UNITED STATES OF AMERICA
	DEPARTMENT OF HEALTH AND HUMAN SERVICES
	PUBLIC HEALTH SERVICE
	FOOD AND DRUG ADMINISTRATION
	CENTER FOR DRUG EVALUATION AND RESEARCH
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	ENDOCRINOLOGIC AND METABOLIC DRUGS
	ADVISORY COMMITTEE
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	MEETING NO. 72
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	Friday, March 26, 1999
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The Advisory Committee met in Versailles Rooms I, II, and III, Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland, at 8:00 a.m., Henry G. Bone, III, M.D., Chairman, presiding.
PRESENT:
HENRY G. BONE, III, M.D., Chairman
KATHLEEN REEDY, Executive Secretary
JULES HIRSCH, M.D., Member
D. ROGER ILLINGWORTH, M.D., Ph.D., Member
ROBERT A. KREISBERG, M.D., Member
MARK E. MOLITCH, M.D., Member

PRESENT (Continued):
GLENN BRAUNSTEIN, M.D., FDA Consultant
JOSE FRANCISCO CARA, M.D., FDA Consultant
COLLEEN A. COLLEY, Pharm.D., FDA Consultant
SAUL GENUTH, M.D., FDA Consultant
ROBERT MARCUS, M.D., FDA Consultant
MARIA I. NEW, M.D., FDA Consultant
RICHARD J. HAMMES, R.Ph., M.S., B.C.N.P.,
Consumer Representative
JAMES H. LEWIS, M.D., Guest Expert
LEONARD B. SEEFF, M.D., Guest Expert
NORMAN FLEISCHER, M.D., Guest Expert
REBECCA W. KILLION, Guest Expert
JAMES M. BILSTAD, M.D., FDA Representative
DAVID GRAHAM, M.D., M.PH., FDA 		Representative
SOLOMON SOBEL, M.D., FDA Representative
ROBERT TEMPLE, M.D., FDA Representative
JEFFREY MILLER, M.D., Public Comment
ROBERT BUSCH, M.D., Public Comment
STEVEN V. EDELMAN, M.D., Public Comment
PATRICK J. BOYLE, M.D., Public Comment
ANNE PETERS, MN.D., Public Comment
RAMACHANDIRAN COOPPAN, M.D., Public Comment

PRESENT (Continued):
TOM HALSTEAD, Public Comment
MEHMOOD KHAN, M.D., Public Comment
THOMAS J. MOORE, Public Comment
JOSE LOUIS BAUTISTA, M.D., Public Comment
DANIEL EINHORN, M.D., FACP, FACE, Public 		Comment
WILLIAM CLARK, M.D., Public Comment
VINCENT PEARSON, Pharm.D., Public Comment
SIDNEY M. WOLFE, M.D., Public Comment
STEPHEN CLEMENT, M.D., Public Comment
GERALD FAICH, M.D., MPH, Sponsor 		Representative
PHILIP HOME D.M., D.Phil., Sponsor 	
Representative
MARK PIERCE, M.D., Ph.D., Sponsor 		Representative
PAUL WATKINS, M.D., Sponsor Representative
RANDALL WHITCOMB, M.D., Sponsor 		Representative
ROBERT ZERBE, M.D., Sponsor Representative

	C-O-N-T-E-N-T-S
	PAGE
Introductions	6
Conflict of Interest Statement	8
Background and Purpose, James M. Bilstad, M.D.	10
Public Comment:
Jeffrey Miller, M.D.	17
Robert Busch, M.D.	21
Steven V. Edelman, M.D.	24
Anne Peters, M.D.	27
Ramachandiran Cooppan, M.D.	30
Tom Halstead	33
Mehmood Khan, M.D.	36
Thomas J. Moore	40
Patrick J. Boyle, M.D.	48
Jose Luis Bautista, M.D.	53
Daniel Einhorn, M.D. 	55
William Clark, M.D. 	59
Vincent Pearson, Pharm.D. 	61
Presentation by Sidney M. Wolfe, M.D.	64
Presentation by Stephen Clement, M.D. 	76
Presentation by David J. Graham, M.D. 	82

	C-O-N-T-E-N-T-S (Continued)
	PAGE
Sponsor's Presentation:
Introduction, Robert Zerbe, M.D.	191
Description of Hepatic Events, Paul
Watkins, M.D. 	197
Estimate of Incidence, Mark Pierce, M.D. 
and Gerald Faich, M.D. 	213, 230
Comparative Safety of Alternative Therapies,
Philip Home, M.B., Ph.D. 	236
Benefits of Rezulin Therapy, Randall Whitcomb,
M.D. 	246
Risk-Benefit Summary, Robert Zerbe, M.D. 	269
Committee Questions of Sponsor	280
Summary, Charge to the Committee, and
Introduction to Questions, James M.
Bilstad, M.D.	364

	P-R-O-C-E-E-D-I-N-G-S
	(8:10 a.m.)
CHAIRMAN BONE:  Good morning, everyone.  I'm Dr. Henry Bone.  I'm calling to order the 72nd meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.
The topic today is a discussion of experience since approval for marketing of the benefits and risks of troglitazone, and also there will be some discussion of triple therapy involving this agent with sulfonylurea and metformin in the treatment of Type 2 diabetes mellitus.
The first item will be to go around the front table to introduce the people who are here from the agency and from the Advisory Committee, and I think we'll just begin with that.  Perhaps we'll start at the far right with Dr. Temple.
DR. TEMPLE:  Thanks.  I'm Bob Temple.  I'm CDER's Associate Director for Medical Policy.
DR. BILSTAD:  Jim Bilstad, Office of Drug Evaluation 2.
DR. SOBEL:  Saul Sobel, the Metabolic and Endocrine Drug Division.

DR. GRAHAM:  David Graham, a medical epidemiologist in the Office of Postmarketing Drug Risk Assessment in CDER.
DR. SEEFF:  I'm Leonard Seeff from the NIDDK and the VA.
DR. LEWIS:  I'm James Lewis from Georgetown University.  I direct hepatology there.
DR. ILLINGWORTH:  Roger Illingworth, Oregon Health Sciences University, Portland, Oregon.
MR. HAMMES:  Dick Hammes, pharmacist, University of Wisconsin.
DR. GENUTH:  Saul Genuth, Case Western Reserve University.
DR. BRAUNSTEIN:  Glenn Braunstein, Cedars-Sinai Medical Center, Los Angeles.
CHAIRMAN BONE:  Henry Bone, Michigan Bone and Mineral Clinic at St. John Medical Center in Detroit.
MS. REEDY:  Kathleen Reedy, Food and Drug Administration.
DR. MOLITCH:  Mark Molitch, Northwestern University in Chicago.
DR. NEW:  Maria New, Cornell University Medical College.
DR. KREISBERG:  Bob Kreisberg, Birmingham, Alabama.

DR. COLLEY:  Colleen Colley, VA Medical Center in Portland, Oregon.
DR. FLEISCHER:  Norman Fleischer, Director of Endocrinology at the Diabetes Research Center at Albert Einstein College of Medicine.
DR. MARCUS:  Robert Marcus, Stanford University and the Veterans' Affairs Medical Center in Palo Alto.
MS. KILLION:  Rebecca Killion.  I'm a Type 2 diabetic.  I'm here as a patient representative.
DR. HIRSCH:  Jules Hirsch, Rockefeller University.
Henry, I can't see you.  So send up a rocket if you want me to comment or something.
CHAIRMAN BONE:  All right.  Perhaps during the discussion we can arrange to have the projector moved.
All right.  Thank you all.
The next item is the presentation of the meeting statement by Kathleen Reedy, the Executive Secretary.
MS. REEDY:  Conflict of interest statement for the Endocrinologic and Metabolic Drugs Advisory Committee, March 26th, 1999.

The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
Based on the submitted agenda and information provided by the participants, the agency has determined that all reported interests in firms regulated by the Center for Drug Evaluation and Research present no potential for a conflict of interest at this meeting with the following exceptions.
In accordance with 18 United States Code 208(b), full waivers have been granted to Dr. Mark Molitch, Dr. Glenn Braunstein, Dr. Henry Bone, and Dr. Saul Genuth.
Copies of these waiver statements may be obtained by submitting a written request to FDA's Freedom of Information Office, located in Room 12A30 of the Parklawn Building.
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 FDA's invited guests, there are reported interests which we believe should be made public to allow the participants to objectively evaluate their comments.  Dr. Norman Fleischer would like to disclose for the record that he serves as a member of Parke-Davis' Speakers Bureau.  In addition, in 1998, Dr. Fleischer attended a meeting on Rezulin sponsored by Parke-Davis.
With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon.
CHAIRMAN BONE:  Thank you.
The next item on the agenda is the remarks upon background and purpose by Dr. Bilstad, Director of the Office of Drug Evaluation 2.
DR. BILSTAD:  Good morning.  First I would like to address the question why we are having this Advisory Committee meeting.
First slide.
There continue to be reports of serious hepatotoxicity despite labeling recommendations for frequent monitoring of liver function tests, which currently are recommended at baseline and monthly thereafter for the first eight months.

In addition, recently we have become aware of a number of reported cases that appear to have had a very rapid course, which raises questions about the adequacy of frequent monitoring to prevent liver failure.
Next.
On the other hand, troglitazone has a different mechanism of action from other approved drugs to treat diabetes, and it is effective in helping to control hyperglycemia in Type 2 diabetics.
We want to review with the Committee the experience with the drug since it was approved for marketing, and we are asking for the Committee's views on the assessment of the drug's overall benefits and risks.
Next.
I would like to briefly review some aspects of the regulatory history for troglitazone.  The NDA was received by FDA in August of 1996, and it was designated as a priority application because of its different mechanism of action.
It was presented to this Committee on  December -- in December 1996.  At that time, hepatotoxicity was discussed only to a limited extent.
The Committee recommended approval for use in Type 2 diabetics who were currently taking insulin, but were not adequately controlled.

Next.
Less than two weeks after the 1996 Advisory Committee meeting, a safety update was submitted to the FDA that included additional cases of hepatotoxicity.  The drug was approved for marketing in the end of January 1997, and the labeling indication was as discussed at the Advisory Committee, for patients who were taking insulin but were judged not to be adequately controlled.
Next.
The labeling at the time of initial approval included hepatotoxicity information and the precautions and the adverse reaction sections based on the information in the safety update.  The labeling stated that 2.2 percent of patients in the controlled clinical trials had an AST or ALT greater than three times the upper limit of normal.
The labeling also reported that two patients had developed jaundice while taking troglitazone which subsided after the drug was stopped.
Next.

Efficacy supplements were submitted by the sponsor to expand the indications.  In August 1997, labeling was approved that allowed for concomitant use of troglitazone with the sulfonylurea drug to improve glycemic control.
At the same time, the labeling indication was also expanded to include monotherapy with troglitazone, provided that the patients had not previously been well controlled on sulfonylureas.
Next.
The first fatalities associated with hepatotoxicity were reported to the FDA by Parke-Davis in October 1997.  Shortly thereafter, the labeling was changed to include a bolded warning about the possibility of hepatic failure, including death.
Recommendations for monitoring liver function tests were also included in the labeling.  The recommendation at that time was that they be checked during the first one to two months of therapy and every three months thereafter during the first year.
Next.
Additional reports of serious hepatotoxicity were received, and in December 1997, a boxed warning about the possibility of hepatic failure and death was added to the beginning of the labeling.

The recommendations for monitoring liver function tests were also changed.  Testing was recommended when therapy with troglitazone was started, to be repeated every month for the first six months, and every two months for the remainder of the first year.
Next.
The last labeling change was made in July of last year.  At that time the monthly monitoring of liver function testing was extended from six months to eight months.  
In addition, the statement was added that troglitazone therapy should not be started if the ALT was great than one and a half times the upper limit of normal.  A statement was also included in the boxed warning that if an ALT was obtained in the range of one and a half to two times greater than the upper limit of normal, LFTs should be repeated within a week and then repeated weekly until the levels returned to normal.
The primary issue that we are bringing to the Committee is for your consideration of the potential overall benefits and risks for the labeled indications, i.e., for the combination with either sulfonylurea drugs or with insulin and for monotherapy.

We are, however, also asking the Committee for comments on the proposed indication for combination with sulfonylureas and metformin.
We also want to raise the issue of how successful the labeling recommendations for monthly monitoring during the first eight months of therapy are in reducing the cases of liver failure.
Dr. David Graham from FDA's Office of Postmarketing Drug Risk Assessment will later address a number of issues relating to hepatotoxicity.
I would also like to point out that we recognize the difficulties in attempting to define and quantitate the potential long-term benefits of drugs used in the treatment of diabetes.  The sponsor will be addressing potential benefit issues with troglitazone, as well as issues relating to hepatotoxicity.
That concludes my opening remarks, and I look forward to the presentations today and to the discussion on certainly this very difficult and challenging subject.
Thank you.
CHAIRMAN BONE:  Thank you very much, Dr. Bilstad.

In a moment we'll start the open public hearing section of the meeting.  As I usually like to remark, it's a very American characteristic to have such an opportunity in deliberations of a committee advising a drug registration authority, and I look forward to the remarks that will be made by each of the people who are scheduled to talk.
I will ask the people to stay within the time that they've agreed on with Kathleen Reedy, the Executive Secretary, and I'll give you a little signal at four minutes like this, and please.  As I said, she's discussed this with you I know.
She has a comment to make first of all about the materials.
MS. REEDY:  Because of the number of people who requested to speak in the open public hearing, letters that were submitted for the open public hearing are printed and available, and everyone at the table has them in their folder, and there are a stack of them where you picked up the agendas if you would like to have a copy, but there are about six or eight letters and another six or eight letters that respond to the citizens petition, which you'll hear more about.
CHAIRMAN BONE:  Thank you very much.

The first speaker in the open public hearing -- with this large number of speakers, it is Dr. Jeffrey Miller of Thomas Jefferson University Hospital in Philadelphia, and if we can have people sort of waiting when they're next so that we don't have too much time in between just waiting for people to come up to the podium, I think that will help us move along.
Dr. Miller.
And I will say:  would any of the open public hearing speakers who have an interest that could be regarded as a financial interest please state that as well?  We've asked that everyone be candid about this.
Thank you very much.  Dr. Miller, please.
DR. MILLER:  Thank you, Dr. Bone.
Ladies and gentlemen, I am on the Speaker's Bureau of Parke-Davis, Eli Lilly, NovoNordisk, Knorr (phonetic) Pharmaceuticals, Bayer Pharmaceuticals, to mention quite a few. 
I am here representing the ten million-plus diabetics who in this country suffer from the epidemic of obesity.  I'm here in my private capacity with no other inclination.

The problem, as I foresee it, in these overweight diabetics who die at the death rate of about 500 people per day is that contrary to what we currently believe -- and I've done a little survey in my own practice, which is probably the largest single handed endocrine-diabetes practice in the City of Philadelphia -- is ask my patients a simple question.  If you don't take care of yourself as a diabetic, what will happen to you?
And the uniform answer is, "Doctor, I will die as a result of kidney failure, blindness, or limb amputation."
Unfortunately, that is not the reality.  That is some five percent of total deaths.  Seventy-five percent of diabetics die as a result of the scourge of cardiovascular disease, and the onus on us as treating health care providers is to provide these people with what I've termed heart healthy.  We need to prolong their life spans by allowing them to be free of atherosclerosis, and it my belief, based on a number of scientific publications, including the Paris prospective study, that in order to prevent cardiovascular disease, we need to go beyond simple issues that we address every day, that is, beyond blood glucose, beyond hypertension, and beyond hypolipidemic indices.

We need to look at the beta cell.  We need to look at the entity of endogenous insulin production as being potentially involved in this whole atherosclerotic process, and this, I believe, is with this new group of compounds, I believe, the most exciting category of compounds to be around in the last 40 years, the thyozolic endiones or the glutazones, as I call them, have really come to the fore.
These are agents that in numerous peer reviewed articles provide cardiovascular protection in terms of improved vascular reactivity, decreased platelet aggregation, decrease in triglycerides, improvement in lipoprotein a, improvement in overall LDL characteristics from an atherogenic to a non-atherogenic potential, to name but a few.
This agent, I believe, has gone beyond simple diabetes management, has gone beyond blood glucose.  Diabetes is no longer a glucose disorder.  To myself as a practicing clinician, educated, diabetes is a vascular disease, and in order to cut down the thrust of this disorder on the vascular system, I have relied very heavily on the insulin sensitizers, first the bioguanides, the midformin, and more recently the even more powerful beta sulresta (phonetic), troglitazone.

Life is an analysis of risk and benefits.  On Wednesday night just before going to be, I listened to the President talking about Yugoslavia and was talking about the risk of American lives in terms of the benefits that we can get out of this war.
The same with our daily lives in terms of medicine.  It's a risk-benefit analysis.  I unfortunately recently heard about a patient, a young lady on antithyroid agents for Grace hypothyroidism who succumbed to agranulocytosis.  That was a risk-benefit analysis on the part of her physician to treat her with antithyroid agents rather than radioiodine which has no deaths attached to it.  The risk unfortunately exceeded the benefit in that situation.
In my own personal practice of some cumulative, about 3,000 people on troglitazone, I've had five liver function test abnormalities.  These are biochemical abnormalities, mild rises in ALT to less than 100.  The agent was discontinued.  All five improved and got better and had no permanent sequelae.
It is my contention that in a risk-benefit analysis in this vascular scourge of diabetes looking at the overall nexus of action of this very exciting compound, troglitazone, that this is the forerunner in order to cut down on the death by cardiovascular disease.

If one looks at a risk-benefit analysis, the benefits so far outweigh the risks that I hope and my charge to the Committee is that hopefully science will prevail and not emotion.
And I thank you very much for your attention.
CHAIRMAN BONE:  Thank you very much for your remarks, Dr. Miller.
The next speaker is Dr. Robert Busch from Endocrinology Group in Albany, New York.
DR. BUSCH:  Thank you for the privilege to be able to present to you today.
I'm a clinical associate Professor of Medicine at Albany Medical College, but I'm a practicing endocrinologist in a group of ten private practice endocrinologists in Albany, New York, and I'm here today representing myself, my ten partners who are endocrinologists, and our 2,000 patients who are on troglitazone therapy.

In practice, we have the luxury of working with a Doctor of Pharmacy from Albany Medical College, and Dr. Michael Kane has tracked our patients, two of the providers who started patients on troglitazone in 1997.  He is submitting this for publication and for presentation at the American Diabetes Association in June.
We had 460 patients who are on our best effort therapy with either insulin, sulfonylurea, or metformin therapy, with a body mass index on the average of 31.  These patients were started on troglitazone in 1997, and over 95 percent of the patients are still on troglitazone therapy.
Five patients had to be discontinued because of ALT elevation between three and eight times normal, which reversed to normal.  That's 1.2 percent of the patients the drug had to be stopped because of transient ALT elevation.
Of the 95 percent of patients still on troglitazone, the average hemoglobin A1c in these patients with our best effort as endocrinologists was 8.2 in 1997, a B minus or C plus.  Now, our average A1c is 7.3, a decrease of .9 sustained over the past year.
This is reminiscent of the U.K. PDS decrease in hemoglobin A1c of .9, which significantly decreased the microvascular complications of diabetes.

I did not bring slides today, but I did bring two of my patients from Albany, Ms. Lucille Lorenzo, who is a woman who has had diabetes for 20 years, on insulin previously.  She's a mother of six, grandmother of 12.  Her A1c was 8.9, today is in the mid-six range on troglitazone with sulfonylurea and metformin.
A second patient, Robert Anderson, who's a leasing manager for the state.  Also, his avocation is as a farmer, and when he was on multiple injections of insulin he had significant hypoglycemic reactions when he was milking his cows.  Now on troglitazone, repeglonide and metformin therapy, he can mow hay with his grandson.
Now, these are just two of the patients that we have as a practice, that we could fill this room with patients who have benefitted from troglitazone.  Unfortunately in our area, a lot of the primary care physicians are influenced by what's in the media, and they're practicing medicine by media, and their patients have not been exposed to troglitazone because of fear of the media.

Now, the public opinion is influenced by whom the public hears, and oftentimes the public only hears silence, and my hope and the faith that I have and my patients have in this advisory panel and in the FDA is you be very loud and very vocal in your reaffirmation of the safety and efficacy of troglitazone in benefitting the lives of our patients with diabetes.
Thank you.
CHAIRMAN BONE:  Thank you very much, Dr.  Busch.
The next speaker is Dr. Edelman from the Veterans' Affairs Hospital in San Diego, California.
DR. EDELMAN:  Thank you for allowing me to testify before you today on this very important issue.
I'd first like to tell you that I am on the Speakers Bureau for Parke-Davis, Bristol-Myers Squibb, Bayer, Lilly, and many other diabetes related companies.  However, I am here today for my patients, and I have come on my own time and my own money.
I am not only a physician who specializes in taking care of people with diabetes, but I have also been living with diabetes for the past 28 years.  Although my type of diabetes is quite different from those who could benefit from Rezulin therapy, we share some of the same day-to-day trials and tribulations of balancing our diet, exercise, and medications in order to maintain good glucose control, and it is not an easy task, and the more tools we have to overcome the many barriers to good glucose control, the easier it becomes.

We know the consequences of poorly controlled diabetes:  blindness, dialysis, amputations, heart attacks, strokes, depression, and unfortunately much, much more.  Every day in America over 400 people die directly due to the effects of diabetes, and it's so important to look at the risk of Rezulin versus the benefits of improved glucose control when you're looking at a very serious disorder that affects the quality of life of millions of Americans on a day-to-day basis.
If one death is too many, then, yes, take Rezulin off the market, but then you must also take off glucofos insulin, sulfonylureas, Motrin, aspirin, Tylenol, and many other medications used to treat patients with cancer and HIV.
I follow over 500 people at the Veterans' Affairs Medical Center in UCSD who are taking Rezulin therapy.  You can't buy this drug back from these individuals because it has helped them to achieve and maintain control over their diabetes where previously it was not possible despite intensive efforts.

This is why two of my patients, James Roach and Ray Cordova are here with me today.  These gentlemen and many other of my patients would be at a serious disadvantage if they were not able to continue therapy with Rezulin in order to achieve good glycemic control over the long term.
I challenge anybody in this room to find a physician who has used Rezulin in more than just a handful of patients and did not find it a very impressive drug not only as in monotherapy, but also as in combination therapy with other drugs and with insulin, especially to achieve the clearly defined goals put forth by the American Diabetes Association.
In my observation, the only nay sayers are the individuals with little or no practical experience with Rezulin, and they have not spoken to the 1.5 million people with diabetes who have benefitted from the use of this drug.
Now, no drug is 100 percent safe.  However, diabetes is a serious disease whose prevalence is increasing quite dramatically not only in the United States, but also around the world.  Every drug has a risk-benefit ratio, and in the case of Rezulin, the benefits of reducing eye, kidney, nerve, and heart disease far outweigh the risk of liver disease, especially with proper liver function monitoring.

Every day 1,600 people in the United States are diagnosed with diabetes, and in any 24-hour period 400 people die directly due to the complications of diabetes.  I think we have to continue to be as aggressive as possible to reduce the huge amount of suffering that's associated with this disease.
Thank you very much.
CHAIRMAN BONE:  Thank you, Dr. Edelman.
Our next speaker is Dr. Boyle, Dr. Patrick Boyle from the University of New Mexico Health Sciences Center.
PARTICIPANT:  It doesn't look like he's here.
CHAIRMAN BONE:  All right.  If Dr. Boyle appears later, if he'll make himself known.
We'll move on to Dr. Anne Peters, Director for Clinical Diabetes Program at the University of California, Los Angeles.
DR. PETERS:  Good morning.  I'm Dr. Anne Peters, and if I can have the first slide.
I'd first like to disclose that I have received funding for research, speaking, and consulting from the following pharmaceutical companies.  I do not own stock in any pharmaceutical company, and no one sponsored me to come here today.

This equation is central to medical decision making.  Recently we've all learned that the risks of a drug can be sensationalized, but psychologists know this.  We all remember traumas far more than we remember the good things that happen to us.  It is the bad things that we tend to recall.
So I'm here today to discuss the benefits of Rezulin and the benefits of treating diabetes, but this does not mean I do not understand the harms.
The woman on the right is my great aunt Helen.  She died last year of a drug reaction to naprosin.  Does this mean that I don't use drugs?  No, but it means that I use drugs with an appreciation for maximizing the benefits and minimizing the risks.
But what of Rezulin?  Let my patients tell you.  This is Delores.  Because of Rezulin, she was able to stop insulin.
This is Sheila.  On a combination of Rezulin and glucophage, she was able to cut her insulin dose in half and is now able to lose weight.
This is Sylvano, who was never even able to come close to a normal hemoglobin A1c level until Rezulin was added.

This is Steffie.  Steffie had such bad pain in her feet and legs from her peripheral diabetic neuropathy that she could barely walk in from her car in the parking lot to clinic.  When Rezulin was added, her hemoglobin A1c level came down to normal.  Her pain is gone.  Just a few weeks ago, she was able to turn in her handicapped parking placard and now can walk through the parking lot to clinic without pain.
And finally, this is the rabbi who says, "What would I do without my Rezulin?"
(Laughter.)
DR. PETERS:  Now, these are but a few of the hundreds of patients I have successfully treated with Rezulin, but what of the risk of diabetes?  Diabetes is a deadly disease.  This slide depicts the 17 people who will die this hour because of the complications of diabetes.
And this, this is Pat.  Just last week Pat went permanently blind from her diabetic retinopathy.  Pat and I are exactly the same age.  Yet Pat is gravely disabled.  She asked me to ask the FDA to hurry and approve new drugs that can help people with diabetes so they don't have to have the terrible complications she has suffered.
And finally, back to the original equation.  I do not believe that an individual physician can determine the risks of a drug therapy.  That is for the advisory panel and the FDA to do.

But I ask you that you do this without bias, that you do this without the bias of emotion, that you do it without the bias of the media, politicians, the pharmaceutical industry, anyone.  These decisions must be made based on the most rational, scientific evidence we have available.
On the benefit side, in my hands Rezulin has been a very safe and effective drug.  I urge you to keep it on the market if, on a population level, this equation continues to be strongly positive.
Thank you.
CHAIRMAN BONE:  Thank you very much, Dr. Peters.
The next presentation will be by Dr. Cooppan, the Jocelyn Diabetes Center in Boston.
DR. COOPPAN:  Thank you very much, Mr. Chairman.
My name is Ramachandiran Cooppan, and I'm a senior physician at the Jocelyn Diabetes Center in Boston, where I've been on staff since 1975.  I've come on my own volition, and I'm not representing the institution, but as a physician who has spent the last 24 years treating patients with diabetes.
I'm also on the Speaker Bureau of Parke-Davis, Bristol-Myers Squibb, NovoNordisk, Eli Lilly.

