and for maintenance.  It would allow us to avoid the risks associated IV access required for IV ganciclovir therapy, and it would provide a simple oral regimen that could improve patient adherence during longer term maintenance dosing.
		Now, as you have already heard, our development program ran into an early challenge when we undertook a pilot study early in our program to explore the potential efficacy of valganciclovir in an induction treatment setting because this had never been done, and we started enrolling this study in January 1997, and that is when we really began to appreciate the full impact of HAART.
		This pilot study intended to enroll 70 patients, and in four months utilizing 17 sites we were only able to enroll 11 patients.
		You have seen a similar graphical representation from a different reference as to what was happening as a result of the introduction of HAART.  This is another reference, but it points to the same phenomenon, and all of the opportunistic infections associated with the HIV were decreasing dramatically after the introduction of HAART.
		This is where we were planning our pilot study, and here is where we were when we were starting enrollment, and this represent the decline in CMV retinitis, newly diagnosed CMV retinitis.
		So at this point in time, we really had to rethink our development program, and although we had planned a traditional program with a pilot study followed by Phase 3 studies, we realized that that would not be possible in this environment, and we certainly appreciate the collaboration that we enjoyed with FDA in trying to work this through and figure out a reasonable way to proceed and continue development.
		This is the program that we ended up with.  Our package includes data on nearly 500 patients.  We did a standard series of clinical pharmacology studies, and we conducted two therapeutic studies that enrolled 372 patients.
		Our primary efficacy and safety study is WV-15376, and I may simply refer to it as "376" as we go forward.
		This was the pilot study.  This started out as the pilot study, and we converted it to our primary efficacy and safety study so that we could maximize the contribution of the patients who had already enrolled.
		And then to supplement that, we conducted an open label safety study, WV-15705, or I may just refer to it as "705," and that enrolled 212 subjects.
		Our 372 patients which we enrolled in our two therapeutic studies enrolled in approximately 26 months utilizing 50 sites and all of the countries pictured on this slide.
		The development program for valganciclovir builds on the proven efficacy of ganciclovir, and because of that, we felt that the question of primary interest to the treating community would be how does valganciclovir compare to IV ganciclovir in terms of efficacy and safety.
		To answer this question, we decided to study it in the induction setting.  We felt that the induction setting would represent the highest efficacy hurdle for any new CMV retinitis treatment, and we also felt that if we could adequately establish efficacy for valganciclovir in induction, that that information coupled with consideration of the PK profiles would certainly allow us to expect that valganciclovir would have efficacy in maintenance as well.
		I'll take you through our studies now and the results.  This is our primary efficacy and safety study, 376.  We randomized 160 subjects to induction treatment with either IV ganciclovir or valganciclovir.  The IV ganciclovir group received standard dosing, five milligrams per kilogram, twice daily for three weeks, and at that time we decreased to once daily, and the valganciclovir group received 900 milligrams of valganciclovir twice daily for three weeks, again, decreasing that to once a day at the completion of three weeks.
		The randomized comparison in the study was conducted between baseline and week four.  So we measured our primary endpoint at this point, the end of week four, and at that time all patients continued on open label valganciclovir maintenance, receiving 900 milligrams once daily so that we could continue to collect safety information and some secondary endpoints.
		The primary endpoint of this study was the proportion of patients who demonstrated progression of their retinitis by week four, and that progression was defined in a very standard way: movement of the border of the lesion by at least 750 microns along a 750 micron front or the appearance of a new retinal lesion of a certain size, and this was assessed by retinal photography.
		And the retinal photography assessment methods were very standard.  We utilized the Wisconsin Reading Center.  We obtained full field bilateral photographs at each ophthalmology visit, and those photos were archived, sent to the Wisconsin Reading Center.  They were scored by an experienced grader who was masked to treatment assignment, and the reading center was not involved otherwise in the conduct of the study.
		And the reader scored these photos for progression, distance of border movement, and various measures of border activity.
		The next several slides deal with some of our statistical analysis considerations in the 376 study.  The question that we were interested in answering was:  is the efficacy of valganciclovir similar to and specifically no worse than IV ganciclovir for induction therapy?
		We chose a noninferiority approach to address this.  The noninferiority test utilizes the lower bound of the confidence interval.  Now, in this trial we were looking at treatment group differences, the proportion of patients in the IV group minus the proportion of patients in the valganciclovir group who progressed, and we were looking at the confidence interval around that difference.
		We chose a noninferiority limit D or delta of minus .25, and that was chosen to represent what we felt was a clinically acceptable treatment group difference, and we settled on that D following consultation with several outside experts, ophthalmologists and treating physicians who were helping us to design the study.  There were also some sample size considerations that went into that selection.
		The next few slides show this in a more visual way that I think will help.  Here is the treatment group difference.  If the treatment group difference was zero, it would fall along this line.  Here is our delta, and so if the lower bound of the confidence interval was to the right of this line, we would be able to conclude that valganciclovir was no worse than IV ganciclovir in induction treatment.
		Here are some hypothetical results just to illustrate our interpretation.  In all three of these cases because the lower bound of the confidence interval is to the left of this line, we could not make that conclusion.
		With these scenarios, in all three cases because the lower bound of the confidence interval is to the right of this line, we could conclude that valganciclovir was no worse than IV ganciclovir.
		And here are the results that we achieved in our 376 study:  essentially no treatment group difference and a narrow confidence interval that certainly  fulfills our prespecified limit set forth in the protocol.
		Now I'll take you through the actual data in more detail.  The 376 study randomized 80 patients in each group, predominantly men in their late 30s.  This is consistent with previous CMV retinitis studies, and the groups were well balanced with respect to ethnic background.
		The groups were also balanced in terms of CD4 count, HIV load, and CMV load at baseline.  We did have two imbalanced that are noted here.  A higher percentage of patients in the IV group had a qualitative, positive CMV's PCR in their plasma, and also had positive CMV cultures.
		Since culture results were not done in real time, we did not have this information at entry into the study.  So although we do have this imbalance in the study, this imbalance could only have been due to chance.
		In terms of HIV therapy at baseline, well balanced.  Again, the majority of patients were taking protease inhibitors.  A certain percentage in each group were protease inhibitor naive, and also a small percentage in each group had not received any anti-retroviral treatment.
		The retinitis presented in a very typical way.  Twenty-four percent of the patients in each group had Zone 1 involvement at time of entry, and 25 percent of the patients had bilateral disease, and a very high percentage, 89 and 85 percent, had active lesions coming into the trial.
		The ITT study population, which was utilized in some of our longer -- some of our analyses that went beyond the four-week time period, utilized all of the randomized subjects, but the primary endpoint and several of our secondary endpoints utilized a standard efficacy population, which was predefined in the protocol.
		We ended up excluding seven patients from each group, and the reasons for exclusion were either that the patient's retinitis could not be confirmed by photo or that subject simply did not contribute any efficacy data after baseline.
		Here's the primary endpoint.  We found that we had comparable efficacy at week four in both treatment groups.  Seven patients in each arm experienced a photo progression by the end of week four.
		The proportion who progressed was ten percent in the IV group and essentially ten percent in the valgan group, the difference, .1 percent, and here's the 95 percent confidence interval with the lower bound of the confidence interval well within the boundaries that were set out in the protocol.
		I might also say that we did conduct an intend to treat analysis of the same endpoint using all of the randomized patients, and the results are the same.
		We looked at progression at week four by the zone of involvement at baseline, and the zone of involvement at baseline did not have an influence.  Patients who had Zone 1 disease coming in, of the 16 who had Zone 1 coming in, 13 percent progressed in the valgan group -- in the IV group; 11 percent progressed in the valgan group.  Peripherally they were also balanced if they had a Zone 2 or Zone 3 lesion.
		We assessed visual acuity and functional vision.  The visual acuity during the first several weeks of the trial were discussed in your backgrounder.  Here is a slide that captures visual acuity and functional vision all the way out to study cutoff.  So this represents a median of approximately ten months of study drug treatment and a comparable proportion of patients in both groups experienced some decrease in visual acuity or a decrease in functional vision.
		Here's the more traditional endpoint for CMV retinitis studies which we did include as a secondary endpoint, the time to progression by photographic assessment.  Now, here is the valganciclovir group, and here is the IV group.  These curves are similar.  
		It's important to note that after week four all patients are on valganciclovir.  So the only treatment difference is occurring during the first four weeks of the study.
		Our conclusion from this set of graphs was that there was no indication -- we took reassurance from this analysis.  We felt that there was no indication that valganciclovir induction treatment had in any way had a negative impact on time to progression later in time, and we thought that was very important.
		In terms of CMV cultures, as I mentioned before, there was a baseline imbalance, but by the end of week four we had a significant and comparable antiviral effect in both groups, and that also applied to the CMV PCR analysis where a very small percentage were PCR positive at the week four time point.
		Now, we did have one issue in the study that we did look at closely after our analysis.  When you look at time to withdrawal by Kaplan Meier, it does appear that the curves are separating, and it looked as though it was happening after the completion of the four-week randomized phase of the study, and so we took a closer look at all of the patients who withdrew between week four and approximately week 12 to see, to really understand what was driving those withdrawals and to make sure that those withdrawals did not have any implications on the conclusions of our primary efficacy analysis.
		The reasons for withdrawal were varied.  They were not all related to safety, and the adverse events that did prompt a withdrawal during this time interval varied.
		What we found, our conclusion was that we could not discern a pattern to these withdrawals, and it's also important to note that of the four valganciclovir patients who withdrew because of insufficient response, what was happening here is that the ophthalmologist -- in three of the cases, the ophthalmologist called a progression, and the patient withdrew.
		In fact though, those three patients were already counted as primary endpoints  in the primary efficacy analysis because they had a documented photo progression that had already been called by the reading center.  So they were counted as endpoints.
		And just to make certain that we didn't have an issue here, we did a time to progression or withdrawal analysis, and you can see that the curves are very similar.  What happened was that the increased number of withdrawals in the valganciclovir arm during that time period ended up being counterbalanced by the increased number of ganciclovir patients who experienced a photographic progression during the same time interval.  So when you do this analysis, the curves come back together.
		We collected PK information during this study in a subset of patients, and the next few curves will show you the PK results.  
		Here are curves for following IV ganciclovir dosing, and then this is ganciclovir from valganciclovir.  This is during week one.  This reflects induction level dosing, and because we're dosing b.i.d., that's why the curves only go out to 12 hours.  So this is the dosing interval during induction.
		And during week four, patients were now taking the maintenance level dosing, and so the dosing interval goes out to 24 hours.  That's why these curves extend.  Again, IV, and then this is valganciclovir.
		Now I've put the two curves together, and you can see between week one and week four, the curves are fairly superimposable.  This is because there is no accumulation, and I've also added to this slide the parent compound.
		So here is valganciclovir appearing again briefly and with a short half-life.  These curves should look very similar to the curves that I showed you earlier in the presentation, and they are, and we're very happy about that.
		Here are the numbers that go along with the curves I've just shown you.  So at week one, this is induction level dosing.  This is maintenance level dosing, b.i.d. and q.d.
		The slide shows you the AUCs as dosing interval AUCs so that they'll be easier to compare.  So this is a 12-hour AUC.  This is a 24-hour AUC.  Both at week one and at week four the AUCs that we achieved for IV dosing and valganciclovir dosing were very similar, and they also were similar across the time points because there's no accumulation.
		And here are the C-maxes, just what we would have expected:  approximately ten with IV and about 60 percent of that with valganciclovir at both time points.
		Now I'll cover the safety aspects of our program.  During the randomized phase of 376, we had three patients who withdrew because of a safety related reason, two an done.  One patient left because of a neutropenia.  One patient died of lymphoma, and another patient died from PCP.
		And during the randomized phase, the adverse event profile that we found with valganciclovir was completely consistent with what we know about IV ganciclovir and were the most common events that are associated with IV ganciclovir.
		So no new toxicities have been detected to date that have not already been described with ganciclovir.  Diarrhea occurred somewhat more frequently in the valganciclovir arm compared to IV, and oral candidiasis was more frequent in the valganciclovir arm compared to IV, and we don't have a ready explanation for that if, in fact, that's a true finding.
		Very importantly, intravenous catheter related adverse events were very much reduced in the valganciclovir arm, and this is consistent with what we've seen before when we've compared IV valganciclovir and oral ganciclovir maintenance treatment.  
		If you can get away with dosing without an IV, you really do reduce some morbidity associated with intravenous catheters.
		Since ganciclovir has hematologic toxicity associated with it, we did look at minimum AMC, minimum hemoglobin, and minimum platelet count, and during the randomized phase of the study, the two treatment groups were in good balance for those three parameters.
		Now, I've shown you the safety during the randomized portion of 376 when we had a direct comparison to IV.  Beyond this time point, all patients are on valganciclovir.  So to give you the most complete picture of valganciclovir;s safety, we have pooled the safety data from the 376 study and from that second safety study that we conducted, 705.
		So let me just show you the 705 design, and then I'll show you all of the safety results.  Seven, oh, five, didn't randomize, just enrolled 212 patients.  It was a single arm study.  Everyone received 900 milligrams once daily of valganciclovir, and they were able to receive an induction course of valganciclovir if needed during this study.
		In terms of the valganciclovir exposure during both trials all the way out to the clinical cutoff for our NDA, you can see that the median times on treatment are much longer than have been described with previous CMV retinitis studies, and this is because patients are living longer.  This is clearly related to HAART.
		But it allows us to accumulate safety data over a longer duration of treatment, and so although the total number of patients that we have in our package's safety database is somewhat less than what you would expect for a new chemical entity, nonetheless because we have these nice, long durations -- and, in fact, these two studies are still running, so we're still continuing to collect safety information -- that gives us a great level of comfort in our safety database.
		Here are the adverse events during the maintenance treatment phase out to clinical cutoff, and this column represents the experience of the combined safety database, 370 patients who received valganciclovir during one of the two trials.
		Again, the adverse events that you see are adverse events that are associated with ganciclovir.  They're the adverse events that we saw during induction treatment.
		Now, just to help put this in context a little bit, I have included on this slide some historical information taken from relevant previous ganciclovir studies.  It's important to know they were for the most part all pre-HAART, and they were much shorter in duration than our current study.  So I think this represents a worst case comparison.
		I have added ganciclovir, three gram, information.  This is oral ganciclovir, three grams; IV ganciclovir; and some placebo experience, not truly placebo, but it comes from our 2304 implant study where patients received a local implant and an oral placebo.  So we feel comfortable that we can consider these adverse events to represent placebo events in this column.
		Just two points to make.  Diarrhea, which was more common in the randomized arm in the valganciclovir group, you can see that when you pool the patients, it's about a third of the patients who experienced diarrhea, and that's in line with what we've seen with our oral ganciclovir formulation.
		The oral candidiasis, when you pool, is about 17 percent; still looks somewhat higher than the other two ganciclovir formulations, and maybe a little bit closer to previous placebo experience.
		Looking at laboratory abnormalities for the combined patient population, they were balanced in terms of these levels of neutropenia, anemia, and thrombocytopenia.
		So we've concluded that the safety profile of valganciclovir is comparable to ganciclovir.  There have been no unexpected toxicities observed, and the most frequent, severe, or serious events are neutropenia and anemia, and the frequency of pancytopenia is similar to what we've seen with IV ganciclovir.
		During randomized treatment where patients received either IV ganciclovir or valganciclovir, we found that the CMV retinitis progression rates were equal; that there was a clear and comparable antiviral effect, significantly fewer IV catheter related and serious adverse events in the valganciclovir group, and the other adverse event rates were similar.
		Valganciclovir provides systemic exposures that are comparable to IV ganciclovir both in the induction and the maintenance treatment setting, and similar long-term rates of retinitis progression and adverse events were seen regardless of the randomized induction regimen.
		Valganciclovir is an oral pro-drug of ganciclovir with high bioavailability.  It is a better way to give ganciclovir, and it provides an effective and convenient treatment for CMV retinitis.
		And that concludes our presentation.  Thank you, and we'd be happy to take questions.
		CHAIRMAN POMERANTZ:  Thank you, and thank you for a very nice overview and presentation.
		So we can take questions now for Dr. Stempien or Dr. Martin or any one of the other people that Roche has brought here from the Committee.
		DR. KUMAR:  I have a question.
		CHAIRMAN POMERANTZ:  Sure, Princy.
		DR. KUMAR:  Can I ask this question of Dr. Martin?
		In the data that was provided to us in our booklet there was a marked difference in progression based on fundoscopic examination versus ophthalmological examination.  I know this bias was seen in prior studies, and what you had implied was this was all from bias from the ophthalmologist.
		My question to you is you chose ophthalmologists that were very well trained in evaluating CMV retinitis.  Is there anything other than bias that could explain this difference?
		I'm just troubled because if you looked at the fundoscopic evaluation by very trained ophthalmologists, you had 16 percent progression in the valganciclovir versus one percent progression in the IV ganciclovir arm, and you had said in your written statements that that could all be explained on the basis of bias.
		DR. MARTIN:  We believe, I believe that that observation is primarily due to bias.  As you pointed out, that's been observed now in a number of studies.  It was seen in 1653, the original oral ganciclovir trial, and if you look at the SOCA trials, there's always a discrepancy between the SOCA, representing the studies with the ocular complications of AIDS, a very experienced group of ophthalmologists following patients with CMV retinitis.  We always miss it.  
		I mean, when you look at the ophthalmic progression rates, they're always different than the photographic progression rates, and so for that reason and randomized clinical trials, it is the photographic progression -- it's pretty hard to argue with a photograph -- that is the standard.
		DR. KUMAR:  Can I ask you a follow-up question?
		DR. MARTIN:  Sure.
		DR. KUMAR:  Can Zone 3  disease be adequately photographed?
		DR. MARTIN:  No, it can't.
		DR. KUMAR:  So can that explain then the difference?
		DR. MARTIN:  It could.
		DR. KUMAR:  Can you say how much?
		DR. MARTIN:  It could, absolutely.  In that photo montage, that actually represents more Zone 3 than I think just about I've ever seen.  You can get a little bit beyond Zone 2, but most of Zone 3, because of the optics, you can't photograph it.
		So, yes, that is one possible explanation, that there were events taking place in Zone 3, but I think that that would be the minority of cases.
		DR. KUMAR:  Can I ask one more question?
		CHAIRMAN POMERANTZ:  One more.
		DR. KUMAR:  Thank you.
		(Laughter.)
		DR. KUMAR:  This is to Dr. Stempien.  
		How many patients had progression?  Do you know where the zone was in Zone 3 in the two groups?
		DR. STEMPIEN:  I'm sorry.  Could you just repeat that question?
		DR. KUMAR:  Most certainly.  My concern again, this is, again, to me as a clinician, when we call up and have a patient when an ophthalmologist tells that there's progression of the disease, we take their word for that, and so I'm concerned in your study because there was such a difference in ophthalmological evaluation versus fundoscopic pictures.  How much of your progression was in Zone 3 in the two groups?
		DR. STEMPIEN:  I think we have a slide here that will help illustrate that.  Yes, I think this would help.  Slide up, please.
		You know, we didn't distinguish between Zone 2 and Zone 3 in our analysis.  We actually put both peripheral -- more peripheral zones together.  So I'm not sure that this slide will completely answer your question because it looks like you'd like to know about each zone, and we don't have that.
		But if you look at the patients with more peripheral disease -- oh, here -- more peripheral disease, Zone 2-3, we had nine percent of those patients progress in the IV ganciclovir arm versus ten in the valganciclovir arm, and those patients who had Zone 1 coming into the study, 13 percent of them progressed in the IV arm and 11 percent in the valgan arm.
		So we feel that both treatment groups showed good efficacy regardless of the zone of involvement coming into the study.
		DR. KUMAR:  Thank you.
		DR. STEMPIEN:  Sure.
		CHAIRMAN POMERANTZ:  Yes, Dr. Bertino.
		DR. MARTIN:  Actually I'd like to add one other thing, if you don't mind.
		Just disease restricted to Zone 3 is extremely uncommon.  The area of retina involved by Zone 3 is very small relative to Zone 2 and Zone 1.  So the probability that there would be disease restricted to Zone 3, first of all, there weren't a large number of these patients.  There couldn't have been.
		And usually when disease progresses, it progresses posteriorally.  It doesn't have anywhere to go anteriorally.  So if it progresses, it progresses into Zone 2.  So it's just highly unlikely that the progressions -- it's a good question, but I think it's highly unlikely that the difference in progressions could be explained, the ophthalmic progressions could be explained solely on the basis of Zone 3 disease.  There are just not many cases like that.
		CHAIRMAN POMERANTZ:  Dr. Bertino, you have a question.
		DR. BERTINO:  Could you review your food effect data for us, please?
		DR. STEMPIEN:  Certainly.  Dr. Georgiou, clinical pharmacology.
		DR. GEORGIOU:  Certainly we can do that.  What we found with food is we found a 30 percent rise in the area under the curve when we give the therapeutic dose at 900 milligrams, and we also see if we go higher up in dose, we also see a progressively higher increase in bioavailability.
		Can I have the slide up, please?
		This is the concentration time curve for ganciclovir and for valganciclovir shown on a linear scale, and as you can see here, here we have the ganciclovir in the fast state, and here we have the concentration time curve in the fed state.
		In other therapeutic dose we do see an effect of 30 percent.
		DR. BERTINO:  What was the meal?
		DR. GEORGIOU:  It was a high fat, FDA breakfast.
		(Laughter.)
		DR. BERTINO:  Thank you.
		Did I misunderstand you?  Did you say that as you increase the dose with food, the percentage bioavailability increases?
		DR. GEORGIOU:  Yes.  Can I have the slide up, please?  Slide up.
		Here we have the data which show the fed versus fasted for the area under the curve.  So as you go higher up in dose from 450 to 200,625, you do get an increase in the area under the curve from a mean of 24 percent to 56 percent.
		DR. BERTINO:  Okay.  In your pharmacokinetic data that you presented for 376, the oral data, were those patients studied with or without food at the two time points?
		DR. GEORGIOU:	 If I understand it correctly, what was the dosing recommendation for the studies?  Is that what you're saying?
		DR. BERTINO:  Well, I'm just trying to find out --
		DR. GEORGIOU:  It was with food.
		DR. BERTINO:  It was always with food?
		DR. GEORGIOU:  Yes.
		DR. BERTINO:  Okay.  So the PK data that you present in the packet where you looked at surrogates for efficacy, that was patients dosed with food?
		DR. STEMPIEN:  That's right.
		DR. GEORGIOU:  Correct.
		DR. BERTINO:  So that would be the recommendation then, is to --
		CHAIRMAN POMERANTZ:  I didn't hear that, but the answer is with food.
		DR. STEMPIEN:  Yes.
		CHAIRMAN POMERANTZ:  All right.  Just speak into the mic for the record.
		DR. STEMPIEN:  Thanks.
		CHAIRMAN POMERANTZ:  I have a question.  I had a question when I read your briefing document, as well as when I talked to the FDA about the case studies.  You nicely brought up the problem or the issue of HAART in doing a study such as this, which is probably the major problem with doing studies on CMV retinitis, although it's certainly not a problem to the patients who are benefitting by it, but to the researchers.
		And one of the things that's the hardest thing to understand is the dynamism of what HAART does in the setting of adding a new antiviral drug.  In the briefing document, it states that everyone was on stable HAART, and I use that in quotes because it's not clear what that means.
		And then when I looked at your slides, you have some that are naive, some that were not on HAART at present, and there was no question of what you would define as stability, meaning when HAART was -- are they stable after two weeks and they enter this study?
		So it may be nitpicking, but it's an important drug, but very little data.  Can you tell me, or one of your people tell us, what truly stable HAART meant in these people and whether you had cases of other entities, such as immune reconstitution disease if HAART was started even after the first four weeks, since you followed them out and showed that data?
		DR. STEMPIEN:  What the protocol asked for was that patients stay on a stable anti-retroviral regimen during the randomized phase of the study, and after we had assessed the primary endpoint, then we allowed any modification of HIV therapy.
		We cannot say specifically how many patients were on HAART because we were not able to define that in the way that we collected concomitant medications.  So what we did is we tracked protease inhibitors, and in our study we're using protease inhibitors as a marker for HAART.
		The way that we verified that HAART was not influencing the randomized comparison in our study was that we collected CD4 counts and quantified the HIV loads at baseline and at week four in both treatment groups, and I can show you those data if you want, but the data confirm that if HAART was playing a role during the randomized part of the study, it was very small.
		There were very minor changes in CD4 counts and in HIV loads during the first four weeks, and those changes did not favor the valganciclovir group in any way.
		So we're quite comfortable that HAART was not interfering with our primary efficacy comparison.
		CHAIRMAN POMERANTZ:  Yeah, let me just discuss that comfort level.  When you say HAART was obviously not affecting the CD4 count, the viral load throughout the randomization as determined by the mean or the median, if you look at the cases though, you need very little changes in one to skew the data in this regard.  
		When you looked at the cases where there ‑- and there are so few cases that you could look at every case -- were there major differences that were just swallowed up by other patients in the group that were not illustrative?
		DR. STEMPIEN:  Well, let me show you the CD4 and the HIV load data --
		CHAIRMAN POMERANTZ:  Okay.
		DR. STEMPIEN:  -- that we have at those two time points.  I think that will help.
		Okay.  Slide up, please.
		Here's the CD4 count at screening, and the median was 26 and 18, and the CD4 in both treatment groups ranged from two to 365 for IV and two to 296 in the valganciclovir group.
		If we -- next slide, please -- if we look at the CD4 count at week four -- slide up -- the median had changed very little.  The minimum now ranged to 309 and to 260.  We also have a distribution of the CD4 changes at week four.
		Yes, that's okay.  Slide up.
		This shows you the median change in CD4 count in both treatment groups was quite small, and the maximum increase in the two treatment groups was less than 100 cells.
		And in terms of the baseline HIV load -- slide up -- the baseline loads were comparable in the two treatment groups, 5.3 logs, mean, and 4.9 median, and they ranged up to about 5.9 logs in each treatment arm.
		And at week four -- slide up -- we see that the HIV load had changed very little and still ranged from 1.7 to 5.9 logs.
		And here's a distribution of the change in viral load at week four.
		Slide up.
		There's a fairly even distribution, but most patients, if they did change, they either had a decrease of no more than a log.  Most were up to a half log, or an increase of about a half log.  Very few patients had a decrease in their HIV load that was greater than one log, and those changes seem to be balanced in the two treatment groups.  They certainly don't favor the valganciclovir arm.
		So that's the basis for our feeling that our primary efficacy comparison was not interfered to any great degree by an impact of HAART during the first four weeks.
		CHAIRMAN POMERANTZ:  Yeah, that's very helpful.
		The patients who were naive or not on HAART at present, therefore, they did not get an anti-retrovirals for those four weeks, correct?
		DR. STEMPIEN:  Yes, that's correct.  That's correct.
		CHAIRMAN POMERANTZ:  Thanks.
		DR. MATHEWS:  This is for Dr. Stempien.
		Could you comment on the management of the ones that had evidence of progression at week four and subsequently?  Were they reinduced?  Were they switched to other drugs?  How are they managed?
		DR. STEMPIEN:  If patients progressed, and this would have been based on the ophthalmologist's assessment because the photo results were not known in real time; so if the ophthalmologist called a progression, then that patient could be reinduced with valganciclovir, and they would simply reinduce with the same induction course that they had received coming into the study, and then if they responded to that, they would go back onto valganciclovir maintenance and stay on, continue on.
		DR. MATHEWS:  Were there patients who were switched to other drugs because of failure even with reinduction?
		DR. STEMPIEN:  There were some patients who might have been with -- who were withdrawn from the study following a progression, and I discussed a few of them when I talked about the withdrawals between week four and week 12 where there were four patients in the valganciclovir arm who withdrew from the study following the ophthalmologist's detection of a progression.
		If they withdrew following a progression, then they were obviously able to receive any other agent that the ophthalmologist deemed suitable.
		CHAIRMAN POMERANTZ:  Dr. Bressler.
		DR. BRESSLER:  I would be very comfortable with the photographic data that you have compared to the ophthalmologist because unfortunately, we as ophthalmologists cannot usually detect these progressions right away, and we see them after they're seen on the photographs.
		So I'm comfortable with that, although you could look at your Zone 1 cases where you know you have photographs and you know the ophthalmologists looked and just confirmed that you saw the same sort of discrepancy.  I suspect it would be the same there.
		That being the case, did the ophthalmologists take photographs in 705?  I know you didn't have them graded at the center.  Did they take any photographs of that?
		DR. STEMPIEN:  No, not in that study.  That study was primarily for safety and tolerability, and so we didn't incorporated a photographic protocol.  So the patients were followed by the ophthalmologist only.
		DR. BRESSLER:  How do you think we should interpret the progression then that is given for 705, which is based on the ophthalmologist assessment?  Should we take it with a grain of salt or say that this is something or what?
		DR. STEMPIEN:  Well, I think that it could be considered as supportive real world data, but it certainly wouldn't stand up to the rigor of a photographic assessment.
		DR. BRESSLER:  And did you have data for the border activity?  And was that similar to what you showed for progression?
		DR. STEMPIEN:  Could you just clarify your question a bit?
		DR. BRESSLER:  You said that the photographers graded both progression, as you specifically defined it, and border activity, but I only saw the data for progression.  Did the border activity also show no significant difference between the two groups?
		DR. STEMPIEN:  Yes.  If you're interested, we could show you border activity data at baseline and also a reduction in border activity over the four weeks, if that data would be of interest.
		DR. BRESSLER:  If it was the same.  Because with all of the limited data, I think you want to use everything you have to show that they appeared equivalent.
		DR. STEMPIEN:  Okay.
		DR. BRESSLER:  So that would be helpful.
		DR. STEMPIEN:  Well, let me tell you that they were balanced at baseline with respect to border activity, and in fact, both groups showed a similar decrease in lesion activity that you could follow out, week two, week four, week six, in both groups.
		DR. BRESSLER:  Okay.
		DR. STEMPIEN:  And it was substantial.
		DR. BRESSLER:  Okay.  That's fine.
		DR. TOERNER:  Do you have that data?
		DR. STEMPIEN:  Yes, yes.
		DR. TOERNER:  Could you show it just for the record for the Committee, please?
		DR. STEMPIEN:  Oh, sure, and I think I'll ask Dr. Martin to speak to it.  Let me get the slide.
		DR. BRESSLER:  And then while he's coming up, the last question is:  how are the visual acuities measured?  Were they just routine office practice measurements or were they standardized protocol visual acuity measurements?
		DR. STEMPIEN:  Well, it was either a Snellin or the early -- I'm sorry --
		DR. BRESSLER:  ETRS?
		DR. STEMPIEN:  Yes.  Sorry.  Yes.
		DR. BRESSLER:  So it was either one?
		DR. STEMPIEN:  Yes, yes.  But it was consistent.  It had to be the same for any given patient throughout the study.
		DR. BRESSLER:  Thank you.  Thank you.
		DR. STEMPIEN:  Well, let me put this slide up then.  This is not the baseline.  I've got the reduction, but I think this may be sufficient.
		Slide up.
		Okay.  This shows the lesion activity reduction measuring the greatest reduction in lesion activity in both eyes between week two and week four.  So you can follow this.
		And the Wisconsin Reading Center used a multiple step scale in determining lesion activity, and you can see that at week two -- and of course, the higher the step reduction, the better result that is.
		You can see at week two, there's -- the groups appear fairly well balanced.  You have a substantial percentage of patients who have had a one step reduction and then smaller numbers have had two, three, and four step reductions.
		And then as you go out to week four, now you're where we assess the primary endpoint.  You can see all of the numbers have increased reflecting further reduction in lesion activity so that at week four we had 27 percent of the IV group and 29 percent of the valgan group who had a four step reduction in lesion activity, and seven percent who had a five step reduction.
		Does that help?
		DR. BRESSLER:  Yes.  Very good.
		DR. STEMPIEN:  Okay.  Thank you.
		CHAIRMAN POMERANTZ:  Dr. Pulido, do you have a question?  And then Dr. Yogev.
		DR. PULIDO:  Actually two.  About a third of the patients develop diarrhea on valganciclovir.  How did that affect the AUC for those patients?
		DR. STEMPIEN:  I'm going to ask Dr. Georgiou to comment, but I don't believe -- in our PK subset, we only did full PK profiling on a subset of patients, and I don't believe that those patients experienced much in the way of diarrheas, but Dr. Georgiou will comment.
		DR. GEORGIOU:  We had a limited PK subset.  We had about 42, 43 subjects in the subset, and we have looked to see whether those with lower AUCs had diarrhea, and we only had one patient in the group, and he was actually within the normal range for about 30 micrograms per mL.
		Now, diarrhea is a manifestation probably of the lower GI tract, and what we have done is we looked at the absorption profile because we had IV and oral data from a number of studies.  So what we have done is a mathematical term, deconvolution, where we tease out the absorption profile because we know the disposition of the compound and the oral data.
		Can I have the slide up, please?
		Here is such a curve, where what we have here is the cumulative amount of ganciclovir that appears in plasma, and what you can see here is that for the majority of the patients by four hours after administration we have almost 80 percent absorption, and by six hours, the absorption is almost complete.
		So it is unlikely that even with diarrhea that patients will actually suffer in terms of their area under the curve.
		DR. PULIDO:  The second one is sort of related to the first, and that goes to one of your ending statements.  It says as with any new drug, there's a risk that one or more uncommon drug related toxicities associated with the valyl ester modification could be observed as larger numbers of patients are dosed.
		And 85 percent of the metabolism of the valyl form occurs in the intestine and 15 percent in the liver.  Somewhere about 14 percent had elevated liver function tests while on the medication, and again, a third had diarrhea.
		Did you look at the valyl, the amount of the valyl form in those patients with diarrhea or elevated liver function tests to see if they had elevated levels of the valganciclovir form?
		DR. STEMPIEN:  No, we did not.  We measured ganciclovir levels only in the patients who were participating in the PK profiling.  We don't have ganciclovir levels on other patients.
		We did do a close look at liver function tests, and if I could have the slide up, just for all patients, we weren't able to detect any hepatotoxicity during the randomized phase of the study.  We looked at several measures of hepatic function, and there were some small changes between week one and week four, but they were rather small, and they were balanced between treatment groups, and there were no differences between the IV and valganciclovir.
		So we have to date within our safety database, we have not been able to discern any toxicity that we could no -- that has not already been described with ganciclovir.  
		Now, the point that you make is absolutely well taken regarding the presence of valyl, a small amount of the parent compound, but in our database, we have not been able to find any signal of additional toxicity that might be related specifically to the presence of the valyl valynated compound, the parent compound.
		Dr. Yogev.
		DR. YOGEV:  A couple of questions.  One follow-up to Dr.  Pomerantz.
		Do you have viral load at 12 week or after to show if what we are seeing is so-called maintenance is not affected by the HAART?
		DR. STEMPIEN:  After the randomized portion of the study we have some limited viral load data, but it rather limited.  It was not collected in a rigorous way per protocol.  We really focused on the randomized part of the study because we realized that after four weeks patients' regimens were all going to be changing, and that's why our time to progression endpoint in those Kaplan Meier curves need to be interpreted, you know, with that understanding, that patient regimens were changing.
		I'd be happy to show you the data that we have, but it's rather sparse, but if you'd like to see it, I'd be happy to show you that now.
		DR. YOGEV:  The reason I mention it is when I look at the first slide that you showed us about how CMV changed, and the epidemic is almost at the same rate that your cure of maintenance.  Now, if you are asking for induction only, that's fine with me, but for maintenance I'm not sure viral load didn't affect it, the HAART did not affect the whole effect.
		The second question is I was a little bit surprised to see how much increase in side effect you have, especially neutropenia, anemia, and platelets, in the longer period of time of follow-up, the 370 patients, and I wondered if the transplant patient that you didn't show any data would help.  If you take this medication for a longer period of time,  is there really such an increase from, for example, 30 percent of the patients had neutropenia versus only less than 20 percent in the ganciclovir?
		Are there any data for a longer period of time to show toxicity is not increasing with time?
		DR. STEMPIEN:  Well, I'd just like to make a few points about  comparing the adverse event data that I've shown you for a valganciclovir package and comparing that to the historical studies.
		The historical studies came from a time that was pre-HAART, and studies only ran for six months or perhaps a little longer, and so the duration of time that patients were on the study medication was much shorter, and that definitely has an impact on the incidence of adverse events in the database.
		Our database has almost twice as much data in it, and absolutely the incidence of adverse events is going to go up over time.  In fact, we did our NDA data cut, and then we did a four-month safety update beyond that.  We're seeing the same adverse events, but each one increased a little bit in terms of incidence because of the longer duration of exposure.
		So it's just important to keep that in mind.  We feel comfortable that the safety profile that we have described so far is consistent with what we would expect with ganciclovir.
		DR. YOGEV:  And last, do you have any plans for pediatric formulation?
		DR. STEMPIEN:  Yes.
		CHAIRMAN POMERANTZ:  Have to ask that question.
		DR. STEMPIEN:  Pardon?
		Okay.  Yes, yes, we do have plans.  We're in the process of developing an oral liquid formulation.  We have a program planned.  We have submitted draft protocols to FDA, and so that's something we look forward to doing.
		CHAIRMAN POMERANTZ:  Dr. Wong.
		DR. WONG:  Yes, I have another question about the safety data.  It looks to me from your Table 11 in the briefing document and also Appendix 18, the Kaplan Meier curve, that the patients who got valganciclovir had a substantially higher chance of developing severe anemia than those who got IV ganciclovir.
		I mean, is that really true, and why is that?  I guess the follow-up is:  does that -- should that tell us anything about the dosage level that you're proposed for maintenance therapy?  Might that not be too high?
		DR. STEMPIEN:  Give me just a moment to look for a slide here.
		Yeah.  I'd like to say, first off, that you're absolutely right.  In our briefing package, we do talk about an increased, more severe, more patient sin the valganciclovir arm experience, more significant anemia.
		Further out in the study, interestingly, not during the randomized phase when they seem to be balanced and we're both getting the higher induction doses, but the more severe anemia appeared further out.
		If that is real, we do not have a ready explanation for it.  It certainly isn't what we would expect.  We're providing valganciclovir at similar exposures to IV.  So we would not expect that there would be more anemia with valganciclovir.  But we certainly recognize that that may be a real finding that we just don't have an explanation for  or it may be related to some other factor that we failed to take into account.
		We did look at some concomitant medications.  The treatment groups were balanced at baseline with respect to their hemoglobin levels.  So this was not an imbalance coming in, but I can show you -- slide up -- this Kaplan Meier shows you the time to development of hemoglobin less than eight.
		And so I think this curve might be in your backgrounder as well, and so the curves are separate, and there is a difference in our study.  Whether that reflects a true difference or whether we just have not found the explanation for it yet, I don't know.
		CHAIRMAN POMERANTZ:  Dr. Fong.
		DR. WONG:  Should we take this into consideration when we're thinking about dosage levels in the maintenance phase?  Might 900 milligrams be too high?
		DR. STEMPIEN:  Well, I'm not sure on what basis we could conclude that because we don't -- the maintenance does that we're proposing for valganciclovir, 900 milligrams a day, delivers a systemic exposure that's comparable to IV ganciclovir, five milligrams per kilogram.
		And so given the fact that we're providing similar exposures of ganciclovir with both regimens, you know, we don't have any basis to -- we acknowledge that there is this anemia finding, but we don't have an explanation for it.  It was not expected, and at this point it would not cause us to think that the dosing regimen that we suggest for maintenance treatment should be modified.
		DR. WONG:  All right, but that assumes that one is guided by the exposure as opposed to the observed toxicity.  One could certainly look at it the other way.
		DR. STEMPIEN:  Well, our selection of doses was driven by efficacy considerations, and we targeted our AUC for valganciclovir based on the efficacy that we wanted to achieve.
		If it turns out that there is more anemia with valganciclovir, I think the treating physicians who are comfortable with ganciclovir treatment and are aware of its safety profile, which has always included neutropenia and anemia, will understand how to watch for and manage that particular toxicity.  The anemia and neutropenia have always been described with ganciclovir, and so I think the treating physicians will be able to manage that appropriately.
		CHAIRMAN POMERANTZ:  An important point.  Let's move on.
		Dr. Fong.
		DR. FONG:  As an ophthalmologist, I don't look at a lot of this pharmacodynamic data a lot, and I wanted to get some clarification on your use of area under the curve versus the C-max, and I wanted to maybe ask you to clarify for me whether there are any implications of not using C-max to compare the two groups.
		For example, is there a risk of, you know, increased mortality or is there a risk of higher development of resistance when we just look at area under the curve versus the C-max?
		DR. STEMPIEN:  Well, that's a very good question.  We have no data that correlates a specific PK parameter with a safety outcome or with a resistance outcome that I'm aware of.
		No, we do not.  So our view that area under the curve is the most important PK parameter is really based on efficacy considerations and just consideration of the general shapes of the curves for both IV ganciclovir, oral ganciclovir, and then valganciclovir, which is actually bracketed by both.
		And since IV ganciclovir and oral ganciclovir are both approved, efficacious formulations, we feel comfortable that the valganciclovir profile is going to provide good efficacy.
		And, no, we can't say that we've established beyond a doubt that AUC is the most important parameter, but it really seems to make the most intuitive sense based on all of the data that we have.
		CHAIRMAN POMERANTZ:  Do you still have a question, Dr. Kumar?  Yeah, Dr. Kumar.
		DR. KUMAR:  I wanted to follow up on Dr. Wong's issue regarding anemia.  When I look through the booklet that you provided, there was one death, and I couldn't figure out whether it was in the 376 or the 705 of a female who died from severe  medullary aplasia.  I know she got a dose that was higher because of renal failure.  
		Could you explain and tell us exactly what happened?
		DR. STEMPIEN:  Well, I can't tell you all the details.  I could get all of the details if you want full details of the case, but I can tell you that she developed -- this is a woman who was severely ill with multiple medical problems, and she developed renal impairment, actually developed acute renal failure, and as her creatinine clearance declined, the dose was not appropriately adjusted, and so, in fact, she ended up with a relative overdose that was reflected about a tenfold higher exposure than what she really should have been receiving based on her creatinine clearance.
		And that certainly had to contribute to the events that led to her medullary aplasia and eventual death.
		CHAIRMAN POMERANTZ:  Dr. Fletcher.
		DR. FLETCHER:  First, just a comment, again, on Dr. Wong's question about the safety and responses about the systemic exposure of val. and IV being the same.