In 1998, the Jocelyn Diabetes Center celebrated its 100th anniversary, an institution that was dedicated itself to the welfare and care of patients with diabetes.
In the last 25 years, we have seen a great increase in our understanding of the pathophysiology of Type 2 diabetes, and one thing is clinically evident to all of us.  We start our treatments far too late with this disease.  At the time of diagnosis, our patients already have complications.  
We have been hampered in the past by not having available multiple strategies and therapies to intervene in this disease.  Furthermore, we're in an era now where we have outcomes data.  The U.K. PDS, United Kingdom Prospective Diabetes Study, and the DCCT give us the information that we need to make the case that diabetes control matters.
When I first arrived at the Jocelyn Diabetes Center in 1974, we only had the sulfonylureas and animal source insulin.  We've advanced our insulin therapy remarkably.  We now have the challenge to open ourselves up to new medications in the oral arena.
The advent of metformin in 1993, which the FDA approved in its wisdom, opened combination treatment to us once again, but this was an old treatment first reported in 1953 by Sam Biezer.

The advent of troglitazone opened a new era for us.  Not only did it open a window into our understanding of the pathophysiology of diabetes, but it addressed a fundamental defect in the disease, that of insulin resistance.
The U.K. PDS has taught us that no monotherapy is going to succeed in diabetes management.  The case has to be made for combination treatment.
In a preliminary analysis of over 2,000 patients taken care of at Jocelyn Diabetes Center, we have had no case of liver failure of jaundice.  We have had less than ten patients who have had elevation of their liver function studies, all of which return to normal with cessation of the drug.
This in no small way was due to the exercising of a great degree of pharmaco-vigilance on our part.  We monitored the patients.  We adhered to the guidelines.  We find that the insulin sensitized troglitazone is a very useful tool in our armamentarium, and we believe sincerely that the future of diabetes management belongs to combination treatment and that, indeed, we will actually see new treatments emerging in the future and combinations of two or three drugs will be necessary.

In conclusion, diabetes has been described as a moving target.  We need to have therapies that are evolving with this disease.  This disease will not only test the science of medicine.  It will also test our art of the practice of medicine.
Thank you very much, Mr. Chairman.
CHAIRMAN BONE:  Than you very much, Dr. Cooppan.
The next speaker is Tom Halstead, listed as President of Hemotherapy.
MR. HALSTEAD:  Thank you, Henry.
I have no relationship to any drug company.
Ladies and gentlemen, distinguished physicians, dearest patients, of the over 3,600 FDA approved drugs on the market, more than 1,100 can potentially damage the liver.  Despite its great benefits to diabetic patients, Rezulin is a member of this latter category and the subject of today's discussion.
Could there be a way to reap the benefits of Rezulin yet obviate its negative effects on the liver?  We believe so.

Hemotherapies offers the only liver assist device available worldwide.  Called the Biologic DT, it has been cleared by the FDA for use in treating patients with liver failure and patients with drug overdose, including those drugs that result in liver failure.
A single treatment by our device can restore the normal liver function to patients with liver failure due to drug effects.  We believe that this detoxification device could dramatically bolster the safety profile of Rezulin and many other drugs.
The Biologic DT was designed to provide temporary support of patients with acute liver failure.  Unlike renal dialysis, the Biologic DT process is much gentler.  The device is much simpler to operate, and lifelong treatments are unnecessary.
Using a unique sorbin suspension, the Biologic DT acts as a second liver, immediately clearly drug metabolites and numerous liver toxins from a patient's system.  The build-up of these toxins can lead to encephalopathy, coma, and even death.

We have seen the benefits of the Biologic DT even for patients in coma due to liver failure.  There have been patients listed as "do not resuscitate" and patients needing liver transplants whose livers have been brought back to normal function by the Biologic DT liver detoxification process, following serious drug overdose or liver failure from other causes.
Some researchers are even using the device with previously dangerous doses of oncolytics with dramatic positive effects against cancer.
The Biologic DT device has only recently been available beyond trial centers in the U.S.  The Rezulin researchers community, physicians, and patients were not aware of this treatment option for patients developing liver problems after the use of Rezulin.  
Although we have no relationship with the manufacturer of the drug, we are confident that when careful liver function monitoring indicates a patient is progressing to liver failure after the use of Rezulin, our technology should enable a physician to treat such patients and assure that they recover normal liver function.  The benefits of Rezulin could then be provided with much greater safety, confirming the wisdom of the initial drug approval.  
We are eager to work with physicians to prove the ability of this new technology to reverse liver failure in the rare patient developing this complication after the use of Rezulin.

Friends, Rezulin is only one of over 1,100 drugs on the market today that can potentially damage the liver.  In fact, one only needs to look in the family medicine cabinet to find a number of drugs which could result in severe liver failure.  For example, when abused, acetaminophen has the potential to cause serious liver harm, especially when mixed with alcohol, a cautionary note to any young drinkers who think that taking an acetaminophen before going out drinking can avoid a hangover.  This is patently false.
Further information on  the Hemotherapy's Biological DT device and the technology behind it is available.  We thank the FDA for giving us the opportunity to raise this option, and our best wishes to all of the patients and their families.
CHAIRMAN BONE:  Thank you.
The next speaker is Dr. Khan from Hennepin County Medical Center and the University of Minnesota Diabetes Unit, and I understand that Dr. Boyle is here.  So we'll work him in in a little while.
DR. KHAN:  Thank you.

Mr. Chairman, ladies and gentlemen, I thank you for the opportunity to speak for a few minutes in front of you.  I am on the Speakers Bureau for a number of pharmaceutical companies and have served as a consultant and advisor to a number, including Merck, Pfizer, and Parke-Davis, amongst others.
I'm here voluntarily and on my own time and expense and to express my views and experience, again, with patients with diabetes in Minneapolis.
As head of the Department of Endocrinology at Hennepin, where we have some 4,000 patients coming through our program with diabetes, the vast majority of those are patients with Type 2 diabetes.  And like many inner city hospitals in this country, a significant majority of those are people of color or indigent patients from the inner city population.  This population is a population which is considered high risk for many co-morbid conditions, including diseases of the liver from many causes, including alcohol, including drug abuse, et cetera.
And in that patient population with effective screening and effective monitoring, we have treated several hundred patients with Rezulin, and to date have had five patients with an elevated enzyme, and most of those, except for one, has recovered.  The other one has only recently been found to have an elevated enzyme, and we anticipate over time that will also normalize.

My point that I'd like to express today is that death or loss of an organ  for any cause is a disaster both for the patient and for the family.  Patients and their physicians don't choose that, but just like that, patients and their physicians don't choose diabetes.  Of all the thousands of patients that we have in Minneapolis coming to our program with diabetes, none of them chose to get diabetes.
And when we choose to pick a drug or drugs for them, we do that because we have no alternative.  Most of these patients, as has been shown in academic trials have been through other therapies by the time they come to an endocrinology practice and are referred for alternatives as to what are my options, Doctor.
And when we look at those options, we have to balance what is safe for the patient and, on the other side, look at it and say, "If I don't treat this patient, what's going to happen?"

Well, we all know that diabetes is the number one cause of blindness in this country.  It is also the major and probably will soon become the number one cause of kidney failure in this country also, as well as the fact of the number one cause of leg amputation and a major cause of strokes, et cetera.  Patients don't want that either, and as we treat them, what we're actually saying to them is that without treatment this is the outcome, and with treatment here are the possible risks.
And members of this Committee know as well as I, in many cases better than I, that we have to balance those two risks.  My battle with patients with diabetes -- and maybe "battle" is not the appropriate word -- but the challenge that I have  is trying to get them motivated and maintained on their treatment.
Ask any physician how difficult it is to maintain a patient with a chronic disease.  That job is not made easier when we have sensationalized media that presents opinions without scientific fact or in a balanced manner.
What that means is that not only does a very difficult job in the clinical setting become ever harder, but we lose patients to effective therapies, and my request to you as a Committee is to look at the science and the balance of the community's experience with all the products, and the reality is that the U.K. PDS has shown we do not have evidence that one drug can maintain diabetes control.  Perhaps in the long term combinations of therapies can.

And finally, we are not just treating blood sugar.  I think this is getting increasingly discussed in the literature.  We know that diabetes has multiple facets, beta cell dysfunction, insulin resistance, and we in the past have been reasonably successful in the short term affecting beta cell dysfunction.  We've not had the ability to treat peripheral resistance, which probably is the major cause of cardiovascular death, alongside the dyslipidemia, hypertension, and diabetes.
And so to conclude, I would like to request that we take this in a balance view.  Patients do not choose to have diabetes.  We do not choose for them to have complications.
Thank you.
CHAIRMAN BONE:  Thank you, Dr. Khan.
Next we have Dr. Moore from George Washington University, Center for Health Policy Research, and we'll have Dr. Boyle after that, to be followed by Dr. Bautista.
MR. MOORE:  Good morning.  My name is Thomas Moore.  I'm a Fellow in Health Policy at George Washington University.
The views I'm expressing here are entirely my own and do not reflect any institution with which I'm affiliated or providing advice as a consultant.

I am the author of a book called Deadly Medicine.  It is a case study of the worst drug disaster we had in our nation's history in which thousands of heart patients died of cardiac arrest because of antiarrhythmic drugs whose hazards were not fully appreciate.
While the risks and benefits of Rezulin are of quite a different order, there are some surprising similarities to the discussion that is being held today and the discussion that was held before some of the antiarrhythmic agents were first marketed.
An issue is not so much the risks, but how we think about benefits.  In this spectrum here, it seems to me the top items are well known to everybody in this room, and that, of course, the drugs that are at the top of the benefit ladder are among the most important scientific discoveries in the history of medicine.

Let me go straight to the part where my views might seem more controversial.  Drugs that prevent harm, and I would include in this group the cholesterol lowering drugs and the hypertension drugs, I place very much down the ladder of benefits towards the bottom, and why do I say so?  Isn't it important to prevent heart attacks and strokes?  And certainly these drugs have that demonstrated capacity.
The answer is that the benefit rate is very low.  On an annualized basis, the treatment of mild hypertension benefits about four per 1,000 treated per year.  The best cholesterol data looks a little better than that, about six per 1,000 per year in terms of clinical benefit, meaning a heart attack prevented, a stroke prevented or something of that order.
Why is that important to think about in discussing Rezulin?  Because if you are only helping about one-half of one percent per year in terms of a tangible clinical benefit, in terms of making them healthier, then you have to be very sensitive to the risks to which you expose those patients.
At the very bottom of that, below drugs that prevent harm are drugs that we don't know for sure because they haven't been out there long enough and tested for enough years, actually provide the clinical benefit, and we hope through using a surrogate endpoint that they do.

But we've had a lot of experience with surrogate endpoints, and we know we're not always right when we make this gamble.  We have had class after class of drugs where the experts are as deeply committed to their patients as are the specialists in this room, believed that positive antitropes, antiarrhythmic drugs, fibric acid derivatives, nesoldipine and Type 2 diabetes.  In all of these cases there were compelling reasons to believe that there was a benefit.  When the long-term studies were done, excess mortality was seen.
So where does the surrogate endpoint -- and when we are talking about the benefit of Rezulin today, we're saying what surrogate endpoint does it have an effect on.  How does HbA1c stand?
It strikes me that scientifically it is actually quite superior to blood pressure and cholesterol lowering as a surrogate marker because it is involved with fewer and less complex body processes.  So on scientific terms, it strikes me as a strikingly valuable surrogate endpoint.
But when we look at the actual clinical effects of this drug as we have seen and actually tested in clinical trials, the results were extremely limited.

You can see all of the items here which everyone has referred to, the U.K. PDS trial earlier.  The overall risk reduction with the sulfonylureas was a mere 12 percent from a combined endpoint that mainly included reduced incidence of photocoagulation treatments.
When we look at the real hard endpoints for diabetes related disorders, we do not see an effect.
We have metformin, which was very problematical, and in fact, in combination therapy the drug seemed to have excess mortality, a warning flag that should trouble us all.
And in addition, we know the benefits are very, very small here because it took ten years and hundreds of patients to even register a small effect on a combined endpoint.
So when we make decisions about the risks and benefits with drugs, we have to realize that what we're doing is this -- oops, not that way.
(Laughter.)
DR. MOORE:  We're gambling.  We are gambling with people's lives, and if you are going to make this gamble, it seems to me that you need to have a drug that, number one, has a dramatic effect on the surrogate endpoint in question and, number two, that has extremely low risk.
Yes.

Now, where in the spectrum of moving a surrogate endpoint does it appear that Rezulin resides?  And here I think we ought to start the simplest way to look at a drug is its monotherapy trial.  
The Committee did not see this.  This is from the supplemental indication for monotherapy, and these patients were placed on this drug, and the trial commenced.
Now, the important thing to remember is of those 314 patients, a very large number of them had been on a previous therapy, and so these were the benefits that were seen.  In fact, as you can see from the medical review, they never actually achieved the level of glycemic control that they had in preceding therapy.  They actually increased from baseline.
Now, I have some questions about the ringing endorsements of a drug which when given to patients as monotherapy, they got worse.

Now, fortunately, I suppose, for Rezulin there was another small group of patients in this monotherapy trial who had not been on -- previously treated on drugs and in fact were on diet therapy alone.  The results were no better, and in fact, in only one group of 15 patients was a benefit found in HbA1c, a reduction of a little over one percent.
Now, the medical review, I think, says rather eloquently the performance of this drug in monotherapy is extremely weak, and in fact, I find this to be among the weakest evidence in support of an indication of a drug in many, many years of looking at drugs.
The issue really I see in looking through all of the indications is responders, and the problem that I see in this drug is the low response rate.  As you can see, I've picked all three indications, and in most cases, the response rate of the patients is really quite low, best with glyburide here.  That's 400 milligrams.  For the three bar that's the 400 milligram dose, but the fact is in terms of achieving a significant change in this surrogate marker, which we hope will predict a health benefit ten years from now, this is not changing the surrogate marker in a large number of patients.

I'm equally concerned when we look at the patients in whom it does achieve a significant clinical effect.  As you see, when patients do respond, we see a significant weight gain, and I think more analysis -- and I would urge the Committee to ask for a separate analysis from the company of whether or not responders consistently across a whole spectrum have weight gain because if you have a small benefit in terms of reduced complication of diabetes and an increased risk because of obesity, it is once again not clear whether you've done more good than harm.
Finally, let's just look at this drug at its best.  Here is a group of patients where you really do have a significant change in your surrogate marker, minus 1.29, in combination with insulin.  What adverse effects were observed in that very same population?
I've subtracted this from the placebo, but in hopes of making a change in a surrogate marker which might help over many years, we see a lot of individuals have suffered actual harm from the treatment.
My view is this drug simply is not worth the risk.  It has too many problems.  There are safer alternatives, and more effective drugs available, and I agree with the British who have found that the benefits of this drug simply do not outweigh its risks.
Thank you.
CHAIRMAN BONE:  The next speaker will be Dr. Boyle.  I understand that Dr. Boyle is here now.

Thank you.
DR. BOYLE:  Thank you. 
It's an honor to have the opportunity to talk to you this morning and perhaps speak on behalf of people with diabetes from a couple of different levels.
I'm a member of the American Diabetes Association, National Board of Directors, and serve as the Diabetes Care Management Coordinator for 3,500 patients with Type 2 diabetes at the University of New Mexico.
These are the bottom line results from the United Kingdom Prospective Diabetes Study, which has been alluded to several times here this morning, and just dropping the hemoglobin A1c from an average of about 7.9 down to 7.0 reduced any endpoint associated with diabetes.  That's blindness, heart disease, amputations, kidney failure by 12 percent.

It reduced microcirculatory disease by 24 percent, and there was a trend, although not statistically significant, from macrovascular complications to drop by 16 percent, but the p value was .052, but all of this is going in the right direction to suggest that small decrements in glucose concentration lead to enormous changes in the risks associated with this disease in the long run.
Yet one of the sad parts of this trial was that in the initial one to two years shown on the X axis there was a nice decrement in this marker of good glucose control, hemoglobin A1c, that was not then subsequently sustained in the years from two out to ten years on monotherapy, and unfortunately in the United States, this is a particular problem, that people stick with one drug rather than thinking of this as an issue that requires multiple different interventions, and it's led to in the United States a hemoglobin A1c on average of nine and a half percent, which is well above the control group used in the USPDS with diet and exercise alone.
So it is absolutely no wonder to us in the American Diabetes Association and those providing care to people with diabetes in this country that we are spending $140 billion a year taking care of this disease process.  That's four percent of the gross national product of the United States to one single disease.

Let me tell you about the population that I serve.  The 3,500 patients at the University of New Mexico who have Type 2 diabetes are, in large part, people of color.  They are over 50 percent Hispanic, and then we have about a 15 percent Native American population that comprise our population, and half of them are medically indigent.
Over $18 million a year are spent on managing their endstage complications.  They are 14.9 percent of the total population of our university hospital.  This is a growing problem.  It is not six percent of the U.S. population.  It is increasingly becoming a disease that is not affecting people in their 50s and 60s, but instead affecting 20 year olds and now people in their teens in my state.
Let me tell you that in 1994, the conclusion of the diabetes control and complication trials for which we were members, we went out and looked in the general medicine clinic and found that the mean glycosylated hemoglobin in our patient population was 5.6 percentage points above the upper limit of normal.  I'm not proud to say that, but one-third of the patients were within one percentage of the upper limit of normal.

By October and November of 1977, with the advent of metformin in the United States and subsequently earlier in 1997 the addition of troglitazone to our armamentarium, you now seen in green that we've taken the same patient population and have over 50 percent of them at target by using aggressive combinations of all of the available tools, and in this case about 14 percent of the patients overall are taking troglitazone because they failed on metformin plus sulfonylurea.
In January of this year, taking 160 of those charts, randomly selected out of the 3,500 patients, we now have 66 percent of our patients to within the American Diabetes Association goal at less than seven percent.
If you look at the toxicities associated with each one of these medications, you can see that all the common things that we use right now carry with them morbidity and mortality, and in fact, if you look at sulfonylureas on the far left-hand side, it's about one in 30,000 mortality rate as noted in the Clinical Endocrinology and Metabolism Journal.
In the middle, in the first million patients put on metformin in the United States, from the FDA's own data in a letter to the New England Journal, you can see that approximately one in 50,000 people in the country in the first million patients put on this medication, which was a major adjunct to our therapy, one in 50,000 ended up suffering a fatal event.

Finally, with troglitazone in the first 1.5 million patients put on this medication there is about an incidence of one in 60,000 fatal events.  
What's killing these patients?  If you look at 1980, going forward to 1996, you can see this information from the U.S. Center for Health Sciences adapted from a summary from recommendations from a congressionally mandated committee called Diabetes Research Work Groups, that since 1980 there's been a rough 20 percent, 25 percent fall and stroke and cardiovascular disease.  Cancer has stayed roughly steady, while diabetes has increased as a cause of death in the United States by 20 to 30 percent over the same time frame.
So I would ask you as members of this Committee not to be blind to diabetes.  This is a major public health care problem for which we need every tool that we can possibly have at this point.  The relative risks of using this medication are no different than any other, and I would say, based on our evidence from 3,500 patients, which is a small microcosm of society, that this has been a major additional tool for our treatment of patients with Type 2 diabetes.
Thank you.

CHAIRMAN BONE:  Next will be Dr. Jose Louis Bautista from Fresno, California.
DR. BAUTISTA:  I'm Dr. Bautista from Fresno, and I thank you for allowing me to speak.
I'm here to -- I'm also a speaker, and I also do research for multiple drug companies.  I'm here to ask you not to remove Rezulin from the market for the following reasons.  
I'm in charge of over 30,000 lives in my practice.  Almost ten percent of those have diabetes, which is close to 3,000.  I stopped at about 400, the number of patients that I have on Rezulin, and two of them have developed complications.  
One is a lady that was on Rezulin, developed Hepatitis A.  I stopped the Rezulin.  The patient is doing fine now, Rezulin.
The other one was a young man who became an alcoholic after he had family problems, on Rezulin, and I stopped the Rezulin.  He's doing fine.  He's still fighting his problems with his wife.

But what I have seen in the last years is that the Type 2 diabetes patient is not created equal.  He presents or she presents with different stages, and I've been able to develop on my own protocol in my group, based on fasting C peptide and fasting insulin, the first stage I have labeled it a normal secreter which has C peptide of 3.0 to 4.0 with a normal insulin, but had a normal hemoglobin A1c and a normal glucose.
This patient, they failed diet, exercise and weight loss.  I put them on an insulin sensitizer like Rezulin, and they do really well, but when I put them on a sulfonylurea, they become hypoglycemic.
The second stage is a group that becomes ‑- that I label hypersecreter, has a C peptide of greater than four, elevated fasting C peptide, elevated hemoglobin A1c, and also an elevated fasting sugar.  These patients do extremely well with Rezulin, but they do lousy when you put them on the sulfonylurea.  They become hypoglycemic.
The third stage, I have labeled them as a hyposecreter.  They have a C peptide of 2.0, but less than 3.0, has a fasting insulin level less than ten, has elevated hemoglobin A1c, and also a terrible fasting blood sugar.  These patients do really well with sulfonylureas, but they do much better when you do a combination treatment with a sulfonylurea and an insulin sensitizer like Rezulin.

And the final stage is a group that I label the microsecreter, have a fasting C peptide less than 1.9, a fasting insulin level of less than, God, five, and also have an extremely elevated hemoglobin A1c and also elevated fasting blood sugars.  These patients do well with insulin, but they do much better when you do a combination treatment of insulin with Rezulin, an insulin sensitizer.
So in summary, I don't have a perfect protocol, but it's working for me.  But what I have seen is that a Type 2 diabetic patient presents in different stages, and we need to be careful with insulin resistance.
All I know is that in my group I see a lot of insulin resistance.  It seems like in all the four stages we see insulin resistance, and we need a good insulin sensitizer.  I think Rezulin pound by pound is the strongest we have, and therefore, I strongly recommend that you don't remove it from the market.
Thank you.
CHAIRMAN BONE:  Thank you very much, Dr. Bautista.
The next speaker is Dr. Einhorn, who is from the University of California, San Diego.
DR. EINHORN:  Thank you.
CHAIRMAN BONE:  And from Sharp HealthCare, I guess, right?

DR. EINHORN:  Yeah, a few too many words there, I noticed.
Thank you for the opportunity to participate.  It's humbling to follow such articulate colleagues.  I've had to rewrite my talk every four minutes to try to not repeat, but let's see if we can offer something to the group.
I'm Daniel Einhorn, and I've been practicing in San Diego since 1984 with my partners, Eric Gold and Ray Fink, and we felt we have to support this process of trying to look objectively at clinical data in a peer reviewed way rather than any other forum.  I'm not sure we realized how popular this meeting would be, but we wanted to help.
And my remarks are based on our experience with about 1,500 patients using troglitazone by and large with other agents, and this experience will be presented at the annual meeting of the American Association of Clinical Endocrinologists.  So I want to make a few disclaimers.

First, I've come as a private citizen, paying my own way, representing my partners and my patients, but like most of the endocrinologists in this room, we do work with whoever can help us participate in clinical research, Speakers Bureaus, including those for Parke-Davis.
But we really have no vested interest in the outcome of this meeting other than we really need to help resolve the ambiguities about troglitazone because we need to know what to teach and how to practice.
We typically see more seriously affected individuals with Type 2 or they wouldn't come to us.  So by and large, since there's no one wonder drug, we're using agents in combination.
There's no question in our experience that troglitazone has enhanced metabolic control, as you've heard from the others.  Of 1,500 cases, and we did very careful liver and, frankly, kidney monitoring from the outset as we do with any new drug, certainly a new class of drugs, and out of our 1,500, we had to withdraw five from Rezulin.  There were three others where clearly it was other issues that had nothing to do with the drug, but certainly that's a safety profile that seems comparable with anything else that we have used, if not better.

I'm not sure why our numbers look a little better than the numbers looked in the studies.  We actually do have patients that maybe take better care of themselves, perhaps less alcoholism and that sort of things, but still it's been a very safe drug.
Our conclusions really are that we have been part of a kinder and gentler approach to managing our patients with diabetes.  I think the issues of improved metabolic control are clear:  improvement in lifestyle.  The ability to, as you heard from some of the other speakers, to come to meetings, to do the jobs you want to do, to be with your family the way you want to be is extraordinary with combination therapy as compared to how things were before.
Do we worry when we prescribe Rezulin?  Absolutely.  We worry when we prescribe anything, and see that as our job, as clinical endocrinologists, to frankly worry about our patients and to do the monitoring carefully, and I think that's not going to change, and that's not going to change with any class of drugs.
And, frankly, if this hearing today does show us strong evidence that we're dealing with something less safe than others, we'll turn on the dime, but in our experience Rezulin has clearly been safe and effective, has had no more of the risk profile than other agents we've used, and has clearly improved the lives of our patients with Type 2 diabetes.

Thank you.
CHAIRMAN BONE:  Thank you very much.
The next speaker is Dr. William Clark from Houston, Texas.
DR. CLARK:  Thank you.
I'm here for my patients.  I'm also on the Speakers Bureau of several drug companies, but I spent my own money to come here today.
I've had experience treating diabetics for 13 years.  I care about the quality of their lives.
For the first ten years, my experience was that they slowly deteriorated.  Then with the development of Rezulin, I felt that had a chance to slow that down or maybe even improve the qualities of some of their lives, and I have over 500 patients on Rezulin.  I've not had any elevated liver enzymes in any of these.
I'd like to tell you about a couple of my patients.  One is now in his late 60s.  He's published a community newspaper there in Houston for over 30 years.  He's been insulin dependent for eight years.  Four years ago he lost the sight in his right eye, and two years ago his left eye began to fail, and he started trying to sell his newspaper.

We got him started on Rezulin.  The vision in that left eye stabilized.  In Texas, they have, I guess, a place where the newspapers submit their best work every year to see who wins the most awards.  Last month he won the most awards of any newspaper in Texas and the most awards that he's ever won.
I have another patient that I think Rezulin has made a big difference in.  This is a patient who's in his mid-50s, had a large counseling practice in Houston.  Two years ago his younger sister died from complications of diabetes.  A few years before that his mother died from diabetes after having both of her legs amputated.
James had sort of a borderline abnormal GTT, had a post prandial insulin that was usually between 30 and 60, but he felt bad.  The oral agents, the sulfonylureas made him feel worse.  He gave up his radio talk show.  He didn't feel like running a big practice.  He decreased the number of his clients, let his health go, and a year ago started on Rezulin.
Since then, I think after two weeks he said he felt the best he's felt in years.  He's now hired back some of his counselors.  He's negotiating to start his radio talk show again.

And I don't know.  I've seen in the 500 patients a lot of examples like this.  I feel asking people to treat diabetes now without Rezulin would be like asking a coach to win a track meet after cutting off a leg of all of his athletes.
I think if you notice here today none of the people that are treating diabetes have advocated pulling this drug off the market.
Thank you.
CHAIRMAN BONE:  Thank you, Dr. Clark.
The next speaker is Dr. Vincent Pearson from Johns Hopkins Hospital.
DR. PEARSON:  Thank you, Mr. Chairman.
Good morning, ladies and gentlemen.  I come to you as a pharmacist, as a clinical coordinator of drug information at the Johns Hopkins Hospital in Baltimore. 
I have received research support from both Bristol-Myers Squibb and Pfizer, but the views I'm going to express are purely my own based upon my experience.
My charge as a drug information pharmacist is to review information about drugs and drug products as they are released in the market, and especially when they come before our hospital's Pharmacy and Therapeutics Committee for review and consideration to be included onto our formulary.