		Well, that's true with area under the curve.  That is not true with trough concentrations.  The trough concentrations are threefold higher with the valganciclovir form as opposed to the once daily IV form, and it's not at all implausible to believe  that you can have two different pharmacodynamic relationships, one for efficacy that may correlate with area under the curve, and one for toxicity that perhaps may correlate better with a trough concentration.
		DR. STEMPIEN:  That's a very good point.  You're absolutely right, but it's also true that the trough concentration for valganciclovir is actually lower than what we achieve with our oral ganciclovir formulation, and we certainly have not seen increased anemia with our oral ganciclovir formulation.
		So you may be right.  It's a bit of a puzzle.  It doesn't all fit together that way, yeah.
		DR. FLETCHER:  My second is actually in a sense a follow-up to Dr. Kumar's and your response about the need for adjusting the dose with renal insufficiency.  You've provide a table in the background that shows the change in half-life, change in pharmacokinetic parameters with various degrees of renal insufficiency, but you've not laid out at least for us to see an algorithm by which someone would actually adjust the dose of valganciclovir.
		So I'd like to see that.
		DR. STEMPIEN:  Okay.  Dr. Georgiou.
		DR. GEORGIOU:  Would you like me to walk you through the way we've done it?
		DR. FLETCHER:  I don't know in any great detail.  I think can I have, you  know, a bottom line table of what you're recommending?
		DR. GEORGIOU:  Okay.
		CHAIRMAN POMERANTZ:  I think he's asking for a slide.
		DR. FLETCHER:  Yeah.
		(Laughter.)
		DR. FLETCHER:  Thank you.
		And then also if you would comment.  Is that creatinine clearance in your studies a measured or an estimated?
		DR. GEORGIOU:  Okay.  Let me walk you through that and then I'll come to the creatinine clearance.  I need to check that, but I think it was an estimated creatinine clearance.
		As we can see, we structured the algorithm so that we can match as much as possible that we have for IV ganciclovir within the bounds of flexibility of the 450 milligram tablets, and what we have tried to do is that we tried to maintain a minimum area under the curve of about 26 micrograms hour per mL, and as you can see here from the different groups of creatinine clearance, we can reasonably achieve that for all the groups with the exception of the patients on hemodialysis, where we cannot use the table formulation to give us the target AUCs that we wanted.
		DR. FLETCHER:  And then just one last question.  Resistance.  You haven't made any comments about the emergence of isolates, seeing the isolates that have resistance to ganciclovir following valganciclovir dosing.  I wonder if you have any information on that.
		DR. STEMPIEN:  Yes, we do.   We did extensive resistance testing in this study and Dr. Noel Roberts, a virologist, will show you those data.
		DR. ROBERTS:  Yes, as Dr. Stempien has said, we've done extensive studies for resistance in clinical trial 376.  I can show you the data in overview form if you wish, but the bottom line is that we saw no surprises.  Both the nature and incidence of resistance that we found was what we would have expected from the previous data that was available for ganciclovir itself.
		DR. FLETCHER:  Maybe you could humor me and show me a slide.  I don't know what no surprises means.
		(Laughter.)
		CHAIRMAN POMERANTZ:  This is sort of the Missouri state today, this show me, yeah.
		DR. ROBERTS:  Okay.  So we look both phenotypically and genotypically for resistance.  Phenotypically we saw no isolates with an IC-50 over six micromolar, but we have to say that there were very few culture positive samples well into the maintenance phase when resistance might have emerged.
		Most precise data, therefore, comes from our genotypic assessment where we performed a detailed kinetic study looking for changes in UL-97.
		Next slide, please.
		We took samples from every patient every four weeks, PMNLs, and we looked for the last PCR positive sample in terms of UL-97, and when we got a PCR positive sample, we assayed that for genotype both by sequencing and by a restriction enzyme digest method.
		We also looked at every sample where the viral load by quantitative PCR was over 1,000 copies per mL.  When we found mutations in UL-97 indicative of resistance, we then backtracked through the four weekly samples to determine the kinetics of emergence of resistance for those patients.  So we went back to a stage usually where the resistant virus was in a mixed population with wild type.
		Next slide, please.
		What we found was we found just 14 instances of mutations in UL-97, six in one arm and eight in the other, but of course, these are all occurring while after all patients are on valganciclovir itself.  So that's 14 out of 148 patients who we looked at.  So that's a total incidence of a little under ten percent.
		The mutations we saw in UL-97, 75 percent of them -- we saw 20 mutations among the 14 patients.  Seventy-five percent of those were positions 460, 594, and 595, and that agrees exactly with previous data.  The other mutations were at position 520, 603 and 607.  Again, that agrees exactly with what has been found with ganciclovir.
		Just one of those patients also had a mutation in UL-54, again, which has been a better described position.
		The median and mean times to emergence of resistance are as shown there, quite a slow emergence of resistance, and if we compare the rate at which resistance emerged with the previous pre-HAART using phenotyping as the endpoint, you can see that the incidence is certainly no more than has been described from past studies.
		So as I said to start with, both qualitatively and quantitatively we're seeing largely what we might have expected.
		CHAIRMAN POMERANTZ:  Are there any final burning questions?
		Well, hold on.  Yeah, at the end?
		DR. PISCITELLI:  Do you have any data on ocular levels either from animal studies comparing the IV with the valganciclovir or maybe from both selected patients who had procedures or something?
		DR. STEMPIEN:  No, not following dosing with valganciclovir.  We do not.
		DR. PISCITELLI:  I think this gets back to the issue of is the peak important because of the higher peak.
		And the second question is I have a few concerns if the AUC really does correlate with the efficacy.  There is the one analyses that you referred to.  It looks like they measured one time point and tried to simulate an area under the curve from one sample.  I wonder if that procedure was validated at all.
		Did you have patients with full curves and pull one out and try to validate that or how that was done?
		DR. STEMPIEN:  We're confident in the PK/PD analysis that we did, but the methodology did have some limitations, and I think the FDA has pointed some of them out, and we certainly accept their opinion on that.  It had to do with some assumptions that we made regarding missed dosing times and also the amount of data points that we had per patient.
		But if you completely set that analysis aside, we view it as supportive, but if you completely set it aside, I think that you can make a reasonably convincing argument just based on PK considerations alone and what we know about our different formulations that it's most likely area under the curve.
		We have not absolutely established that, but we feel that that's compatible and consistent with all of the data that we have and what we know about the efficacy of ganciclovir.
		Oral ganciclovir works very well in maintenance treatment.  Now it has never been equal to IV, but it does work.  It has efficacy.  Patients usually progress about a week earlier if they're on oral maintenance.
		And the C-max of oral ganciclovir is tenfold lower than the C-max for IV ganciclovir.  So that amount of difference would not help the argument that C-max is going to be the most important parameter because there's just too much of a difference, as opposed to AUCs where the oral formulation is about 50 percent of the AUC of the IV formulation.  
		That seems to make more sense then and explain the efficacy that we see a bit better.  So just strictly in PK considerations, that's what we feel.
		CHAIRMAN POMERANTZ:  Dr. Sun.
		I also want to tell the Committee there will be time for other questions after the FDA makes their presentation.
		So Dr. Sun.
		DR. SUN:  Could you comment on the mode of administration in the four-week randomized portion of the study?  In other words, were both arms self-administered or was just the oral formulation of val. self-administered?
		And then related to that, could you comment on any data on compliance that you have in the two arms with respect to each other?
		DR. STEMPIEN:  Yes.  Just one moment.
		I think I understand your question about mode of administration.  Are you thinking was the oral formulation, was that somehow directly observed?  Is that what you're getting at?
		DR. SUN:  Right. Was the IV arm administered by a physician or nurse or was it self-administered, and the same question for the oral?
		And depending on the answer, did that have an effect on differential compliance?
		DR. STEMPIEN:  Yeah.  I don't think we had any particular restrictions within the protocol on the setting of administration, and I would imagine that we were fairly flexible in that regard, that the patient could have received their dose in the clinic or at home through a home nurse.
		And Dr. Martin indicates that at least at his center they were mostly at home, and the oral administration was provided to the patient, and the patient came back to the clinic and then reported how much they had taken, and we also did capsule, tablet counts.
		We do have some information on how many patients completed dosing during the first four weeks.
		Slide up.
		And in the protocol we wanted patients to complete at least 21 days out of the first 28 days of treatment, and the groups look very comparable with respect to the actual amount of dosing that was completed, at least 21 days, 20 days or less than 20 days.
		Slide off.
		CHAIRMAN POMERANTZ:  Any final burning questions before we take a break?
		DR. RODVOLD:  Can I ask one?
		CHAIRMAN POMERANTZ:  I guess it's burning, yeah.
		(Laughter.)
		DR. RODVOLD:  Considering that AUC, C-min, C-max seem to be the parameters that you're trying to base some of the conclusions and/or recommendations, is there an attempt to do just a simple demographic model that would be able to be predictive of AUC, C-min, C-max based on creatinine clearance, age, gender, simple things, bedside?
		And if that does correlate with that, can you then link it to efficacy and toxicity either at a 24-hour marker or a cumulative exposure, in other words, all the way through the trial?
		DR. STEMPIEN:  Boy, if that's a question for me, I have no idea.  I'm sorry.
		(Laughter.)
		DR. STEMPIEN:  It would be certainly worth thinking about, but I do not know if that's possible.  I'm sure there are other people around the table who know more about that than I do.
		CHAIRMAN POMERANTZ:  Actually I'm not one of them.
		Is there a comment on that question from anyone?
		DR. RODVOLD:  Just in the aspect of other drugs that are simply renal excreted you can do that, quinalones, aminoglycosides, things like that.  That way you could estimate an AUC from data of people that you don't have serum concentrations.  So subsequently we'll be able to expand that database of all patients enrolled to do that, and it should be a consideration that should probably be done.
		CHAIRMAN POMERANTZ:  Thank you.
		Well, the time is by my watch four minutes to 11.  Why don't we go till ten minutes after and take a break?  And then we'll come back with the FDA's comments.
		Thank you all.
		(Whereupon, the foregoing matter went off the record at 10:56 a.m. and went back on the record at 11:11 a.m.)
		CHAIRMAN POMERANTZ:  Okay.  Welcome back.
		We're now going to go into the FDA presentation.  I believe the starting person is Dr. Jose Toerner.
		DR. JOSEPH TOERNER:  Good morning.
		I would first like to thank the applicant for their clear presentation this morning, and now I would like to present the FDA review of NDA 21304, valganciclovir for the treatment of CMV retinitis in patients with AIDS.
		This is how we viewed the valganciclovir NDA.  The efficacy portion consisted of study WV-15376, and I'll refer to this as the induction study.  As well, multiple pharmacokinetic studies provided support for the maintenance therapy of CMV retinitis.  And finally, three studies comprised the safety database in this NDA:  the induction study and study WV-15705, and this is a single arm safety study in patients who had a previous diagnoses of CMV retinitis and received open label valganciclovir for the maintenance therapy.
		However, we felt that this study provided only safety data, given that there was no comparison group, and the impact of highly anti-retroviral therapy would have on an efficacy endpoint.
		And finally, the applicant is conducting currently a study in solid organ transplant recipients, study PV-16000, and this is a study of oral ganciclovir versus valganciclovir for the prevention of CMV and organ disease in solid organ transplant recipients, and this provides a very small portion of the safety database that was submitted recently in a four-month safety update.
		Because the pharmacokinetic profile of ganciclovir after valganciclovir administration is different than that of intravenous ganciclovir, in particular the C-max, the DAVDP requested clinical data in support of efficacy.
		And Dr. Birnkrant this morning highlighted some of the regulatory background in terms of valganciclovir development for CMV retinitis, and I just wanted to highlight a few additional points as it pertains to the induction study.
		It was generally recognized that an adequately powered study for equivalence would require approximately 200 patients per arm.  However, in the current epidemiological climate of CMV retinitis, a feasible study to conduct would be approximately 75 patients per arm, and it was recognized that this would be under powered to demonstrate equivalence.
		Therefore, an ongoing Phase 2 study, the induction study, was expanded into a Phase 3 trial, and outside academic consultants, as well as the FDA concurred with the use of a four-week endpoint of progression of CMV retinitis.
		As you heard this morning, the induction study enrolled patients with newly diagnosed CMV retinitis.  It was an open label.  Twenty-one-day induction therapy was given in a randomized fashion, intravenous ganciclovir, five milligrams per kilogram, twice daily or oral valganciclovir, 900 milligrams twice daily.
		And this was followed by maintenance therapy at the assigned treatment regimen for an additional week, and then after week four, all patients received open label valganciclovir.
		Just to provide some additional comments about the four week primary endpoint, this was a photographic assessment of CMV retinitis at the week four endpoint compared to baseline.  The retinal photography was conducted in a standardized fashion at each of the multiple treatment sites.
		This type of photographic assessment was used in previous registrational trials, and the photographic assessment was performed by the University of Wisconsin Fundus Photograph Reading Center, which has a considerable amount of experience in interpreting these photographs.
		We recognize the potential limitations of this study.  First of all, it had a small sample size.  Agreement was not reached between the applicant and the FDA on the lower bound of the 95 percent confidence interval of minus 25 percent as being a clinically acceptable lower bound.
		And finally, the analysis of the primary endpoint was not prespecified.
		The applicant in their presentation this morning reviewed the demographic characteristics in the induction study, and as you can see, it is well balanced between the treatment groups.
		As well, the baseline HIV characteristics were well balanced between the treatment groups, and you can see that the study consists of patients who are profoundly immune suppressed.  An equal proportion had a history of protease inhibitor use, and very similar proportions of patients at enrollment had ongoing use of protease inhibitors.
		You can see that a very high proportion of patients in this study had opportunistic infections or opportunistic malignancies other than CMV retinitis, and on this next slide, I wanted to highlight some differences that we found between the treatment groups.
		And I wanted to highlight these differences because it suggests to us that the patients who are randomized to the valganciclovir arm may represent a sicker patient population.  We found that 20 patients who were randomized to the valganciclovir arm had at baseline disseminated mycobacterium avium complex infection and 12 patients had this opportunistic infection in the intravenous ganciclovir group.
		As well, a higher number of patients, 15 in the valganciclovir group, had esophageal candidiasis in comparison to eight in the intravenous ganciclovir group.
		Other than cryptococcal meningitis, for which there were small numbers, the rest of the AIDS defining conditions at baseline were well balanced.
		And as well, the characteristics of CMV retinitis were well balanced between the treatment groups with nearly a quarter of patients having Zone 1 retinitis, 25 percent having evidence of bilateral retinitis, and a high proportion having greater than 50 percent border activity at the CMV lesion.
		So our analysis of efficacy is as follows.   We first sought to evaluate the retinal photography that was conducted by the University of Wisconsin, and we asked our FDA colleagues, and specifically had asked Dr. Boyd who gave this morning's presentation, to perform a masked review of the original retinal photographs that were submitted with this NDA.
		And Dr. Boyd found complete agreement with the result of the University of Wisconsin Eye Center, with the exception of one patient.
		The applicant's primary analysis is based on evaluable subjects and excluded deaths and loss to follow-ups.  In our analysis we consider a sensitivity analysis, which ranges from a per protocol analysis to an intent to treat analysis and will test the robustness of the 95 percent confidence interval, the lower bound of the 95 percent confidence interval.
		Here is how we accounted for patients in the study at the four-week primary endpoint.  There were seven patients in each arm who had evidence of CMV progression at the week four endpoint.  Those who had non-progression included 63 in intravenous ganciclovir group and 64 in the valganciclovir group.
		Three patients died before the four-week endpoint in the study.  Three patients discontinued study before week four due to an adverse event and, therefore, did not contribute week four interpretable data in the study.  And finally, one in each arm had failed to return in this study, failed to return before the four-week visit, and 11 patients either did not have baseline photographs that were submitted for evaluation or did not have evidence of CMV retinitis at baseline.
		And one patient, who was included in this group is the patient that Dr. Boyd found which was different than the University of Wisconsin Reading Center, and it was a patient who had a previous ocular ganciclovir implant that was discovered after enrollment in the study, and we agreed with the applicant that this person should be excluded from the analysis.
		Actually this particular patient had evidence of CMV nonprogression and would have fallen into this category.
		Our intent to treat analysis includes those patients who had baseline photographs that were submitted for review, and so therefore, our first analysis highlighted in dark red is the patients that we would like to exclude from our intent to treat analysis.  So, in other words, these were patients who either did not have CMV retinitis or did not have baseline photographs.  
		So, therefore, in our intent to treat analysis, we included only those patients who had baseline photographs that were evaluable.
		And four our intent to treat analysis, we'll consider those who died before week four, those who had an adverse event before week four, or those who failed to return.  We'll count those as CMV progressors.
		So this is our first intent to treat analysis where, in summary, all missing four week photographs equals progression, and we find that 11 out of 74, or 14.9 percent, fall into this analysis in the intravenous ganciclovir group, and valganciclovir group, 14.7 percent, or 11 out of 75.  This leaves us a difference of .2 percent and a lower bound of the 95 percent confidence interval of minus 13 percent.
		Our next analysis sought to include only those patients who died as CMV progressors.  Therefore, we exclude this group of patients here highlighted in dark red.  We're excluding patients who discontinued due to an adverse event and discontinued patients who failed to return.
		And that leaves us with two additional patients to count as CMV progressors in intravenous ganciclovir and one patient to count as a CMV progressor in valganciclovir.  It leaves us with a denominator of 72 in each of the treatment groups.
		And so the second analysis where deaths equal progression, we have 12 percent in the intravenous ganciclovir group and 11 percent in the valganciclovir group, for a difference of one percent, and the lower bound of the 95 percent confidence interval is minus 11 percent.
		And finally, we show here the applicant's analysis, which essentially includes all patients who have evaluable baseline and evaluable week four photographs.  It leaves us with these denominators:  70 in the intravenous ganciclovir group and 71 in the valganciclovir group.
		And so in this analysis seven out of 70, or ten percent, in the intravenous ganciclovir has evidence of CMV progression.  Seven out of 71, or 9.9 percent, in the valganciclovir group had evidence of CMV progression.  It gives us a difference of .1 percent in a lower bound of the 95 percent confidence interval minus 11 percent.
		Let me just back up a bit.  So this is a summary of our endpoint evaluation where we find that in a conservative intent to treat analysis where all missing values equal progression, we have a lower bound of the 95 percent confidence interval of minus 13 percent.
		And you can see that with the sensitivity analyses the lower bound of the 95 percent confidence interval is relatively consistent among these analyses.
		You heard in this morning's presentation by the applicant that there was a differential dropout rate between weeks four and 12.  There were four patients who were counted as dropouts in the intravenous ganciclovir arm, and 14 patients who were counted as dropouts in the valganciclovir arm.
		We sought to, first of all, categorize how these patients who dropped out -- where they fit into the four-week endpoint, and we found that four patients, one who was randomized to intravenous ganciclovir and three who were randomized to valganciclovir, were already counted as having evidence of CMV progression by the photographic review, and we accounted for these in our previous analyses.
		The discontinuations due to an adverse event or those who did not have a baseline photograph that was submitted for evaluation or did not have evidence of CMV retinitis, those we also accounted for in our previous analyses, and so therefore, we focused our attention on those patients who were counted in the analyses as having no evidence of CMV progression.
		And in order to understand this chart, it's important to remember that patients were being treated by the ophthalmologist and did not have knowledge of where their patient was fitting in the four-week endpoint category.
		So we asked the question:  are disproportionate dropouts failures of induction therapy?
		And we still found that even after accounting for the week four progressors and the week four dropouts, there was still a disproportionate dropout rate with two in the intravenous ganciclovir arm and seven in the valganciclovir arm.
		We also sought to evaluate the retinal photography that was taken between weeks four and 12 to see if any of these patients were having evidence of CMV progression during this time period because patients were still contributing retinal photographs in the study.
		We also looked for reasons why people were discontinuing from the study, and again, to emphasize that the ophthalmologist was making on-study treatment decisions, and that the photographic scoring was not provided in real time.  So we sought to look at the ophthalmologist's clinical diagnosis.
		We were somewhat reassured to find that -- and again, we had asked Dr. Boyd to review the retinal photographs that were submitted, and we were somewhat reassured to find that only one patient -- and it was a patient in the valganciclovir arm -- had evidence of CMV progression between weeks four and 12.
		The reasons for discontinuation included four deaths.  There were three deaths in the valganciclovir arm during this time period, one death in the intravenous ganciclovir arm.  There were three voluntary withdrawals.  All three were in the valganciclovir arm, and finally, three requested ganciclovir ocular implant, one in each arm.
		Furthermore, we found that the treating ophthalmologists were more likely to classify patients in the valganciclovir arm as CMV progressors regardless of the photographic determination, and therefore, we feel that the disproportional dropout rate was driven by the open label study design, and that the differential dropout rate does not represent a failure of induction.
		We were also interested to see how patients performed in the study who had Zone 1 retinitis, and about a quarter of patients in each arm had evidence of Zone 1 retinitis.  And the reason we looked at this is that previous registrational trials have excluded patients with Zone 1 retinitis, and we found that the outcomes were very similar to the overall patient population in this study.
		And Dr. Pomerantz raised this question this morning.  We also raised this question during our review of what was the impact of protease inhibitors on the primary endpoint in this study.