When troglitazone was first introduced over a year ago, I was very impressed with the published data that was surrounding the product.  However, we were all acutely aware of the liver toxicity that was associated with the product.  Therefore, the committee, in its wisdom, opted to table a decision on the drug.
We still have yet to bring this to closure.  Why?  Because myself and several other people on our faculty have tried as best we could to get our arms around the scope and the depth of the liver toxicity issue, unfortunately to no success.
In our minds, there are several key issues that I would like to leave before this Committee this morning.
First, we must get a true handle on the numbers of deaths that have been at least associated with the drug and get as strong a collection of that number as it can be.

Second, we must take that number and from that ask ourselves which of those deaths are truly due to the drug's playing a significant role, my personal definition of the word "significant" being a large enough and broad enough role such that in the absence of any other confounding factors this drug can truly be said to be at least a causative factor.
Once you've taken that number, the next charge is to put that number over a denominator that consists of the number of patients who have received the drug and have done well on the product.
I'll admit my bias is towards the in-patient population.  So most of my experience comes from those patients who have had adverse reactions due to the drug.  My charge is to monitor the adverse drug reaction monitoring system as mandated by the Joint Commission of Accreditation of Hospital Organizations in our hospital.
Lastly, I would ask that once you have looked at that numerator of deaths that are truly significantly due to the drug versus the denominator of people who have gotten the drug and have done well, we must ask ourselves:  are we comfortable with this ratio?
If we are comfortable with this ratio, then the drug deserves to remain on the market.  However, if we are not comfortable with this ration and can truly feel that we can do better with drugs that are either currently available or are coming through the pipeline, then the drug deserves serious consideration from being pulled from the market.

I will leave as my parting shot one last thing that we haven't talked about this morning.  As a practicing pharmacist, we are charged with filling medication orders for many different prescribers.  One of our common problems is not having the correct information to field questions from prescribers regarding the status of drug products.  
Therefore, I would ask that when we finally reach a decision regarding this drug, that the information upon which that decision was based is made readily available to most practicing pharmacists.  Thus, if a pharmacist gets the question from a prescriber what became of troglitazone, the pharmacist can confidently go back and say, "This is what happened to true troglitazone, and this is the reason why it happened."
Thank all of you for your attention.
CHAIRMAN BONE:  Thank you very much.
This concludes the regular open public hearing section.
We have now remarks by Dr. Sidney Wolfe, Director of the Public Citizens Health Research Group.
DR. WOLFE:  Thank you.

The last time I appeared before this Advisory Committee concerning a diabetes drug was 22 years ago.  The drug was phenformin, also said to have a unique mechanism of action and whose withdrawal from the market was strongly opposed by many diabetes experts.  Like troglitazone, it also had a unique type of toxicity, lactic acidosis, fatal in about 50 percent of those patients who developed the abnormality.
After a lawsuit against the FDA by our organization, it was banned as an imminent hazard to the public health in 1977.  By then hundreds of patients had died as a result of this drug.
I'm going to talk first about some case reports concerning this drug and then some incidence discussion of the problems.
John Doe was an otherwise healthy 45 year old Washington, D.C. policeman started on Rezulin in the late summer of 1998, preceded by perfectly normal liver texts.  Within a week after starting the drug, well before he was due for another liver test, he became seriously ill, was hospitalized at Johns Hopkins with acute liver failure, ALT and AST of around 3,000 or 70 times higher than the upper limit of normal; had a consultation for a possible liver transplant.

After a week in the hospital, he turned out to be one of the few lucky patients with drug induced liver failure who neither died nor required a transplant.
Because of the incompleteness of the spontaneously reported adverse reaction data currently made available to the public by FDA, it's difficult to accurately count even the reported number of deaths or injuries caused by Rezulin or any other drug.  This is because individual adverse reaction reports don't have a unique numerical patient identifier which would allow several reports to be determined to be just follow-ups on the same patient.
As a result, it's possible to over match these reports and under count, assuming what are actually several different patients appear to be the same or the reverse.  The fault lies with the cumbersome and difficult to use format FDA is now using to supply data to the public.
Compounding this uncertainty is the widely agreed upon under reporting which may result in as few as ten percent or even one percent of cases which actually occur being reported to FDA.

With these caveats in mind, our estimates of liver deaths from Rezulin up through the beginning of February of '99, with the help of former  FDA pharmacologist Elizabeth Barbaham and Dr. Larry Sasich on our staff, who did a lot of these analyses, 43 deaths, including American and Japanese cases, from liver toxicity from this drug.
Although Warner-Lambert has stated there have been no new liver deaths since the July relabeling, this statement appears to be clearly false.
In addition to the deaths, there are several additional cases of American patients who had liver transplants and survived, making an estimated 45 to 50 cases of liver failure, deaths and transplants apparently caused by Rezulin.  An estimated additional 60 or more patients who neither died nor had liver transplants were hospitalized in whom there is evidence of liver damage.
By June 5th of 1998, according to a February 19th, 1999, several weeks ago, letter published in the Annals of Internal Medicine by FDA endocrinologist Dr. Robert Misbin, quote, FDA had received 560 reports of troglitazone associated hepatotoxicity.

Now just a little brief discussion of incidence.  The best and possibly only source of information concerning the incidence of liver damage from Rezulin comes from the company's own 2,510 patient randomized clinical trials prior to approval.  Of these 2,510 patients, 48, or 1.9 percent as Dr. Bilstad mentioned before, had abnormal liver tests of three times or greater of the upper limit of normal, which is 40 as opposed to .6 percent getting placebo having this much elevation.
Treatment was discontinued in 20 of these patients because of the tests, but in none of the patients getting placebo.  Two were jaundiced; two had liver biopsy.    In 18 of the 20 cases, the patients were described as having, quote, liver injury, end quote, of a hepatocellular type.  
Although information about the 1.9 percent of patients with liver test abnormalities is mentioned in the FDA approved label for the drug, the following subgroup analysis is not.  Ten of the 2,510 patients, or one out of 250, had an enzyme elevation of more than ten times the upper limit of normal, in other words, greater than 400, and five of these had enzyme elevations of more than 20 times normal, or greater than 800.

I would estimate that even if one-fifth of these patients in the real world with the highest enzyme elevations, most of whom are not being adequately monitored as I'll discuss in a minute, instead continue on the drug because it is not known they're developing a toxic reaction, there may be as many as one out of 2,500 could possibly develop hepatic failure, fatal or requiring transplants in most cases unless the device which we heard about is better than I'm skeptically thinking it is.
(Laughter.)
DR. WOLFE:  The real world of medical practice is unlike the artificially vigilant circumstances of the clinical trial where the drug was immediately discontinued in those with the worst abnormalities, more than 20 times normal, because of the close monitoring, and all recovered.
Although this clear evidence of Rezulin hepatotoxicity was known to the company prior to marketing and was eventually published a year ago in the New England Journal, it was not discussed at the December 1996 FDA Advisory Committee meeting in which there was a unanimous recommendation to approve the drug.

In addition, briefing materials handed out by Warner-Lambert to members of the Committee were dismissive of liver toxicity, claiming in those studies reviewed, not all of the 2,510 patients at that point, that the incidence of elevations of liver tests above normal, quote, was lower for troglitazone than for placebo, end quote, page 90 of the handout, and the text concluded that, quote, elevations meeting threshold criteria for clinically important changes, more than three times normal, occurred at a similar incidence in both groups, troglitazone/placebo.
Given the findings described in the published article about the one out of 500 patients in the randomized trials who developed severely abnormal liver tests, greater than 20 times above normal, and liver damage demands explanation why no requirements to do liver tests was made in Rezulin's initial labeling and why such recommendations were to wait until it had been on the market for seven months and many people were already starting to die of predictable liver failure.
Evidence of serious noncompliance with liver tests.  We have obtained data on the prescribing patterns and liver functions, AST, from an academic teaching hospital and medical center.  Actual testing was compared to the amount of testing required by the label at the time Rezulin was first prescribed for each patient.

There were a total of 160 patients prescribed Rezulin through the beginning of March 1999.  Of these, 69 were first prescribed the drug prior to the first relabeling in late October of '97 and so were not subject to any testing requirement when they began using the drug.
Of the remaining 91, only 36, or 40 percent, had even a baseline liver function test.  Among the 40 patients prescribed the drug after the third and most recent relabeling, it was still 40 percent.  Only 40 percent had a baseline test.
I notice there's a little improvement in the data that was just handed out that the FDA is going to present, but it is still pretty pitiful.
At the time of the first relabeling, liver function test -- late October -- was recommended three times in the first month.  Then it was escalated to the point where in the first six months it's now recommended seven times.
To repeat, the overall compliance with the baseline testing requirement was dangerously inadequate, only 40 percent of 91 patients who were started on the drug after liver testing was added to the label getting a baseline test.

Only one of 26 patients, or four percent, who were taking the drug for at least six months or more  after the liver testing requirements went into effect were in full compliance with the requirements for testing after baseline.  
A necessary precondition for a labeling requirement to reduce toxicity is that the labeling requirement must be adhered to.  This has clearly not been the case.  The same lack of compliance with labeling was seen with Duract, also an hepatotoxic drug, and Posicor, leading to their withdrawal from the market.
Cardiac toxicity.  In a September 1997 memo from FDA Diabetes Group Leader Dr. Alex Fleming, there's a section entitled "Troglitazone Continues to Carry Concerns About Fluid Distribution Among Body Tissues and Cardiotoxicity."
It states, quote, troglitazone is a member of a class of compounds that have been associated with cardiac toxicity.  In Study 032, 15 patients, or four percent, on troglitazone as opposed to none of placebo developed peripheral edema.  One patient on the drug developed pulmonary edema, which is evidence of heart failure.  It is hard to believe that patients with cardiac, liver, or renal disease would not be adversely affected by the drug, end quote.

In reviewing the spontaneous adverse reaction reports filed with the FDA, we found a total of about 50 patients with heart failure, including six patients who died with heart failure who were taking the drug.
Evidence that others have decided Rezulin is not necessary.  Dr. Joseph Lowenstein is an endocrinologist for years at Case Western Reserve University School of Medicine and Meridia Hospital, and now Professor of Medicine at the School of Medicine at Texas Tech Health Sciences Center.  He was a member of your Endocrine and Metabolic Advisory Committee from 1980 to 1984 and Chairman of your Committee from '82 to '84.

In response to my question to him about troglitazone, he replied on March 11th, a copy is attached, quote, "You asked me if the removal of troglitazone from the market would impair my ability to provide good care for diabetic patients.  My answer is unequivocally, no, it would not.  I see a large number of diabetic patients in our faculty and resident clinics, and I have not seen a single patient in whom I thought troglitazone was essential.  While troglitazone appears to increase tissue sensitivity in insulin, the published data fail to convince me that its benefits outweigh its risks of fatal liver toxicity.  For this reason I do not prescribe the drug, and when I see a new patient who is already taking it, I discontinue it."
Dr. Lowenstein is hardly alone.  Group Health Cooperative of Puget Sound in Seattle, one of the largest HMOs in the country, with 450,000 patients and 575 physicians, also decided that Rezulin is not necessary for the practice of good medicine and have never had it on their formulary.
To their credit, they also never put the three recently banned drugs, Redux, Posicor, and Duract, on their formulary, thus sparing the patients in their consumer run cooperative of a large number of serious adverse reactions.
In other countries, such as all of the European Union, diabetes patients are all cared for without the use of Rezulin, as it has never been on the market in the rest of Europe and was taken off the market in the U.K. in December of '97 by Glaxo Wellcome, its manufacturer there, because of an opinion strongly shared by the British government that its risks outweighed its benefits.
Although Glaxo has now changed its mind, the British government has not and this week rejected Glaxo's efforts to reintroduce the drug in the U.K.

In our petition to the FDA in July of 1998 to take troglitazone off the market because of hepatotoxicity, we stated, quote, "How many more Americans will have to die or require liver transplants before Parke-Davis and the FDA take action to protect people in this country by banning the drug?" end quote.
It is clear one and one-half years after the label first recommended liver test monitoring that most patients are not getting the recommended number of tests or even the baseline test.  It is time for the United States to join with the overwhelming proportion of countries where the drug is not on the market and protect American patients from a drug with no evidence of a long-term benefit in mortality, as mentioned before by Thomas Moore, and clear evidence of relatively short-term increased risk of death from liver toxicity.
I point out that a lot of patients who are started on the drug don't stay on it for a long time because it doesn't work that well or, in combination with insulin, causes more hypoglycemia, not less, and therefore, they are getting risks without any benefits.

It is clear that the, quote, label remedy, end quote, is not effective for those drugs which are inherently too dangerous to remain on the market, such as Duract, Posicor, and Rezulin.  Every additional month on the market for Rezulin means longer duration of therapy for hundreds of thousands of patients with concomitant increased risk of liver damage and possible death or the need for transplantation because of liver failure.
Thank you.
CHAIRMAN BONE:  Thank you, Dr. Wolfe.
The next speaker will be Dr. Stephen Clement from the American Diabetes Association.
DR. CLEMENT:  Good morning, distinguished panel.  
My name is Stephen Clement.  I'm an endocrinologist at Georgetown University Medical Center here in Washington, D.C.  I'm here today as an official spokesperson of the American Diabetes Association.
I am pleased to be here to present the American Diabetes Association's point of view regarding the use of Rezulin for the treatment of Type 2 diabetes.

I think all of you understand the seriousness of Type 2 diabetes and the enormous challenges it poses for the health of Americans and the American health care system.
I think all of you know the economic impact this disease has and its growing prevalence.  We saw slides of that earlier, and I'm sure you will appreciate the statement made by the Centers of Disease Control and Prevention that diabetes is the epidemic of our time.
Last, I hope all of you know or at least appreciate the fact that relatively few people with diabetes in this country have levels of glycemic control that are equal to or even approach normal glycemia, and we saw some of those slides earlier as well.
Since we now know based on the diabetes control and complications trial and the U.K. prospective diabetes study that glycemic control is related to the likelihood of developing complications of diabetes, it comes as no surprise to health care professionals who must work very hard to help patients achieve the best glycemic control they can.

Many factors influence the ability of a patient to achieve good glycemic control.  Today all of us are here to talk about pharmacotherapy.  In this regard, the American Diabetes Association's comments will address two questions.
First, how valuable is Rezulin in achieving glycemic control?
And, second, how should the FDA approach the approval and review process of a drug that is first in its class?
First, how valuable is Rezulin?  One answer is to look at the impressive rise in the use of the product since its introduction just a short time ago.  Certainly effective sales and marketing have influenced the results seen, but in addition, Rezulin is a drug whose mechanism of action is not shared by any other approved glucose lowering agent, and because of that fact it has afforded health care professionals an important advance in pharmacotherapy.
As a practicing endocrinologist, I often face the fact that the present panel of available medications, including Rezulin, cannot adequately control a patient's blood glucose level.  As with the other endocrinologists who presented, I find that for patients who are unable to achieve good glycemic control on other medications or combinations of medications, the use of Rezulin often has a dramatic benefit.

This benefit can be sustained over time, as well.  Therefore, I have always appreciated and greatly valued having available many drugs, each acting in different ways to lower blood glucose.
To that end the American Diabetes Association believes that Rezulin has been a very useful drug for many patients, and its unique mechanism of action has been valuable for countless individuals who for many reasons cannot achieve good glycemic control with the other drugs available.  Thus, Rezulin is clearly the major benefit to a great number of patients.
Of course, the benefits of Rezulin must be weighed against its risk, and like all other drugs, we know there are risks with taking Rezulin.  The American Diabetes Association cannot speak objectively or quantitatively about the risk or Rezulin, nor can we speak about the extent to which monitoring of liver tests has decreased adverse events.  We do not collect or review such data.
We do, however, respect and support the FDA's review process, and we have the utmost confidence in its ability to weigh the evidence and decide appropriately whether the benefits or Rezulin outweigh these risks.

The topic of benefit versus risk brings me to answer the second and last question which I said I would address, that is, how should the FDA approach the approval and review process of a drug that is first in its class.
Of course, one could answer that question in many ways.  For example, the rigor of the review process could be different.  Less or more data could be required.  The bar of effectiveness could be changed.
Through all of these possibilities, the American Diabetes Association would say that no change is warranted.  The approach used now is appropriate and effective.
On the other hand, given the difficulty in effectively treating diabetes and given the shortcomings of all other therapeutic options, the FDA should also factor those variables into the benefit side of the ledger in weighing whether to approve a drug that is first in its class.
In other words, not only is absolute clinical effectiveness of importance, but some consideration on the benefit side should be given to a drug that represents a novel way to treat an intractable disease.

Conversely, if a drug does not have a novel mechanism of action, a risk-benefit analysis may well lead to a different conclusion.  Thus, we believe there cannot be a single risk-benefit ratio at which a drug is approved or not approved or removed from the market.  Other factors, such as uniqueness and the benefit of its mechanism of action, must also be taken into consideration.
With regard to Rezulin, we know that this drug is unique, and it's clearly invaluable for many patients.  Those facts must be taken into consideration.  How many deaths due to this drug diminish this benefit?
The American Diabetes Association cannot answer this question or express an opinion because we do not have all the facts.  We trust this distinguished panel and the FDA to make these decisions.
In summary, we can say that diabetes is serious.  We can say that Rezulin is uniquely effective, and we know that Rezulin carries a risk of serious adverse events.  Today the benefits of Rezulin may outweigh its risks given the other therapies that are available.

In the days to come, our knowledge about the type of physiology of diabetes and its complications will change, and new therapies and new drugs will become available.  At that time, the FDA may need to reassess the benefits of Rezulin, as it should all drugs previously approved to treat diabetes, and the American Diabetes Association has confidence that the FDA has the experience, ability, and proven track record to make these decisions.
Thank you very much.
CHAIRMAN BONE:  Thank you, Dr. Clement.
Well, we are doing very well, I want everyone to know, and thank you to all.  We came quite close to the scheduled time.
The next presentation will be by Dr. David Graham of the FDA Office of Postmarketing Drug Risk Assessment.
DR. GRAHAM:  I have to wait for Proxima to get started.  We knew they shouldn't have turned it off.
CHAIRMAN BONE:  We're going to have to speak to the devices people about which projector they approved.
(Laughter.)
DR. GRAHAM:  Parke-Davis can vouch for the difficulties we've had with Proximas.

CHAIRMAN BONE:  Can we do something about this light?  This is shining directly in the eyes of several of the panelists, and I hope something can be arranged so that it won't do that.  Thank you.
(Laughter.)
CHAIRMAN BONE:  Dr. Graham is always illuminating and probably doesn't need to be shiny.
DR. GRAHAM:  Lanh, will we be airborne shortly?
I hope that this technical glitch won't count against my time, Chairman.
CHAIRMAN BONE:  I once hear that any truly innovative technology has the appearance of magic, and I wonder if we could have a spell here to make this work.
(Pause in proceedings.)
CHAIRMAN BONE:  You know, here's what we're going to do.  We're going to eliminate the break that was scheduled for after Dr. Graham's talk unless this is ready immediately and take it now.
We'll be returning.  I have 9:50.  We're going to start up no later than 10:05, and I really mean start.
(Whereupon, the foregoing matter went off the record at 9:50 a.m. and went back on the record at 10:04 a.m.)

CHAIRMAN BONE:  Will all the members of the Committee, the FDA staff, and the audience please take their seats immediately?  We're ready to start.
The next presentation will be made by Dr. David Graham of the FDA Office of Postmarketing Drug Risk Assessment, whose technology is now working for him rather than against him.
DR. GRAHAM:  Is it all right to begin?
CHAIRMAN BONE:  Please, go ahead.
The audience will please either take their seats or leave.  Okay?  We can't have the speaker, the presentation interrupted by this milling about.  So please sit down and listen to Dr. Graham.
Thank you very much.
DR. GRAHAM:  Good morning.  Thank you, Dr. Bone.
My name is David Graham, and the slide that you see here is an imagine of Jan Vermeer's view of Delpht, and it's here to remind members of the Committee that what follows represents our view, the FDA's view, of the scientific data we have available on the risks of hepatotoxicity with troglitazone.

So I'll provide first some background information on acute liver failure.  This slide shows the classification system we use to classify case reports of liver failure reported to the FDA.  This classification system is based on the length of time that it takes a patient to go from the appearance of jaundice to the onset of encephalopathy, which is the defining characteristic of acute liver failure.
All of these acute, hyper acute, acute, and sub-acute, are all part of the syndrome of acute liver failure, but they are substratified by  the time it takes a patient to become encephalopathic.  The hyper acute is very quick, within seven days; the acute within four weeks; and then the sub-acute going out to 84 days.
It's important to understand that overall, about ten percent of all acute liver failure in the United States is due to drugs other than acetaminophen, which itself causes about 15 percent of all acute liver failure.  About 70 percent of acute liver failure is caused by hepatitis viruses.  
The mortality rate associated with viral acute liver failure is about 40 to 60 percent.  The mortality rate associated with drug induced acute liver failure is about 90 percent.

The clinical features of acute liver failure are characterized by the development of coagulopathy, multi-organ failure, and sepsis.  Each of these is caused by the acute liver failure and is not a cause of the acute liver failure.
Next slide, please.  Oops, if you could go back -- I'm sorry -- to the previous slide.
This slide summarizes information from five U.S. transplant centers in the modern era, giving information on basically what is the outcome of patients who are diagnosed with acute liver failure, and what we see is about 75 percent of patients with acute liver failure, if you take either die or transplant; if you take these two numbers and this number and add them together; about a quarter of patients manage to survive their acute liver failure without a transplant.
So that means that there are patients who do recover spontaneously.  These are usually patients with lower degrees of encephalopathy.
Next slide, please.
It's also important at this point to talk about acute liver failure in diabetes.  The question is:  does diabetes account for the reports of acute liver failure we've seen with troglitazone? 

This slide is to emphasize that there is no evidence to associate diabetes with the development of acute liver failure.  There is a small ecologic association with chronic liver disease.  This is suggested by the national hospital discharge summary, which suggests the relative risk of about 1.3.  So that would be about a 30 percent increase in the occurrence of chronic liver disease.
However, there are lots of problems with this estimate.  It is confounded by alcohol.  Alcohol causes liver disease.  Alcohol is also associated with diabetes.
Now, from the United Network on Organ Sharing, we obtained data on the prevalence of diabetes in patients who are registered for acute liver transplantation.  Now, these data were facilitated by D.W. Chen and his folks at Division of Transplantation in  HRSA.
From that data, we learn that about 4.8 percent of patients who are registered for liver transplantation in the United States over the years 1995 through 1998 had diabetes.  That prevalence is no different than that seen in the general population matched for age, gender, and race.
So from that data we conclude that there's no association between diabetes and being sick enough with acute liver failure and lucky enough to be registered for a liver transplantation.

However, if you review the literature on acute liver failure, you will find that in none of these is there any association made with development of acute liver failure and diabetes.  So from this we conclude that there is no support in the literature or in available data to implicate that the cases of liver failure seen with troglitazone patients is the result of their diabetes.
We'll now discuss how troglitazone is used in the U.S. population.  This first slide is from IMS Health Data, their national prescription audit, and it shows the monthly prescriptions of troglitazone in the United States from the time of marketing in March of 1997 through December of 1998, and what we see is that there was a steady increase in prescribing up through late '97 and then a sort of a leveling off, if you will, of prescriptions.  These are monthly prescriptions now.
Total prescriptions to date are about 7.9 million, and we estimate that about 1.23 million patients have been treated with troglitazone in the United States.
Next slide, please.

These data come from IMS Health's national disease and therapeutic index, and it describes the characteristics of patients treated with troglitazone.  What we learn is that about 43 percent of use is in women.  So the majority of troglitazone use is in men.
The mean age of a patient receiving their first troglitazone prescription is 61.  If you look at the age distribution of how troglitazone is used, about 90 percent of its use is in patients 45 years or older, which corresponds pretty roughly with the demography of Type 2 diabetes.
Next slide, please.
This slide comes from data from United Health Care, which is a large health insurance management plan with which FDA has a cooperative agreement arrangement that allows us to do research in the real world, in real populations, of how drugs are used and what the health consequences and effects of those drugs are.

This study is based on 9,400 patients treated with troglitazone since it came on the market in this database that covers 3.5 million lives in the United States over a geographic distribution of nine states, and what we see is that the number of patients who use troglitazone long term, if you were to take a cross-sectional snapshot December 31st of 1998, that very few patients have continued troglitazone for a long time.  Most of the use of troglitazone is limited to patients who have been on the drug for only a few months.
This slide is shown by number of prescriptions filled.  It turns out that the average prescription length is 31 days.  So there's very tight correlation, and this is basically one month, two months, up through two years.
And what we see here is that if you go out to this, this is the one-year mark.  This next line here is 13 months.  Less than 16 percent of patients have been on troglitazone for more than a year, and that's very important for what will follow.
If we could go to the next slide, please.
Okay.  We will now discuss the cases reported to the FDA of acute liver failure and other serious hepatic injury with troglitazone.  We'll begin with a few definitional slides so that the Committee will be oriented to the approach that we took.

We used the classification scheme of O'Grady published in The Lancet in 1993 of acute liver failure, which we showed in an earlier slide.  We measured the interval from the onset of jaundice to encephalopathy, transplant or death as one of the metrics that we use for classifying cases into a category of hyper acute, acute, or sub-acute.
If the timing of jaundice was unknown, we used the time of onset of other symptoms suggested by hepatitis, or if those weren't present in the report, the date when they stopped troglitazone use as a marker for that onset of jaundice.
Next slide, please.
We also classified cases as probable or possible or less likely.  We based our analyses on those cases that we classified as probable or possible.  These classifications were based on the presence or absence of other potential etiologic factors.
All cases that we classified as probable we believed had an overwhelming evidence that troglitazone was responsible and not other potential factors.

Two of the concepts that are necessary to understand.  One is the concept of rapid riser and the other is the unknown riser.  A rapid riser is a patient in whom irreversible acute liver failure developed within 37 days of a previous normal test result.  We came up with 37 days because we had the monthly monitoring interval that's been proposed in the labeling, and data on compliance with monitoring that we will present in a few minutes, we used an operational definition of plus or minus seven days of that 30-day interval.
So plus seven days added to 30 would bring us up to 37 days as the time period of a monitoring interval under current recommended guidelines.  So rapid riser is somebody who has a normal enzyme level, and then within that period of time goes from normal to irreversible liver failure.
An unknown riser is a patient in whom the time course of the development of abnormal liver enzymes is unknown simply because monitoring was not being performed.
Next slide, please.
This is an overview of the 43 cases of acute liver failure and the 81 cases of hepatitis that have been reported to the Food and Drug Administration.  Of the 43 cases of acute liver failure, 38 of them were probably caused by troglitazone.  This is nearly 90 percent.

In the sponsor's briefing document, they mention a number of potential confounding factors that they believe may make these cases too complicated to input causality.  If the Committee desires during the question period, we can discuss this.  However, we believe in our judgment and in the judgment of a three to four member panel of FDA reviewers that in every probable case troglitazone appeared to be responsible and other factors played either no role or were of a minor contributory nature.
Next slide, please.
In these 43 cases, we show the outcome in this slide.  About 13 percent of patients survived without requiring liver transplantation.  The remaining patients required transplantation or died.  We had 70 percent of the patient population in this review died from their disease.
This survival rate of 12 percent without transplant is very consistent with the data I presented earlier on the natural history of acute liver failure.  If you recall on that slide, however, the overall survival rate for acute liver failure is about 25 percent, but that's taking acute liver failure of all comers.