		And as Dr. Stempien had mentioned the protocol required that patients not change their heart regimen during the first four weeks, but because patients were receiving a new diagnosis of CMV retinitis, we thought that a change in heart therapy might occur commonly in this study, and so we sought to do a review to find patients who had changed their heart therapy during the induction phase, and we found that nine patients changed heart therapy, four patients in the valganciclovir arm and five patients in the intravenous ganciclovir.
		So we're somewhat reassured that the impact of protease inhibitors on the week four endpoint was minimal in this study.  At week four, we found that a majority did change their heart therapy, and that likely this change had a significant impact on the time to progression.  In the study, this time to progression was much longer in comparison to historical studies.
		So in summary, we found that the proportion of patients having evidence of CMV retinitis progression is similar between the treatment groups.  The maximum lower bound of the 95 percent confidence interval in our sensitivity analyses is minus 13 percent.
		The results of our primary endpoint was confirmed by an FDA masked review of the retinal photographs, and as the applicant had presented this morning, the visual acuity scores were similar between the treatment groups.
		And now I'll move on to the safety database in the study.  Again, the three studies provided safety information.  The induction study, which enrolled 160 patients, but two patients did not receive study drug just after enrollment; so 158 patients contributed to the safety database.
		The safety study enrolled 212 patients, and as you recall, this is a single arm, open label study of valganciclovir for the maintenance therapy in patients with a previous diagnosis of CMV retinitis.
		And finally, the PV-16000 study, which is a study of oral ganciclovir versus valganciclovir for the prevention of CMV disease in solid organ transplant recipients that's an ongoing study and which has enrolled 121 patients thus far, and because I still have a captive audience of ophthalmologists, I'll refer to this as a masked study, and the data are still masked.
		This slide represents the number of patients contributing to the safety database, and you can see that 293 patients have completed at least six months of therapy with valganciclovir.  Two hundred and thirty-eight patients have completed at least 12 months of therapy with valganciclovir in the two, the induction study and the safety study.
		And the induction study provides a comparison between the treatment arms, and gastrointestinal adverse events were the predominant class of adverse events seen in the study.
		There was a somewhat higher proportion of patients with diarrhea who were randomized to the valganciclovir arm, and a somewhat higher proportion of patients had nausea who were in the intravenous ganciclovir arm, but overall the gastrointestinal adverse event rate appears comparable between the treatment groups.
		As well, during the first four weeks the hematologic adverse events, and these are all great adverse events, were comparable between the treatment groups.  We did note the difference in this Grade 4 anemia that was seen further out in the study.
		We also sought to find an explanation as to why this was occurring, and it's important to remember that all patients were receiving open label valganciclovir at this point in the study.
		We found that a somewhat higher proportion of patients were taking concurrent zidovudine who had evidence of anemia.  There were seven patients with anemia in the valganciclovir arm and three patients with anemia in the intravenous valganciclovir arm who were taking concurrent zidovudine at the time of anemia, and I showed you earlier the data on disseminated mycobacterium avium complex infection, and we're not sure if those two factors were involved in the difference in the rate of anemia, but we feel that that may be a contributing factor as to why further out in the study a difference in the rate of severe anemia was seen.
		And the only clinically meaningful difference in other adverse events that were reported in the study during the first four weeks is catheter associated infection, which occurred at a much higher proportion in patients in the intravenous ganciclovir arm.
		We looked at deaths that occurred in the study, and in the first four weeks there were three deaths, two in patients who were randomized to intravenous ganciclovir, one in patients who were randomized to valganciclovir.
		At the week 12 time point, there were ten deaths, five in each arm, and these deaths are all primarily due to underlying AIDS.
		At one year there were 28 deaths, 18 in the intravenous ganciclovir arm, ten in the valganciclovir arm, but again, all patients were on open label valganciclovir.  So it's difficult to draw any firm conclusions.  And, again, the 28 deaths were primarily due to underlying AIDS.
		We also pooled the adverse event rate for both the induction and the safety study, and we found that gastrointestinal and hematologic adverse events were the predominant classes of adverse events, and we also found that the adverse event rate was very comparable to that of the formulations of the approved ganciclovir.
		And finally, in the PV-16000 study, CMV prevention in solid organ transplant recipients, again, the total number of patients as of August 2000 that have enrolled is 121.  It's a 100-day course of therapy, and 39 have completed the 100-day course of therapy.
		And, again, the data are still masked.  Forty-one patients have reported 60 serious adverse events.  In the four-month safety update in this NDA, only the serious adverse events were included, and we see that hematologic and gastrointestinal adverse events were reported.  Six percent reported postoperative infectious complications.  Three percent reported increased creatinine, and four percent with graft rejection.
		So other than graft  rejection, we find that these are an expected type of adverse events to be seen in ganciclovir.
		So, in conclusion, the safety database of patients completing at least six months of therapy is just under 300 patients.  Hematologic and gastrointestinal adverse events were the predominant classes of adverse events, and we found the adverse event profile to be similar to that of ganciclovir.
		And I'd like to acknowledge the valganciclovir review team.  The medical officer team leader, Dr. Cvetkovich.  Dr. Breazna and Dr. Soon provided the statistical support for my talk.  I'd like to thank Dr. Boyd, whose tremendous amount of work I had summarized in just one or two sentences.  And Dr. Reynolds of the biopharmaceutics team.
		And now I'd like to introduce Dr. Robert Kumi, and Dr. Kumi will be presenting the pharmacokinetic data that will provide support for the maintenance therapy in the treatment of CMV retinitis.
		DR. KUMI:  Good morning.
		The primary focus of my talk will be on the pharmacokinetic information submitted to support valganciclovir use in maintenance therapy for CMV retinitis.
		Next slide, please.
		The outline of my talk will be as follows.  I'll give a background on the delivery systems available for systemic delivery of ganciclovir.  This will be followed by studies and analysis conducted to support valganciclovir use during maintenance therapy, a summary of these study results, and then I'll offer conclusions.
		There are two formulations of ganciclovir that deliver ganciclovir systemically.  These are the IV formulation and the oral formulation.  The oral capsule has a poor bioavailability with a value of less than ten percent in the presence of food.
		And presently for this NDA, we're considering valganciclovir hydrochloride, which is a pro drug of ganciclovir, and it is an alternative formulation to the IV formulation.
		Next slide.
		Valganciclovir is a pro drug of ganciclovir, which is rapidly and extensively converted to ganciclovir and valine upon oral administration.  Following its administration, the ganciclovir bioavailability in the presence of food is approximately 60 percent, and this represents a substantial increase in the bioavailability relative to the oral ganciclovir formulation.
		Furthermore, the pro drug has very low systemic exposure with a value of less than five percent of ganciclovir exposure.
		Two studies and analyses were conducted to support valganciclovir use during maintenance therapy.  These were the exposure response or PK/PD analysis and the pharmacokinetic comparisons of the ganciclovir delivery systems.
		The applicant concluded that in study GANS-2226 that AUC average of ganciclovir was the best predictor of time to first photographic progression.  I'll present more details on these two studies in the next series of slides.
		The primary objective of the PK/PD analysis was to determine if there were any ganciclovir PK parameters that would predict response during maintenance therapy, and this response was measured as the time to first photographic progression.
		The methodology comprised of administering three oral ganciclovir dose regimens and one IV ganciclovir dose regimen to patients with CMV retinitis.  
		In the PK analysis, PK parameter estimates are obtained using the population approach, and then in the subsequent PK/PD analysis, the population pharmacokinetic parameter estimates were used to evaluate the PK/PD relationship.
		However, there were limitations in the PK/PD analysis, the primary one being that there were errors anticipated in the pharmacokinetic parameter estimates due to the insufficient dosing time records.
		The second limitation was in the uncertainty of the accuracy of individual parameter estimates, and this was because of the sampling scheme used.
		So we concluded that the population pharmacokinetic analysis results cannot be used for further PK/PD analysis.
		Due to the limitations in the PK/PD analysis, we sought an alternative to determine how useful valganciclovir would be during maintenance therapy.  This involved plasma concentration time profile comparisons.  We looked at the three ganciclovir delivery systems, at the recommended and proposed doses, and we looked particularly at during maintenance, and these formulations were intravenous ganciclovir, valgan. and oral ganciclovir.
		The next series of slides I'll show the pharmacokinetic profiles obtained following administration of these delivery systems.  
		Here we have the ganciclovir plasma concentration time profiles in HIV positive, CMV positive patients.  On the Y axis is the ganciclovir concentration in microgram per mL versus the time in hours, and here is plotted on a linear scale.
		This first profile, IV ganciclovir was given as a one hour long infusion once daily during the efficacy trial, and we obtain a typical pattern for an IV infusion.
		The next slide I've included the ganciclovir profile resulting from administration of valganciclovir at its proposed dose of 900 milligrams.  Here we see there are three main points I would like us to look at for this plot.
		Basically the C-max for ganciclovir resulting from valganciclovir administration is lower than that of IV.  However, the AUC, which is the measure of the total systemic exposure is comparable for the two profiles.
		And finally, approximately three hours after dosing the ganciclovir levels due to valgan administration are actually greater than that of IV ganciclovir.
		The final slide on the pharmacokinetic comparisons has included the maintenance dose for oral ganciclovir, which is administered as 1,000 milligrams three times daily, and the two main points from here are that we do not have as much concern with the lower C-max for valganciclovir because this C-max is actually greater than that obtained with oral ganciclovir.
		And, secondly, IV ganciclovir and valganciclovir have higher levels relatively of ganciclovir for a similar proportion of time relative to the oral formulation.
		So now the conclusions of these two studies.  We conclude that the ganciclovir plasma concentration time profile comparisons of valganciclovir to the two approved ganciclovir regimens, which are IV and oral ganciclovir, support the use of valganciclovir for CMV retinitis maintenance therapy.
		And secondly, the PK/PD model, though it's useful, is not needed to support valganciclovir use during maintenance therapy.
		I'd like to acknowledge the valganciclovir review team and Dr. Sue-Chi Lee, who performed the pharmacometrics consult.
		This concludes the FDA presentation and we'll be willing to entertain any questions you have.
		Thank you.
		CHAIRMAN POMERANTZ:  Thanks to Dr. Toerner and Dr. Kumi.
		And we do now open the questions to the Committee.  Dr. Bertino.
		DR. BERTINO:  For Dr. Kumi, before you leave the podium -- I try to get you before you ran off.
		DR. KUMI:  Okay.
		DR. BERTINO:  Did you guys repeat the GANS-2226 PK/PD analysis?
		DR. KUMI:  I guess, no, essentially we did not.  We looked -- basically we looked at the applicant's procedure and saw these I would say limitations in terms of the dosing scheme.  I mean the sampling scheme and the recording of dose records, and we concluded that they would not be appropriate.
		DR. BERTINO:  Yeah.  I mean, I guess I got from the FDA briefing material that the FDA's conclusion was that the one point population pharmacokinetic estimates were not accurate.
		DR. KUMI:  Right.
		DR. BERTINO:  And therefore, that data couldn't be used, which then goes back to raising the question about the relationship of the area under the curve to efficacy.
		How many patients had total pharmacokinetic profiles, more than one point?  Do you know?
		DR. KUMI:  During the GANS-2226, I think basically it was just the IV data, which had complete profiles, and that was from actually a different study, but during the actual PK/PD part, it was just like one or two samples per patient on two different occasions at week two or week six, and if there was an event like progression and retinitis or an adverse event, I think for those they might have taken the complete profile.  I'm not sure.
		DR. BERTINO:  Okay, and Dr. Pomerantz may want to defer this until this afternoon with the sponsor to ask more about this PK/PD analysis that was done since --
		CHAIRMAN POMERANTZ:  Why don't you do it now?
		DR. BERTINO:  Okay.  Okay.  I guess the question --
		CHAIRMAN POMERANTZ:  This afternoon we would like to do mainly in voting.
		DR. BERTINO:  Okay.  Could the sponsor kind of walk us through their PK/PD analysis and how they came up with this relationship of AUC to efficacy?
		Because I thought what I heard from Dr. Kumi -- and correct me if I'm wrong -- is that the FDA did not believe that the data that was obtained was useful data for doing population pharmacokinetics.  Did I misquote you?  I think that's what you said.
		DR. KUMI:  I don't know if the applicant has maybe the table with the dosing time scheme and the how the assumptions were made.
		DR. STEMPIEN:  I'm sure that we could speak to this and take you through some of the data if that is considered important for your deliberations.  My sense though is that the agreement is that this analysis, although it may be useful, it has limitations, and that we can just set it aside and make -- well --
		DR. BERTINO:  I mean, I think that's fine.  My concern actually goes back to what Dr. Wong raised this morning about toxicity because I see at the dose that's being recommended for maintenance, you're actually giving about almost a little more than 50 percent more maintenance dose per day orally versus IV.  Even when you correct for bioavailability, you're looking at five mgs. per kg. IV versus I came up with 7.8 mgs. per kg. in a 70 kilo person, which was your average weight in the study and an average bioavailability of 60 percent.  That's one question.
		The other question has to do with did you look at exposure in induction versus maintenance where they handle differently.
		DR. STEMPIEN:  Yes, yes.  Actually in our 376 study we have pharmacokinetic profiling during maintenance therapy, and that might be the best data to show you.
		If I could go back to the primary presentation.  Hang on.  The 376 PK data, P-78, please.  Yes, slide up.
		Here are the data that we obtained in our 376 study.  At the end of week one, which reflects induction level dosing, patients were receiving twice daily dosing, and at the completion of week four, which reflects maintenance dosing, 900 milligrams once daily and five mgs. per kilogram once daily.
		And for comparative purposes the AUCs as represented as dosing interval AUCs, and you can see at both under induction level dosing conditions and during maintenance dosing conditions that the AUCs are comparable.
		So the maintenance dose that we are recommending of valganciclovir is providing a systemic ganciclovir exposure that is comparable to the ganciclovir exposure that patients are seeing now when they receive the approved IV ganciclovir maintenance dose.
		DR. WONG:  But how much data --
		CHAIRMAN POMERANTZ:  Dr. Wong wants to.
		MR. WONG: -- goes into these numbers?  I mean, do we have multiple points on multiple patients?
		DR. STEMPIEN:  These are full profiles.   These are full PK profiles on 18 to 25 patients.  This is not a modeling exercise.  This is full PK profiling conducted during our pivotal efficacy and safety study.
		CHAIRMAN POMERANTZ:  Are you guys all right with this thing?
		DR. BERTINO:  I think Dr. Rodvold  --
		CHAIRMAN POMERANTZ:  We'll get to Dr. Mindel in a minute.  All right.  One of you.
		DR. REYNOLDS:  My question is that when you look at this data in the week one, you're using area under the curve for 12 hours.  So during the day you double it, and when do that, you double the differences between areas, which is about 4.2 there, which means right now there's a 4.2 different in micrograms per hour per mL for 12 hours, which means there's an eight micrograms per mL difference between -- there's a pretty big difference when you look at 24 hours there.
		And then when you go multiple days because you're going to daily dose this for three weeks, that's a bigger exposure.  So my question comes back to is that exposure giving you -- driving this dose a little bit higher.  It comes back to this question on the table.  Is this the right dose, necessarily truly equivalent?
		And I like your outcome data, and so I'm not worried about that, but I think you've got to be a little cautious here of saying this is equivalent on AUCs.  I think that you are a reasonably amount higher over there.
		DR. STEMPIEN:  Please take into account the coefficient of variations on these.
		DR. BERTINO:  But they're equal.  So the coefficient of variation is fairly equal between those two groups.  So you can work around the means unless your median data is different.
		In fact, those are almost identical.  So the standard deviation around those numbers is fairly safe, and so that's why I'm using that as a difference there.
		CHAIRMAN POMERANTZ:  Dr. Mindel.  
		DR. MINDEL:  There were some patients at entry that didn't have CMV retinitis.  Were those patients diagnosed on ophthalmologic grounds as having CMV retinitis in Zone 3?  By what criteria were you determined not to have CMV retinitis?
		DR. STEMPIEN:  I'm going to ask Dr. Martin to speak to that in just a moment, but when we say that the photos could not confirm CMV retinitis, that is precisely what we mean, and there are about five different reasons, some of them related to the technical aspects of the photo that I'll ask Dr. Martin to speak to, that can explain that.
		We are aware of two patients in this trial that the ophthalmologist felt during the course of the study that a lesion that they felt represented CMV retinitis at study entry over time; they altered their judgment in that regard, but those are the only two that I'm aware of.
		So the others that are simply a matter of the photo being unable to confirm retinitis, and there are reasons for that, and I'll ask.
		Oh, Dr. Martin doesn't feel he needs to add.
		DR. BRESSLER:  Could I clarify it then?  You said that -- you both said that there were six cases in one group and five in the other that had no photos or no CMV retinitis.  So I think Joel was asking how many of those actually had photos, but there was no CMV retinitis noted on them?  
		Because those obviously could progress.  They could go from zero to something.
		DR. MARTIN:  The answer is none of them had CMV by photographically, and when we started this trial, the full effect of HAART was just becoming known, and what we were seeing for the first time, sometimes patients coming in with scars in the peripheral that were inactive that sort of looked like old CMV.  People weren't sure what it was, and there were a couple of cases like that that in retrospect probably weren't CMV.
		There were a couple of -- I continue periodically to see a patient who is thought to have CMV retinitis because of a color change in the RPE out in the mid-periphery when you add a little microangiopathy, a little dot hemorrhage.  That can be mistaken for CMV.
		We believe that happened a couple of times in this study, and then the other reasons why CMV wasn't seen on the photograph had probably to do or may have had something to do with the execution of the protocol, the photographic protocol.
		DR. MINDEL:  Well, sort of a related question also is at the end of the study there were some diagnoses of CMV retinitis that you felt caused people to drop out of the study that were ophthalmologically driven, I think was the phrase that was used.  Were those patients also in Zone 3 that caused this relief of progression?
		DR. STEMPIEN:  No.  Everyone came into the study with CMV retinitis diagnosed by an ophthalmologist.  During that period of time where we had differential withdrawal rates, there were a number of patients where the ophthalmologist diagnosed a progression, and that that prompted the patient to withdraw from the study.
		But I do not believe that they were Zone 3 lesions involved in those patients.
		CHAIRMAN POMERANTZ:  Dr. Yogev.
		DR. YOGEV:  You said in the conclusion that patients completed at least six months have similar RS profile to ganciclovir.  Looking at the data for the four weeks, for example, neutrophil less than 750 went up from 11, 12 percent to 30 percent; anemia from nine percent to 16 percent.  Is that statement refer to historical data on ganciclovir more than six months?  Because in this data none of them got the IV ganciclovir,  So where that comparison of those who got at least six months came from?
		DR. TOERNER:  We, as well, pooled the safety data from the two studies, the safety study and the induction study because all patients were receiving open label valganciclovir after week four, and so the only comparative data we have in this NDA package is the first four weeks of the induction study.
		DR. YOGEV:  If you compare, it's much higher.  It's triple -- sorry -- double in the valganciclovir group in the maintenance, and you're suggesting they are similar.  That's why I'm asking.
		DR. TOERNER:  You mean there's about a quarter of patients having evidence of immunoneutropenia.
		DR. YOGEV:  Correct.
		DR. TOERNER:  And that's about what you would see intravenous and oral ganciclovir.
		DR. YOGEV:  In other studies, not that were represented today.
		DR. TOERNER:  In other studies that are included in the ganciclovir labeling.
		DR. YOGEV:  Okay.  So we can put the other one.  The other question I have is you mentioned out of the possibility of the anemia was patient on AZT.  I just share with you my personal experience.  You mentioned that most of the patient changed therapy at four weeks.  Usually on the second and third salvage will have less patient on AZT because they already got it.
		Is it still true that in the maintenance anemia might have been because of AZT?
		DR. TOERNER:  It's possible.  Actually I have a back-up slide that describes this difference in anemia that I found as well, and it's back-up slide number four.
		And, again, it's hard to draw any firm conclusions that there was a true difference between the treatment groups because, again, all were receiving open label valganciclovir, but we found that severe anemia occurred in ten percent overall during the study in those who were originally randomized to intravenous ganciclovir, and 18 percent in those who were randomized in the original first four weeks to valganciclovir,
		And again, all anemia was a little bit more proportional between the treatment group, and the proportion with concurrent zidovudine use at the time of anemia, there were three patients, intravenous ganciclovir, and seven patients in valganciclovir, and I also mentioned MAC infection at baseline.    I sought to look at those patients who did have MAC and to see if they were contributing more data to the severe anemia in the valganciclovir arm, but unfortunately my hypothesis didn't pan out to be true.  I did not find that all patients who were -- I did not find that the MAC infection at baseline drove the difference in the rates of severe anemia.
		CHAIRMAN POMERANTZ:  Yes.
		DR. HANNUSH:  I'd like to switch gears a little bit here, but I think it's appropriate for the morning session.  With Dr. Pomerantz's permission, I'd like to make a comment and then ask a question probably to the sponsor, to the applicant.
		I've been involved in this panel or a similar panel for the past several years, and when we reviewed the applications for intravitreal ganciclovir implant, as well as for intravitreal formaversin injections, the infectious disease experts on the panel, and if my memory serves me correctly, Dr. Kumar may have been there, constantly warned us that we are concentrating on an end organ, and perhaps by doing so, we would be ignoring the other manifestations of an otherwise systemic disease.