We're dealing with a subset of that, which is drug induced liver failure, which carries a higher mortality rate and so would be expected to have a lower survival rate.  If you recall, the literature suggests that the mortality rate from drug induced acute liver failure is about 90 percent.  That would translate to ten percent survival rate without transplant, which is very close to what we find in our case material.
Next slide, please.
The important message of this slide is that about 75 percent of cases have an extremely rapid time course of onset and progression of this disease, and what's also important to recognize is that for most of these patients jaundice is the first indication that they're in trouble, and by then the horse is out of the barn.
Next slide, please.
The patient characteristics in the 43 cases were that 70 percent of them were women.  If you recall from the NDTI data, about 43 percent of use is in women.  So this is a possible risk factor, gender.  It's the only hint of a risk factor that we found in all of our analyses.  The mean age was 63, which is very close, virtually identical to the mean age of somebody who starts troglitazone, 61. 

The duration of therapy, on average, was about four months, and you see the range here.  We had cases reported at every dose level.  We also had cases reported with monotherapy.  The number of cases at monotherapy was about 20 percent of our total cases, and the risk looking -- there was no way to say that looking at the proportion of cases caused -- in patients with monotherapy against those who were on combined therapy, there's no apparent difference.  In other words, we don't believe that other treatments that patients are receiving for their diabetes in addition to troglitazone are responsible for the acute liver failure.  It's the troglitazone, not the other drugs.
A couple other things just to point out on the previous slide.  Jaundice is the first symptom at 62 percent, but by the time people come and present, 90 percent of them are jaundiced.  So there are patients who might develop other symptoms of nausea, vomiting, or abdominal pain or malaise, symptoms of hepatitis, who within a short period of time generally then go on to develop jaundice, and that's when they present to the doctor, when the jaundice comes, and 90 percent of them have jaundice at that time.
And as we said before, it's a very quick time from jaundice to encephalopathy.
Next slide, please.

This slide just summarizes for the Committee the initial presenting indication of liver injury in the 43 cases of liver failure.  Most were jaundice.  Other symptoms of hepatitis were found in 24 percent.
In 14 percent there were transaminase abnormalities.  They were otherwise asymptomatic.  In six we don't know what the first indication of liver injury was.  
Okay.  This slide needs to be focused on paying attention to each bar separately so that they don't relate to each other.  Each represents a separate category and a separate idea that I'm trying to communicate.
For a baseline testing among these cases, about 45 percent, 46 percent of the cases, 20 out of 43, had some time of baseline test done, but we were very generous in our definition of a baseline test.  Basically if the report said that in the last year or so some test had been done, we considered that baseline. 
In the data that I'll show later, our enzyme monitoring study, that is not a definition that we viewed as appropriate for baseline testing.

Monthly testing, there were seven cases out of the 43 where there was some evidence of monthly testing being done, but this is an inflated number for the following reasons.  It includes one patient from an NIH controlled clinical trial that by protocol was required to have liver enzyme monitoring.  So you subtract that one out.
Then there were three other cases that were from more general populational sources where monitoring was being done more or less, but there were gaps and breaks in it.  So they were not fully compliant. 
Only three cases, about 15 percent of what's been reported to us, had full compliance with monitoring.  
Twenty-one percent of our cases, nine, had what we define as the rapid rise in liver enzymes.  This is people who had normal enzymes and within a month of that presented with irreversible acute liver failure, and then for the bulk of patients, we have no idea what the course of enzyme elevation was.
Next slide, please.
This slide is intended to give the Committee an appreciation for what we mean by a rapid riser.  What we show here are the liver enzyme levels and functions and the date when different things happened.

And you can see this patient had a baseline test done on February 5th of '98, an ALT of 20.  They started troglitazone a few days later.  No monitoring was done until August.  In August they had normal testing.  The patient went on a vacation, experienced some nausea, had some liver tests done at a hospital.  I believe it was in Italy.  The alkaline phosphatase was 93.  The bilirubin was .6.  The patient came back to the States.  Five days later, still on troglitazone, became jaundice, presented at the hospital in acute liver failure.  This patient became encephalopathic, required liver transplantation, and died.
The time from this normal enzyme to this point of irreversibility was 15 days.  It's possible that irreversibility actually occurred within five days.
Next slide, please.
This slide is intended to show the time course in an unknown riser.  This is the majority of the patients the case material that we have in hand.  The format of the slide is identical to the previous.
This patient began troglitazone on December 1st of '97.  Two days later they had a baseline test done.  The ALT was called normal.  We discovered that the value was 11.

Additional monitoring wasn't done.  March 1st the patient became anorexic, presented to their doctor a few days later.  The doctor got enzymes, said 252, a little touch of drug induced hepatitis here, six times the upper limit of normal.  We'll follow the label.  We'll stop the drug.  The drug is stopped.
But the process was already irreversible.  Within three weeks this patient returns with jaundice, an ALT of 1,400.  Two weeks after that the patient is Stage 3 coma, and three days after that a liver transplant.
Next slide, please.
This slide summarized a number of observations that impressed me in reading over the case reports that we had.  I was struck by the fact that many patients had long prescriptions, and what this allowed to happen was for patients to continue on the drug and not come back to their doctors to have monitoring performed.
It also allowed doctors to sort of basically forget about these patients and not realize that, oh, that patient is still on the drug.  So that was one problem area that I saw in these cases.

Another one is that there is, in general, in the real world a time lag between when a patient presents and has the blood test drawn, when those results are determined, and then when those results get communicated to the doctor and then to the patient.  There's a built in time lag.
Now, that time lag might be as short as a day.  It might be as long as a week, and I can't say because we have no evidence that if the time lag were instantaneous that it would make any difference, but the fact is that we have to recognize that there is a time lag, and it's built into the way health care is delivered in the United States.
Another observation was that for most of the patients when they present jaundiced they have enough intelligence to stop the drug.  However, there were patients who developed nausea or vomiting or a little bit of abdominal pain and who continued on the drug after the onset of those symptoms.  In our previous slide, you see how many patients that was.

This can be compounded by lack of physician awareness of the hepatotoxic risks of troglitazone, and we have one case of acute liver failure in which the patient was on the drug for several months and developed a little bit of nausea and a little bit of abdominal pain.  They went to the emergency room to be seen.  This is in April of 1998.  So it's after three "Dear Doctor" letters and all this other stuff  saying troglitazone/liver failure, do liver monitoring.
This patient presents to the emergency room with symptoms of hepatitis.  She gets sent home with a diagnosis of a viral illness, continues on her troglitazone, no liver enzymes were done.  She comes back to the hospital two weeks later with liver failure.
And then finally, a fractionation of patient care that we have patients who were seen by multiple doctors who are managing different aspects of the patient's medical conditions, and this leads to sort of breakdowns in the system.  People drop the baton.  One person gets the test.  They don't send the result to the other person, and the patient can continue on the drug with abnormal liver enzymes.
The next slide, please.
In this slide, I want to focus now on the issue of enzyme monitoring and rapid risers and is liver failure predictable or preventable.  We had data on the time course of enzyme changes for 12 patients.  In nine of these 12 cases with enzyme data, 75 percent, the transition from normal to irreversibility occurred within a range of four to 34 days.

For most, the time course of liver enzyme change is unknown.  The question is:  are these people with the unknown time course, are they rapid risers or are they slow risers?  Can we prevent it or is it pretty much unpreventable?
Would they be prevented by the current monitoring or by more frequent monitoring, say, weekly monitoring?
We don't know the answer to any of these questions.  We compared the group of rapid risers with the group of non-rapid risers for all clinical characteristics that we could abstract data from the case report forms, and in none of the clinical or demographic features was there any difference between the rapid risers and the unknown risers.  In other words, they are clinically indistinguishable from the rapid risers.
So this raises concern in our minds that the majority of unknown risers may also be rapid risers, and this has implications for any consideration of a monitoring program.

Clearly, monthly monitoring would miss the rapid risers who comprise 21 percent of the cases that we have in our series, and the concern we have is that monitoring might miss upwards of 75 percent, or three-quarters of all cases if these prove to be rapid risers as well.
Next slide, please.
We'll now talk briefly about under reporting of cases because that is an element that we are dealing with here.
This slide summarizes reports from the literature in which serious or fatal adverse drug reactions have been studied to see what is the completeness of reporting.  On average ten percent or less of serious or fatal adverse drug reactions were discovered to have been reported.
Of note, even fatal INH hepatitis, which is well known and well described, only ten percent of cases were reported in the study.  In that study where that ten percent figure was obtained, they believed that they actually under ascertained the actual index cases of hepatitis by a factor of twofold, which would bring the reporting rate down to actually five percent.
Next slide, please.

The idea has also been proposed by some that the reporting of acute liver failure with troglitazone is more complete and that actually it may be totally complete because of publicity created by "Dear Health Care Professional" letters and by media attention.
This slide is a scatter plot of every case of acute liver failure reported to FDA.  It plots the date of diagnosis of acute liver failure on the X axis against the reporting date, the date that FDA received that case report.
We also have shown sort of two bellwether times.  This is the December 1st "Dear Doctor" letter, and this is the July 28th "Dear Doctor" letter, and then we have the same thing on the Y axis.  This is the December 1st "Dear Doctor" letter.  This is the July 28th "Dear Doctor" letter.
Important features to note in this slide is that there has been a steady stream of cases reports up through the end of the period that we're reporting on.  There has been also no apparent clustering of cases in any given time period.
Where publicity has been looked at and studied, it has been found that there can be a very short-term boost in reporting that follows a publicity event.  The duration of this publicity effect is less than a month.

If we look at this slide and we look at the time periods of the "Dear Doctor" letters and the associated publicity with them, let's go back to December 1st, 1997 and look at the time period right before.  We had cases getting reported sort of within the month before that, and look at the month after.  We don't see a burst of reports.
Now, let's go to July 28th.  We have some reports after, and look at that.  Look at all of the publicity there.  This is two months before a case came in. 
The fact is we do not see evidence that there is substantial publicity effects. 
One additional point about publicity.  Where it's been studied, the reports that come in are consumer reports.  They're from the people who experienced these adverse reactions, but it's not from their doctors.  It's not the doctors reporting the adverse reaction.  It's consumers.
If you look at the case reports of acute liver failure, less than ten percent of our case reports are from consumers.  Over 85 percent are from physicians, and the remaining percentage are from allied health professionals.

So we conclude from this that there is no evidence that publicity has stimulated the reporting of cases of liver failure with troglitazone, and so we believe that the reporting rate for troglitazone is probably in the neighborhood of about ten percent, and near the end of my presentation I'll give additional data that supports that belief.
Next slide, please.
I now want to shift gears.  We're going to stop talking about individual cases, and now we're going to put on our population hats, and we're going to start talking about the epidemiology of acute liver failure with troglitazone, and we're going to start talking about things like rates and risk, and so as we go along, I'll try to educate you if you don't already know these things, and please don't interpret that I'm trying to talk down to you.  What I'm about to talk about is very complicated, and it all deals about time.
Time is the key to understanding toxicity, liver toxicity, with troglitazone.  So keep your eye on time.  Time is the answer.
Next slide.

The methods that we used to estimate the risk of acute liver failure with troglitazone.  One of the methods was we used a standard life table analysis.  In a life table analysis, you do that because not all patients stay on a drug forever.  You have some patients that stay on a drug for one months, others for two months, other for three months.
In the sponsor's own clinical trials, we had only 45 percent of the patients out of their whole NDA who stayed on the drug for six months or longer.  So most of the patients in the NDA were based on data of patients treated for five months or less.
So what's necessary then, you do a life table analysis to account for the fact that people don't stay on the drug for comparable periods of time.  You have to think of time now as the denominator, not numbers of individual patients, and a life table allows you to do that.
We use the pattern of troglitazone usage from our United Health Care database to pattern the use of troglitazone in the entire United States, and then we calculated the rate of reported acute liver failure for each separate month of drug usage, and this is important.  This is what we call the interval specific hazard rate.  A rate incorporates the idea of time.  It is the number of cases that occur in X amount of patients over X amount of time.
A way of thinking of it is X amount of events in X amount of person-years.  So the person-year is now the denominator.  It's taking the number of people over the amount of time. 

Next slide, please.
Okay.  This slide presents the life table analysis.  It's based only on cases reported to the FDA.  It is not adjusted for under reporting.  I'll orient you to the slide.
The left column shows the duration of troglitazone use in intervals expressed as months of use, and we have cases reported as far out as eight months of use on troglitazone.
For each of these intervals of time we calculated the number of patients who were treated in that interval and the amount of time that they contributed to the overall model of risk.  From that we could calculate an interval specific hazard rate.
We have chosen to use as a reference point rates expressed per million person-years, and the reason why we do this is because the background rate for acute liver failure of idiopathic cause is one per million per year.  That's the risk of being struck by lightning in the next year in the United States.  That's the U.S. risk.  It's one per million per year, and that's the background rate for acute liver failure in the United States.

So one can look at these interval specific hazard rates and just based on case reporting by itself, not accounting for under reporting, can interpret this as a relative risk, or you can just look at it as an interval specific hazard rate.
Then we have our last column, which is the cumulative risk.  What this demonstrates, it's expressed in terms of one case per how many users in that interval.  So, for example, in the first interval where we had all 1.23 million people who have been treated with troglitazone, where all of them got the drug, how many cases did we produce?  You know, we had five cases in that group.  That gives you one case per 209,000 people in that first month of use.
But it translates to an interval specific hazard rate of 56 per million person-years which, as I've said before, is over 50 times higher than the background rate.
Now, the thing about hazard rates is that the longer you stay on a drug, the longer you accumulate risk.  It's kind of like compounding interest.  Well, the longer you stay on troglitazone, the more you compound the interest of developing acute liver failure, and that's expressed in the cumulative risk column.

And so what we see here is that during the first three months of use with troglitazone we have a fairly stable but elevated risk, and then in months four, five, and six the hazard rate nearly more than triples, up to a peak of 185.
By this time, however, if you remember from the slide that I showed earlier of the pattern of troglitazone use in the population, the number of people who are still on the drug is down like now below 30 percent of all people who have used the drug.  So we're getting really small denominators, and so confidence limits start to get increased.
Confidence limits tell you how certain are you of your point estimate, and the point I'm trying to make is that although the point estimates seem to drop here, the confidence limits are such that these rates are completely compatible with the rates staying at the level of the peak rate that we've described here.

Under no circumstance, however, is there any evidence that the risk declines.  We see no evidence that the risk stops.  We have cases reported out to eight months.  We don't have cases reported of liver failure out beyond that.  We do have cases of severe hepatitis that have been reported to us as far out as 16 months, and in the sponsor's own NDA clinical trials, they had patients out as far as 18 months who were withdrawn from the study because of elevated liver enzymes.  I think I misstated that -- who had liver elevations that were more than three times the upper limit of normal.
They ran into the same problems with their studies that we run into here.  You've got that shrinking denominator of people who are at risk to experience the event far enough out in time.  So you've got to keep your eye on time.  Time is the answer.
What we see here is that the cumulative risk increases so that by the time you get out to eight months on the drug, based on case reports by itself, the cumulative risk is one in 15,000 individuals treated with the drug.  That's accounting for no under reporting.
Let's go to the next slide, and we'll see what the impact of under reporting is on cumulative risk.  This slide is slightly mislabeled, and I apologize for that.

What we mean here is the level of actual reporting or the efficiency of reporting.  So cross out the "under," and what we're showing here is what would the cumulative risk look like in the patient population treated with troglitazone at three months, six months, or eight months of use if the reporting efficiency is 25 percent, that is, if we've received 25 percent of the cases.  This would be an exceptionally high reporting rate in our estimation.
If ten percent of reports were received, this is the column that would apply.  This is the number that we believe most accurately describes reporting with troglitazone, and then I've shown five percent because there was a survey of  Rhode Island physicians that found reporting less than three percent of serious hospitalized or fatal ADRs, and what's beautiful about that study is that they showed that Rhode Island physicians were identical in their pattern of reporting to physicians in the United States overall.  And so it's not inconceivable that the reporting rate could be as low as five percent.
In any event, let's just pick one cell on the slide, and I'll explain to you what it means.  Let's take this one.
A patient on troglitazone for six months of use, and what this slide suggests is that based on the models of hazard rates and cumulative risk and adjusting for under reporting, that one in 1,800 patients may have experienced acute liver failure.

I'll present additional data subsequently that will show how this rate estimate is very consistent with the data which we have from population based sources.
Next slide, please.
This slide finally is intended to give a visual display so that you can understand the interplay of hazard rate and cumulative risk.  The hazard risk is the upper line.  It's plotted on a log scale along the right side Y axis, and we've got rates that go from about 50 up to 185, close to 200, and you can see the time course by time out to eight months.
Along the left-handed Y axis we've plotted in a linear curve the cumulative risk, and this is expressed per million users, and what we see is a steady increase in risk, and I don't have a ruler here that I can display, but it looks pretty linear to me.
The question is the hazard rate shows on sign of decreasing.  The cumulative risk continues to rise.  The longer you stay on troglitazone, the higher the risk you accumulate.  The question is we know maybe what's happening out to eight months.  What happens to the person who stays on troglitazone for 12 months, for 24 months, for 36 months, for ten years?  We don't have the data.  We don't have the answers.  We have this.  And what we see isn't reassuring.

Next slide.
I'll now explore population based data which we have to try to come to grips with what the level of risk is that we may be dealing with with troglitazone for the development of acute liver failure.
Next slide.
This slide summarizes population based epidemiologic studies that provide information about what the background rate for acute liver failure, idiopathic acute liver failure is in the United States.  Here causes such as viral hepatitis, acetaminophen overdose, and other recognized causes of acute liver failure have been removed, and then what remains?
The slide is sorted in terms of size of the study, in terms of how many person-years of observation were present in the study, and the larger study found a point estimate of close to one per million person-years for idiopathic acute liver failure.
A number of other studies failed to find any cases, but that's more a function of their lack of statistical power to detect a rare event.

If you were to summarize all of these slides -- and I'm only doing it for instructive purposes; I'm not trying to present a meta analysis here -- the rate would be under one per million per year, but we believe that the background rate that we're working with is probably in that neighborhood, one per million per year.
And I would remind the Committee that that is similar to the risk of being struck by lightning in the United States over the course of a year.
next slide, please.
Before discussing this slide, I'll just mention that from the United Network on Organ Sharing we also received information through review of the literature on rates of transplantation for drug induced acute liver failure, and the rates on a population basis for transplantation from drug induced acute liver failure is .1 per million person-years.  Okay?
So we've got a background rate of one per million per person-year for all acute liver failure and a background rate of transplantation for drug induced acute liver failure of about .1 per million per year.  So those I think are very sort of complementary.

Okay.  Now, in this slide we summarize population based data on the risk of acute liver failure with troglitazone, and I'll need to spend a lot of time on this slide.  So bear with me.
We summarize a number of different studies that have information that bear on the subject.  The number of individuals in that study are shown in this column, and then the proportion of patients in each study that had six months or more treatment with troglitazone is shown here.
The reason why I have included this is because we don't know what the power of these studies are to find acute liver failure.  We do know from the hazard rate information that we've developed that the rate seems to peak at six months and then may continue at that high level beyond that.
So it seemed to us that using a benchmark of six months or longer of treatment would be at least a crude indicator of a study's power to detect acute liver failure if troglitazone causes acute liver failure at the kind of rates that we're talking about.

We then also summarized the number of person-years encompassed in that study, and what I'd like to point out here is the whole thing about time.  You can have a lot of patients, half that amount of time.  You can have a lot of patients, but not a lot of time.
Look at this.  Sixteen hundred patients, less than 400 years of person-time.  You can treat 5,000 patients for two months and not see acute liver failure, and that study in terms of the value that it contributes is almost uninformative because it doesn't have the power to show the effect.  If the effect happens later and you don't look with substantial power later, you're not going to find the problem.
Okay.  Now, let's go and look at each of the studies.  From the NDA they had 2,500 patients, about 45 percent at six months or longer, 1,400 patient-years.  There were no cases of acute liver failure that were identified in that study.  So you get a point estimate of zero.
But the important thing to focus on when you're dealing with safety isn't the point estimate.  It's the upper bound of the 95 percent confidence interval.

This Committee is most comfortable and most familiar, I am sure, in dealing with issues of efficacy.  When one concentrates on efficacy, you focus on the lower bound, the lower 95 percent bound of the confidence interval, and you do that because you want to see is the effect we're seeing with this drug distinguishable from whatever you're comparing it to, whether that be placebo or another drug.
But what you're looking at is the lower bound because the lower bound is what tells you about statistical significance.  
When you're dealing with drug safety, you've got to flip and reverse.  You've got to look at the upper bound.  You have to think of it in terms of what is the capacity of this study to rule out a particular level of risk.
When you do that what you see is that this NDA lacked the power to rule out an incidence rate of about 2,600 per million person-years.
If you further dissected out this study and focused on just the patients who got six months or longer therapy, you would see that the study lacked the power to rule out a relative risk of almost 6,000 per million person-years.  
In other words, what I'm saying is although the NDA found on cases, it's more a question of a lack of statistical power to do so.  It's not evidence of a lack of an association with acute liver failure and troglitazone.

Now let's go to the next two studies that have been -- these first three studies, by the way, are familiar to the FDA and have been reviewed by the FDA.  We've received information on them.   The studies that I'll talk about at the end of the slide, the data have never been presented to the FDA.  They have not been reviewed by us.  The first time that we saw them was in the sponsor's briefing package to the Committee, but I've listed them here so that I can discuss and instruct the Committee in ways they need to evaluate these studies to understand risk.
We'll now move to the diabetes and prevention program study, which is done by the National Institutes of Health.  This study was looking at patients with impaired glucose tolerance.  So these are patients who aren't yet diagnosed with diabetes, but they're patients who are at higher risk of developing diabetes.
One of the arms in that study was an arm treating patients with troglitazone.  So they had patients with impaired glucose tolerance being treated with troglitazone.  Five hundred and eighty-five patients were enrolled in that clinical trial.  Eighty-six percent of those patients had six months or more treatment.  So you can see there's a real contrast there in a sense in terms of study power.

You know, they've got a lot of patients who had exposure at the time when the risk sort of goes up the highest.
Person-years were about 580.  On average, the patients in this study were treated for a year.
They had one case of acute liver failure that resulted, and that translates to an incidence rate of about 1,700 with an upper confidence bound that goes up to about 9,500 per million person-years.
Now, remember when you're thinking about this incident rate per million person-years, the background rate is one.  So this number, this incidence rate is actually an estimate of the relative risk.  That upper bound is an estimate of what the relative risk might be that this study is not capable of ruling out.

Then we'll go to the third study, the REACH study.  This is a postmarketing study done by Parke-Davis studying the use of troglitazone in patients with Type 2 diabetes.  This case produced a patient with acute liver failure when about 2,400 patients were enrolled in the study.  The company was kind enough to provide us with information on the time of enrollment of patients in that study or at least the number of patients in the study, and we had to make assumptions about how patients were enrolled.  So we made the simplest assumption one can make, which is that patients were enrolled in a continuous fashion over the time period that the study occurred.
If one does that, we arrived at an estimate that about 17 percent of the patients in this study were on drug for six months or longer at the time this case of liver failure occurred.
The total number of patient-years acquired in that study by that time point was about 780.  The incidence rate from that study would be 1,274, with confidence bound that goes up to about 7,000.
We'll now talk about just two of a number of studies that the sponsor included in their briefing document.  In their briefing document, they present a lot of studies, and they combined them.  Here we've taken a couple of individual cases, studies, and we showed them individually, and we do this because it's more appropriate to look at individual studies than to group studies where one wasn't originally planning to group them.
So we don't believe that a meta analysis is the way to look at that.  You lose certain information when you combine the data.  You lose information about what the actual power of a study was to show an effect.

So the appropriate way to look at any study that's done to look at the risk of acute liver failure with troglitazone is to look at the study by itself, to look at the power that study has, to identify the problem we're interested in, and then what is the upper 95 percent bound on that study because that tells you what relative risk that study is consistent with.
A study from Glaxo was included int he submission that had 3,000 patients.  We have no notion of what the demographics of use were, the duration of use.  We know that the total person-years was about 1,200 person years.  That would work out to less than five months per patient.  So clearly, this percent mark, this unknown is less than 50 percent.  It's probably in the neighborhood of 30 to 40 percent, I would guess.
No cases occurred, but what's the upper 95 percent bound?  It's 3,000.  This study had the bulk of the patients the bulk of the time at the place where the hazard rates were lower and hadn't moved into that period where the hazard rates get higher.

Now, let's go to Sankyo study, 1,600 patients.  These patients were treated on average for under three months.  So, you know, the percent that are on it more than six months might be one percent.  I mean we don't know.
No cases got produced, but look at the upper bound.  It's like nearly 10,000.  So the take home message from this slide is that we have some population based evidence from clinical studies.  I mean both of these things were basically randomized clinical studies.  DPP was a randomized clinical study that had monitoring and baseline testing and everything else.  REACH was a randomized study.  it had monitoring, baseline testing, and everything else, and lightning struck twice, here and here.
We had these other studies.  They're not powered sufficiently to see the problem.  They are all compatible with and all consistent with the rates observed in this study.  You have to look at the upper bound.
Next slide.
I'll now present data on liver enzyme monitoring and severe liver injury in patients treated with troglitazone from the United Health Care database.

UHC is a health care management company with health plans in nine different states across the U.S.  It maintains a research database covering 3.5 million people.  It collects computerized data on prescriptions, diagnoses, lab tests, and procedures.  It does not collect data on the results of lab tests.
FDA has a cooperative agreement with the United Health Care to conduct postmarketing drug safety studies.  We use this database to study enzyme monitoring and the occurrence of severe liver injury in troglitazone users.
Next slide.
This slide outlines the criteria for inclusion in our enzyme monitoring study.  We require that all subjects in the study have received troglitazone and have at least 90 days in the database before that first prescription to be included in the study.
The reason why we did this is we wanted to be sure that patients who we saw as a first prescription of troglitazone in our study were, indeed, receiving their first prescription.

The other criteria we had was it related to disenrollment or the end of a study interval.  If the time point came where a liver test should be done and that time came after the time point when a patient disenrolled because they changed insurance plans or after a time period when the study interval ended, we didn't count that patient in the denominator for calculation of a rate at that time point.
Next slide.
This cartoon helps to graphically demonstrate the design of the study.  We've got March '97 when troglitazone came on the market up through about October 25th when the first "Dear Doctor" letter went out alerting the health care community about reports of liver failure with the drug.  
Any patient who started troglitazone during this time period and who met the previously described enrollment criteria were included as cohort one.  About 2,300 patients were included in that cohort.
We then created a second cohort out of all troglitazone users.  That is bracketed by December 1st, 1997.  That's the date of the first "Dear Doctor" letter that recommended very specific monitoring requirements, and we included in this cohort any patient who started their first troglitazone prescription was between that date and the end of June of '98.  Cohort two has, as you can see, about 2,800, 2,900 patients.