		With that comment in mind, I'd like to know from maybe Dr. Stempien:  was there any evaluation of collateral benefit from the use of the drug as opposed to this exhaustive discussion of side effects?  Was there any evaluation of other manifestations, any beneficial manifestations of the drug which may be behind your great interest in getting this drug approved?
		DR. STEMPIEN:  With respect to the uninvolved eye at baseline for patients who had unilateral retinitis coming into the study, we found that the occurrence of bilateral retinitis was comparable in the two treatment groups.  So that's another measure of comparable efficacy.
		In addition, we did follow all patients for the development of extraocular CMV disease, and within our 376 study, we had only one patient who developed extraocular CMV, and that was a patient who developed gastrointestinal CMV.
		Now, you have to put that into context.
		CHAIRMAN POMERANTZ:  And just to follow that up, nobody came into it with extra intestinal CMV?
		DR. STEMPIEN:  We had one patient who came in at baseline, one patient who came in at baseline who had both CMV retinitis and also had CNS CMV disease, had polyridiculopathy, and that patient did not do well at all.  That patient really was not appropriate to be enrolled.
		The patient only received two doses of study drug and withdrew because they needed combined agents for their CMV CNS disease, and that's the only other patient that came into the study that we know of.
		CHAIRMAN POMERANTZ:  Thank you.
		DR. HANNUSH:  So I can understand this correctly, are you saying that of all the 160 patients that were enrolled in the study, the only manifestation of CMV disease was their ocular manifestation with the exception of these two?  There were no other manifestations of disease that may have been controlled or arrested?
		DR. STEMPIEN:  Yes, that's correct.  That's what I'm saying.
		CHAIRMAN POMERANTZ:  That's actually fairly common, Dr. Hannush.
		DR. KUMAR:  Can I ask a question?
		CHAIRMAN POMERANTZ:  Yes, Dr. Kumar.
		DR. KUMAR:  Dr. Stempien, can I ask in reference to this question that was raised how did you collect the extraocular manifestations?  Was it systematically looked for for each presentation or was it collected ad hoc?
		DR. STEMPIEN:  No, it was not a rigorous surveillance as we employed in our ganciclovir prevention study where we had specific criteria for every diagnosis of CMV.  That was not the main concern of this study.
		This was a retinitis treatment study, but we did collect all diagnoses of extraocular CMV.  So this is per the investigator's report to us, and we did not collect biopsy information, culture data to verify that.
		DR. KUMAR:  May I just follow-up on that question?
		Were most of your investigators ophthalmologists or were they infectious disease attendings?
		DR. STEMPIEN:  We had a mixture.
		DR. KUMAR:  Could you give us a --
		DR. STEMPIEN:  Usually --
		DR. KUMAR:  -- a proportion of who was what?  I'm just interested in that.
		DR. STEMPIEN:  I would have to look that up, Dr. Kumar, but most of the principal investigators were infectious disease working closely with ophthalmologists.
		CHAIRMAN POMERANTZ:  Are there any other burning questions?
		You're burning over there, Dr. Fletcher.  Yeah, I know you're going to.
		DR. FLETCHER:  Just back to that about no other manifestations of disease.  Just to clarify, you mean of end organ CMV disease; is that correct?  Because certainly some proportion -- I think it was over half -- had CMV in their urine. 
		DR. STEMPIEN:  Yes.
		DR. FLETCHER:  So when you say no other manifestations --
		DR. STEMPIEN:  No, no, no.
		DR. FLETCHER:  -- you mean end organ.
		DR. STEMPIEN:  Yeah, I'm not talking about viremia or shedding.  I'm talking about end organ, yes.
		CHAIRMAN POMERANTZ:  All right.  For the sake of time, let me just very quickly review what we've heard this morning because it's a very interesting application.
		We've heard for one of the first times the use of an anti-opportunistic agent to affect in this case CMV in the setting of HAART.  HAART has changed everything.  We've talked about this.  This is an important paradigm not only for CMV, but for the future.
		But we have a couple of questions that have come up.  Certainly the issues of whether this is useful for induction has been well characterized, and we will discuss it more this afternoon, but maintenance is a separate issue with this, and whether we are dealing with efficacy or whether we have to deal with only PK data and the changes in chart regimen that really confound the analysis of maintenance at least for efficacy.
		There's been a lot of discussion from my pharmacological colleagues about whether AUC is a proper parameter, and that will certainly be part of the discussion this afternoon, and safety as well, in particular, anemia and some discordance in the two groups will come up, I'm sure, this afternoon.
		So I see four or five major issues that will be tightened into these four questions that we're going to ask and answer this afternoon.  Just so you know what we're going to do, we're going to ask each question separately.  I will ask for discussion from the Committee.  Everyone will not have to give a blurb though.  So you're not going to be forced, but everyone is going to have to vote of the voting members on each issue, except for the last.
		I thank you.  I'm going to take Chairman's prerogative and take five minutes off of our lunch hour, and ask you to come back at five after one.
		Thank you.
		(Whereupon, at 12:10 p.m., the meeting was recessed for lunch, to reconvene at 1:05 p.m., the same day.)

	A-F-T-E-R-N-O-O-N  S-E-S-S-I-O-N
	(1:07 p.m.)
		CHAIRMAN POMERANTZ:  All right.  So we have an afternoon of digesting a few things.  
		We're going to start before we get into the digestion of our classic open public hearing.  What I'm going to do, there's one person signed up.  We will then ask if there are others since it is an open public hearing, and the first person for this open public hearing is Mike Marco of the Treatment Action Group.
		Michael.
		DR. MARCO:  Thank you, Dr. Pomerantz.
		I just wanted to say that I'm Michael Marco from the Treatment Action Group.  I'm the Director of Infections and Oncology, and I am pleased to finally be able to be in front of all of you to discuss valganciclovir.  
		I'm glad this day has come.  TAG does support the approval of valganciclovir for induction and maintenance for CMV retinitis in people with AIDS, and, Dr. Pomerantz, I appreciate your comment that said that while HAART had delayed getting valganciclovir to this point and it's been problematic for the sponsor, it has been good for the patients.
		I want my comments to be brief because I know we all want to get out of here soon.  So I'd like for all of you to remember me for my brevity and not my astute comments.
		(Laughter.)
		DR. MARCO:  There is a position paper from the Treatment Action Group that's out on the table.  It's been passed out to all of you on the Committee, and I want to draw your attention to it.  I promise that I will not go over it word by word.  It's pretty self-explanatory.
		I do want to point out one typo that I find sort of interesting.  It's under valganciclovir's pivotal CMV study section.  It's the second sentence.  I say, "In 1997, the FDA would approve valganciclovir solely on pharmacokinetic data."  It should say "would not approve valganciclovir solely on pharmacokinetic data."
		In retrospect, I actually think that the FDA probably should have.  I think that we have IV ganciclovir and we have oral ganciclovir, and I think the comparable PK data could have warranted the approval for this drug.
		Just quickly I'm going to steal some of the thunder of the Committee, and I want to go through the questions.
		As far as the first question, do the data submitted for the NDA support safety and efficacy, and I say yes.  I want you all to remember that this is basically more data than we've ever had for other CMV drugs.  CMV drugs after valganciclovir were basically approved using immediate versus deferred design.  That was basically placebo controlled.
		And so it's possibly the Agency to not do their job years ago when they should have had certain drugs like foscarnet or cidofovir compared against cyclovir. 
		So I do take my hat off to the sponsors for taking their oral drug and comparing it to IV, which is the gold standard.  That has not been done before in a registrational study.
		And you should also pay attention to the FDA's analysis.  They did an excellent job, and I truly believe that they showed that they were both comparable as far as safety and efficacy, at least in the induction.
		As far as the second question, I do believe that this has enough information for maintenance therapy.  Oral ganciclovir is approved for maintenance therapy.  Hoffman LaRoche will know that I'm probably the harshest critic when it comes to oral ganciclovir.  I don't like the drug.
		I don't like the drug because I'm not sure how effective it is at least for prophylaxis.  For maintenance therapy you need at least 12 tablets a day.  There are investigators who think you should almost take 16 to 20.
		I think all of you know that HAART regimens have a myriad of pills that patients have to take.  So if somebody has CMV retinitis, adding 12 to 16 pills extra is just too much.  Resistance is easy to this drug, and so if we can just bring it down to two pills a day hopefully that will help out with resistance.
		I fear that the Committee has gotten a little too stuck on the anemia question and the problems with anemia.  For those of us who have been doing this work for a great deal of time, and I know many of you have who see patients, Dr. Kumar, Dr. Owens, we all know that IV ganciclovir does cause anemia, and I know that most every clinician is aware of it and knows how to treat it.
		So putting somebody on valganciclovir, I think clinicians will be monitoring anemia and all of the cytopenias that come along with it.
		I, lastly, just wanted to say that I'd like to see Roche work hard and even harder on getting this drug approved for prophylaxis.  Oral ganciclovir I do not find effective at all for prophylaxis of CMV, but I do think that valganciclovir will be an excellent drug and should do well in studies, and they should help support the ACTG team if they need to find additional site.
		And if valganciclovir is approved and also approved later on for prophylaxis, they can take oral ganciclovir off the shelves.
		Thank you.
		CHAIRMAN POMERANTZ:  Thank you, Michael.
		This is an open microphone right now.  So is there anyone else or any other group that would like to make comments on the drug before us today?  Speak now or forever hold your peace.
		(No response.)
		CHAIRMAN POMERANTZ:  Okay.  We will close the open public hearing and move right to the Committee's discussion and votes.
		As I said in the morning, what I'd like to do is deal with each question obviously separately for a discussion from the Committee, and then at the end of the discussion, we'll have a person-by-person vote which will be tallied by Tara.
		All right.  So can we have the slides with the questions up there now?
		Okay.  So we're in revised questions to the Committee, not the first one in your handout.
		Do the data submitted in this NDA support the efficacy of valganciclovir for induction therapy of CMV retinitis?  If the answer to this question is yes, in your discussion please consider the limited sample size in a study with an equivalence design and the clinical significance of the lower bound of the 95 percent confidence interval of minus 13 percent.
		If the answer to the question is no, in addition to the above considerations, please comment on what further clinical data should be required.
		This question is open for discussion.  Someone has to say something.
		DR. BRESSLER:  I'll start.
		CHAIRMAN POMERANTZ:  Neil.
		DR. BRESSLER:  I'll start.  I would say the answer answer for me would be yes.  The long answer is that although the data is limited because of the size, that's nothing that you can ever overcome, although the data is limited because of some people lost to follow-up.  That's data you can't overcome.
		The important thing to do me is that the effect on progression was so close between the two sides, despite the limited numbers and that even the details shown for border activity was so close despite the small numbers that were done that it seems logical to present this data to physicians, let them use that if they believe it's the best way to induce the patient, and they are not confined to only using this drug if they see some progression.
		And although once there's progression, there's permanent loss of visual acuity in that peripheral field.  It's usually not going to be so fast that the physician couldn't necessarily switch to some other regimen, and so because the effects see so similar, because the totality of the evidence seems to suggest that it's okay, for me it overcomes any of the design limitations, which there are and which physicians should recognize when they decide, okay, I'm going to try this.  It has a few limitations, but I'm comfortable.
		CHAIRMAN POMERANTZ:  Yes, Dr. Mindel.
		DR. MINDEL:  I'd say no.  I think there's basic flaws in the way the study was formulated.  Dr. Martin's first patients showed progress at two weeks, and he said this is not uncommon, and it's true.  It's not uncommon that you can get progression at two weeks.
		So I think a four-week study is too short.
		And also the criterion then of 750 microns necrosis is a fair amount of necrosis in a short amount of time.  So just on that basis, I don't think the data are convincing.
		CHAIRMAN POMERANTZ:  Yes.
		DR. PULIDO:  Point of clarification.  Maybe I didn't hear Dr. Martin properly, but I didn't hear anything about progression of the case that he showed.
		PARTICIPANT:  That is correct.  He showed that it failed to completely resolve.
		CHAIRMAN POMERANTZ:  Hold it, hold on.
		Dr. Martin, could you clarify that, please?
		DR. MARTIN:  That is absolutely correct.  There was no progression at two weeks or at four weeks or eight weeks.
		CHAIRMAN POMERANTZ:  Neil, Dr. Bressler?
		DR. BRESSLER:  I was just going to say it just didn't completely resolve at two weeks.  So there was still evidence of that whitish retinitis.  It was less than before.  It hadn't progressed beyond its original area.
		DR. MARTIN:  Typically when one starts induction therapy, it takes several weeks before the border of pacification to clear.  Very common at two weeks to still have some border of pacification.  The important thing is that there was no expansion of the lesion during that period of time.
		CHAIRMAN POMERANTZ:  Dr. Mindel, you had some comments.
		DR. MINDEL:  No, other than it's my impression though that it isn't unusual for there to be continued progression in the initial few weeks of therapy.  Is that incorrect?
		DR. MARTIN:  There can be continued movement beyond 750 microns during that time point.  That is correct, but it did not happen in that patient.
		CHAIRMAN POMERANTZ:  Neil.
		DR. BRESSLER:  Perhaps it would be useful, and, Joel, this might be helpful to address your concerns as well.  The 750 microns can be important if it wipes out your foveal center.  The sponsors and the FDA said that the visual acuity outcomes were not different between the two groups or they were similar, and they didn't show any large deteriorations in that first two to four weeks for most of the patients, and the deteriorations were similar.
		It might be helpful to have more detailed visual acuity analysis to confirm since we have such little data.  You know, we're working with very small numbers, to have the actual visual acuities because the ranges that were used were, you know, your 20-40 or better or your 20-50 to 21-20 or your 2200 or worse, and those are quite broad in a way.
		But it implied at least to me that whatever progression did occur didn't necessarily cause more vision harm in one than the other, and this was important since this study did look at the Zone 1 cases, which are the ones that would impact visual acuity, which we wouldn't see with other cases where there isn't a lot of Zone 1 disease being looked at, where peripherally it has to come a long way to impact visual acuity.
		CHAIRMAN POMERANTZ:  Dr. Ram Yogev.
		DR. YOGEV:  I'm struggling between academia and practicality, and I have to say yes at the end because if you look at what we approved in the past, not specifically as a Committee, but the FDA, and the n of patients it was approved on and we accept today that the ganciclovir IV, five milligram is the drug of treatment, this data that were presented to us to me are sufficient to say that at least for the induction I would support that this drug should be approved.
		CHAIRMAN POMERANTZ:  Other comments?
		Yeah, Dr. Fong.
		DR. FONG:  I agree with everything that everybody has said this morning.  I agree with you with the use of HAART nowadays.  It's very difficult to do studies with CMV, and it's particularly difficult to sort of look at the time to progression.  So I think given all of these limitations, I'm very convinced that there is equivalence between valganciclovir and IV ganciclovir.  So I would vote yes for approval.
		CHAIRMAN POMERANTZ:  For induction approval, yeah.
		DR. FONG:  For induction.
		CHAIRMAN POMERANTZ:  Other comments? 
		(No response.)
		CHAIRMAN POMERANTZ:  We're going to get to a quick vote here.
		I have one comment, and that is I understand Dr. Mindel's feelings.  Four weeks is short and worrisome, and there is a lot of confounding variables that can get into this, even with all of the very nice work the group did to alleviate my concerns, and I am more comforted now that HAART did not have a lot of problems in affecting this analysis at least in the first four weeks.
		But that being said, there is the question of a real world component here, and although I remain somewhat concerned, I, too, would vote yes knowing that this is a bit of a paradigm shift, but so was HAART development and the change in the epidemic.
		Other -- yeah.
		DR. FLETCHER:  A point where I need some statistical clarification is on the issue of equivalence.  From the data we have, can we really conclude that these are equivalent or is it more appropriate that valganciclovir is not inferior?
		Now, maybe that's splitting a fine hair, but perhaps someone from the FDA would want to comment on what the most correct interpretation of the data are, equivalence or not inferior.
		DR. YOGEV:  What's the difference?  I mean there's either equivalence --
		CHAIRMAN POMERANTZ:  If you're going to talk, talk in -- hold on, hold on.  We're not recording of that.  You've got to talk into the microphone.
		DR. YOGEV:  I don't understand.  What's -- if it's not equivalent, it's either inferior or superior, what other levels are there?
		DR. FLETCHER:  I'm not sure there's a difference either, but the sponsors seemed to take care in their presentation to say that the design was a not inferior design, and in the question that the Committee is being asked it says it's an equivalence design, and I'm looking for some guidance.
		Are those, indeed, the same?
		CHAIRMAN POMERANTZ:  Are there some comments from the FDA?
		DR. BIRNKRANT:  Dr. (unintelligible) will be answering for the FDA.
		PARTICIPANT:  Yeah, there really are no difference between the inferiority and equivalence, you know, for analysis.  Both of they use the lower bound of 95 percent confidence interval.  That's the number we should be looking at for the inference to describe similarity of the two drugs.
		CHAIRMAN POMERANTZ:  Final discussion points?  Yeah, FDA.
		DR. CVETKOVICH:  If I could just clarify one maybe, I don't know if this will help you or not, but the reason we emphasize our analysis and looked at the lower limit of the confidence interval was, you  know, the question is if it's as -- you know, on one hand it could be better, and on the other hand, it could be worse based on the confidence intervals.
		What we're really concerned about it, would it be worse?  If it's better, super.  But the clinical relevance of being potentially 11 to 13 percent worse than proven therapy, and that's really what we're here to decide, whether that is okay, whether there are limitations to that, what we think about that.
		I don't know if that helps.  I think whether it's a noninferiority or -- the name of it is probably not going to change the way you think about it.
		CHAIRMAN POMERANTZ:  Courtney.
		DR. FLETCHER:  It does because I'm wondering how would you contemplate translating that into the label.  How do you communicate then that to the patients or the physicians that prescribe the drug, the patients, you know, that will take this drug?
		Is there a way then to say it is no worse than -- I'm trying to find the -- you know, it's not more than 13 percent worse.
		DR. FONG:  Drugs aren't compared to each other on the label in general.  Isn't that so?
		DR. CVETKOVICH:  Yeah, we knew from the outset that we would have trouble or this would not be exactly the same as other studies because of its size limitations, and we knew it would be under powered to really demonstrate equivalence.  And I guess what we'll come down to is adequately qualifying it, and what we had envisioned would be to provide the confidence interval, and that should indicate both by the width and the directions, you know, the amount of uncertainty that's there.
		If you think it doesn't, I guess we need to hear that, but that's what we have.
		CHAIRMAN POMERANTZ:  So you're going to provide it on the label to let physicians decide what they can make of that?
		DR. BIRNKRANT:  If labeling is developed for this drug, then we will put in a description of the clinical studies, as well as the analyses, which will include the 95 percent confidence intervals.
		CHAIRMAN POMERANTZ:  Thank you.
		Yeah, Ram.
		DR. YOGEV:  I think that when you discuss that you have to pay attention also there are four times more side effects which are life threatening.  I'm talking about catheter induced, and if you put that into it, it would be more than minus 13 on the ganciclovir IV as worse, as a whole for the patient -- and that's why I say it's academia versus practical.
		And I think when you put those together, I feel relatively comfortable with minus 13 as the worst scenario.  That does not mean that that's what would happen.
		CHAIRMAN POMERANTZ:  Thank you.
		Yes, Dr.Dr. Hannush.
		DR. HANNUSH:  This may be a little bit of elaboration on what Dr. Yogev just said.  Again, having done this for several years, I'd just like to make a couple of comments. 
		First of all, this being the seventh drug to be approved for this indication, I don't think the FDA would be coming to us if the science was clear, meaning this may have been approved internally if the science was clear.
		Therefore, they're coming to us because the science is not clear, and that's why we're having this discussion, and I feel that if you'll excuse the pun, we have to make an inductive leap here in making a decision where we make a decision based on the human factor, based on other factors we're trying to take into consideration as to what is in the best interest of our patients.
		Do we want another option for our patients considering many factors?
		With that in mind, I think it's reasonable, and I find myself in a situation where we are like a jury ignoring the judge's recommendations, so the Judge being the science here.  The science is clearly -- with a four-week study, the science is clearly not conclusive here.
		But I think we need to take all of that into account and make a decision in the interest of our patients, and with that in mind, the answer to the first question in my mind is yes.
		Now, historically also I have been accosted after the meeting, and with all due respect to the statisticians and to the doctors of pharmacology, they would come to us after the meeting, and one person I remember specifically who I had an encounter with after the meeting who after many explicatives says to me, "You M.D.s are always negating the science and making decision based on factors that were not presented at the meeting."
		Well, we are the ones taking care of the patients, and we have to take the human factor into consideration, and I think that plays a big role.
		So in my mind if there's not significant harm done, and I think the safety data is equivocal, I think it's reasonable to err in favor of giving the patients another options.
		CHAIRMAN POMERANTZ:  Our one nay vote, Dr. Mindel, so far.
		DR. MINDEL:  Well, does the FDA want us to answer the question or does the FDA want us to answer a question should this drug be approved?
		CHAIRMAN POMERANTZ:  The FDA is asking you to answer this particular question right now.
		DR. MINDEL:  This particular question.  So if you look at that question, how are you going to answer it?
		I mean, it seems to me a lot of this discussion is answering a different question, and I might vote in favor of approving this drug even though I might say that the data doesn't support it.  I want that option left open.
		CHAIRMAN POMERANTZ:  We don't approve drugs here.  We make recommendations based on the data.
		DR. MINDEL:  No, but I'm saying I might vote for approval, even though I might vote no on every one of these questions.
		CHAIRMAN POMERANTZ:  Well, you're not going to be asked that though.
		DR. MINDEL:  Okay.  Well --
		CHAIRMAN POMERANTZ:  I mean, it's like a study section at the NIH.  You're not asked whether you're going to fund the grant.  You're asking what you think of questions on the science.
		So if you want to answer this question as no, then your answer is no.
		Dr. Wong.
		DR. WONG:  I guess I disagree on the issue of the science, and in my mind the sponsor has demonstrated the efficacy of this drug in the induction phase.
		The four weeks doesn't bother me.  It seems to me the results are clear, and I guess as an additional comment, I think that the old study design under which the previous CMV drugs have been analyzed probably is unethical in 2001 to do.  So that some other design has to be derived, and I think this one was fine.
		CHAIRMAN POMERANTZ:  Dr. Mindel.
		DR. MINDEL:  I would agree that the results of the study are clear, but the question is whether the premises on which it was based are reasonable.  That is a four-week study and 750 microns of necrosis, additional necrosis within that period to show a difference.
		CHAIRMAN POMERANTZ:  Are there any other comments?  Dr. Fong.
		DR. FONG:  I'd like to hear how you'd follow up with that.  If you don't think the study design is good, what would you recommend?
		DR. MINDEL:  I would recommend -- I wouldn't -- I understand the difficulties that the FDA is facing.  You can't change your therapy, your heart therapy.  You have to keep your basic therapy the same, and you're adding another drug.  If the disease is going to progress, how long are you going to -- but when you don't know the answer, a month is a reasonable study.
		It's not that I disagree with that.  It's just a question of whether you accept the data as answering the question.  I don't know how else to say it.
		CHAIRMAN POMERANTZ:  No, that's a very important point.  Are there other -- in particular, I'm asking ophthalmologists here who feel that the data does not answer that question to support efficacy.
		There are other ophthalmologists here.  Comments?
		DR. BRESSLER:  You can get progression in these cases within four weeks, and the fact that the progression by careful photograph analysis was so similar between the two and that the reduction in activity was so similar between the two suggests to me that there was a true induction effect by the drug to a level that appears to be safe enough to attempt for the patient at this time.
		CHAIRMAN POMERANTZ:  Other comments?
		DR. FONG:  I think -- I'm sorry.
		CHAIRMAN POMERANTZ:  Yeah, Dr. Fong.
		DR. FONG:  Well, I think given the use of HAART therapy, I just think you would just have to follow these patients for too long a period of time to do the kind of study that would satisfy, you know, what you're looking for.
		CHAIRMAN POMERANTZ:  And importantly, no one is going to not change HAART therapy in the setting of a new opportunistic infection obviously with some caveats.
		We're going to have a vote on this question.  Do the data submitted in this NDA support the efficacy for valganciclovir for induction therapy of CMV retinitis?
		There are some people who are nonvoting guests:  Dr. Chan, Dr. Piscitelli, Dr. Sun, Dr. Crittenden, and obviously everyone at the table from the FDA.
		But I will go around the room and ask for a yea or nay without comment vote at this time.
		Dr. Wong.
		DR. WONG:  Yes.
		DR. YOGEV:  Yes.
		CHAIRMAN POMERANTZ:  Turn on your mics, yeah.  Okay.  Dr. Yogev?
		DR. YOGEV:  
		CHAIRMAN POMERANTZ:  Dr. Pulido?
		DR. PULIDO:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Rodvold?	
		DR. RODVOLD:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Mathews.
		DR. MATHEWS:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Mindel.
		DR. MINDEL:  No.
		CHAIRMAN POMERANTZ:  Dr. Bressler.
		DR. BRESSLER:  Yes.
		CHAIRMAN POMERANTZ:  I vote yes.
		Dr. Kumar.
		DR. KUMAR:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Fong.
		DR. FONG:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Hannush.
		DR. HANNUSH:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Fletcher.
		DR. FLETCHER:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Bertino.
		DR. BERTINO:  Yes.
		CHAIRMAN POMERANTZ:  Okay.  All yeas with one nay.
		We will now move on to the next discussion.  That's actually the way that it happens here a lot.  So that's okay.
		Do the data submitted in this NDA support the efficacy -- that you for putting that slide up -- efficacy of valganciclovir for the maintenance therapy of CMV retinitis?  Maintenance therapy.
		If the answer to this question is no, please comment on what further clinical data should be required.  
		This question is now open for discussion.  Dr. Yogev.
		DR. YOGEV:  Well, I think everybody would agree we don't know because most of the patients were on ganciclovir, all of them.  So you get a curve, which looks nice, but what I'm comparing it to?  So unless I resort to historical data, which were not exactly presented over here, I have a problem to answer yes or no because the honest answer would be I don't know.
		CHAIRMAN POMERANTZ:  So right now you're going to abstain courteously?
		DR. YOGEV:  Yeah, unless somebody can give us some data.  What type of a maintenance without the drug?  You see, I'm impressed that ganciclovir oral is approved for maintenance when if we look at the PK, I'd be fascinated if somebody would show me the maintenance --
		CHAIRMAN POMERANTZ:  Yeah, but you can't do a therapy with induction without maintenance.  That I think by anyone's idea would be unethical.
		DR. YOGEV:  I'm just trying to raise the point the data presented both by this company and the FDA did not allow us to make a decision because all of the curves you saw were valganciclovir alone doing something.
		It would be nice if somebody can show us what ganciclovir oral maintenance did, some comparison.  Otherwise I'm not sure that's enough.
		CHAIRMAN POMERANTZ:  That's a reasonable question.  If there are historical controls, we'd like to talk about, here that maybe the FDA or the applicant would like to talk about, comparing to historical ganciclovir controls?  A reasonable question.
		DR. FONG:  Well, can I make one observation before they speak?
		CHAIRMAN POMERANTZ:  Please, Dr. Fong.
		DR. FONG:  I mean, in the presence of HAART therapy there are people who talk about not using any treatment at all, assuming the CD4 count, the T cell count is up.  So I think that comparing to history may or may not be useful.
		I think that, you know, if we believe that this drug is good enough to do induction, certainly reached high enough levels, and it certainly in terms of the pharmacokinetics looks better than the oral drugs, and the oral drug is approved for maintenance.
		I would have to say that, yes, I would advocate that valganciclovir be approved for maintenance.
		CHAIRMAN POMERANTZ:  So you've given your discussion and your vote there.  Thank you.
		DR. FONG:  Yes.
		CHAIRMAN POMERANTZ:  Ram.
		DR. YOGEV:  I just want to -- you hit the nail on its head.  See, I'm very concerned that this I heard from the FDA was not presented by the company.  Most of the patients change HAART at four weeks.  So I look at it as two different studies, one which was without change of the HAART, which obviously didn't work if you look at the viral load of five or four log, if you look at the CD4 are low, and then most of them are changing therapy, and then you see a curve which comes down.
		As I mentioned before, it's very reminiscent of population curve of what happened to CMV in the population without valganciclovir and so forth.  That's why I'm trying to suggest that this combination of changing HAART, which we know will have an effect within the next six to -- eight to 12, 16 weeks, and that's what we've got, versus is it really valganciclovir what we saw, or is it the HAART.
		And that's why if you agree with that, I have a problem to say that valganciclovir is doing good.
		DR. CVETKOVICH:  Can I just may --
		CHAIRMAN POMERANTZ:  Please, please.
		DR. CVETKOVICH:  -- help to address that issue?
		I think that it sounds as though at least for you we have not adequately made explicit why we believe that the approach of approval based on pharmacokinetic supported by safety data is a reasonable approach for the maintenance therapy.
		We never viewed the continuation  part, the maintenance part of the induction study or the open label safety study because they were single arm studies.  Certainly we looked at them and were there anything alarming we would have taken note, but in truth, without a comparison, as you say, we can't draw any conclusions about the efficacy, clinical efficacy in maintenance.
		However, we didn't believe that that was necessary because we have a very adequate pharmacokinetic argument, as well as adequate safety data, and I think Robert could maybe clarify for you what our position on the pharmacokinetics is, and then, Dr. Stempien, if there's anything you want to add, we'll do that.
		Is there anything you want to add at the moment?
		DR. STEMPIEN:  I'll follow.
		DR. CVETKOVICH:  Okay, great.
		DR. YOGEV:  Just before I get answered, I did want an answer to the Question 3, which you raised, but that's what my major concern is.  I don't think that we don't have a different toxicity.
		CHAIRMAN POMERANTZ:  We're not going to talk about safety now.
		DR. YOGEV:  No, just because you mentioned ‑-
		CHAIRMAN POMERANTZ:  I know, but we're not going to do that because we'll get to it, and we can deal with it.  Let's deal with what we just asked about.
		DR. YOGEV:  But to me the PK being above doesn't always mean it's okay.  If you try to ignore ‑-
		DR. CVETKOVICH:  No, and we wouldn't think that either.  You have to understand that it's bracketed.  The ganciclovir levels that are achieved with the administration of valganciclovir are bracketed by two approved doses or formulations and doses of ganciclovir, the IV and the oral.
		And maybe, Robert, you could explain that a little further.
		CHAIRMAN POMERANTZ:  Robert.
		DR. KUMI:  I don't know if it's possible to have the slide from before.  I think it's number 11.
		All right.  There's the IV profile which has the highest C-max, as you can see, and that's an improved regimen, and then there's the oral ganciclovir, which is kind of the lowest profile, which is also an approved regimen.
		And from the plots, the ganciclovir concentrations are basically between those of the two approved regimens.  So we have some -- I guess we have less concern about the concentrations being so different between valganciclovir and the oral ganciclovir, it's like kind of closer to IV, if anything, than to oral ganciclovir.
		DR. CVETKOVICH:  Could I -- 
		CHAIRMAN POMERANTZ:  No, we haven't gotten to our application.
		Sure, please.  You have comments?
		DR. STEMPIEN:  I just wanted to add a few clinical comments to the discussion.  You know, the dose of IV ganciclovir has always been limited more by tolerability issues than by a maximum efficacy, if you will, and that's how we settled on the dose of IV ganciclovir in the past.  It was we dosed as high as we could, and we ran into tolerability issues, and we ended up with the approved dose that we have.
		We believe that the PK profile of valganciclovir is about as close as we can get to matching an IV formulation with an oral medication, and even with this similar PK profile, if I could have the slide up, even coming fairly close to matching systemic exposures -- this was from my primary presentation -- you can see that even delivering IV ganciclovir exposures with valganciclovir, this was my -- the curve from the 376 study, which showed that patients were still progressing.
		Now, keep in mind after four weeks everyone is on valganciclovir getting systemic exposures comparable to IV, and patients are still progressing over time.  This is regardless of modifications to their underlying HIV regimens because after four weeks, physicians were able to modify HAART or any other HIV medication that patients were on.
		And if I could have the next table, slide up.  C-25, please.
		Well, the point that I wanted to make with the next table that I was calling for was the -- here it is.  This is the table from which that Kaplan Meier was generated. 
		I just want to point out that when you follow time to progression out to clinical cutoff in our study, half of the patients are progressing, and this is over about ten to 12 months of study conduct, and the median times to progression, while they are somewhat longer than what we've seen in pre-HAART studies, nonetheless, I don't think we should be satisfied with this.  The median time to progression of 160 days.
		So I would hate to see us dismiss or deemphasize the importance of maintenance dosing in patients who really may need it for a period of time, and I do think that the treating community has such a good experience with ganciclovir, which has been on the market for 12 years, that they will be able to manage the safety profile of valganciclovir.
		And if I could just have that slide up.
		Here's the slide of adverse event withdrawals in our 376 study, and this shows you the reasons for a patient to withdraw, safety reasons, all the way out to clinical cutoff.
		I just want to point out we only had one patient in each group who left our 376 study because of anemia.  So I just don't want to see too much emphasis being put on the anemia issue.
		Thank you.
		CHAIRMAN POMERANTZ:  I'll tell you my feelings on this for just a second, and I'll get to everybody.
		I understand what Ram is saying all too well.  I personally feel that the maintenance is the most troublesome arm simply because I like to see efficacy data, and I don't believe you can interpret as the applicant has alluded to at times that HAART was allowed to be changed.
		Once you change HAART, everything is off, I would say, on efficacy.  You could have the immune reconstitution syndrome in some patients.  You could have people who were not on HAART getting started.  That had dramatic changes in their immune function.
		There are a whole panoply of things that confound that.  That being said, this is in my mind going to be the coin of the realm in the era of HAART, meaning you will have to allow this to happen in a variety of anti-opportunistic infections because you have this large anti-retroviral armamentarium, and unfortunately we do have to rely -- I'm not a pharmacologist -- unfortunately you do have to rely only on PK data.
		I am not putting much to the -- I mean, it's nice that the efficacy looked like it was okay, but there's enough there so that I agree with Ram.  I can't scientifically say that there isn't enough black boxes there to confound it.
		That being said, the PK data is extra ordinary, and I think for what we have so far, it makes sense and will continue to be unfortunately, or fortunately for the patients, what we have to do in the post-HAART era.
		Yeah, Dr. Mathews.
		DR. MATHEWS:  I agree with what you've just said, and I think for the intellectual integrity of the Committee's functioning we should request that the question be reformulated because I think very clearly we don't have data to answer the question based on demonstrated efficacy.  There was no comparative group for that part of the study.
		On the other hand, if you -- and the historical controls are not particularly relevant here  because the historical controls have progression, median time to progression, I think about half of what this observed is.
		So really the question is:  do we think they're pharmacokinetically equivalent, and the answer is --
		CHAIRMAN POMERANTZ:  I mean that's a very big thing.  Let me ask the FDA if they want anything to be changed in the semantics of the question.
		DR. BIRNKRANT:  We would be willing to amend the question to clarify it so that it could read, "Do the pharmacokinetic data submitted in this NDA support the efficacy for maintenance therapy?" given that we do not have any comparative efficacy data.
		CHAIRMAN POMERANTZ:  So it would read as what?  So tell me again.
		DR. BIRNKRANT:  Just substitute the word "pharmacokinetic" before "data."  Do the pharmacokinetic data?
		DR. YOGEV:  Can you take away the word "efficacy"?
		(Laughter.)
		CHAIRMAN POMERANTZ:  I think she --
		DR. YOGEV:  Because the PK support maintenance therapy, but we cannot discuss the efficacy.
		CHAIRMAN POMERANTZ:  I mean then you --
		DR. BIRNKRANT:  I'm willing to do that, as well.
		CHAIRMAN POMERANTZ:  Hold on.  So you would say do the pharmacokinetic data submitted in this NDA support the use?  The what?
		DR. BIRNKRANT:  The use of valganciclovir as maintenance therapy.
		CHAIRMAN POMERANTZ:  Does that make Dr. Ram happier?
		DR. YOGEV:  Much happier because I would say yes by the PK.  I don't know the efficacy.
		CHAIRMAN POMERANTZ:  What about Dr. Mathews, who brought this up?
		DR. MATHEWS:  Yeah, you know, if this drug had a much more adverse toxicity profile, it would be a more significant question.  So if it were much more toxic and long-term use so that someone could make an argument, well, it's a great drug for inducing, but you wouldn't want to use it long term.  
		But that's not the case here.  We're not seeing anything new in the longer term exposure.
		CHAIRMAN POMERANTZ:  No, those are good points.  Once again, would you be happy with those changes as outlined by the FDA?
		DR. MATHEWS:  Yes.
		DR. BRESSLER:  But I'll just point out that is a different question because as you had mentioned earlier, you said there was no efficacy data.
		DR. BIRNKRANT:  There's no comparative.
		DR. BRESSLER:  I understand.
		CHAIRMAN POMERANTZ:  There's just no good efficacy data.
		DR. BRESSLER:  Okay.
		CHAIRMAN POMERANTZ:  There's efficacy data.
		DR. BRESSLER:  All right.  Because the efficacy data that was given in the briefing by the sponsors is not what you are saying is efficacy data.  You know, there was something that they put under the title of efficacy, and then you were stating that, well, that's not efficacy.  So asking this question is a different question then.
		CHAIRMAN POMERANTZ:  Let the FDA respond.
		DR. BIRNKRANT:  I think the applicant would agree, and they can speak to this as well, that the data to support the maintenance use of valganciclovir is being driven by the pharmacokinetic data, as well as the safety data that's been provided.
		CHAIRMAN POMERANTZ:  Does the applicant have  a comment on that one?
		DR. STEMPIEN:  We're satisfied with that.  We feel we do provide efficacy data, but the point is well taken.  We have no direct comparative efficacy data beyond that four-week period.  So that's absolutely fine.
		CHAIRMAN POMERANTZ:  Do you have a question there, Dr. --
		DR. BERTINO:  I do.
		CHAIRMAN POMERANTZ:  Yeah.
		DR. BERTINO:  Oh, sorry.  Could we pull up Dr. Kumi's slide number 11 again?  I just want to --
		CHAIRMAN POMERANTZ:  That's impressive.  You memorized the slides.
		(Laughter.)
		DR. BERTINO:  He actually passed me a note.
		I just want to throw this out, and just food for thought, which is if you look at -- we all remember what his slide looks like -- so if you look at this slide here for oral ganciclovir, that gram three times a day dose, the AUC average is 13.  So if the -- you know, based on what we heard this morning where an AUC for efficacy is related to an AUC of 26 to 30, this data for oral ganciclovir in terms of efficacy was produced back in the early '90s before HAART therapy, and it's approved for maintenance.
		So I'm going to bring this up again with safety, Dr. Pomerantz, but my concern about the efficacy in maintenance has to do with the dose.  Is the dose -- can we go better with side effects?
		I understand we're saying, well, you know, the side effect profiles for IV and oral weren't different, but I'm asking the question:  can we go better with side effects by using a reduced dose?
		And does the old data for oral ganciclovir at a gram three times a day back before HAART support lower exposures being more effective for maintenance therapy?
		And, once again, we'll bring that up with safety.
		CHAIRMAN POMERANTZ:  Roche's response?
		DR. STEMPIEN:  Yeah, I'd like to speak to that point.
		CHAIRMAN POMERANTZ:  Please.
		DR. STEMPIEN:  The IV ganciclovir and oral ganciclovir formulations are both approved for efficacy, but we have a big black box warning in our label with the oral formulation warning the treating physician that patients who take oral ganciclovir will progress earlier.
		So oral ganciclovir has never been positioned as equivalent to IV.  It does not match IV ganciclovir efficacy in maintenance therapy.
		And now we have an oral agent that can provide systemic exposure comparable to IV.  There is no reason to compromise on efficacy in a maintenance setting anymore.  We have a formulation that can match IV ganciclovir exposure.  This is what the treating ophthalmologists want.
		DR. BERTINO:  I understand that, but I'm still asking the question:  do you need that dose for maintenance therapy of valganciclovir?  Could you use less?
		DR. STEMPIEN:  No.  I feel we should dose ‑-
		DR. BERTINO:  You're shaking your head, but that wasn't done.
		DR. STEMPIEN:  IV ganciclovir, if we could give more IV ganciclovir, we would have.  The dose of IV ganciclovir has been limited by tolerability issues, and that is just -- it's primarily neutropenia and anemia.  So the efficacy, if we could push for more efficacy, we absolutely would.
		Half of the patients are progressing.  They're still progressing despite HAART.  So it's not a matter of do we have adequate efficacy.  We want maximum efficacy within tolerability limits, and we can deal with neutropenia and anemia today much better than we could several years ago.
		So we feel that our objective is to drive the efficacy here.  We feel that the treating community understands the safety of ganciclovir, and they will understand valganciclovir, and they'll be able to manage it.  That's our belief.  We're confident in that.
		CHAIRMAN POMERANTZ:  There was a question for Dr. Piscitelli and then Dr. Wong.
		DR. PISCITELLI:  So getting back to the PK issues, I think the pharmacology people agree that this AUC analysis wasn't acceptable.  So we don't know what's important here.  Is AUC?  Is C-min?  Is C-max?
		Now, if I understand this correctly from Dr. Kumi, the AUC of this drug, it's higher than the oral, and it's equal to the IV.  The C-min is greater than the IV, but less than the oral.  The C-max is greater than the oral, but less than the IV.
		So there's no magic statistics here.  It's more of an eyeball approach.  It follows in there, and I'm just clarifying.  Are you comfortable with that sort of eyeballing of the data?
		DR. KUMI:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Wong.
		DR. WONG:  I guess the comment that I would want to make is with your reformulated question, it's very easy to answer it, but I would go back and suggest that that's really not the right question, that what we're being asked to consider here is prolonged use of a drug to prevent a clinical outcome, and to my mind the sponsor has not addressed that question in the studies presented in that there are no clinical outcomes shown beyond four weeks.
		So that, you know, to me there should be some demonstration of a favorable clinical outcome long term.  Otherwise the answer is no.
		CHAIRMAN POMERANTZ:  Comments from the FDA.
		DR. BIRNKRANT:  Well, I don't really think to be able to please everyone we should have two questions.  I think that could be confusing as well.
		CHAIRMAN POMERANTZ:  It would confuse me.
		DR. BIRNKRANT:  I think the bottom line is the data are what the data are for maintenance.  This is what we have in this particular application.