Cohort three is comprised of all individuals who started troglitazone and met the other enrollment criteria from August 1st of '98 following the July 25th "Dear Doctor" letter through the end of December 1998, 1,400 patients in the final cohort.
Next slide.
This cartoon demonstrates the analysis plan.  We've got time line here.  We've got a patient who receives their first prescription for troglitazone.  We define the baseline monitoring period as that time going from 30 days before to seven days after that first prescription.
We then looked at the monthly anniversary date from that index prescription for as long as the patient remained on troglitazone and looked plus or minus seven days from that date for evidence of reporting a billing claim for enzyme monitoring.
Next slide.
This gives an overall picture of the flow of patients in the study.  Within the UHC database there are almost 9,400 patients who received troglitazone, contributing a total of nearly 4,900 person-years of time.  Seventy-six hundred met the 90-day and prior enrollment screen, and 6,500 met the disenrollment or end of study interval screen.
So the data that I'm about to present now on enzyme monitoring is based on these 6,441 patients.

Next slide.
This slide summarizes the proportion of patients who started troglitazone in each of the time periods, the initial time period, the time period between the "Dear Doctor" letters, and the time period after the second "Dear Doctor" letter, the proportion who had baseline testing done, had a billing claim for baseline testing done within 30 days before to seven days after.
And what we see is that there has been an increase that corresponds to the "Dear Doctor" letters, but even in the final cohort, only 45 percent of patients had a baseline monitoring test.
Next slide.
This slide shows data on full compliance with monthly monitoring and baseline testing for troglitazone in this study, and to orient you, we've got each of the cohorts shown here, corresponding to the different rows, and then the number of months of treatment that a patient was experiencing.

And the way to read this slide, for example, is let's just take cohort three at three months.  What this says is that in patients that start troglitazone in that last time period and were on the drug for three months and so were eligible to be tested at that time, only 2.7 percent of those patients had a test done at three months, two months, one month, and a baseline.   
At four months, it was less than one percent.  At five months, it was zero, but we don't show the data there.  At six months we had nobody in this last cohort who had opportunity to be on the drug for six months because our study period was only five months long.
To give the Committee a sense of study power, could we go to that previous slide for a minute, please, Lanh?  Thank you.
To give the Committee a sense of the study power that we have here, we had 1,400 patients remember in that cohort who had a baseline test.  This was 1,166 patients who were eligible; 9.3 percent of 1,166 had an enzyme test done.  The denominator here was 636.  Here it was 366.  Here it was 182, and at five months we had 16 individuals, and as I said before, there were zero individuals out here.
So that gives you a sense of what we're talking about here.  Okay.  
Next slide.

The question comes us:  what's the completeness of the data that we've used based on claims lag?
Claims lag is you go and you have the test done, and then the place where you have the test done, they've got to process the claim with the payee, with United Health Care.  So United Health Care collects data on how long does it take for claims to be processed and how complete are claims at different time periods.
In any event, based on those analyses, the claims data for cohort one are 99 percent complete, for cohort two 99 percent complete, and for cohort three they are better than 85 percent complete.
Next slide.
In this study we also looked at occurrence of clinical outcomes in patients, and we identified three patients who had codes that may signify acute liver failure, one with a code for transplant and two with codes for hepatic encephalopathy or acute necrosis.
Those last two patients, they processed no claims after that hospitalization.  In other words, they are hospitalized with those diagnoses, and then they ceased to file claims.  United Health Care says that that is a pattern that is seen in patients who die during that event.

We are in the process of obtaining medical records for those.  So these are not validated at this time.  We have only the claims data to base it on, but based on the claims data, these are the incidence rates for possible acute liver failure, for hospitalization with drug induced hepatitis, and for the combination of both from this study.
Next slide.
There are several other issues that I have to rush through before concluding.  The question comes up, well, you know, there are other drugs on the market, and they cause liver toxicity.  What are their risks.
The purpose of this slide is to give people kind of an overall sense in a general way of what we're talking about.  We went to the United Network on Organ Sharing to obtain information on the drug association, the drug that was listed -- oh, here.  Let me start again.

For patients who are registered for liver transplantation with UNOS because of acute liver failure due to a drug, what is the drug that was held responsible that it was attributed to, that liver failure?  This information was obtained from UNOS through the Division of Transplantation in HRSA, and so we thank them for it.
What we show is the drug group, the number who were registered for transplants.  From IMS Health, we obtained the number of prescriptions for those drugs that were issued over the five-year period that these data encompass.
And then finally, we calculate a liver transportation registration rate per billion prescriptions with 95 percent confidence intervals, just more as a heuristic thing to sort of show people what we're talking about with troglitazone.
We've included sulfonylureas and metformin as other diabetes drugs.  There were no registrations with liver transplantation for those.  So we see what we have there.
With troglitazone, there were three in this time period, with 7.9 million prescriptions.  So this is the liver transplantation registration rate and the confidence limits.
For nonsteroidal anti-inflammatory drugs, these are widely reported in the literature.  There's a whole literature on NSAIDs and liver disease.  The thing is, yes, NSAIDs do cause liver disease, but they cause it at a low rate.  It can have a population impact because so many people take the drug.

So if we look there, in this five-year period there were six patients registered for transplantation and 372 million prescriptions, and so you've got a number of 16 for NSAIDs.
Now, Bromfenac-Duract is another NSAID, and it had two cases registered with 2.6 million prescriptions, and you can see the reporting rate there.
Finally, we include the statin drugs, the coase reductase inhibitors.  They are reported to cause liver disease, but it's not generally severe liver disease, and we had one report in 206 million prescriptions, and you can see the rate.
So in this analysis, very qualitatively speaking, troglitazone looks very different than most other drugs.
Next slide.
Another question comes up.  Metformin and lactic acidosis, the risk that it poses to diabetics, and so we have to be able to tolerate risks because it's a risk-benefit equation.
Well, the data we have on metformin and lactic acidosis comes primarily from studies based on reporting rates.  It's not based on population based estimates.

However, there are two population based studies done in diabetics looking at the issue of lactic acidosis.  One looked at patients studied who were taking metformin.  The other was studying Type 2 diabetics who were not taking metformin.  This latter study was performed by Kaiser Permanente Northwest in Oregon, but was funded by Bristol-Myers Squibb.
What we see here, however, is that the rate per million person years of observation for patients with metformin or Type 2 diabetics without metformin is identical.  This is for lactic acidosis.
Furthermore, all of the cases that were identified in either of these two studies had recognized factors capable in and of themselves of causing lactic acidosis.  So the question arises, you know, we talk about tolerable risk with metformin, but maybe what we should have been thinking about was, well, what's the risk in the study base, the base population, diabetics in general.
It may be that people who use troglitazone have the same risk of lactic acidosis as this group of patients, Type 2 diabetics, who don't use metformin.  These are the only two studies that are available.  There are not other population based data that we're aware of.

Next slide. 
This summarizes the rates, the death rates per million person-years that seem to apply.  For metformin/lactic acidosis we have a rate of 15 per million person-years.  This comes right out of the FDA approved label, which says that the background rate is three per 100,000 per year, which would be 30 per million per year, but the death rate with lactic acidosis is about 50 percent.  So we divided 30 by two, and that's where we get the 15, but the place where it comes from is the FDA approved label.
For sulfonylurea/hypoglycemia and death from that, we took the numbers from the sponsor's briefing package, 14 to 33 per million person-years, and then for troglitazone and acute liver failure, the estimates that we have are from population based studies.
Next slide.

I want to revisit under reporting once more before concluding.  We presented before literature to suggest that reporting rates might be in the neighborhood of ten percent.  Now that you've seen the data on the population based studies, we can do an observe to expected analysis using the rates seen in those studies to calculate what would be expected to have happened in the entire U.S., compare it to what was reported, and come up with the reporting rate.
So from the DPP or REACH, UNC, we've got it all here.  You can see for liver transplantation or death, the reporting rates, the reporting efficiency range from about two percent up to about nine percent.  For hospitalization with hepatitis and troglitazone, the setting of troglitazone, somewhere between eight and ten percent.
We believe that these data provide internal corroboration of the literature that suggests that under reporting is substantial with troglitazone, and these data would lead us to believe that our estimate that we received only about ten percent of the cases is a fair assumption, and that the life table analysis adjusted for a reporting rate of ten percent is an accurate and fair portrayal of the data.
Next slide.
Okay.  We've made it to the end, and if I have the Chairman's permission to go over my time by two or three minutes to complete these slides.
CHAIRMAN BONE:  You recall that we were expecting to allow for the Committee members to ask questions in that time, but please wrap up.
DR. GRAHAM:  Okay.  Thank you.

CHAIRMAN BONE:  Finish your remarks, but please be concise.
DR. GRAHAM:  Thank you.
Okay.  I want to make a few comments about benefit and risk and the way an epidemiologist looks at it from a population perspective.
We've seen today and we've heard today, this morning, that there's no question that individual patients have benefitted from the use of troglitazone.  These benefits, however, have been in the short term, and in many of them they've related to things that relate to quality of life, and those are difficult things to quantitate.
We now have to sort of look at risk and benefits from a population perspective, and we have to realize that the major health benefits that we're talking about with diabetes therapy in general, troglitazone in particular, will be realized in the future, five, ten, 15 years down the line.

And I think it's important to focus on residual benefit, the residual benefit that troglitazone affords over other available treatments because that's really the appropriate benefit-risk decision to be made.  It's not the total benefit of troglitazone necessarily, but it's its residual benefit over other therapies if the Committee decides that those other therapies are safer than troglitazone.
The average troglitazone user is 61 years old.  Well, what that means is competing mortality or lack of effectiveness of the drug will substantially reduce the pool of people who can stay on the drug long enough to realize these delayed benefits.
So what you have to think about is what's the present value of avoiding something that happens ten years or 15 years down the line.
Next slide.
The background rate for acute liver failure is about one per million per year, and for multiple population sources, we have estimates that suggest that it could be in the neighborhood of over 1,000 per million person-years.
The life table analysis, adjusting for under reporting, suggests a risk of 1,000 per million person-years at six months of use of the drug.  That's very consistent with the data that we've presented here above.

The question is, from the other studies that we showed that were under powered, we really can't rule out a relative risk that may be as high as 3,000 or 6,000 per million person-years.
The hazard rate is elevated with the first month of use.  It peaks at six months and then appears to remain high.  We see no evidence that it declines.  The cumulative risk progressively increases with continued exposure.  So the question is:  the longer you stay on the drug, what happens to that cumulative risk?
Most troglitazone users, while we have the under reporting and we think that we've only got maybe ten percent of the cases, the important thing for the Committee to realize is that most troglitazone users have not yet passed through the period of peak risk.  So you have to consider that as well.
Last slide.  There are no obvious predictors of who is at risk of developing acute liver failure with troglitazone.  Acute liver failure appears to be unpredictable.  The point of irreversible determinism seems to occur early in the process, and this is highlighted by the issue of rapid risers.
Enzyme monitoring occurs at a low level and in an irregular manner.  We can't point to monitoring and say that this intervention has had any impact on the incidence of acute liver failure.

Finally, there are no data available on the efficacy of monitoring in the wave of preventing acute liver failure.  That is, we don't know if monitoring can prevent this disorder in the first place.
That's the end of my presentation, and I thank the Committee for their attention.
Oh, final slide, just to acknowledge the people who helped us from United Health Care and FDA.
CHAIRMAN BONE:  Thank you, Dr. Graham.
I'm sure there will be a number of questions about the content of your presentation.  I think the plan will be for both the agency presentations and the presentations by the sponsor to ask specific questions that are related to the information presented, and then to reserve more extended discussion for the time designated for discussion.  We did intend to include some question time, however, in the allotted time.
Are there questions from the Committee regarding Dr. Graham's presentation?
MR. HAMMES:  Richard Hammes, University of Wisconsin.
CHAIRMAN BONE:  Dr. Hammes.

MR. HAMMES:  To get this in a little more real perspective, is there any data in terms of the death rate of diabetics over age 45 in terms of deaths per million person-years?
DR. GRAHAM:  Oh, I'm sure that data is available, and I haven't done the research on that, but what we're focusing on here is death due to a specific cause, not death due to heart attacks or stroke or the other things that diabetics deal with.  We're focusing on the issue of hepatotoxicity with troglitazone, and in that context the appropriate thing to focus on is the rate of death or the rate of occurrence, the incidence of acute liver failure.
CHAIRMAN BONE:  Was your question related to how to relate this to potential reduction in death from other etiologies or how did you intend that to be?
MR. HAMMES:  Well, in looking through some of the written things here, there was one letter that came in that suggested that the risk of dying from diabetes was like one in 30.  Well, you know, a risk from liver failure of one in 10,000 compared to the risk of dying in one in 30 has a whole lot different perspective than a risk of being struck by lightning.
DR. GRAHAM:  Oh, yeah.  Let me address that, please, Dr. Bone.

That risk of one in 30 of dying of diabetes is the background rate that all diabetics face regardless of the treatment they receive.  What we're looking at is the incremental increase, the relative increase in risk of death.  We're looking at a very specific cause, and it may be true that one in 30 diabetics die over some particular time period.
The fact is, however, that applies to all drugs.  You sort of have to keep these things separate.
If you look at the relative risk estimate, what this says is if I had two diabetics or 2,000 diabetics in each group and I had one group that's being treated one way and one group that's being treated another way, they're all going to experience the same background mortality rate, this one in 30 or whatever it is, but then there will be a residual difference that's due to the drug, that's attributable to the treatment they receive, and that's what we're focusing on here:  the attributable death rate that occurs with troglitazone from acute liver failure.
And so it's important not to confuse these two things because then you lose sight of what the role and the effect of the drug is, and that's what we're focusing on here.

CHAIRMAN BONE:  Dr. Braunstein.
DR. BRAUNSTEIN:  Well, there's a lot of data presented.  Let's see if I understand this.
The risk for an individual patient who is taking the drug for one year with full reporting would be one in 1,000 for having liver failure or death; is that right?
DR. GRAHAM:  Suing the full reporting slide, not the slide adjusted for under reporting, I think we had, if I recall, at eight months it was like one in 15,000.
DR. BRAUNSTEIN:  Well, let's say we just captured everybody.
DR. GRAHAM:  Okay.  if we capture everybody, then we go to that under reporting slide.  It would be in the neighborhood probably of one in 1,000.  We only model it out to eight months because that's as far out as our life table permits us to go.
So if you take somebody, say, at six months, the example that I gave, where the cumulative risk would be one per 1,800 individuals who stayed on the drug for six months, person time-wise you have to divide that number by two because it's six months' of time for a person-year.  So that would be one per 900 person-years.

If it turns out that the hazard rate does continue and there's an increase in cumulative risk, we did not model it for this Advisory Committee, but sort of the short answer is that the absolute risk to an individual patient would be greater than one in 1,800 patients.  Whether it would be one in 1,500, one in 1,200, one in 1,000, I can't exactly tell you, but that's the notion of cumulative risk
CHAIRMAN BONE:  All right.  Dr. Seeff.
DR. SEEFF:  Could I just get a clarification on the timing of the development of liver disease?  You've shown some slides here about the time from jaundice to encephalopathy.  You've told us, I think, that there are three manifestations of liver disease.  One is jaundice.  One is elevated enzymes, and one is symptoms.
Within each of those three categories, what does the timing from receipt of the drug to the development of each of these manifestations mean and a range?
DR. GRAHAM:  From the receipt of?

DR. SEEFF:  From the receipt of troglitazone, among those who develop an abnormality ‑- let's start with jaundice -- what was the mean time from receipt of troglitazone to the development of jaundice?  And I'd like to have it as a mean and a range, if possible.
DR. GRAHAM:  Right.  We don't have those data here.  We have the database here so we could actually run those analyses and get the answers to those questions for you, in general.
But clinically, there are only a handful of patients with abnormal labs, first, and in those cases the abnormalities weren't necessarily particularly severe, and the patients with symptoms in most of those patients, the timing of the symptoms was only a matter of between a couple of days and a couple of weeks before jaundice occurred.
But we could do those analysis, but it's only a handful of cases.  The bulk of the cases were jaundice.
DR. SEEFF:  The primary manifestation is jaundice then?
DR. GRAHAM:  Yeah, and the interval from symptoms to jaundice for those other patients is only a matter of days to at most a couple of weeks.  It's a very short range.

DR. SEEFF:  And see that in at least one instance the duration between, I guess, the development of jaundice and hepatic encephalopathy was as short as four days.
DR. GRAHAM:  Actually you can have patients who present with encephalopathy before jaundice.  The very hyper acute cases can occur in such a fulminant fashion that patients don't have opportunity to develop jaundice before they become encephalopathic.
This is an interesting point, and I'm glad you raised this question because there were two cases that we had that presented with elevated ammonia levels and encephalopathy prior to the development of transaminase elevations, and I don't know if it suggests anything mechanistically, but these were patients who sort of metabolically were already in liver failure before apoptosis or whatever other process occurred began to occur.
CHAIRMAN BONE:  There's some questions over here.  Let's see.  We'll just start with I think Dr. Hirsch had his hand up first.
DR. HIRSCH:  Yeah, I just wanted to clarify one thing, if you can help me out.  I'm a little confused about the fact that so few people have been taking troglitazone for more than six months.  I assume this means that they're just starting to take it now.

DR. GRAHAM:  Right.
DR. HIRSCH:  Do we have any notion of the number of people who took it and stopped taking it for any reason?
DR. GRAHAM:  From the data that we have available, we're not able to make any inference about what the reason was for stopping the drug, and the reason why you sort of have that slide that shows things coming down like that is, in part, patients who start it and stop it, but also it's because you have a constant infusion of new patients who start the drug.
DR. HIRSCH:  So you don't know what the combo is.
DR. GRAHAM:  That's correct.
DR. HIRSCH:  How many are starting versus -- we don't have good data.
DR. GRAHAM:  Well, we could.  We didn't do that for this presentation, but we could show what the contribution was due to the influx of new patients.
DR. HIRSCH:  It would b every interesting to know the number of people who took troglitazone and stopped taking it for all reasons.
DR. GRAHAM:  Right.

DR. HIRSCH:  And what that is.  Obviously that's a very important denominator in another calculation that I just want to point out to you.
I just want to make sure I'm correct in this.  My mathematics here, as you were talking and going along, is something like one per 1,800 at six months in the whole population, with the ten percent reporting rate, and also your model is a linear model.  In other words, it's two per 18, et cetera, et cetera.
So, you know, if Rezulin were something like insulin, a great drug in diabetics, you'll be taking it all the time.  It isn't something ordinarily that you would stop.  So it's not much of a calculation to show that at five years if your model is correct and if all the Type 2 diabetics in America were taking this, you'd have in excess of 50,000 cases of acute liver failure.  That's not a hard calculation to do.  Is that meaningful or is that a stupid calculation?
DR. GRAHAM:  No.  We didn't model the data beyond where they go.  What we say is that based on the data we have, we're experiencing very high rates and accumulating risk.
DR. HIRSCH:  So that is a possibility.

DR. GRAHAM:  And that it is quite possible that that would happen, and we see no evidence to suggest to us that that won't happen.  I mean, you have uncertainty about what happens in the future, but based on what we see, we don't see anything to tell us that that won't happen
DR. HIRSCH:  So that would be the major cause of liver failure kind of of all time if that were -- you know, 50,000 cases of acute liver failure would be rather remarkable, right?
CHAIRMAN BONE:  Let's confine ourselves to specific questions, please.
I think Dr. Marcus had a question and we're coming right along.
DR. MARCUS:  Yeah, I'd like to follow up on that one in 30 issue.  Let us suppose the background -- there's another shoe that needs to drop on that -- the background mortality rate, let's say, per unit time is one in 30 for someone with diabetes, and if you're going to add to that an incremental mortality rate of, say, one in 600, then that's like adding another five percent to that one in 30, and so if you had a treatment which reduced mortality that one in 30 by as much as ten percent, then that favors the drug in terms of the overall effect in the population mortality.

But if the treatment effect is only five percent, then is it fair to assume that any savings of mortality you're achieving due to the beneficial effects of the drug in general on diabetes are a wash, given the incremental mortality due to that additional five percent?
DR. GRAHAM:  Right.  Well, a couple of comments.  One, I think, and I would urge the Committee not to confuse the background rate of death from diabetes with the issue of death from adverse reactions to the drug because the mortality rates for cardiovascular disease and everything else will dwarf just about anything that we're talking about here.
DR. MARCUS:  But the drug could cause a ten percent reduction in that.
DR. GRAHAM:  Well, it could.
DR. MARCUS:  I'm not saying it does, but it conceivably could.

DR. GRAHAM:  It could, and what you have to do, the way to do that analysis appropriately is not to be looking at the deaths from cardiovascular disease, but what you do is if you wanted to do it this way, you take a large cohort of troglitazone users, a large cohort of SU users, a large cohort of metformin users, a large cohort of insulin, whatever you want to do; a large cohort, and then you follow them through time to see what happens.  What is their mortality experience?
And you look and see where people drop out, you know, and what they die of, and then you can sort of see what the years of potential life lost are, and then you have to really focus in on cause specific mortality.
If 95 percent of your mortality is cardiovascular disease, you can look to see what is the incremental change in cardiovascular mortality, but then you also have to look at, well, what's your death rate from lactic acidosis, what's your death rate from liver failure.  They have to be treated independently.

And when you do that and you look at these different drugs, I think you could take the major -- I mean, an appropriate thing might be to take the major mortality, the major adverse side effects of the different drugs and the mortality risks associated with them, hypoglycemia with SUs, lactic acidosis with metformin if you believe that it's different than the background rate for diabetics, the risk of desk from liver failure with troglitazone, and compare in comparable cohorts what the mortality experience would be, what the years of potential life lost would be in those cohorts due to those adverse effects.
That's the appropriate way to look at this.
DR. MARCUS:  We don't have that luxury.
DR. GRAHAM:  No, we don't have that luxury, but you do have the rates.  You have the rates.
CHAIRMAN BONE:  Well, I think Dr. Marcus is commenting that that would be informative if we had a quantitative estimate of the beneficial effects.
DR. MARCUS:  I guess I'm trying to model what the degree of benefit to the mortality would have to be to overcome the added increment, to overcome by a factor of ten or a factor of 100, to find out --
DR. GRAHAM:  I think it would have to be substantial, but I'm not an expert in diabetes, but what I've read from diabetes and the experts that I've talked to in diabetes, nobody has yet made the claim that there are data that show that there's a convincing impact on mortality experience to the treatment of diabetes.
We do have other endpoints where there appears to be beneficial effects, and so if your outcome is mortality, I think unless you have the data, it's difficult to do that balancing.

CHAIRMAN BONE:  We're going to probably hear a lot from our diabetologist to discuss that point during the discussion section.  I'd like to keep our time right now on the specifics of Dr. Graham's presentation, and we'll come right around the table in the pattern we started with.
And I think Dr. Fleischer has a question.
DR. FLEISCHER:  I wanted to know, given the relatively short duration in patients on the drug, how powerful do you think your linear model of increasing risk over time is?  Because that's a really critical calculation.
DR. GRAHAM:  Well, when you're lost at sea without a compass, you use whatever you have, and this is a compass that we have, and what I've tried to do is use multiple compasses.
We've got this model that's based on spontaneous case reports and the literature that's suggested under reporting, and it gave us one suggestion.  We went to population based data and in multiple different places, you know, lightning struck, and the compass points in the same direction.

And then we go back and we look at what do those studies predict about what the under reporting rates might be for liver failure with troglitazone, and, lo and behold, it comes back and kind of sort of internally validates the model.  
So I've got these different compasses, and they're all kind of pointing the same place.  Now, how good a compass is it?  Well, I won't know until I get to the North Pole, and so I would submit that the information is informative and that it is predictive in a certain general sense, and certainly the clinical trials all do point to a high, a high relative risk and a high incidence rate, and certainly the experience through eight months, that one in 1,800 patients could experience acute liver failure on the drug, I think that that is probably not far off the mark.
DR. FLEISCHER:  And that's at six months?
DR. GRAHAM:  Right, and that experience, the majority of patients on troglitazone haven't reached that six-month point yet.
CHAIRMAN BONE:  Let's see.  Go ahead, Ms. ‑-
MS. KILLION:  Killion.
CHAIRMAN BONE:  -- Killion.  I'm sorry.
And then we'll come around in order, please, from now on.

MS. KILLION:  I was looking at one of your benefit-risk analyses where it says that there is no predictor of who's at risk, but when I was looking through some of the other materials, it seemed to me that you said 43 percent of troglitazone users are female, and yet when you look at the 43 cases of acute liver failure, 70 percent of them were female.  Wouldn't that be an indicator of a higher risk to women for liver failure?
DR. GRAHAM:  It may be.  I'm reticent to put a statistical test to case reports, but the clinical impression is there, that women may be at higher risk.  This is something that's seen with other hepatotoxins, that women are at higher risk.  So it wouldn't be at all unexpected, I suppose, that that's the case here.
The fact is even though women have higher risk, it doesn't mean that men are without risk.  What it might mean, we have a composite risk.  Let's say the composite risk is 1,500 per million person-years.  Well, what that means is the risk in women might be 2,000 or 2,200, and the risk in men might be 1,000 or 800.  It's still elevated in men as well as in women, but women are subject to a higher level of risk.
CHAIRMAN BONE:  Thank you.

Let's see.  Dr. Colley, did you have a question?  No or yes?
DR. COLLEY:  I was impressed by the abysmal adherence to recommended monitoring that you found, and my question is are you able to determine if monitoring in the most recent labeling had been adhered to, would you be able to detect those cases?
DR. GRAHAM:  If monitoring had been done, sort of like we're agreeing that it hasn't been done, but had it been done could we have detected what, people who would have abnormal liver enzymes?  Could we have prevented liver failure?  Is that the question?
MS. KILLION:  Yes.  
DR. GRAHAM:  Well, that is what I was trying to get at with the rapid riser issue, and the problem is we only had 12 cases out of the 43 where we sort of know the time course, where we've got liver enzyme measurements close enough to when liver failure was diagnosed, when they had reached that irreversible place, to sort of know what the time course was.

For nine of those people what we found was that they went from a normal enzyme to irreversibility in like basically one month, one monitoring interval.  For the other three, they had enzyme abnormalities that were seen to increase, you know, sort of from one month to a next month and then to irreversibility.
So we have an N of 12, and nine of them, you know, 75 percent, the answer to your question would be would fail in a monthly monitoring system to prevent that, and then the question is:  for everybody else that we don't know, well, what happens to them?
And so we looked at the clinical content and saw no distinguishable characteristics that would allow us to distinguish who a rapid riser is from any of those people, leading us to wonder, you know, are most of them rapid risers as well.
CHAIRMAN BONE:  Thank you.
Dr. Cara, you had a question?
DR. CARA:  Yeah, I have a question that will hopefully help me separate out a little bit the apples and oranges that we're getting in all this information, and it primarily relates to the sort of numerators and denominators that you versus the sponsor are using.

They've limited their comments about hepatic failure and risk of hepatic failure primarily to their studies.  However, when you estimated the risk of acute liver failure with troglitazone it was more of a, quote, unquote, real world sort of situation where you took patterns of troglitazone use from the UHC database.
My question is:  was that database specifically evaluated in terms of diagnosis?  In other words, did you essentially take all troglitazone prescriptions?  Were these specifically for people with diabetes?
DR. GRAHAM:  We took anybody who was treated with troglitazone.
DR. CARA:  Regardless of the diagnosis?
DR. GRAHAM:  Well, you can't -- unless you go back to the medical records, you won't be sure of the diagnosis, and based on the age of the patients, we had very few patients who were under the age of 45 who started the drug, and so --
DR. CARA:  Well --
DR. GRAHAM:  Well, our presumption is that most of them are Type 2 diabetics.
DR. CARA:  Well, but that may not be an adequate presumption because troglitazone is being used more for other sorts of conditions, including --

DR. GRAHAM:  Well, then here's another statistic then that maybe will help nail this down.  Only 12 percent of the entire UHC population was on troglitazone monotherapy.  All other patients, so 88 percent of the patients, were on other drugs used to treat diabetes.  Most of them were on sulfonylureas, metformin and insulin.
I have a slide.   We had it in the original slide show.  It got cut.  You saw we went a little over time.  That slide would have taken ten minutes for people on this Committee to understand because of its complexity.  I think it may have been in the original package that went out.  I don't recall.
But in any event, these data would lead us to believe that the overwhelming majority of troglitazone is used to treat Type 2 diabetics, I mean.
CHAIRMAN BONE:  Thank you.
Let's see.  Let's just so over there.  Go ahead.
DR. KREISBERG:  Okay.  Dr. Graham, I'd like to address two issues with you, and, Henry, I'd like to be able to come back to Dr. Graham after the sponsor has a chance to make a presentation because I think that --
CHAIRMAN BONE:  Well, let's see how the program can go.

DR. KREISBERG:  Okay.  The first issue is, and I'm addressing now a slide that shows up on page 17 of the handout, which is called "Summary of Population Based Data on Risk of Acute Liver Failure with Troglitazone," in which you do modeling, and based upon two actual cases, you come up with specific recommended rates that range in the range of 1,200 to 1,700 per million patient-years with very wide confidence intervals.
But I'm impressed that you even come up with confidence intervals where there are no cases of liver toxicity.
DR. GRAHAM:  No, no.  That's binomial.  I mean, that --
DR. KREISBERG:  Well, you're way over my head, but it just intuitively doesn't make much sense to me.
DR. GRAHAM:  No, what that confidence limit tells you on a study with no outcomes is it speaks back to the power of the study to rule out a certain level of risk, and what we're saying here is that these studies are basically uninformative as to what the point estimate is.
They are informative, however, in telling us what the rule out level is and what one could do if thinking sort of in risk-benefit.  I'll give you an example.

DR. KREISBERG:  You don't have to do that.  I understand what you've said.
DR. GRAHAM:  No, no.  This is an important example to understand risk-benefit and the use of confidence limits.
In designing studies for safety one goes to design them to rule out an upper level of risk, that one is comfortable still permits a favorable benefit-risk analysis, and so these give us information on that, on what the upper bound might be.  These studies don't exclude those risks, and so the Committee could use that information in its formulation of benefit-risks to say are we comfortable with the risks being at this particular level, at that upper 95 percent bound.
DR. KREISBERG:  In this slide you have two documented cases of acute liver failure in five studies that you reviewed, and on the basis of those two cases, you make an estimate.  Now, what I want to ask you about this particular slide is how do you know that this is not a Type 2 error, and that is, how do you know you're assuming that a difference exists when one actually doesn't exist based upon the infrequency of the events?

DR. GRAHAM:  It has to do with the background rates, that one in a million background rate, and if I had put P values on these studies, you'd see P values that are like ten to the minus six.  I mean we're talking about P values that are just unheard of.
And to have it happen in two different studies, it's sort of the same way when you guys go and review two different clinical trials to say that the drug is effective, and you require that both of those trials be a .05 level.
And the reason for having two studies is because your probability of making a Type 2 error with two positive studies is like basically .05 times .05.
You've got two studies here where lightning struck, and the question is:  what's the probability of a ten to the minus 12 event happening and not being real?
And then you do the modeling as well and all of the other evidence about under reporting, and it comes up with the same exact answer.  So the fact that you've got zeros in these under powered sponsor studies is a fact that relates perfectly to their being under powered.

If I had had 20,000 patients on troglitazone for one month and I found nothing because those patients hadn't gotten to the period of high risk, or 20,000 patients on the drug for one week or one day, and it gives you a certain number of people and you don't see the events, it's not told you very much about what the actual risk is because it doesn't have the ability to find it.
DR. KREISBERG:  Can I ask my other question as well?
DR. GRAHAM:  Go ahead and finish.
DR. KREISBERG:  Okay.  The other issue has to do with what you said and the estimate that Dr. Hirsch made about 50,000 cases of acute hepatic failure, and that sounds to me as if you're saying that this is not an idiosyncratic reaction because over time, you expect to see a cumulative increase, and that suggests that time will bring it out.
What's the possibility that time will bring out the reaction in those individuals who are susceptible to it, but not in those individuals that are not?

DR. GRAHAM:  That's perfectly possible.  What you're doing then might amount to sort of almost a eugenic sort of selection process though because what you're really doing then is let's propose, for example, that it's due to an underlying metabolic polymorphism, and we're selecting out people who are sensitive.
Well, we have to identify what that polymorphism is and the mechanism and everything else to select those patients out so that they don't get exposed to the drug, and if you were able to do that, then maybe if that were the mechanism, then maybe you could eliminate acute liver failure from happening.
The fact is we don't know what the mechanism is.  All we can do is say what we observe in the rates, and what we observe in the rates is that as far out as eight months we have not weeded the population of everybody who's susceptible to acute liver failure from troglitazone.  They're still there.
DR. KREISBERG:  Thank you.
CHAIRMAN BONE:  Dr. New.
DR. CARA:  Just can I just make a follow-up comment?
You're assuming that the population that is on troglitazone is constant.

DR. GRAHAM:  Well, no.  What I'm assuming is based on the data that we have up to now, is that you'll continue to have new people who get on board who start at month one and then have to ride basically the train through six months and then out beyond.  so they've got to ride the trade from a period of background rate, when they're not on troglitazone of, you know, one per million per year, hop on the train in the first month, have a rate of 56 or whatever it is with under reporting, and then take the train up the hill to 185 or whatever it is, and then follow at that high altitude until I don't know how long.
And so somebody who starts the drug today, these are sort of the mortality risks that that patient will have to pass through as they go through time.
CHAIRMAN BONE:  Okay.  Thank you.
Dr. New.
DR. NEW:  Dr. Graham, did you control for the possibility that at the moment that there is a rapid rise or a sudden fatal hepatotoxicity that induces death, as you've just said, in the absence even of liver function abnormalities, that this could be due to the fact that somebody was taking another medication?
DR. GRAHAM:  In virtually all of the cases, other medications were excluded.  About 20 percent of these patients were taking concomitant statins for hypercholesterolemia, which is the exact percentage found in the United Health Care database.

Acetaminophen wasn't implicated in any of the cases, and there was not a common thread in any of the cases.
In terms of those two case, it's not that they didn't have liver enzyme abnormalities.  It's that the ammonia elevations preceded by a couple of days the development of high transaminase levels.
DR. NEW:  Dr. Bone, I just want to refer back to Dr. Marcus' question about putting the risk of troglitazone on the background of the risk of diabetes, and I think we have to come to that because I don't think patients care whether they die of troglitazone poisoning or of diabetes.
DR. GRAHAM:  Well, could I make one comment on that, which is --
CHAIRMAN BONE:  We're going to have our discussion later.  We're going to concentrate on specific questions about Dr. Graham's presentation.  We've already spent quite a lot of time trying to get at that as pieces of information.  I think we should focus on that for the rest of this time period.
Dr. Molitch.

DR. MOLITCH:  I have a couple of questions that deal with the interval specific hazard rate and then the cumulative risk, and perhaps my naivety as a statistician, and in addition, I have a question about the nature of the under reporting of acute liver failure and your estimate that it's only ten percent.
But I understand that you made a number of other efforts talking to transplant centers, UNOS registries, et cetera, to ascertain these 43 cases of acute liver failure.  Do you really think, in fact, over this time period that there are 400 cases of liver failure occurring in this country and not 43 or do you feel that that 43 is actually a fairly close representation of the true number of case?
DR. GRAHAM:  No, I think that the number is closer to 400 than it is to 43, and that most cases with acute liver failure don't make it to transplant centers, and that most patients with acute liver failure due to drug induced cause don't receive transplantation for it.

I mean we'll leave -- the University of Texas has -- I don't know where he gets the data from, but it's in two of his publications that only one in ten patients with acute liver failure get transplanted.  So I do believe that the number of cases of acute liver failure with troglitazone is much closer to 400, and the internal consistency of the data would suggest that it's about ten times as much as the number of cases we have reported.
DR. MOLITCH:  But the internal consistency of the data, again, deals with one case in a couple of large series that come up with that same kind of figure.
DR. GRAHAM:  Well, now, you've got the DPP.  You've got the REACH study, and although it's not validated, we have from the United Health Care what appears to be data that are consistent with the other two, and then we have the modeling that we did that ends up giving us a predicted rate, that 1,000 per million person-years at six months that's virtually on the nose with everything else, coming at it from an entirely different angle.
And so it's sort of like different threads of information coming from different sources that are unrelated, giving rise to very similar estimates of risk are what we find sort of persuasive, or at least I find it persuasive.
DR. MOLITCH:  I just find a very thin thread, and with all of the media hype that has gone on over the last year, I wonder whether, in fact, it's still just a ten percent under reporting.

DR. GRAHAM:  Well, what we know about stimulation of reporting, we don't see the evidence of it in the cases.  I mean, you know, it's always possible that some cases are stimulated, but you still have, you know -- if it turns out that we've got, you know, 12 percent of the cases instead of ten percent or 15 percent instead of ten percent, we don't have 25 percent.  I mean that's an unheard of reporting rate in the United States.
DR. MOLITCH:  My second question deals with the interval specific hazard vapors as cumulative risk, and it looks like the intervals specific hazard rate does go down after six months; is that correct?
DR. GRAHAM:  Well, what happens though is that the confidence bounds go up.  So the point estimate has gown down.  It's still above what it was in the preceding months, and in the last month, it flips up to a level that's intermediate, but the confidence limits on that are such that who's to say that it does in truth.  We'll only know with the accumulation of additional cases.

DR. MOLITCH:  But to take that to a specific patient situation where we have a patient in the office that we're treating, if we are seeing a patient who has had normal liver enzymes for six or eight months, is that person still at the same increased risk at month nine, is what you're say, than what they were at month four?
DR. GRAHAM:  Yes, yes.  Clearly, at month four whether they're at the same risk as month six, I would feel less comfortable about saying that it's exactly the same.  I would say that qualitatively it's the same.  It is still far above what the background rate would be.
DR. MOLITCH:  Was this information known when you came up with the eight month recommendation for the liver function testing?
DR. GRAHAM:  Oh, no, no.  I mean, I think that eight months -- well, Dr. Bilstad and Dr. Sobel could talk about how that number was come up with.
These analyses were not done until preparation for this Committee.
CHAIRMAN BONE:  Thank you.
I think Dr. Temple had a question for Dr. Graham.

DR. TEMPLE:  Yeah, I do.  Just one point on the last discussion.  Many times people think that the so-called idiosyncratic liver reactions are things that only occur early.  So the crucial question isn't so much whether you can pin down the exact rate as to whether the risk is essentially gone after a period of time, and I think David would argue he can't pin the numbers down, but he's saying it looks like it's not gone.  You continue to get late cases.
I had a question about page 17 also.  You explained why you decided not to pool the various population based data, but by doing that, in a certain sense you give the studies that didn't have any cases no credit at all.
So my question to you is whether you did, even though you don't think it's the right thing to do, do an overview of those studies and come up with a rate.
CHAIRMAN BONE:  Excuse me.  For the Committee, where is this?
DR. TEMPLE:  Oh, I'm sorry.  It's page 17 of the handout.
CHAIRMAN BONE:  Which handout?  There are several.
DR. TEMPLE:  David's slides.  It was already referred to once.  It's called "Summary of Population Based Data on Risk of Acute Liver Failure."
PARTICIPANT:  The material we received, page 17 has something else.
DR. TEMPLE:  NO, no.  I think it's a handout that just came around.  It's his slides.

CHAIRMAN BONE:  Oh, this handout.  All right.  Not the briefing book.
DR. TEMPLE:  No.
CHAIRMAN BONE:  I'm sorry.  Please go ahead.
DR. TEMPLE:  Okay.  It's a list of five studies.  It's the one that people have been discussing.
CHAIRMAN BONE:  Yes.
DR. TEMPLE:  It shows two cases among five studies.  Three studies don't show any, and you have confidence limits for them, but what you don't get is what might be called an overview of those data, which you can guarantee will give a somewhat lower rate.
DR. GRAHAM:  Well, now a couple -- okay.  Thank you, Lanh.
DR. TEMPLE:  let me just finish my question.  I did it crudely.  I get a rate of about 500 per million, which you know, is close enough to 1,500 so that it may not matte.
DR. GRAHAM:  Right.
DR. TEMPLE:  But it is different.

DR. GRAHAM:  Okay.  Well, a couple of things that I'd say about that, Dr. Temple.  One is that there are a number of other studies that aren't shown on this slide.  We can only fit so many on a slide, but they were in the sponsor's briefing document.
If you were to contemplate grouping these studies together in some sort of meta analytic way, I would say that it's absolutely necessary to create strata that cover different time periods on drug because of the way the hazard changes over time, and that when you do that, it's a shame.  This is a slide that was in the talk, but it was another one that had to get pulled out because it's too complicated.
If Dr. Bob O'Neill were here in the audience, he could discuss it because it was from an article that he wrote, but what it basically says is that you've got to take the patients who are on the drug, say, from zero to three months, and then for more than three months up to six months, then eight months, and take those different strata and the proportions in each study, and then basically do a Mandell-Henzel analysis that looks at the power within each of those strata to identify the risk.

Now, in the talk, I gave a discussion about that I did that for the NDA study, and what I found is that the grouped analysis gives you this upper bound of 2,500, but if I looked at the place where the risk is really greatest, in this group over six months, that the upper bound was actually 5,600 or close to 6,000.
And so it actually works opposite.  You get the smaller confidence limit, but it's because you're grouping all this time, this two months and one month in the Sankyo study and this Galaxo study and all those other studies, and so you're diluting the effect.
So if you were going to do a meta analysis and you were going to combine these data, you'd have to stratify for time.
DR. TEMPLE:  I guess I'd say that depends on what you believe most about which the data are.
CHAIRMAN BONE:  Okay.  Thank you.
We're going to come around, and we have other members and we'll come around.  Let's see.  Dr. Lewis.  
We can leave this slide up for the moment if you'd like or just have it read to retrieve.

DR. LEWIS:  I'd like to come back to the issue of exactly when the cases are occurring among these 43 that we know about.  If we look at page 8, the slide on that that talks about the characteristics of the 43 patients, the duration of therapy is a fairly -- it's short at four days and it's up to 236 days.  How many of the patients were actually within the first month --
DR. GRAHAM:  Of the cases?
DR. LEWIS:  -- of the case.
DR. GRAHAM:  Right.
DR. LEWIS:  Where they were only taking troglitazone for 30 days and the event occurred.
DR. GRAHAM:  Right.  I think it's unfortunate.  That was another slide we had in our talk, and it got censors.  I'm just saying this to let Dr. Ho know.
CHAIRMAN BONE:  We're really short on time, and we don't need that discussion.  Let's go.
DR. GRAHAM:  I think the answer was five.
DR. LEWIS:  So only about ten percent were in the first month.  So most of these occurred within the subsequent few months, and it doesn't seem like there was anybody after eight months of treatment.

DR. GRAHAM:  But we have no reported cases of liver failure after eight months.  The problem is that the denominator of use of patients who are at risk to develop it is down there below 30 percent of the population, and so what that means is that in order to sort of produce cases that get through the under reporting and everything else, you really have got to wait for time to accumulate there, and then we'll be able to test the hypothesis fairly.
CHAIRMAN BONE:  All right.  Dr. Illingworth, did you have a question?
DR. ILLINGWORTH:  From your analysis of the results, is it possible to estimate how many patients were on other drugs or were taking other drugs briefly that are metabolized by the cytochrome P3A4 system?
DR. GRAHAM:  Okay.
DR. ILLINGWORTH:  And may be potentiators of inducing toxicity under stable conditions?
DR. GRAHAM:  Right.  The majority of patients, the drugs that they --  were basically only on drugs for the treatment of their diabetes.  About 20 percent were on statins, and then there were two or three patients who were on various NSAIDs, and there were a few patients on calcium channel blockers, but the majority of patients were on those drugs.
DR. ILLINGWORTH:  I'm thinking specifically of a patient, say, that had been given erythromycin for an acute infection.  Could that have been the trigger in some case or was that looked at?

DR. GRAHAM:  Yeah.  In no patient was there a setting like that.  Patients, you know, started the troglitazone.  If they were on other treatments, most of the time those treatments had been continuous, and the troglitazone was added to it, and there was no like particular drug that stood out as a common thread in, you know, more than a few cases at a time.
CHAIRMAN BONE:  I think Dr. Genuth is next.
DR. GENUTH:  Could you put up the slide again, the infamous page 17 slide?
When I looked at that slide, like Dr. Kriegsberg, I was intuitively puzzled.  So I'd like to ask his question just a little differently.
You want us to focus on the 95 percent confidence intervals and, in particular, the upper for safety purpose.
DR. GRAHAM:  Right.
DR. GENUTH:  So I'd like to know in your calculation, in a study where there are no events or even a study with one event, how reliable is your estimate of the upper 95 percent confidence interval?

DR. GRAHAM:  Well, it has the statistical properties of a 95 percent upper bound, and what a 95 percent upper bound says is that we can be 95 percent sure, and if you do it one sided and you make it 90 percent bound, we just say that there is a five percent chance that the rate that we're observing could be greater than that.
DR. GENUTH:  No, I understood that.  I want to know how reliable the 95 percent confidence intervals are when there are zero events or one event.
DR. GRAHAM:  Well, no.  I'm not a statistician either, but you use programs like SAS where they've worked out the statistics of it, and it's statistically accurate.
What level of, say, imprecision there is is expressed in the width of the confidence interval.  That's sort of the best answer I can give.
DR. GENUTH:  I know we're short of time.  Let me try to get at it slightly differently.
DR. GRAHAM:  Okay.
DR. GENUTH:  When you calculate a 95 percent confidence interval in a study where there are ten events versus a study where there are zero events ‑-
DR. GRAHAM:  Right.
DR. GENUTH:  -- is there a difference in the confidence you can have as to what that upper bound is?

DR. GRAHAM:  No.  Well, what you know is that the bound -- when you have more events in a given study, your upper bound will come in closer.  So part of the problem of what we're dealing with here though is that you're dealing with an event that has a background rate that's just so incredibly low that in order to bring that bound down to, say, closer to the point estimate if the point estimate is 1,000 or it's 1,200, to bring that upper bound down to 1,500 or 1,800, the size of a study that you'd need to do that, I mean, dwarfs the imagination, I mean, because you're dealing with a background expected rate of one in a million.
And so you're sort of trapped in this dilemma, but what we're pointing in that upper bound risk is basically the incidence rate.  What is the upper possible incidence rate from these data?
CHAIRMAN BONE:  Let's see.  Dr. Braunstein, did you have another question or comment?
Do I understand correctly then that the number of cases of idiopathic acute liver failure in the United States is about 200 per year?
DR. GRAHAM:  That's correct.
CHAIRMAN BONE:  Have we seen a tripling of the number of cases of idiopathic acute liver failure?

DR. GRAHAM:  They don't collect statistics on that.  So you have to sort of -- you can look at transplants, but most patients don't make it to the transplant centers.
There's no central place where this data is all collected that you could sort of look for for secular trends.  One might be able to -- I mean even death certificate data is incredibly difficult to use.  So there's not an easy answer to look to see has there been a secular effect.
CHAIRMAN BONE:  Yeah, and how many transplants are done a year?
DR. GRAHAM:  It's about 4,000, 4,500, and as I showed you before, about six percent, it turns out, are done for acute liver failure, and of that six percent a smaller percentage, you know, less than, you know, a quarter are due to transplantation for drug induced causes.
CHAIRMAN BONE:  Well, let me see then.  That would mean that you would have how many done per year for drug induced causes?  A quarter of --
DR. GRAHAM:  Well, I mean, it's really hard to answer these questions without having -- we have a lot of these slides in sort of like background material.

CHAIRMAN BONE:  Just please do the arithmetic.  You said about 4,000 liver transplants.
DR. GRAHAM:  Right, and about six percent.  Six percent of 4,000 would work out to like 240.
CHAIRMAN BONE:  Two hundred forty, and a quarter of those would be 60.
DR. GRAHAM:  Well, it's less than a quarter.  There's a slide, Lanh, that was the UNO slide on transplants, and it was like .66 per million and .11.  So about a sixth of transplants for acute liver failure are due to drug induced causes.  That's like about 15 percent.
CHAIRMAN BONE:  And you don't think that that 40 or so -- that's about 40 a year.  So you think that --
DR. GRAHAM:  Yeah, 40 or 50.
CHAIRMAN BONE:  -- if we had ten percent of the people going to transplant, that would double the number, but you don't think you'd have picked that up in your --

DR. GRAHAM:  Oh, not in the -- the data that we have don't go through the period of time, and actually we know from our data of like about four or five patients with hepatitis who were placed on a transplant list, and then we have the seven patients that we know were transplanted, and all of these occurred before December '99, but they're not reflected  yet in the UNOS data.
So I can't explain what the lag is there on their end.
CHAIRMAN BONE:  All right.  You can see where I was trying to get a little corroboration.
DR. GRAHAM:  Right.
CHAIRMAN BONE:  I think one of the concerns that many of us would have had to do with the estimate of the under reporting and the validation.  I had a little trouble following the relationship that you have found between your estimate and the number of cases that you had from the HMO data.
DR. GRAHAM:  Can I explain that?
CHAIRMAN BONE:  Yes, concisely, please.
DR. GRAHAM:  Okay.  Take a study.  Let's take the DPP study or the REACH study.  Take the REACH study, and in the REACH study we had a rate of like what, about 1,200 per million person-years for liver failure.  Well --
CHAIRMAN BONE:  That's with confidence limits of 32 to --
DR. GRAHAM:  Right.
CHAIRMAN BONE:  -- 7,000 for those who don't have the slides.

DR. GRAHAM:  Right, and I based the under reporting rate on the point estimate, which I think is a reasonable thing to do, and what you do is you say:  well, okay, in the United States what's the cumulative person-year time of exposure to troglitazone?
The answer is about 676,000 person-years of time, all troglitazone use from March up through December '98.
Okay.  Divide that number, 676,000, by the number 1,274, and that will give you the number of expected cases, and then compare that number with the number that's reported, and that's your reporting rate, and that's called an observe to expected analysis, and I had slides to talk people through this one, too.
CHAIRMAN BONE:  Excuse me, Dr. Graham.  You've made that point several times.  The point is here though --
DR. GRAHAM:  Well, no, but it would help if you could see it to focus on.
CHAIRMAN BONE:  But it also appears to me that if you -- but when you're making that estimate, it has extremely wide confidence limits on that estimated occurrence rate.

DR. GRAHAM:  Well, we can recalculate it going with the lower bound and recalculate it with the upper bound.  In the end, you're kind of left with, you know, having to make a decision, and the point estimate to me just seemed to be the fairest place because the point estimate is what was observed.
CHAIRMAN BONE:  Well, yeah, that's one case, and that's the point that's been made here.
DR. GRAHAM:  Well, but it's a very rare event and --
CHAIRMAN BONE:  Let's don't have a debate about this.
The other question I specifically had though was relating your occurrence rate in cases of acute liver failure or hepatitis and the HMO group that you had.  You had three cases of acute liver failure, I think, and four --
DR. GRAHAM:  Yeah, that's claimed, and four of hepatitis, hospitalized --
CHAIRMAN BONE:  And those cases have not been investigated?
DR. GRAHAM:  We have not obtained the medical records yet.  That's correct.

CHAIRMAN BONE:  Okay.  Now, did you use those estimates from that database?  I thought I understood you to say that you attempted to relate that to this reporting rate question, and that's what I was trying to get at here.
DR. GRAHAM:  No.  In a slide right before my summing up slides, I took the study, the DPP study, the REACH study, the UHC study, and the NDA study and calculated what the reporting rates would be using those rates just to give people a full flavor.  You could cross out the UHC line if you wanted to cross it out.
CHAIRMAN BONE:  No, I was just trying to understand.
DR. GRAHAM:  But the fact is that actually the UHC line gives you a higher reporting rate than with the other studies.
CHAIRMAN BONE:  Well, with unadjudicated cases.
DR. GRAHAM:  Well, there we had three, but they're not validated yet.
CHAIRMAN BONE:  That's right.  I mean, we don't know whether they had viral hepatitis or something, too.
DR. GRAHAM:  Well --
CHAIRMAN BONE:  We can't use those cases.

DR. GRAHAM:  -- we don't know it exclusively, but the codes that we have don't indicate that, and usually --
CHAIRMAN BONE:  That's what I was -- I was trying to get at how you'd use those cases without having reviewed the records.
DR. GRAHAM:  But I think we presented it in the context of all the other data that are available.
CHAIRMAN BONE:  I understood that part.
DR. GRAHAM:  Okay.
CHAIRMAN BONE:  Thank you.
Dr. Lewis or anyone else?  We have final questions here.
It's now noon.  So we're going to have to make some plans about how we're going to proceed after this discussion, but go ahead.
DR. LEWIS:  Just in terms of these severe adverse drug reactions and the under reporting, is it the same for fatal adverse reactions as it is for headaches or diarrhea?
DR. GRAHAM:  No.  For hospitalization or death, the reporting rates seem to be very similar.  For less severe adverse reactions, the belief is, and in places where it's been looked at, those reporting rates are even poorer than for the severe reactions.

DR. LEWIS:  Right, because as a practical matter, we're not seeing this epidemic of fulminant hepatitis due to drug or other things.  I mean it's been a fairly constant rate.  There are several hundred cases a year of viral hepatitis that are fatal and a number of drugs, some of which are known to be the drugs and some are not.
And the question about how many people get transplanted for acute drug induced liver disease that's failed, it doesn't mean that they all don't get the transplant centers.  More and more people are actually being evaluated, but they don't necessarily get transplanted because of co-morbid disease.  They may simply be too sick when they get there, and we don't have really good numbers on that.
DR. GRAHAM:  Right.
DR. LEWIS:  But, you know, whether it's 43 cases or whether it's really been 430 cases, it doesn't sound like it would be the 430 from what you just said when we do have better reporting of the more severe toxicity.