		So the question we're asking you is:  is this in the end effective for maintenance therapy for CMV retinitis?  Do the pharmacokinetic data support the use and efficacy of valganciclovir for maintenance?
		CHAIRMAN POMERANTZ:  No, there's no "efficacy" word in this question.
		DR. BIRNKRANT:  Okay.
		DR. BRESSLER:  But if you put it back in, then it makes it a much harder question to answer because the suggestion is that we don't have evidence so far that the maintenance therapy is efficacious in progression compared to maintenance therapy that's used right now.
		But if there is data to that effect, then I think we should have it quickly reviewed because that would affect the efficacy question.
		DR. BRESSLER:  Right, and if I can come back, I mean, I think for maybe not specifically for this drug, but you know, a lot of people are going to consider the decisions that the agency makes for this drug in designing how they approach things in the future, and I think it would be very dangerous, you know, as a long-term statement to let everyone know that we as a Committee or the agency is prepared to draw conclusions about clinical outcomes in the long term based on clinical outcomes in the short term, plus pharmacology.
		I mean, I don't think that that is very wise.
		CHAIRMAN POMERANTZ:  Roche has a comment.
		DR. STEMPIEN:  We don't have comparative data in a maintenance setting between valganciclovir and ganciclovir, but if you would be interested, we could show you data on how time to progression with valganciclovir maintenance compares to time to progression with ganciclovir maintenance, although the ganciclovir would be more historical data.
		Would you --
		CHAIRMAN POMERANTZ:  That's what we talked about a few minutes ago.  Why don't we throw that up there?
		DR. STEMPIEN:  Okay.  I'm going to ask -- maybe Rebecca can help me -- I'm going to ask the slide up, please.
		Okay.  So here is a time to progression, Kaplan Meier analysis, photo documented progression, and this is 376, both arms combined because recall after four weeks everyone is on valganciclovir, and this compares our data to previous ganciclovir time to progression curves that were gleaned from four prior ganciclovir studies.
		And so here is the ganciclovir time to progression curve.  So this is historical data.  Some of it is pre-HAART, but here is the valganciclovir time to progression curve.
		Don't know if that helps you in any way.
		DR. YOGEV:  Is that all --
		CHAIRMAN POMERANTZ:  Welcome to the post-HAART era.  This is what we've been talking about.  You can compare before and after, and I don't fault Roche at all.  We kept prodding you to show this.  So there it is.
		DR. STEMPIEN:  Yeah.
		CHAIRMAN POMERANTZ:  And the data is the data.
		DR. STEMPIEN:  I'd also just like to make the point that the way that we approached this, knowing that we couldn't do a direct comparison and maintenance study, was that we felt that if we could establish efficacy in the induction setting, which is recognized as the highest hurdle for efficacy for a CMV retinitis therapy; that if we could show you that valganciclovir is efficacious in that setting, that given that efficacy data, which is a direct comparison to standard of care, and then coupling that with our PK profile information, that you would feel reasonably comfortable that there's no reason to expect that valganciclovir would not have efficacy in maintenance.
		I mean, there's nothing magical about the maintenance setting.  It's just a question of dose.  So the same disease process is going on.  You're treating the same lesion, the same virus.  So we felt that that combination might give you some comfort that although we did not have direct comparative data, that you could conclude that valganciclovir should be efficacious in that setting.
		CHAIRMAN POMERANTZ:  One thing that I should say as a virologist is that induction and maintenance therapy have taught us are different, and even though it's the same virus, it's not always the same disease.  
		We know that HIV maintenance therapy, except in newly configured regimens, doesn't work, while the same approach cannot be said for induction.
		So it is a question.  I see your point.  I don't disagree with it, but I think we get into this because the data is not as robust as we might like to start talking around the issue, but this is it.
		Courtney, you have comments.
		DR. FLETCHER:  Yeah.  I'm wondering if anyone else other than myself may want to draw an analogy to the Cidofovir data, which at least in terms of when the trial was done was at the very early era of HAART and showed a median time to progression of 120 days.
		So while I don't know all of the details of that study and where regimen change is allowed, it nevertheless may be some closer historical data within the era or HAART, probably very early HAART, that would have a very similar time to progression as to the valganciclovir data.
		CHAIRMAN POMERANTZ:  Comments on that?  Yeah.
		DR. MATHEWS:  Well, I think that's a more relevant historical comparison than what we were just shown, but you know, I think we ought to put in the context that this was a drug whose development at least for this indication was close to being dead in the water a few years ago, and it's unquestionable that there's a very definite need for it.
		And so I don't agree that this is setting some kind of precedent that's going to be regretted subsequently.  You know, it's impossible to get the kind of data that we would like to hold for the standards that we've used in other contexts.
		But, on the other hand, I don't think we should give the impression that a reasonable person wouldn't conclude that this drug is very efficacious not only for induction, which we've seen good data for, but very likely for maintenance based on the pharmacokinetic data and the historical data with all of the caveats that have to go with that.
		So I would like to just say --
		CHAIRMAN POMERANTZ:  We're going to go to the F -- sorry.
		DR. MATHEWS:  -- that I think both the agency and the sponsor should be commended for pushing this development program along because it's going to make a big different in patient care to be able to avoid having to put in central catheters even for three to four weeks.
		CHAIRMAN POMERANTZ:  A comment from the FDA?
		DR. REYNOLDS:  I just wanted to point out that using the PK data really isn't setting that much of a precedent.  Since the oral and IV are both approved for maintenance therapy, if this formulation were identical to oral for maintenance therapy, we wouldn't be asking our question, and if this were identical to IV, we wouldn't be asking our question, and it's in between, and that's why we're calling for -- PK data are used to approve generic drugs all the time.
		CHAIRMAN POMERANTZ:  In the setting of antivirals?  In the setting of an anti-retroviral?
		DR. REYNOLDS:  If they were identical, the generic would be approved.
		CHAIRMAN POMERANTZ:  Has it ever happened?
		DR. REYNOLDS:  I don't think they're off patent yet.  We have new formulations that have been approved.
		CHAIRMAN POMERANTZ:  See, that's why HIV is always different, and it really is.  I mean, we don't usually use that as the paradigm because there are two viruses interacting here.  There's enough that make everybody nervous in setting, as Dr. Wong said, a precedent that may come back to bite you.
		I personally fall on the side, as I've alluded to, of approval for this maintenance indication, but I do understand the worries.
		DR. REYNOLDS:  We have had changes in formulations approved based on PK data for anti-retrovirals.
		DR. CVETKOVICH:  Can I just add to what Dr. Reynolds is saying?  What we're trying to tell you is that -- and perhaps it's confusing that we asked the question, but I think we believe we need to.  You know, we're here to explore the data and hear what you think about it, and maybe we should have asked the question in somewhat of a different fashion because we do do this.  We approve -- you can approved drugs without clinical data.
		Say this was absolutely bioequivalent to the IV.  We would have no requirements for clinical data.  This is bracketed by two approved products so that we don't feel that we're in much of a bind here with this one.
		You know, there's no way that you can know because we've not dealt with this, as you say, in the anti-retroviral arena very often, and in fact, a lot of these decisions would be made without ever bringing it here.  So you may not be as aware of how these things work.
		But we don't have a big problem with this.
		CHAIRMAN POMERANTZ:  Unfortunately obviously the Committee has.
		DR. CVETKOVICH:  Yeah, what's wrong with you guys?
		(Laughter.)
		CHAIRMAN POMERANTZ:  Now, I'm going to ask for two final comments, and then we're going to decide what the question is and then we're going to vote
		Ram.
		DR. YOGEV:  Let me tell you what's wrong with us guys.
		(Laughter.)
		DR. YOGEV:  Okay.  With me.  
		CHAIRMAN POMERANTZ:  You did start it.
		DR. YOGEV:  My problem is the separation between Question 2 and 3 and why the sponsor would allow itself to show it as a response.  My problem is exactly what my good friend Dr. Fletcher showed, is the minute we use HAART, everything moved to a longer period of time.
		How much of local efficacy here is because of the change of HAART and how much we are paying with safety issue?  And to me, it's very surprising that 25 patients had less than 6.5 hemoglobin, gram percent, and yet only one was removed from the study.  That's where the toxicities are.
		So do we need such a high dose?  Do we need a lower dose for the maintenance because we have everything to avoid toxicity, and I don't have an answer for that, but that's where my concerns are.
		If you look at the IV ganciclovir, we have to take a lot of patient maintenance just because of toxicity, and interesting enough, they have the same rate of progression, which suggests to me that the five milligram IV is not enough also.
		So we're comparing it to something which is not perfect on something which showed to me at least increased toxicity in maintenance.  Am I doing the right decision?  And that's why the whole argument when you don't have clear-cut efficacy data.
		CHAIRMAN POMERANTZ:  Yes, sir.
		DR. BERTINO:  Looking at it from the point of view just presented, is it at least as efficacious as oral ganciclovir for maintenance therapy???
		I would have to say yes because oral ganciclovir for maintenance therapy has such poor efficacy that it's hard for me to believe that with this PK data we wouldn't even have better efficacy than oral ganciclovir.
		CHAIRMAN POMERANTZ:  Why don't we cut it there?
		DR. BIRNKRANT:  So then question number two then becomes -- the wording for that is:  do the data submitted in this NDA support the use of valganciclovir for the maintenance therapy of CMV retinitis?
		CHAIRMAN POMERANTZ:  So we are now on version 3.0.
		DR. BIRNKRANT:  Exactly.
		CHAIRMAN POMERANTZ:  So let me read it again.  Do the data submitted in this NDA support the use of valganciclovir for the maintenance therapy of CMV retinitis.
		DR. BIRNKRANT:  Understanding that the data are pharmacokinetic and safety, for the most part.
		CHAIRMAN POMERANTZ:  But that's parenthetical.  That's not in the question.
		All right.  So do the data submitted in this -- now we're going to do this.  Okay?
		DR. BIRNKRANT:  Right.
		CHAIRMAN POMERANTZ:  So get ready to vote.  Listen to me.
		Do the data submitted in this NDA support the use of valganciclovir for the maintenance therapy of CMV retinitis, question mark, et cetera?
		And we're going to go clockwise this time and start with Dr. Bertino.
		DR. BERTINO:  I was afraid you were going to do that.
		CHAIRMAN POMERANTZ:  Yes or no.
		DR. BERTINO:  Filling in at Palm Beach County.
		Yes.
		CHAIRMAN POMERANTZ:  Is the chad dangling?  Oh, okay.
		DR. BRESSLER:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Fletcher.
		DR. FLETCHER:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Hannush.
		DR. HANNUSH:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Fong.
		DR. FONG:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Kumar.
		DR. KUMAR:  Yes.
		CHAIRMAN POMERANTZ:  I vote yes.
		Dr. Bressler.
		DR. BRESSLER:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Mindel.
		DR. MINDEL:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Mathews.
		DR. MATHEWS:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Rodvold.
		DR. RODVOLD:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Pulido.
		DR. PULIDO:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Yogev.
		DR. YOGEV:  Yes.
		CHAIRMAN POMERANTZ:  And Dr. Wong.
		DR. WONG:  Yes.
		CHAIRMAN POMERANTZ:  It was much easier when we voted, wasn't it?
		(Laughter.)
		DR. MINDEL:  Well, it's much easier when you rephrase the question.
		(Laughter.)
		CHAIRMAN POMERANTZ:  The rephrase for the Committee is we got rid of the word "efficacy."  "Use" can be construed in a variety of ways that we'll leave to our FDA colleagues.
		Okay.  Shall we press on?
		All right.  Now we get to Ram's favorite one.
		DR. FONG:  Dr. Pomerantz.
		CHAIRMAN POMERANTZ:  Yes.
		DR. FONG:  For Question 2, there was also if the answer -- well, actually can I comment?
		CHAIRMAN POMERANTZ:  No, that's part of the discussion.  This is a yes or no vote.  You had that time to discuss it.
		DR. FONG:  Can I just add something?
		CHAIRMAN POMERANTZ:  You want to put something in the record?  Sure, go.
		DR. FONG:  Well, if there's always a discussion about whether the dose is too high, why don't we, you know, have the sponsor consider doing a study with a lower dose?
		CHAIRMAN POMERANTZ:  So your suggestion, and we may get to that in further trials.
		DR. FONG:  Yeah, could make some data.
		CHAIRMAN POMERANTZ:  But you might suggest that.
		Yeah, now do you want a counterpoint then?
		DR. MARTIN:  I want to provide a little perspective then that may be being missed here a little bit.  You know, intravenous ganciclovir is a great drug, but most clinicians really aren't even happy with that dose.
		And that's the whole reason why we moved to the ganciclovir implant and other treatments.  And so at least for me, I would never even consider moving to a lower dose provided that there aren't egregious toxicities, which I think we've shown you that there is not.
		For me if there's a higher exposure, great, bonus.  I mean, we're trying to treat CMV retinitis.  That was the reason why you started therapy, and the blood-ocular barrier is such that you can't forget that.  If you're going to get drugs into the eye, you can't drop the dose.  You don't want to.  There's no scientific reason to want to do that.
		So I just want to keep that perspective in mind.
		CHAIRMAN POMERANTZ:  Thank you.
		Dr. Bertino.
		DR. BERTINO:  Just one comment to the FDA then, since we've answered one and two, which is that when you work on the label, I think it's imperative to put in that the drug should be take with a high fat meal.
		DR. STEMPIEN:  Well, I just want --
		DR. BERTINO:  I was sure there'd be a comment.
		DR. STEMPIEN:  Yeah, I'm sorry.  But I just want to make sure you understand that although in our clin-pharm studies we gave them the high fat standard FDA breakfast, in our clinical trial we simply said, "Please dose with food."  So the actual clinical data that was generated here is not high fat.  It's just dose with some food.
		CHAIRMAN POMERANTZ:  Give only with McDonald's cheeseburgers.  Is that what you're trying to say?
		DR. STEMPIEN:  It should be comparable to what we have in our ganciclovir labeling, which we conducted it the same way.
		DR. FLETCHER:  But you can't have it both ways.  You can't have it an indication for maintenance based upon PK and the PK coming through a well designed, well controlled, pharmacokinetic studies where the patients got a high fat meal, and that is what shows pharmacokinetic equivalence, and then say in the label, "But you can take it for maintenance and you don't have to take it with food."
		You're trying to have it both ways, and you can't do that.
		CHAIRMAN POMERANTZ:  But there's a difference in my way of thinking between a high fat meal and take it with food.  What are you saying?
		DR. FLETCHER:  Well, I'm saying, if I understand what the sponsor said, when we saw the pharmacokinetic data from week one and week four, we asked what was the meal, and they said, "That's the standard FDA meal for those studies."
		DR. STEMPIEN:  No.  So there is a misunderstanding.  Let me set the record straight.  One of our earlier clinical pharmacology studies did dose with a high fat standard breakfast.  The full PK profiling that I showed you from the 376 study where we had 20 patients with full PK profiles at week one and week four, we did not dose it with a high -- it was not standardized that way.  We simply suggested, "Please take your dose with food or snack."
		So we did it exactly the same way as we've done our prior oral ganciclovir studies, and so the label should look just like ganciclovir, oral ganciclovir.  That's truly what we did.
		DR. FLETCHER:  I don't know what the label looks like for oral ganciclovir.  Does it say "with food"?
		DR. STEMPIEN:  Yes, it does.
		DR. FLETCHER:  Okay.
		CHAIRMAN POMERANTZ:  All right.  We've gotten rid of the fat, and we're leaving food.  Why don't we move on?
		Do the data submitted in this NDA support the safety of valganciclovir for the treatment of CMV retinitis?  This is Question 3.
		If the answer to this question is no, please comment on additional safety studies that should be required.
		Question is open for discussion.  Sir?
		DR. PULIDO:  I have a question for my colleagues on the panel.  I'm still concerned about what happens to the valyl ester in the presence of diarrhea where the intestinal esterases may not be functioning properly or in the presence of hepatic toxicity, which by the way there was, as I had mentioned before, 14 percent incidence of lab abnormalities showing some hepatic toxicity from this drug.
		It looks to me like there is no data to show what happens in these cases.  Should we be worried about toxicity of the valynated form?
		CHAIRMAN POMERANTZ:  Any comments to that question from either side?
		DR. BERTINO:  I think a couple of questions though to think about.  One would be I think we heard from the sponsor that about 25 percent of the drug is cleaved in the liver.  Is that --
		PARTICIPANT:  No, 15 percent.
		CHAIRMAN POMERANTZ:  Turn on the mic.
		DR. BERTINO:  Fifteen percent in the liver.
		And so the question is:  can the liver do moire?
		I guess the other question is if the drug is being absorbed in the upper part of the small intestine, what happens to esterases there based on diarrhea?  Do we know?
		One of the things that I always think about when the liver is involved is the liver has got enormous reserve, and the gastroenterologist's definition of liver disease and the pharmacologist's definition of liver disease really are pretty different.
		CHAIRMAN POMERANTZ:  Well, before you say that, that brings up a point that I wanted to bring up in the morning, in that more and more HIV CMV is being complicated by Hepatitis C virus, and the tripartite viral infection is a big problem, and the question is:  if you're going to look for liver dysfunction, is there any data on the use of this in someone who has Hepatitis C?
		DR. STEMPIEN:  I don't think we have any clinical data on that.
		CHAIRMAN POMERANTZ:  Because if there's going to be one problem in HIV infected individuals that might give you liver dysfunction, that might get you into trouble with those hypothetical questions, it's more and more becoming Hep. C.
		DR. STEMPIEN:  We don't have clinical data, but we do have some preclinical data that addresses the intestinal and hepatic esterase, and Dr. Sue Malcolm, preclinical, can take you through that.
		DR. MALCOLM:  We were concerned with the effect as to impairment or competing activity for the esterases in both the intestine and the liver.  So we did conduct some in vitro studies to look at this problem.
		And what we found is that the capacity of these enzymes is so high that you can knock them out by a long way before you see much of an effect.  As a result of the in vitro studies that we conducted, we developed a model which actually predicted quite well to the in vivo situation, and from that model we could then say, well, if we knocked out the esterases in the intestine, what would the effect be.
		And perhaps I could just show you a quick slide of the results of that.  If I could have NC-11, please.  Slide up, please.
		What you've got here is a series of bar charts representing ganciclovir in green and valganciclovir in orange, where it's on a log scale because I tried to let you see this little tiny blip here for the bioavailability of valganciclovir.
		This is what we see measured in vivo.  From the model this is what we predict, and this has given us some confidence in the model that we've developed.
		So if you say, "Well, I'm going to knock out the esterases to 80 percent in the intestine," what's the effect on bioavailability, which is what I think your concerns are?
		Obviously our major concerns are on valganciclovir, and you can see that the change in bioavailability, the reduction is really quite small because of the high capacity of this system, and if you knock out in the intestine, if you knock out in the liver, and in this worst case scenario where you knock out in both the intestine and the liver, the actual effect on ganciclovir is quite small.
		Obviously there is a rise in the exposure to valganciclovir because the original bioavailability is quite low.
		Slide off.
		CHAIRMAN POMERANTZ:  I'm sorry.  I missed that.  That was in what animal model?
		DR. MORGAN:  The original result, the original data were generated from human in vitro studies, in both the human intestinal S-9 and human liver S-9.
		CHAIRMAN POMERANTZ:  So you've never done anything like this in an animal setting of any type except for the in vitro human cells, right?
		DR. MORGAN:  No.  We just looked at the human metabolic capacity.
		CHAIRMAN POMERANTZ:  Courtney?
		DR. FLETCHER:  An area of safety there I have some concern, individuals that have renal insufficiency.  So we talked a little this morning, you know, about the data showing the need for dose adjustment and a dose adjustment algorithm that you've proposed.
		If my understanding from the two studies is right, all of the patients in those trials had creatinine clearances great than 50 mLs per minute.  So that with the data we have right now, we really don't have experience in dosing the drug with individuals that have creatinine clearances less than 50 where the need for adjustment becomes much more important.
		So I'm wondering.  I don't know.  If it's in the briefing package I must have missed it, about the study in organ transplant patients that's going on, and in particular, in renal transplant patients, if you have any information there on how this dose adjustment algorithm is working.  Is it really providing the areas, you know, the exposures that you're looking for or not?
		DR. STEMPIEN:  We don't have any data of that type available to us yet.  That study is in an enrollment phase, and, no, I'm sorry.  We don't.
		DR. FLETCHER:  I'd just add I think that in a label there will be some need for some caution about dosing and renal insufficiency while the algorithm can be, you know, made based upon creatinine clearance.  Whether it's really going to work or not is another thing, and is it going to provide the same type of safety profile?
		I think that's going to be something that can be very important to make sure that that's communicated.
		CHAIRMAN POMERANTZ:  I think that's a good point.  Clearly, sort of the elephant in the room here is how this is going to be used for transplantation, and one that we've stayed away from on purpose at this committee at this point.  Maybe we'll hear more about that at a later meeting.
		Other comments on safety?  Yes.
		DR. PISCITELLI:  Just a question getting back to the anemia and neutropenia.  Just a clarification.  Three, seventy-six, did that protocol allow for growth factors, like GCSF or EPO?  And what kind of use was that in the two groups?
		DR. STEMPIEN:  The protocol did allow for that, and let me just get that slide up for you.
		Slide up.