DR. GRAHAM:  Well, one thing to say about that has to do with attribution of the liver failure to a drug, and in several studies where that's been looked at even, say, for fatal INH hepatitis, the attribution gets made in only about a quarter of the cases, and so you run into this problem that when you look at acute liver failure and the way it's classified by transplant centers and you have this category that's called drug induced, and then you've got this category that's called "unspecified," which is basically they haven't made the attribution, and we have examples of cases here where patients presented and the attribution wasn't made initially because it just didn't click.  
So you have that problem to deal with as well.
DR. LEWIS:  That runs about 25 percent.
CHAIRMAN BONE:  All right.  Let's see.  Wrap-up questions as far as Dr. Graham's presentation?  Dr. Genuth.
DR. GENUTH:  I realize you don't have this data now, but in your collaboration with United Health Care, is it possible for you to learn what proportion of patients who start Rezulin stop it for lack of efficacy?
DR. GRAHAM:  I'd have to think --
DR. GENUTH:  In the doctor's mind or patient's mind.

DR. GRAHAM:  Right.  Such a study could possibly be designed, but what it would involve is our having to go back to the physicians to understand what was going on, and that would be a more complicated and expensive study, and it wouldn't be the focus of what our cooperative agreement is intended to do, which is to study the adverse effects rather than something like this.
So it theoretically could be done, but it would be a difficult study for us to do.
CHAIRMAN BONE:  Thank you.
Thank you, Dr. Graham.
This is a final question, Dr. Cara, about Dr. Graham's presentation.
DR. CARA:  I'm concerned about the fact that when you look at the date from the sponsor, again, there is about half of their cases of acute liver failure were patients on monotherapy, whereas in your population based data you said that about 80-plus.
DR. GRAHAM:  I don't think 50 percent of the cases were on monotherapy with troglitazone.
DR. CARA:  Twenty out of the 43?
DR. GRAHAM:  No, I don't think that that's correct.

CHAIRMAN BONE:  Maybe we can clarify that during the lunch hour and have actual facts instead of standing --
DR. GRAHAM:  Right.  We can check our database.
DR. CARA:  Thank you.
CHAIRMAN BONE:  It's now 12:06 by the Chairman's standard time.
(Laughter.)
CHAIRMAN BONE:  The sponsor has agreed to give their presentation straight through following the lunch recess, which will be for -- we are really going to start at 12:45.  So that's going to compress the lunch slightly.
Please be here in your seats ready to go at 12:45.  We've got to get back on track.
(Whereupon, at 12:06 p.m., the meeting was recessed for lunch, to reconvene at 12:45 p.m., the same day.)

	A-F-T-E-R-N-O-O-N  S-E-S-S-I-O-N
	(12:46 p.m.)
CHAIRMAN BONE:  The first presentation of the afternoon will be the introduction by Dr. Robert Zerbe of the sponsor, and then there will be a series of presentation as you see in the program.  
We are going to go straight through the sponsor's presentations since we have already taken the lunch recess.  Committee members have been asked to reserve their questions until the end of the presentation.
Please be quiet in the back, please.  The Committee is in session, and we're proceeding now.  Thank you.
The company has advised me that they anticipate that questions that may arise during some of the earlier presentations will be answered as they go along with the subsequent ones, and in the interest of efficiency and flow, have asked that we reserve questions until after their presentation.
We'll then have a period specifically directed to questions about the presentations by the sponsor's speakers, and then we'll have a general discussion.  So we'll try to stay on task on those two separate areas.

Thank you.
Dr. Zerbe.
DR. ZERBE:  Yes.  Dr. Bone, Advisory Committee members, and guests, I'm Dr. Robert Zerbe, Senior Vice President for Clinical Research and Development at Parke-Davis, and it's my pleasure to introduce our presentation on the risk-benefit assessment of Rezulin, a novel treatment for Type 2 diabetes.
We appreciate the opportunity  to share this valuable information in a scientific forum, and we look forward to your comments.
It was a little over two years ago when we presented for the review of this Committee the initial clinical efficacy and safety data for Rezulin.  The review at that time was based on an NDA submission filed in July 1996 which showed significant improve in glycemic control when Rezulin was added to insulin in patients who were inadequately controlled with insulin alone.
Following a positive recommendation by the Committee, the FDA granted approval of the initial application in January 1997.  

An SNDA submission to extend the indications to include both sulfonylurea combination and monotherapy was submitted in February 1997 and was approved in August 1997.
In November 1998, another SNDA was filed to extend the indications to include the addition of Rezulin to patients who had failed the combination of sulfonylureas and metformin.  This efficacy supplement will be discussed today.
Rezulin has shown excellent efficacy  as demonstrated by significant reductions in hemoglobin A1c whether it is added to a treatment regimen of patients who have failed diet, failed sulfonylurea, failed insulin, or failed the combination of sulfonylurea and metformin.  Clinically significant reductions in hemoglobin A1c resulted.
In the groups which continued previous therapy, the hemoglobin A1c either remained the same or increased, as indicated by the white bars.  These clinically significant effects will be discussed extensively later in the presentation.
Clearly, Rezulin is quite effective when administered in a variety of situations, and this efficacy has translated into wide use of the drug since its launch approximately two years ago.  Since that time over 1.5 million patients have been treated with the drug.

Now, over that time, there have also been significant label changes related to safety.  Dr. Bilstad reviewed these in detail.  So for the sake of time, we will not repeat them.
Sine the initial observation of severe hepatic failure, Parke-Davis has worked closely with the FDA and outside consultants to better understand the mechanism and epidemiology of these events.  We have tried to better define populations that can gain the greatest benefit and, perhaps most importantly, professional educational initiatives were undertaken to inform physicians and patients about the importance of monitoring.
Fortunately, these efforts have reduced the occurrence of severe liver events.  The data shown here, which will be presented much more extensively later in the presentation, demonstrate that the reports of jaundice have been decreasing since this series of label changes were initiated by Parke-Davis.

A similar trend is evidence in death and transplant reports, as you will see later in the presentation.  This has occurred despite an ever increasing number of patients who are exposed to the drug each month.  This decreasing incidence is due in part to the recommended monitoring, but perhaps more importantly it's due to the very high awareness of this problem that has been generated and shown in surveys of prescribing physicians.
In today's presentation, we will outline the reasons which we believe that the benefits of Rezulin in the treatment of Type 2 diabetes clearly outweigh the highly publicized risks.
Following this brief presentation, Dr. Paul Watkins, Professor of Medicine and Professor of Pharmacology at the University of Michigan, who is a well recognized expert in hepatology and drug metabolism and has systematically reviewed these cases for us, will describe our current state of knowledge of the pathology, time course, and possible pathologic mechanisms of these idiosyncratic liver events.
Dr. Mark Pierce, Vice President of Clinical Research and Parke-Davis will discuss our estimate of incidence and the positive impact of label changes on these incidence estimates.
Dr. Gerry Faich, who is formerly head of the Drug Postmarketing Surveillance at the FDA and is currently President of Pharmaceutical Safety Assessment, has assisted us in this analysis and will join Dr. Pierce in the presentation.

Drs. Pierce and Faich will show a different picture than that that has been portrayed by earlier presentations, and they will show that these events are rare, and the rate is decreasing.
Dr. Philip Home, Professor of Diabetes Medicine and Endocrinology at the University of Newcastle in Great Britain and Vice President of the International Diabetes Federation, will discuss the comparative risk of troglitazone.  Dr. Home, who has researched and published in the spectrum of therapies in diabetes will present data which show that the risk of Rezulin treatment is comparable to the risk of therapy with other agents available to patients with Type 2 diabetes.
Dr. Randy Whitcomb, Vice President of Clinical Research at Parke-Davis, will present a summary of the data that demonstrate the benefits of Rezulin therapy in a wide range of Type 2 diabetes patients.
And finally, I will conclude the session with an overall summary and assessment of the risk-benefit ratio, which we feel remains quite positive.
In addition to the presenters, the following additional consultants will be available for comment:

Dr. Thomas Buchanan, Associate Professor of Medicine at USC;
Dr. Andrew Drexler, Director of the Mount Sinai Medical Center;
Dr. Judith Jones, former Director, Division of Drug Experience at the FDA, and currently President of the Degge Group.  Dr. Jones has some valuable information which we will try to include in our presentation.  If that's not possible, we would be very happy to present it in the discussion period.  It is relates to an employee database cohort looking at the background incidence and comparative risk of liver events in treatments for Type 2 diabetes.
Dr. Chris O'Conner, Associate Professor of Medicine at Duke University.
Dr. Jerry Olefsky, Professor of Medicine and Head of Endocrinology and Metabolism at UC, San Diego.
And Dr. Ken Polonsky, who also helped us in the evaluation of this, was unfortunately unable to join us, but he's head of medicine and head of the Division of Endocrinology at the University of Chicago.

Our series of presentations will clearly demonstrate that the risk of liver related death and transplant is low and declining.  The risk compares favorably to the risk of serious events associated with other available treatments; that physicians have a high awareness of the risk and the need for monitoring; and that Rezulin through its unique mechanism provides marked benefit in combination and in monotherapy to hundreds of thousands of patients.
I'd now like to introduce Dr. Paul Watkins, Professor of Medicine and Professor of Pharmacology at the University of Michigan, to provide a description of the liver events with troglitazone.
DR. WATKINS:  I am Professor of Medicine and Professor of Pharmacology and Director of the Clinical Research Center at University of Michigan.  I am practicing hepatologist there.
I have consulted at some time with most of the major pharmaceutical companies, and I've listed here the active consulting contracts I have.  I do not receive, own stock in or receive research support from any of these companies, including Warner-Lambert, Parke-Davis.  I also have a consulting contract with the Food and Drug Administration, but have not consulted with them on issues related to troglitazone.

By way of background, what we are talking about here is hepatocellular injury.  This is when a drug or the metabolite of the drug injures the liver cell in a global fashion, causing liver cells to leak or die, breaking open, releasing their contents into the blood, and that content included alanine amino transferase or ALT.
In an otherwise healthy liver, the height of the serum ALT should correlate with the extent of injury that's occurring, and by convention, three times the upper limit of normal has been considered clinically significant, although the actual degree of injury occurring at that level is quite mild.
When jaundice occurs in an hepatocellular injury as opposed to other types of injury, severe liver injury has occurred, and the purpose of ALT monitoring is to prevent the onset of jaundice.
This is a typical patient manifesting ALT elevations in the clinical trials, and what's shown here in light blue is the serum ALT as a function of time on drug with monthly monitoring, and as was characteristic, there was no evidence of liver injury until in this patient about four months on drug when the serum ALT gradually rose.
The drug was discontinued.  You may not be able to see the yellow line there, and then the serum ALT returned to normal, indicating resolution of the liver injury.

Characteristically in the clinical trials, the ALT elevations were between two and seven months on drug.
Now, the rationale for monitoring is that by catching the ALT rise before jaundice -- you can see the bilirubin was not affected, shown in orange ‑- you prevent progressive liver disease to jaundice and perhaps worse.  So you would assume that stopping the drug at this point prevented the progression of disease, and certainly that appears to be the case in some individuals.
However, we were able to learn from the clinical trials that that's not always the case, and that was because in the pre-approval clinical trials, or most of them, there were no stopping criteria based on ALT, and ALT elevations were generally asymptomatic.  So that in about half of the patients who developed an ALT elevation greater than three times the upper limit of normal, the physician elected to continue therapy with the drug.

And what's shown on this slide is one such patient who manifested the typical elevation -- this is a constricted time scale -- over a couple of months, then had the serum ALT return to normal, but in fact, stayed on the drug until almost two years later when the study was discontinued.
And actually there were five patients in the clinical trials treated through ALT elevations greater than ten times the upper limit of normal.  When the serum ALT returns to normal with this type of injury, the liver is normal, and there was never any change in the serum bilirubin, and what this tells us is that with this drug, as with other drugs such as propathyaurasil tacrin, the liver does have the ability to adapt to the initial injury.
We are forced, however, to stop all people whose ALTs elevate because we don't know which subset -- we're incapable of identifying them that will go on to an aggressive injury.
Now, I was brought in immediately after the first severe liver event was noted postmarketing in the fall of 1997, and since then I've reviewed all Med Watch reports of liver related events on a weekly basis.  
In the last several months we formed a team.  That's myself and two other hepatologists at the University of Michigan, who have contacted the institutions, tried to speak to the relevant physicians, to obtain complete information on all the cases.

In addition, we have called in other renowned hepatologists at various times to review the cases.  Willis Madre in Dallas has reviewed essentially all of the cases.  Additional hepatologists have seen some cases have been Steve Shanker in San Antonio and Neil Kaplowitz in Los Angeles.
Before I show you the results of the actual analysis, I want to make two points that have come up earlier.  One is there is an increased background of liver disease in the diabetics due to nonalcoholic steatohepatitis or NASH, an increased in viral Hepatitis C.  There's no question these can progress to cirrhosis, hyperbilirubinemia, encephalopathy, and death.
However, as you've heard before, these would not be expected to cause an acute liver failure picture.  However, their presence would predispose individuals to develop an acute liver failure picture where they otherwise might not have.

This is another point --I'm sorry if some can't see it in the back  -- that was made earlier.  This is the most recent review of acute liver failure cases that occurred at 13 academic medical centers between 1994 and 1996, and the point made -- there were 295 total cases -- actually what they call cryptogenic or non-A, non-B, non-C hepatitis accounted for 43 cases or 15 percent of the total cases.
This is not a category because of lack of a complete work-up.  There does appear to be a discrete entity which acute liver failure of unknown cause, and there's been nothing characteristic or even pathomnemonic of troglitazone induced acute liver failure, including histology.
So with any individual case, it's not possible to say with absolute certainty that the drug was the cause.
This makes a point that has not been brought up previously, and that's that we anticipate when looking at spontaneous reports of hepatocellular injury postmarketing to find the number of jaundice cases to outweigh the number of deaths, that is, the number of those jaundice patients who go on to die by about ten to one, that is, a ten percent incidence of death amongst those that are jaundiced, and I've listed several drugs here.  I've picked these because they're still on the market.  

This trend actually applies to other drugs now off the market, such as tiolinic, and to show you how to read it, I'll just go with the nonsteroidal diclofenac, where a recent review by several respected liver experts concluded that 90 cases reported to the FDA -- this was over a one and a half year period -- of jaundice was due to the drug.  This is hepatocellular jaundice, and seven went on to die, or about a seven percent death rate in those with jaundice.
And there are two points in this.  One is we expect in looking at hepatocellular injury to see a jaundice to death rate of about ten to one.  That's what's anticipated as generally seen.
The other point is that ten percent of people who are reported to jaundice will go on to die.  So although we've heard about 43 cases of acute liver failure, the most conservative approach is really to look at all patients who have become jaundiced.
Now, I'm going to go to the actual analysis here and give you the actual numbers.  There were a total of 290 cases where jaundice or an equivalent term, yellow eyes icterus, was present somewhere in the Med Watch report.

Ninety-six in this review process were felt to be unlikely or unrelated to drugs, such things as metastatic cancer to the liver, for instance, leaving 194 cases of jaundice that were considered to be probably related to drug, possibly related to drug, or to have insufficient data to draw any conclusion.
My charge from the beginning from the company has been to consider all cases to be due to the drug unless an alternate, more likely etiology can be identified.  So we'll assume that 194 cases of hepatocellular jaundice were due to the drug.
Now, what that tells us from historical precedent is we would anticipate approximately 20 of those to go on and succumb from the injury.
These are the tally of U.S. deaths and transplants.  Within that 194, there were 75 total cases, and I will show you in a subsequent slide all of the numbers.  Sixteen were judged to be probably related to the drug, and another 12 were judged to be possibly related to drug, coming up with a total of 28, or close to the ten-to-one ratio anticipated.
Now, within these 28 patients, there were confounding factors, and I've summarized them on the next slide.  Seven had clearly documented, significant preexisting liver disease.  Three had Hepatitis B surface antigenemia.  Two had confirmed cirrhosis.  One had biopsy proven NASH, and one patient had cytomegalovirus infection concomitantly, and I'll talk about that case in a minute.

Nine were on drugs known to produce severe hepatocellular injury, and 12 had neither drugs known to produce hepatocellular injury or documented preexisting liver disease, but actually each of these cases is quite complicated, and I urge the Committee members to look at the summaries and the company has binders with the actual Med Watch reports for those who want all of the available information.
This is building on the last slide.  We see our 28 probable/possible.  There was an additional 12 patients who had insufficient data to arrive at a conclusion, and if you add those 12 to the 28, you would come up with a number of 40 patients who had a liver related death or transplant that could be attributed to the drug.
Thirty-five of these cases, to have them all add up, I think there's been universal agreement that they're unlikely related to the drug.  So the FDA number of 35 deaths and transplants in the U.S. reported experience obviously lies between 28 and 40, and in discussions between the company and the FDA, that is the number that is agreed upon, and that is the number that was taken forward.

We heard another number, which is 43, which includes people fitting the definition or appeared or may have fit the definition of acute liver failure.  The bottom line:  there are people who almost died but didn't, and of course whenever you have a population of 194 jaundice patients and 35 succumb, some will come very close to dying and pull back from the edge.
So as I see it, there's really no discrepancy in terms of agency and other numbers.
Now, one of the things that is most disturbing and compelling is the fact that there were two acute liver failure culminating in death in the two clinical trials that you heard about.  These two cases are within the 16 that have been categorized in this process as probably related to drug.
It is interesting though.  In the entire worldwide experience in clinical trials, which now is over 15,000 individuals, there have only been four patients who have apparently developed jaundice.  Two were in the preapproval clinical trials when there were no stopping criteria for serum ALT, and the other two are the two cases in the clinical trials that went on to have acute liver failure and died.

Now, this is not following historical precedent.  I'd be happy to expound on other ideas, but it does at least raise the possibility that there might be something unusual about these two patients who died in the clinical trials.
In fact, there were issues with each of these patients.  I'm going to give them and allow the Committee to draw their own conclusions.
The patient that was in the NIH trial had a flu-like prodrome prior to elevations of serum ALT greater than three times the upper limit of normal.  This was apparently due to an acute CMV infection, as documented by IgM antibodies to the cytomegalovirus.  The liver was involved because a viral inclusion body was noted in an hepatocyte in liver biopsy.
The patient went to transplant, at surgery was found to have necrotic colon, which was resected.  This is a very unusual complication for acute liver failure.
The NIH got their own team of very distinguished hepatologists listed here.  This is their entire concluding paragraph in the letter indicated, stating, "According the Committee concludes that hepatic necrosis in this case was probably caused by troglitazone and believes that an important contributory role in the fatal outcome may have been played by bowel necrosis, a lesion for which the CMV infection is speculatively incriminable."

The second case was admitted, had acute liver failure on admission or shortly thereafter.  The relatives gave the history that this patient had a very substantial liver intake or alcohol intake.  I'm quoting directly from the Med Watch form when I say 12 beers daily for 20 years.
Could this have been an alcohol related liver injury?  The serum AST was higher than the ALT, consistent with alcoholic hepatitis on admission.  However, the height of the serum AST and ALT, which was above 1,000 is really not consistent with alcoholic hepatitis alone.  No liver histology was obtained in this individual.
So I think troglitazone unquestionably contributed to the liver injury in each patient, and I think it is appropriate that they are part of the 16 probable troglitazone related deaths.  However, I think it's reasonable to assume that both patients probably had underlying liver disease that reduced their ability to survive the drug related injury.
This summarizes the nine cases we've heard about that were called rapid risers, and I realize this is a difficult slide to see.  The numbers here in parentheses actually refer to the case summaries in your briefing document.

These cases have been reviewed through our process, and the bottom line is that four of them seem to fit the definition as described, that is, an ALT elevation or onset of what has turned out to be a very severe liver injury, possibly acute liver failure with a documented normal serum ALT less than 30 days before.
The remainder -- and I don't have time to go into them -- we either felt had other unlikely etiologies or felt the data didn't support that.
Now, the first patient is actually someone who complete had a very acute event actually and completely recovered.  So it's a semantic issue.  Is this a failure of monitoring if the person has entirely recovered?
But in any event three or four patients that appeared to have fit that definition of such a rapid rise, monthly monitoring would not have caught it.
By the way, these three death cases are the only three cases in the 35 that fit that criterion.

Now, in my final minute I've been asked to say some comments about the mechanism of hepatotoxicity.  It is not known.  In part, this reflects the nature of studies with essentially all idiosyncratic hepatotoxins, which is that there is no animal yet identified that gets the toxicity, and in vitro models, such as cell cultures, develop toxicity only at very high blood concentrations.
In fact, data in a cell culture needs to be cautiously interpreted since the human disease does not develop until two to seven months on drug.  It's not an acute event.
However, there have been three specific mechanisms that have been actively pursued.  One is the quinone metabolite.  One is a comment we heard earlier, the fact that troglitazone appears to induce an enzyme in liver called CYP384, and then possibly PPAR gamma activation itself within the liver, and I'll make quick comments about both.
This is the troglitazone molecule.  The three major metabolites are listed here.  Two are sulfate and glucuronide conjugates, respectively.  The third is the so-called quinone metabolite.  This is the moiety here.  Troglitazone has a well publicized Vitamin E moiety on it.  It's this moiety that produces this quinone metabolite.  

Quinones have a track record for causing acute , predictable liver disease, and follow-up compounds in this class lack this moiety, do not make this quinone metabolite, and are rumored to have lower incidence of ALT elevations, and for all of these reasons there's been intense interest to determine whether the quinone metabolite is, in fact, involved in the toxicity.
In spite of a lot of people trying, the quinone is stable.  It's been produced in large quantities, injected into animals, added to cell culture media.  I'm unaware of any data that suggests the toxicity is higher than parent troglitazone or others in the class, and I think people from the company are prepared to talk about this later if people are interested.
The other comment though is actually this quinone metabolite is made from Vitamin E itself and is actually detectable in the blood of people who don't even receive exogenous Vitamin E.  Vitamin E has not been associated with acute liver failure, to my knowledge, and that should be of some comfort to those of us who take this supplement daily.

The next mechanism is CYP3A4 induction, which is believed to involve an intracellular receptor called PXR.  Troglitazone enjoins other drugs that have this property.  Some, such as the antibiotic rifampin, the anti-seizure drugs phenytoin and carbamazepine, have been associated with acute liver failure, but others, such as glucocorticoids have not.  So the role this may play is unclear.
Finally, it is possible that PPAR activation itself within the liver could be involved in the toxicity because this activation has caused a change in cell differentiation, apoptosis under certain conditions, but to my knowledge, there's no evidence that supports this.
So to conclude my talk, acute liver failure due to troglitazone is a rare event.  I believe it is idiosyncratic, and I can talk about timing, change of risk over time if people are interested.
Assessment of many of the cases is not straightforward.  Nonetheless, the agreed upon number of U.S. deaths and transplant due to the drug is now 35.
The mechanisms involved in troglitazone hepatotoxicity are unknown, although this remains a very active investigation.
Thank you.
I think I will now introduce the next speaker, which is Dr. Pierce from Parke-Davis.

DR. PIERCE:  Thank you.
In the previous presentation, Dr. Watkins outlined the pathophysiology of the adverse liver events associated with Rezulin therapy.  In this presentation, we turn our attention to the incidence of those events in different populations of patients.
I will present data on the risk of serious hepatic events from two different sources.  First, I will discuss the incidence of such events in clinical trials of Rezulin conducted worldwide.  Second, I will turn to incidences from the marketed drug experience.  I will present three different estimates.
One, the overall rate since launch; 
Two, the rate before and after implementation of labeling changes incorporating liver enzyme monitoring requirements;
And, three, the rate as a function of duration on therapy.
These data will confirm that the rate of adverse events is declining.

Now, let me turn to the clinical trial data.  Troglitazone has been simultaneously developed by three different pharmaceutical companies:  Parke-Davis in the U.S., Glaxo Wellcome in Europe, and Sankyo in Japan.  The three companies collectively have studied troglitazone in approximately 15,000 patients.
In addition, the NIH sponsored a clinical trial which included troglitazone and studied diabetes prevention.
The first column of this table shows the number of patients taking troglitazone in Parke-Davis, Sankyo, Glaxo Wellcome, and NIH sponsored trials. 
The second column shows the number of those patients who developed jaundice.
And the third column shows the number of those patients who died because of liver failure.
Note that the two patients who died also experienced jaundice.  These patients appear in both columns.  These patients have also been discussed in detail by Dr. Watkins.
Overall, based on the two deaths in 15,591 individuals exposed to Rezulin in clinical trials, the incidence of liver related death or transplant is one in 7,800.  Because the incidence is based on only two events, the small numerator leads to a very wide, 95 percent confidence interval, ranging from a high of one in 2,200 to a low of one in 62,900.

Because of the wide confidence interval, the small number of cases, and their complexity, the incidence rate may have little predictive value for purposes of estimating the true incidence.  It is, therefore, not possible to confidently extrapolate this estimate of risk from the clinical trial experience to the setting of marketed drug.
I would also like to comment briefly on the data presented by Dr. Graham to estimate the incidence of liver related death or transplant in clinical trials.
Dr. Graham did not include in his presentation data from several Parke-Davis clinical trials, all of which have been submitted to the FDA.  In fact, the total of Dr. Graham's slide was 10,141.  Approximately an additional 5,000 patients were in the clinical trials done by Parke-Davis and submitted to the FDA.
Also I'd like to clarify another point.  I understood Dr. Graham to say that the Sankyo and Glaxo Wellcome data were not submitted.  They were submitted to the FDA.

We believe all data must be considered to have a complete and accurate understanding of what transpired during the clinical trials.  Importantly, there were no liver related deaths, no transplants, and no cases of jaundice in the trials that were not presented by Dr. Graham.  
The excluded trial data are poolable, in our opinion with the other data, and the best estimates of risk are derived from looking at all of the data as we have done here.
Now, let me turn to the question of the postmarketing incidence.  Overall the incidence of liver related death or transplant during the postmarketing experience is approximately one in 45,000 individuals.  For the purposes of this presentation, we will focus on an unambiguous case definition, namely, death due to liver failure and liver transplant.
We will also use the 35 cases of liver related death or transplant considered by the FDA to be possibly or probably associated with Rezulin, although I note that outside expert hepatologists do not agree with some of those attributions.
Our denominator is based on new therapy starts since launch.
May I have Slide 57, please?

The source for our denominator is the NDC source retail pharmacy database.  This is a database generated from very detailed tracking of prescriptions at 11,000 U.S. retail pharmacies.  These pharmacies provide detailed new prescription starts and persistency data.  These 11,000 pharmacies are distributed throughout the United States.  They're very representative of the entire U.S. population.
The next slide, please.
In order also to evaluate the issue of persistency, which is very important in understanding the issue of risk as a function of duration on drug, we have conducted three different studies evaluating persistency.  
In May 1997, we commissioned them to follow 5,020 patients, and they do this in a very detailed way.  Each patient is given a unique identifier, and that patient's return to the pharmacy every month is followed.  That is how the data is generated.
Because of a great deal of publicity, negative publicity, I might add, we were concerned that perhaps the persistencies were changing over time.  So we subsequently conducted or commissioned two additional studies looking at a cohort which began therapy in March of 1998, as well as one that began therapy in September of 1998, and you can see the numbers in each of those cohorts.
Next slide, please.