		Now, we've looked at the use of colony stimulating factors after baseline up until week four.  So this would reflect induction level dosing, and then from baseline all the way out to the data cut.  So that would be the total experience.
		Regarding support for neutropenia, 13 percent of the IV patients and 15 percent of the valgan patients required did received GCSF or GMCSF, and that percentage did increase over time comparable between the two groups.
		When you look at blood products and EPO use across those two time periods balanced during induction, and then you see blood product use was balanced all the way out, this does go along with the anemia finding that we found based on lab data.
		So patients had more severe anemia.  Now, we don't know how this is related.  It may be that the patients who we identified as having more severe anemia required support for that, and so they utilized more EPO.  So the two bits of data travel along together, and so they do support the presence of an anemia difference in that study.
		But we don't have -- this does not explain why, of course, and we don't know if it will end up being a real difference or not because all patients were on valganciclovir maintenance at the time that they developed the anemia.
		CHAIRMAN POMERANTZ:  For the sake of discussion, I'll be one second.  Is there anyone who's shading towards no on this question?  Because there's another part of the discussion for those noes here to at least address before we go on with it.
		Dr. Yogev.
		DR. YOGEV:  Well, it's not an absolute no, but I think it's very important to realize if you can put this slide back again, the clinical 205.  Is that the one?
		PARTICIPANT:   Pretty good.
		DR. YOGEV:  Thank you.
		CHAIRMAN POMERANTZ:  Another one who memorizes slides.
		(Laughter.)
		DR. YOGEV:  If you look at it, what's so fascinating to me, and this is, by the way, a smaller study because just to point the original point, the 11 patients who got it, when out of 370 patients, 57 of them on maintenance had less than eight grams hemoglobin.  So it depends when you start erythropoietin.  Some of us like to start it even earlier not to get to that point.
		So I wonder if you go to nine or something like that, you might get even higher, but if you compare four weeks versus whenever that is cut off, which we don't know exactly, is that 12 weeks or longer?  There's a continuous increase in --
		DR. STEMPIEN:  Oh, I'm sorry.  I didn't mean to interrupt.  Go ahead.
		DR. YOGEV:  -- an increase in toxicity that whether it's compared to ganciclovir or not, it's secondary, and I think we need to mention that's where the patient is going to pay on our lack of understanding the efficacy in Question 2 with toxicity that to be left open to the physician to take the balance and make the patient aware of it, and that's where it's not an absolute no, but I need to see something done in that direction.
		CHAIRMAN POMERANTZ:  No, that's why I opened it up that way.  
		Yeah, there is a comment from the applicant.
		DR. STEMPIEN:  Oh, no, I just wanted to point out you were asking about the length of time from baseline to data cut, and that would represent a median of approximately ten months of drug exposure.
		CHAIRMAN POMERANTZ:  Yes, now Dr. Bertino.
		DR. BERTINO:  Before you take that slide down, because I haven't memorized the number on it, when you say "blood products," I assume that just means packed red cells, not platelets, not fresh frozen plasma, things --
		DR. STEMPIEN:  Oh, exactly.  It's red, red cells.
		DR. BERTINO:  And the other question then is patients that got EPO, could they also receive blood products?  And do you know what the crossover is?  Are these separate patients?
		DR. STEMPIEN:  These are independent measures.  So, yes, indeed, it could have been one patient who may have receive both.  They would be counted in both categories.
		DR. BERTINO:  Okay.
		CHAIRMAN POMERANTZ:  I think that's important because if you look at blood products in EPO and you just add up to the two right-hand columns, it looks like patients that got the oral agent needed more red cell intervention, so to speak, but if there were crossover patients, then that may not be so.
		DR. STEMPIEN:  Yes.  I can't tell you to the extent that that happened, but these are independent measures.  So the same patient could show up in both.
		CHAIRMAN POMERANTZ:  And one other question.  Was the use of blood products in EPO left up to the investigator or was there a cutoff where you said below this value consider using these or use these?
		DR. STEMPIEN:  We had recommendations in the protocol that were consistent with ganciclovir.  They were the standard recommendations that we use in ganciclovir protocols, that if ANC drops below a certain level or hemoglobin drops below a certain level, you can consider the following options, either support with a colony stimulating factor, a brief dose interruption.
		So we didn't mandate it.  We just set out some guidelines, and this was what actually happened would have been driven by the investigator's judgment.
		CHAIRMAN POMERANTZ:  I think your question is a good one because it also brings up clinically how different people will address low red blood cell count due to whether it's AZT against cyclovir (phonetic) or valganciclovir.
		There are physicians who, as you know, would rather do anything than give someone blood products, even if they're HIV infected, and there are others that are loathe to use a lot of erythropoietin.
		So your question, it may confound the -- your question shows the confounding part of the analysis, which is that it wasn't mandated what everybody would do at one particular state.  It was left up with some considerations at that point.
		And I think it's very hard to judge that when it's left that open.
		DR. BERTINO:  And just what time frame was that pivotal study done over?  From what year to what year?
		DR. STEMPIEN:  Well, it's still running.  It started enrolling in early '97 and --
		DR. BERTINO:  The reason I asked that, I don't know if other people have found this, but I can tell you at my institution the threshold for transfusing people with packed red cells has -- the threshold has increased so that they have to get to a lower hematocrit now before they get transfused.
		CHAIRMAN POMERANTZ:  Absolutely.  We find that I would say that's probably country-wide.
		Other comments on Question 3?  Chris Mathews.
		DR. MATHEWS:  Yeah, one thing to keep in mind also is that in the maintenance phase many patients will go off maintenance therapy, and we didn't see the follow-up CD4 counts on the patients in the pivotal trial here, but because of that phenomenon and the guidelines recommending or at least suggesting that people who get over 100 can go off maintenance therapy, you're going to be selecting for a poorer prognostic group of people, patients who will continue on maintenance therapy, who will be at risk for other infections, too, which makes the toxicity data even more difficult to interpret.
		CHAIRMAN POMERANTZ:  I would also add the fact that those recommendations have changed over the time of this study.  A hundred is pretty new that many people are comfortable with stopping maintenance therapy.  So knowing how long this trial has been moving along, I would imagine it will make it even harder to interpret it because people wouldn't have stopped at 100 even a year ago.
		Other comments?
		Because we're getting close to a third vote here.
		(No response.)
		CHAIRMAN POMERANTZ:  Okay.  That's what we're going to do.  This time we don't have to change the question.
		Do the data submitted in this NDA support the safety of valganciclovir for the treatment of CMV retinitis?
		And we're going to go back to the other way and go with Dr. Wong.  Yes or no?
		DR. WONG:  Yes.
		CHAIRMAN POMERANTZ:  Dr. Yogev.
		DR. YOGEV:  Abstain.
		CHAIRMAN POMERANTZ:  That's a new one.  Okay.  Dr. Pulido.
		DR. PULIDO:  Abstain.
		CHAIRMAN POMERANTZ:  Rodvold.
		DR. RODVOLD:  Yes.
		CHAIRMAN POMERANTZ:  Mathews.
		DR. MATHEWS:  Yes.
		CHAIRMAN POMERANTZ:  Mindel.
		DR. MINDEL:  Yes.
		CHAIRMAN POMERANTZ:  Bressler.
		DR. BRESSLER:  Yes.
		CHAIRMAN POMERANTZ:  Pomerantz votes yes.
		Kumar.
		DR. KUMAR:  Yes.
		CHAIRMAN POMERANTZ:  Fong.
		DR. FONG:  Yes.
		CHAIRMAN POMERANTZ:  Hannush.
		DR. HANNUSH:  Yes.
		CHAIRMAN POMERANTZ:  Fletcher.
		DR. FLETCHER:  Yes.
		CHAIRMAN POMERANTZ:  Bertino.
		DR. BERTINO:  Yes.
		CHAIRMAN POMERANTZ:  Okay.  We have 11, with two abstentions.
		Okay.  We're going to get to the fourth question, but I just want to recap what we have here in the three official votes for the FDA.  The first question, do the data submitted in this NDA support the efficacy of valganciclovir for the induction therapy of CMV retinitis, 12 to one -- one is a no -- was the vote, 12 positive.
		The second was a changed question.  Do the data submitted in this NDA support the use of valganciclovir for the maintenance therapy of CMV retinitis?  That was 13 positive, no, zero noes, zero abstentions.
		And the last one you just heard.  Did the data submitted in this NDA support the safety of valganciclovir for the treatment of CMV retinitis?  Eleven vote yes, zero vote no, with two abstentions.
		Okay.  This one doesn't require a vote, and it just requires some discussion.  Number four is if the answers to the above questions are yes, and most of us voted yes on these, are there additional clinical trials that you would recommend to the applicant conducting as Phase IV studies?
		Open for discussion.  Ram.
		DR. YOGEV:  Well, my usual on over pediatric, which I mentioned.
		But on a personal note, older --
		CHAIRMAN POMERANTZ:  So noted.
		DR. YOGEV:  Yeah, and on a personal note, older than 65.  I'm almost getting there.  So I would like to use the drug, and they don't have data on that.
		I think we need to request a longer period of follow-up on safety and toxicity, and patient with liver disease or peritoneal (phonetic) dialysis, we need to collect data on those to see how should we replenish the drug.
		CHAIRMAN POMERANTZ:  Other comments?
		I have one actually because I think Ram brings up a couple of good points, and that is not only for this drug, but for most anti-CMV drugs, Phase IV trials that take into account age, be it at the beginning or the later half of life, is an important one.  There are clear differences certainly in the very young, below two.
		And now we know more and more that immune reconstitution differs greatly whether you're -- and I'm sorry, Ram.  The data from Mike McCune suggests that it's age 40 when the thymus really starts going away, not at two.
		If you monitor that by TREK, by thymic replication circles, 40 is where it falls off, and so there's not real clear data whether there's going to be a difference in how people on HAART, even those that do well, will do depending on whether you're less than 40 or, I'm sorry to say, greater than 40.
		And so age is a clear indication for new trials as they come forward and as the epidemic expands.
		I think the other point that we had brought up before is the question of what HAART does to maintenance therapy.  We left it as a bit of a gamisch (phonetic) here in the maintenance therapy, allowing people to change their regimen.  I would like to see a Phase IV or whatever you want to call it trial where HAART is at least segregated in some ways based on changes in a trial so that you could figure out whether there truly is efficacy in the HAART era, whether it's IV ganciclovir, valganciclovir, and what it is because a lot of alterations in HAART will change the efficacy.  Anti-HIV medications are anti-CMV indirectly, but there.
		So that would be something for the company to think about I would hope for both this and for a variety of other drugs that affect CMV.
		DR. FLETCHER:  Two things for me.  One, drug interactions.  We kind of gave a pass on any kind of drug interactions.  The background briefing says, you know, anything that is there for ganciclovir will be there for valganciclovir, and as a place to start, I think that's fine.
		But ganciclovir clearly hasn't been studied in this new era of HAART, and as Dr. Pomerantz has mentioned now, there will be additional drugs as we treat hepatitis and so on.  So there really does need to be an active program to look for drug-drug interactions.
		The second one is the dosing issue.  I think you heard from several members of the Committee that were not confident that we have the best dose for maintenance therapy.  
		I would at least encourage you to not give up on the population PK/PD issues.  The current study that was done was unfortunately just not well done.  But there can be a wealth of information that can come out of these.  You'll have some, I think, nice opportunities to look at a range of systemic exposures as you look across organ transplant patients, as you look across HIV infected patients.
		And I would encourage that and ask you to remember that these types of studies aren't just random things.  Population pharmacokinetic studies dynamics really need to be a well designed study just as any other study needs to be.  They can use information, you know, SMARTS information, but they still need to be a very well designed study.
		CHAIRMAN POMERANTZ:  Dr. Bertino.
		DR. BERTINO:  Well, I'll put in my usual song, which is most of the pharmacokinetic data was done in men, and so sex differences, I think, has to be investigated for this drug.
		One of my concerns, I think, kind of extends into what Dr. Fletcher said, which is I'm a real skeptic myself of population pharmacokinetics just as I'm a skeptic of using age and sex and ethnicity and calculated creatinine clearance to figure out dosing regimens, and I think dose is not a measure of exposure for most people.
		And I think that both with this drug and with future drugs that come to this Committee and all of the FDA committees, that we need more individualized dosing information.
		Yeah, it's really easy for the practicing physician to only have to remember one dose for everybody, but I think 20 years from now we're all going to say, "Gee, we were pretty naive about how we're using drugs back 20 years ago," and I think we need to start incorporating more of that information, including genetic information, into the equation.
		So that would be my comments.
		CHAIRMAN POMERANTZ:  Other comments?  Yes, Dr. Mindel.
		DR. MINDEL:  I'd like a study looking at frequency of dosing.  The IV is given twice a day for induction and cut down to once a day because of ease of giving the drug and matters of quality of life.
		The oral drug gives an opportunity to continue the twice a day dosing, possibly at a lower dose and getting a good response and maybe with less toxicity, maybe with more.
		CHAIRMAN POMERANTZ:  Thanks.
		Chris.
		DR. MATHEWS:  One area that I think needs further investigation is this issue of how long to continue  therapy in the maintenance phase and what are the consequences of discontinuing therapy, and maybe the ophthalmologists here could comment on this entity of immunity recovery, the tridis (phonetic), which my impression has been from the cases we've seen in San Diego that they're nearly always in people who  have been taken off antiviral therapy after they've had immune recovery, and that entity is very frequently vision threatening, with poor outcomes unless managed aggressively.
		So I think one relevant clinical question is to propose a study that would randomize people either to continued therapy with valganciclovir or stopping maintenance therapy once they've met the threshold of immune recovery to see if both rates of progression, as well as this immune recovery syndrome differ in those two arms.
		CHAIRMAN POMERANTZ:  Comments from any of our ophthalmological colleagues?
		DR. BRESSLER:  No, but I just would like to ask the people who are treating many people with CMV retinitis right now as ophthalmologists what their current approach is to maintenance because -- and, Dan, maybe you could address this -- it's my feeling that there's a gamisch of ideas being done out there, and it may be worthwhile using the limited data you have on valganciclovir to expand on it and figure out is this needed for maintenance.  Is there a better maintenance?
		You showed a curve that said, you know, there was progression in 40 or 60 percent.  I think it was 60 percent by the time it got out to almost a year's time.
		Well, what if oral ganciclovir does it to 40 percent or something.  Is that what people should be on or whatever?
		DR. MARTIN:  I think you've articulated that very nicely.  The bottom line is that we still don't know, although we certainly know more now than we did two years ago.
		The idea of withdrawing therapy really began in about two years ago, two and a half years ago, and at that point, at the threshold that many people were using, was 200.
		It has become clear over time that this is like all clinical scenarios.  It's not as simple as just a single lab value cutoff.  The decisions whether or not to withdraw therapy is multi-factorial based on the -- it's all risk-benefit -- location of retinitis, you know.  If you have Zone 1 disease splitting the fovea, you tend to err on keeping those patients on a longer period of time.
		The extent of retinitis, the degree of immune recovery, the HIV viral load, which would impact the duration of the CD4 count; it's not so simple as just one laboratory cutoff.
		But I agree there are certainly more studies that would be indicated.  I personally tend to follow patients on maintenance therapy, and at least for me what works quite well is to follow them, following their CD4 count, and not using an individual threshold, but waiting until they're main standard deviations beyond what we had ever seen in a pre-HAART era, and then considering withdrawal of therapy.
		I also do want to make one more point on the impact of HAART on maintenance therapy.  In the curve that we've shown now several times, some people look at that and have the mistaken idea that somehow CMV disease is easier to treat because of HAART.  That's not necessarily so.  That's a very heterogeneous population you're looking at.  You're looking at a population, you know; you're looking at a median over the whole population, but when you try to apply that to the individual, it's much more problematic.
		You have some patients in there who have failed anti-retroviral therapy, and despite multiple manipulations of HAART, they don't develop immune recovery, and for those individuals, they're going to need long-term maintenance therapy versus those who have a quick response and they never progress.
		DR. BRESSLER:  So what are you using for maintenance therapy now is my question.
		DR. MARTIN:  I typically --
		DR. BRESSLER:  Typically?
		DR. MARTIN:  Typically will use -- well, first of all, a lot of my patients who are in the valganciclovir trial are continuing on 900 milligrams of valganciclovir once daily.  For those patients who had multiple progressions, I added an implant on top  of that, and so that's typically what I have used.
		DR. BRESSLER:  But for the patients who are not on valganciclovir, who walk in tomorrow and finish their induction, they do on what?
		DR. MARTIN:  We tend to stratify patients -- I do -- depending on what I think their options for immune recovery are.  For example, if someone is HAART naive and this is their first OI and it's their wake-up call, and now they're going to start their HAART regimen, that's someone who I'd probably put on oral ganciclovir, one gram t.i.d., hoping for immune recovery.
		If it's someone who has exhausted all therapy options that have disease that's splitting the fovea, I'm probably not going to give them an opportunity for pure maintenance.  I'll probably put an implant in and then continue them on oral ganciclovir.
		DR. BRESSLER:  So that's what I would compare to maintenance valganciclovir, and that's the study I would recommend because I'd like to know which is the best regimen to maintain them on.  Should they have the implant put in?  Should they just take a pill?
		Previously when you didn't have the pill option, it wasn't as good or when the pill was so onerous for some of them to take, it wasn't as good.  Now, you do have to watch the side effects that they're pointing out, but that's to me what I want to know in managing them.
		CHAIRMAN POMERANTZ:  But what I would point out, Neil, I agree, and I like what you're saying about how you manage them down at Emory, but I can tell you you can put three retinal specialists in a room, and you're going to get three different answers to that question.
		DR. BRESSLER:  Okay.
		CHAIRMAN POMERANTZ:  That standard of care is very different.  That makes sense to me, and I think you look at the nuance as well, but I think it's going to be a difficult study to do because I would imagine that not everyone does that, and you would have to really come up with a standard of care to do it, and we're not quite there yet.
		DR. BRESSLER:  You're right.
		CHAIRMAN POMERANTZ:  Because the disease is evolving so quickly.  You know, not o behavior the point, but as we talked about, all CD4 cells are not alike.  That's an immunological broad brush stroke.  In the first few weeks, it's redistribution.  In the second few months, it's repopulation of memory, and naive goes out to two year unless you're over 40, where it may never come back.  I'm over 40.
		So I think you're right to look at it, but look at it as an evolving entity, and I think Neil also has a good point, but I think it's going to be a difficult study to do now because the ground will change under you as soon as you start getting that study together.
		DR. BRESSLER:  True.
		CHAIRMAN POMERANTZ:  Other comments?  Dr. Hannush.
		DR. HANNUSH:  You're waiting for me to drop a bomb again or something.
		CHAIRMAN POMERANTZ:  No, the votes are already in.  Go on.
		DR. HANNUSH:  This is a follow-up to what 
Drs. Bressler and Martin just said, and I'm curious because, and it may speak to the issue of labeling.  There was a question in the previous version of the questions to the Committee as to how valganciclovir should be used in relationship to other available therapies for CMV retinitis, especially when the fovea is threatened.
		Should there be something in the labeling of this product that speaks to this issue, that perhaps this is not a drug to be used if we have sight threatening?
		There are four retina people in the room.
		DR. BRESSLER:  See, that's right.  When you have no data, you have to then, I believe, use your judgment.  Unless you had a study specifically looking at that, I'd like the physicians to read as much as you end up publishing on this.  I'd like them to look at as much as there is on the implant, as much as they know about that patient, and then have to make a decision from the choices you have.
		I think it's very hard to put into a label when the fovea is threatened, you must put an implant in and not take a chance with this or vice versa.  You must give them this drug.
		CHAIRMAN POMERANTZ:  Dr. Martin?
		DR. MARTIN:  I agree.  I appreciate your concern, but even most patients who have severe sight threatening disease, most of us don't just do one thing.  It's very common just to give an intravitreal ganciclovir injection right there in the office.  That way I have no question about whether or not their therapy has been started, and then I'll start them on intravenous ganciclovir or valganciclovir.
		I mean, I think most clinicians, if it's really severely sight threatening are not going to rely purely on this.  They'll augment as they see necessary.
		DR. HANNUSH:  Did you say intravitreal ganciclovir?
		DR. MARTIN:  Yes, yes.
		CHAIRMAN POMERANTZ:  This is what I mean.  I'm sure you can have a debate among the -- I know I've had that at Will's a few times.
		Other comments or questions about this interesting but still difficult issue?
		(No response.)
		CHAIRMAN POMERANTZ:  Well, I want to thank the Committee and the FDA and Roche, in particular, because it's not only an important drug for us and probably for other groups of patients, other than what we've discussed today, but it's a real, as I said at the beginning, a real paradigm change in the year of HAART.
		And I'm going to suspect that we'll always have to wrestle at least for the next foreseeable future with how you approve drugs such as this, knowing that the studies are bound and the companies are bound by the good part of what is the HAART revolution.
		I think that what the FDA heard today is that even though you're comfortable more with these things, these changes, even though they make sense teleologically, which is what the PK data shows, we still like to see patients get better on it and with nonconfounding variables, and I think that was the major problem with at least Question 2.
		But I will imagine that we'll hear this done again at this Committee.
		If there aren't any other final comments, I'll adjourn it at this point and thank everyone for their participation, guests, consultants.  See you all.
		(Whereupon, at 2:53 p.m., the meeting was concluded.)