This data shows the persistency of those three cohorts.  You can see in red is the cohort begun in May of '97, in blue the cohort begun in March of '98, and in green, the cohort begun in September of '98.
This is actual Rezulin patient persistency, and it's a percent of the patients who began.  You can see that there's an issue.  The patients are given a 30-day grace period in the calculation, and that's the reason that the first two dates show both the 100 percent.
Then the persistency is followed, and you can see by looking, for example, at month six approximately 60 percent of the patients are still on drug.  Since the total new therapy starts amounts to 1.58 million, this amounts to one million people who have been treated with the drug for up to six months.  That means that there's half a million people approximately who have been treated with the drug for more than six months.
You can see that despite the negative publicity that the basic curves for these persistencies have not substantially changed.
Next -- leave that.  Back one slide, please.  Yes.

Based on this data source, we estimate the number of patients to have taken Rezulin since launch at 1.58 million.  As the slide shows, this yields a simple rate for liver related death and transplant associated with Rezulin since launch of one in 45,000.
I might also add that from another data source, the Physicians' Drug and Diagnosis Audit, which follows the prescribing of 3,400 physicians monthly, we have a number from that of 57 percent of the patients that are being prescribed Rezulin being female.  This differs from the number presented by Dr. Graham.
Of course, this number, one in 45,000, is only an estimate.  Dr. Graham noted that there is some degree of under reporting of adverse events for Rezulin, as well as for all other drugs.  
However, both theoretical, as well as empirical, data suggest that the level of reporting of liver related deaths and transplants in the Rezulin patients is quite high.

Let me turn to the factors that tend to increase reporting rates.  The first such factor is newness of the drug.  The rates of reporting for new drugs tend to be significantly higher than reporting rates for older drugs, with the number of reports typically peaking the second year of market.
Reporting rates for Rezulin, which was first marketed in early 1997, would share in this phenomenon of newness.
The second factor is severity.  Simply put, a large proportion of reported events for all drugs is serious events, and that is what we are discussing today.
The clarity of the signal is also an important factor both in the detection and the reporting of adverse events.  Events such as jaundice are readily identified as signals of organ damage which may be drug related, making it more likely that a physician would report the occurrence.
Another important factor is the overall trend in adverse event reporting.  During the past 20 years, there has been a significant increase in the number of reports filed with the FDA.  For example, in 1980, on 10,000 advertise event reports were filed.  By 1997, the number of yearly reports for all drugs had increased to 240,000.

Thus, Rezulin was introduced in 1997 into a medical milieu already undergoing rapid growth in adverse event report.  Although this has not been discussed in the literature, to our knowledge, I would suggest that active liver function test monitoring, particularly with the stopping rule, is another factor that would tend to increase reporting.  It is very likely that such monitoring would enhance reporting of liver related adverse events because physicians have become intensely attuned to the possible association of the drug to the event being monitored.
Another factor is product marketing efforts.  Rezulin is part of the intensely competitive market of oral hypoglycemic agents and is actively detailed.  Parke-Davis has several contacts each year with approximately 80 percent of physicians who issue 80 percent of all Rezulin prescriptions.  These contacts have increased awareness of Rezulin safety and likely have led to an increase in reporting.
It is also worth noting that sales representatives from other companies do not hesitate to remind physicians of Rezulin safety.
(Laughter.)
DR. PIERCE:  Lastly, but perhaps most importantly is the publicity factor.  Rezulin has been the subject of extensive publicity in both the lay and medical media, and a substantial proportion of this publicity has focused specifically on adverse liver events.

The stimulating effect of publicity on the reporting of adverse events in the case of Rezulin is demonstrated on the next slide.
This figure shows the number of cases of jaundice, hyperbilirubinemia in the orange bars reported by month since launch.  These bars also include all of the deaths and transplants because all of these patients also were jaundiced.
We used jaundice hyperbilirubinemia because the data is more robust than purely looking at deaths and transplants to show the effect of publicity.  The labeling changes, "Dear Doctor" letters and attendant media publicity in the fall and winter of 1997 and in the summer of 1998 stimulated two peaks in adverse event reporting.  There's one, two.
Also note that the number of reports has declined from these peaks.  This is not due to the decline in drug usage, since the number of patients taking Rezulin has continued to increase since launch.
Lastly, as reflected in the blue bars which show the number of reports by date of onset in a given month, note that some events were occurring, especially early, but unreported until the publicity associated with the "Dear Doctor" letters.

Each of these noted factors is well known to increase reporting rates, and each is applicable to Rezulin.  However, in order to get a better understanding of the level of reporting, we have tested this conclusion in two ways.
First, we contacted the United Network of Organ Sharing, the National Liver Transplant Registry.  Because UNOS records virtually all transplants in the United States and because its records reflect relevant drug usage by the patient, this database provided us with an opportunity to determine whether any transplants associated with Rezulin usage were unreported to Parke-Davis or the FDA.
According to their database, 4,394 liver transplants were performed in the U.S. in 1998.  Four of the liver transplants were in patients who had taken Rezulin, and each of these cases had been reported to Parke-Davis and the FDA.
Conclusion:  there is no evidence of unreported transplants in 1998.

Next, to further test the level of AE reporting for Rezulin, Parke-Davis commissioned a third party to conduct a survey of physicians in February of 1999.  The survey had two goals:  one, to determine the physician's likelihood of reporting adverse events; and, two, to determine actual monitoring practices for patients taking oral hypoglycemic drugs.
To minimize bias, the survey contained an equal number of questions about safety monitoring and reporting practices for metformin, sulfonylureas and Rezulin.  It is important to note that the physicians did not know who sponsored the survey, and they were assured that their responses would be kept confidential.
Six hundred physicians were selected at random from a pool meeting the following criteria.  First, they had to be in the top nine deciles of Rezulin prescribers, and each specialty matched the specialty mix in a general prescriber population.
The results showed that 92 percent of physicians stated they would report liver related death and transplant associated with Rezulin.  Confirming the clarity of signal and severity points mentioned earlier, physicians were much more likely to report serious outcomes, such as liver failure and death, compared to other symptoms.

Note the contrast between the high reporting rates for fatal outcomes either from liver failure of lactic acidosis and the low rate, 17 percent, for hypoglycemia.
Now I'd like to digress for a moment to discuss the additional data derived from the physician survey.  In addition to the level of AE reporting, we also inquired as to the level of compliance with monitoring requirements, as set forth in the labeling for Rezulin.  The data were encouraging, but point to an area where we can intensify our efforts.
The results showed that 96 percent of physicians were aware of the need for liver enzyme monitoring for Rezulin.  The physicians stated that 97 percent of their patients received baseline liver function tests prior to the initiation of Rezulin and 82 percent of patients received monthly monitoring for the first eight months according to the label.
You will notice that these results conflict with the monitoring data presented by Dr. Graham.
(Laughter.)
DR. PIERCE:  The next slide.
I'm going to suggest why that might be.

As confirmed by the Chief Medical Officer of United Health Care, there are several significant issues with the data.  In a letter provided to Dr. Bilstad and shared with Dr. Graham so as not surprise him or blind side him, and we provided this data to the FDA this week, the Chief Medical Officer noted: 
One, that claims data from laboratory service providers is missing as much as 40 percent of the time.
And, two, claims data are not submitted at all.
And, three, delays in receipt of claims processed common extend from 120 to 150 days or more.  Only this latter problem was addressed by Dr. Graham.
Accordingly, he concluded, and I quote, quote, "Simply put, a retrospective analysis of available UHC claims data cannot be relied upon to assess actual monitoring of patients by physicians."
Those circumstances are not unique to UHC and do not reflect on the quality of services provided by that group, or compliance with LFT monitoring.  Because of such problems with lab data capture, however, the claims data should not be interpreted to reflect the absolute level of monitoring.  Rather, the data are best interpreted as showing trends only.
In fact, the data suggest a doubling, if not tripling, in the number of patients being monitored during the period covered by the labeling changes.

So where does this leave us?  Based on the available data, the rate of monitoring compliance appears to be reasonably high, but as Dr. Zerbe will describe later, we will act on these results to intensify patient and physician awareness in an effort to increase compliance with LFT monitoring.
This would be expected to further increase the incidence -- decrease the incidence of liver related death and transplant.
For the reasons previously described, the level of reporting of adverse events associated with Rezulin is high, although it simply is not possible to conclusively determine what percentage of events are reported.  Accordingly, any estimate is speculative at best, and we do not believe that such speculation is appropriate in this context.
Moreover, risk estimates for other drugs rare, if ever, account for possible under reporting.  Because the comparative risk discussion that you will hear in a moment is so crucial to an understanding of the Rezulin risk-benefit assessment, and because that discussion is based on data relating to other drugs which is expressed without reference to under reporting, it is important that we compare apples to apples.

In addition to the overall incidence since launch, another important question is this.  Has there been a change in the incidence of serious liver adverse events with the labeling changes?
The incidence rates of jaundice hyperbilirubinemia, blue line, and death due to liver failure and transplant, orange line, expressed as reports per 100,000 patient-years are shown in this figure.  Shown are all cases of jaundice and hyperbilirubinemia regardless of attribution to troglitazone by date of onset.
Twenty-one cases of jaundice hyperbilirubinemia and one death could not be included in this figure because the onset date for these events was not known.
This slide shows that the reporting rate peaked in late 1997.  Thereafter the rates for these events have declined.
This table shows the reporting rate for death due to liver failure and transplant over time expressed another way.  In the first column is the time interval.  In the second is the number of cases in each period based on their date of therapy start.  In the third is the number of new patients taking Rezulin and each time interval.

The data show that in 1997, the incidence rate was one in 36,000.  Following the initial labeling changes, including adding a boxed warning, the rate fell to one in 57,000.
So far I've presented data on the incidence of serious liver events as a function of calendar time.  An equally important question is the incidence rate as a function of duration on therapy.
This slide shows reports of jaundice hyperbilirubinemia and death and transplant expressed in these terms.  The figure shows that 240 jaundice hyperbilirubinemia cases in the blue line and the 34 cases of death due to liver failure and transplant, yellow line, in which the duration of therapy is known.
One patient was excluded from that because we don't know the onset date of the therapy.  So we can't use that data in this calculation, in this figure.
The figure shows that for both events, the rate declines after approximately six to eight months of therapy.

Note the curve for jaundice hyperbilirubinemia beyond 16 months represents only three cases, actually one case in 16, 17 and 18 months, one case each at this point.  The increase in this curve represents a decline in the denominator.  In that case you're getting out to very long periods, and there's a cohort driven effect for people both because of persistency and because these patients actually began very early in the marketing of Rezulin and began in a very small cohort.  There's a very rapid drop-off.
Finally, we also note that we have no cases with death due to liver failure or transplant beyond 11 months of therapy.
Based on all of the data that I've presented, three conclusions may be stated regarding incidence.  First, the incidence of liver related death and transplant associated with Rezulin is low.
Second, the risk for jaundice and death due to liver failure and transplant substantially declines after six to eight months of therapy, and most importantly, the rate of such events has decreased following labeling changes and increased patient and physician awareness of the issues under discussion.
I now turn over the podium to Dr. Faich.
DR. FAICH:  Mr. Chairman, could we have the lights up, please?

You'll be happy to know I don't have slides.  What I want to do is just highlight a few of the remarks that Dr. Pierce made and make a few additional remarks from the viewpoint of having used spontaneous reporting systems and data bases for many years related to some of Dr. Graham's comments.
Firstly, I would like to commend Dr. Graham on a very thorough analysis and presentation, but as he and others, as we will emphasize, precision, accuracy, reproducibility are all important, and that's what I'd like to comment on.
Let me first comment on under reporting, then talk a little bit about use of databases, and talk about the trial reports once more.
I'd like to emphasize again that it is my distinct impression that reporting rates for liver failure in this situation are almost certainly inordinately high.  You've just seen demonstrated to you when you look at jaundice that after each publicity wave, there was a wave of reports.
We saw that with Suprofen.  It's a well recognized phenomenon.

Moreover, this is severe organ damage.  All of the literature would suggest that reporting rates for organ damage, particularly when there's a suspicion of drug induction, is higher than other reporting.
And then lastly, remember the secular trend in reporting.  Reporting is much higher today, on the order of over 250,000 reports a year, than it was just five and ten years ago.  Some of the literature that Dr. Graham cited related to isoniazid and other drugs is all old literature, in each instance things like aplastic anemia.  It was not accompanied by this kind of publicity, and it wasn't particularly related to one drug.
The other thing and maybe the last thing and the most telling thing that might suggest that reporting here is quite high is, as Dr. Graham pointed out, one ratio that one might consider is that about one in ten transplants, actually one in ten acute liver failures actually get transplanted.  Seven of these cases have been transplanted.  That might suggest that the total pool of cases to date is on the order of 70.  We're looking at 45 or 43 that have been reported.
So again, what I'd like to leave you with is that extrapolations based on under reporting by multiplying by five or ten or 20 are probably inappropriate.

In terms of accumulated risk, Dr. Graham showed us using survival table methods a distressing picture of increasing hazard, cumulative hazard, culminating at a rate of one in 15,000.  I must say the method is not an unreasonable method, but the numbers are probably not right.  The reason I say that is Dr. Graham was using United Health Care persistence data to answer the question how many patients are still on drug at three months and six months.  You need those kinds of data to factor into the analysis.
What we've shown you from National Drug Source data, which is actually cohort collected data on a very large and representative sample, is that our estimates of persistence are quite a bit higher than his.  As Dr. Pierce just pointed out, we estimate that 60 percent of patients are still on drug at six months; 40 percent are still on drugs at one year.  That changes that calculation because the denominator is larger.  The numerator remains the same and has some of the same uncertainties we've talked about.
If you recalculated using our numbers, you'd get about a doubling, that is, or halving of the rate on the order of one in 30,000.  So there should be some comfort in understanding that because it's important.

In terms of trial data, as you've just heard in both previous presentations, there is some uncertainty about the two cases in the clinical trials.  There's no question that they were liver failure.  The question is:  what's their etiology and could they have been screened out using monitoring?
In addition, there's a question about what's the appropriate denominator.  Most of the patients in the trials weren't in the trials for more than three months.  It is, indeed, true that many of them were not in trials for more than six months, but it is also true that most of the reported cases have had onset within six months of therapy.
That would suggest that if one wants to use the right numerator, it's probably the usual numerator in clinical trials which alls patients as opposed to person-time.  That also makes sense because we're likely talking about an idiosyncratic as opposed to a cumulative toxic reaction.  If it was cumulative toxic, then person-time becomes very important.
So in this instance it's like to be two over 15,000, so that the point estimate is one in 7,500.

Dr. Graham has also emphasized that in considering safety one ought to look at the lower bound and take the lowest number in the 95 percent confidence limits.  I, indeed, think that's a real philosophical question.  I think what one should take is the best point estimate, which in this case is one in 7,500, and recognize that there are wide confidence limits and recognize that there's uncertainty in the numerator as well.
In terms of database issues, the use of the three cases mentioned for United Health Care at this point in time is certainly inappropriate.  Everyone knows when you use an automated linked database you have to go back to the chart and look at the clinical data and validate that what's in the automated database is, indeed, the correct diagnosis and look at the clinical course.
Now, I'm fully aware that Dr. Graham is intending to do that, and I applaud that effort, but I think it's very preliminary to suggest that those three cases, indeed, are drug related at this point in time.

Lastly, where is the epidemic?  If we're talking about a rate of one in 1,000 for patients who have been treated for more than six months or on that level, we heard at the beginning of this meeting four clinicians describe their management of over 5,000 patients.  I didn't hear one case of hepatic failure mentioned.
If we're talking rates of one in 1,000, you'd expect a case or two or three.  I don't believe for a moment that there's an epidemic out there that has gone undetected at the transplant centers.  All of this links up to how complete is under reporting.
I'm not suggesting that there may not be an association here.  I'm just suggesting that the magnitude of the risk has to be examined with great care.  
Thank you.
Let me now introduce Dr. Philip Home, please.
DR. HOME:  Hi.  It's good to be with you.
I'm Philip Home.  I'm a physician from Newcastle upon Tyne in United Kingdom.  I've had no previous contacts with Parke-Davis, but I have been Chairman of Glaxo Wellcome's International Advisory Board on troglitazone, and I'm also a lead external advisor to NovoNordisk, to Sanofi Pharma, and to Hoeschst Marion Rousseau on diabetes products.

I'd like to talk to you today about comparative safety of anti-hypoglycemic therapies, and in doing so I'm concerned that I may be accused perhaps of trying to knock other products, and I'd like to show you first that this is not the case.
This is data taken from our diabetes center in Newcastle, where we see about 4,000 people with Type 2 diabetes under care.  I've taken the data from the database, as complete as it is so far, for 1998, and you will see that we treat about 25 percent of our patients, perhaps extrapolated in total around 1,000 people on metformin, rather large numbers on sulfonylureas, and insulin, and many of these people on combination therapy.
I have to say we do this enthusiastically, and you'll realize that in terms of this number of patients managed over 20 years, I have experience of the adverse events with metformin and with sulfonylureas that I'm going to talk about, and that we continue to use these therapies despite those adverse events.
Type 2 diabetes, as we heard earlier from the ADA submission and others, is a serious condition, of course, which treatment is required and we now know is effective.  We have a limited number of treatment options, all of which we have to use sometimes in combination, and all these options have potential for adverse effects.

At the end I'm going to return to the question of benefits in relation to risks.
The severe adverse events causing death that I'm going to refer to are, of course, disabling hypoglycemia for the sulfonylureas and for insulin; lactic acidosis for metformin; and acute hepatic injury, of course, for troglitazone.
But I'm going to begin first with metformin, and the reasons for choosing this. though we've been using this in Europe for over 30 years, is that it is, of course, a recently approved and introduced drug here in the U.S., and therefore, there is a comparative postmarketing experience with it.
It has had similar exposure to troglitazone, and its adverse event profile has, of course, been well characterized over the 30 years we've known it.
This information is taken from the letter of Dr. Misbin published in New England Journal of Medicine in 1998, and it relates to the U.S. postmarketing reports within the first 12 months for metformin.

It's estimated that around one million people were exposed to the drug and used it in that time, and that there were 47 cases of confirmed lactic acidosis, leading certainly to 20 deaths.  This gives an estimated event rate of 4.7 per 100,000 patients, or for deaths, of course, 2.0 per 100,000 patients.
Now, Dr. Misbin has more recently published exactly similar parallel data for troglitazone in the Annals of Internal Medicine, although, of course, they relate to a different time period.  The exposure in terms of numbers of people with diabetes is broadly similar, with just over a million for troglitazone, and here is the number of fatal events, the 20 we've just seen for metformin and 17 for troglitazone.
Those of you who have read that article will perhaps spot the 17 as slightly lower than the number quoted in the article, and that's because here we're only quoting deaths which occurred within the USA.
The rate then for troglitazone comes to 1.7 per 1,000 patients, comparable to that for metformin in its first year.

There are other data available to us on metformin, and I've chosen here that particularly from the Swedish Adverse Drug Reactions Advisory Committee.  This is because I regard this data as more reliable than others.  Sweden is a relatively small country, socially cohesive, and its medical population is well trained and used to reporting. Indeed, from 1975, it's been a legal requirement to report serious adverse events.
This data then is all from the same database.  You will see here the death rates that Ian Campbell and Willy Berger calculated using the data from Dr. Wiholm was 2.4 per 100,000 patient-years, and all the rest of the data I'm going to give in this presentation is going to relate to this rate per 100,000 patient-years.
You'll see that broadly comparative rates of lactic acidosis reported over different time periods, and this death rate, I think, is probably the most reliable figure we have, although it may have come down a small amount since that time.
Other data is available from the literature.  I think it's less reliable.  The Swiss data was based on a postal survey, the U.K. data collected in a less sophisticated fashion.  You will see that the data from Canada, from Saskatchewan, gives a rather higher death rate from lactic acidosis in metformin, but I personally have some problems with some of the cases and ascertainment in that study.

In the January Diabetes Care, there is a paper from the Kaiser Permanente HMO in Northern California by Selby, et al., giving I calculated even a higher rate than that, but again, I have some problems with that because of the small numbers involved.  So I'm not going to include it here.
In summary then, in taking those and other papers together, we end up with a death figure of around .9 to nine per 100,000 patients per annum, and I'm going to carry that forward to later in the talk.
Again, from the Swedish Drug Advisory Committee, this is the information that is available in sulfonylureas.  Asplund published two papers  in Diabetelogia and Diabetic Medicine, one of glyburide and one on gliptizide, although in different time frames.
Ian Campbell has calculated the death rates and case rates from this.  Asplund just gave the numbers in the original paper, and the rates here, again expressed per 100,000 patient-years, have been calculated from that.

For the purposes of this talk, I have performed exactly the same calculations on gliptizide, and you will see that the bottom line death rates here are, again, comparable to the figures we've just been talking about, the 3.2 per 100,000 patient-years for glyburide and 1.6 for gliptizide.
There are data giving higher rates of hypoglycemia as a serious adverse event in the literature.  These two come from major databases, this from the Tennessee Medicaid-Medicare database and this from the VAMP database based on U.K. general practice, and you will see that their rates here for the event itself, cases, are very much higher, and this relates partly, I think, to definitions of what is and is not hypoglycemia between studies and also to the nature of the place this information was collected.
The Shorr data calculates that around one percent -- this is percent of the people with hypoglycemia -- around one percent resulted in death.  That is a lower figure than much of the historical literature, but higher perhaps than I'm prepared to accept at the moment.
Sulfonylureas then, I think, on that basis will give you a death rate, again, which is not dissimilar to what we've seen before of around 1.4 to 9.8 per 100,000 patient-years.

The U.K. PDS does give rather lower figures for severe hypoglycemia, and this is merely defined as requiring assistance in the same way as the DCCT of 400 and 600 for chlorpropamide and -- sorry -- it's bliperite, respectively, but I put this slide mainly to deal with the question of insulin, and you will notice that they did have one event which was possibly or probably associated with hypoglycemia as a death within the insulin group, but there is a lot more hypoglycemia as a severe event with insulin.
I think for insulin we have to say that while death is perceived uncommon due to hypoglycemia Type 2 diabetes, the U.K. PDS has one death per 1,500 patients.  The risk estimates are really rather too uncertain to calculate.  Much of the information relates to Type 1 diabetes.
And in the next slide I've actually put my estimates here in brackets to respect its uncertainty.
So these are the figures carried forward for metformin and for sulfonylureas, and now for insulin, and to this I've added the figure for troglitazone.  This is based on the last 12 months' data up to March 1999, and the dates are on drug exposure you've just heard about.
And you will see, I think, and all the point I make is that these figures are at least comparable for the four classes of agents involved here.

So what about the question of benefit?  And this is a difficult one to tease out.  If we look at U.K. PDS and we try to look at the diabetes related death rate, it comes out as about 1,100 per 100,000 patient-years.  So we're talking about figures which are quite different from the two or 1.4 or whatever deaths we were just talking about as a side effect.
If we actually think about what is potentially preventable in terms of the percentage of those deaths, I've chosen here a figure of ten percent, and you should be aware that I've chosen that because it is half, half that prevention that would be expected from the epidemiological data in the U.K. PDS, and it coincides with the point prevalence data in one of the intensive cohorts within U.K. PDS, although it's actually only a quarter of the benefit, statistically significant recorded for death, with metformin in that study.
So this is a conservative figure, and if you relate it to the death rate, then you're saving about 110 people per 100,000 patient-years, which gives you a benefit ratio over that figure of two of about 50 times.

As I've said, this is conservative, however.  If we look at Ron Klein's Wisconsin data published in Diabetes Care, the number of deaths is much higher as a rate than in U.K. PDS, and that's due to the selection and the relative health of the U.K. PDS cohort, which is not typical of Type 2 diabetes as we see it.
And if you apply that ten percent data to the Wisconsin study, then you're ending up with 350 saved people per 100,000 patient-years.
You can, I think, go higher, and if you choose the figures for metformin within U.K. PDS or you allow with troglitazone for its effects on lipids and on matters of endothelial cell function, then I think probably you will be getting up to somewhere around 1,000 here, and on that basis I would say a conservative estimate of the benefit-risk ratio is 50, and a best estimate, somewhere around 500 based on our current data.
So all drugs for treatment of Type 2 diabetes carry some risk.  The risk is, I think, low and particularly low by 50 to 500 times compared to the benefit.
The risk from troglitazone is comparable to that with established therapies, and as we've heard just now from Dr. Pierce, the risk with troglitazone appears to be decreasing with time.
Thank you very much.

Sorry.  That was going to be the last talk before lunch.  So I now have to introduce Dr. Whitcomb.
(Laughter.)
DR. WHITCOMB:  You have to introduce me.  Okay.
Well, the presentations to this point have focused on the risk portion of the risk-benefit analysis for Rezulin.  I would like to shift focus now and look at the benefits of Rezulin.
As with all diabetes therapies, this information is critical to put the risk information in perspective.
This slide overviews the metabolic staging of diabetes.  Patients develop insulin resistance as an early event in the course of their disease.  This defect is the principal target for troglitazone's action.
Over time, progressive beta cell dysfunction and continued insulin resistance leads to the development of progressive diabetes and its complications.

Our development efforts to this point have focused at patients on all stages of this spectrum.  Because of troglitazone's complementary and differential mechanism of action, the majority of our efforts have focused on demonstrating the efficacy of troglitazone when it is added to patients who have failed other therapies.
We also think, however, that troglitazone is appropriate as initial therapy for many patients.
The data that I will be showing you today is going to focus on several studies that we have completed.  We'll be looking initially at insulin combination.  We'll we showing you data from the triple therapy, troglitazone, sulfonylurea and metformin studies which have been submitted to the FDA.  We'll be showing you data in combination with sulfonylurea, some data as monotherapy, and looking at two emerging areas of interest:  first off, the impact on beta cell function and atherosclerotic risk factors, and then I will give a little bit of protected risk reduction using some recent data that we have for impact on microvascular endpoints.
These are data that were shown to this Committee approximately two years ago with the original submission.  They were published last year in the New England Journal of Medicine.  

This is our combination study with insulin in which these patients were on seven to three units per day, on average.  They'd had insulin requiring diabetes for about five years and diabetes altogether for about ten years.  They were obese.
However, in spite of these large doses of insulin, they were poorly controlled with A1c's of 9.4 percent.
These are the fasting serum glucose and HBA1c data from this trial.  I'll be referring to HBAC repeatedly during this.  This is hemoglobin A1c, for those in the audience unfamiliar with this term.  This is a measure of glucose control over approximately 90 to 120-day period.
The fasting serum glucose went down in a dose dependent fashion, down to nearly 50 milligrams per deciliter in combination with troglitazone at 600 milligrams, and the A1c went down as well in a parallel fashion to 1.4 percent after six months of treatment, both of these being statistically significant.
Remember, again, these were people who were on, on average, 74 to 75 units of insulin per day.

What we saw in this trial was a reduction in insulin dose as well.  This was not a design or goal of the study, but in response to the lowered blood sugars which were seen, there was a reduction of 29 units at 600 milligrams per day, which was nearly 40 percent in the insulin doses of these particular patients.
So in combination with insulin, we've been able to demonstrate significant benefits as manifested by an improvement in glucose control and lower insulin requirements in patients uncontrolled on insulin.
Now, I'm going to work my way back up from that curve.  We started with late stage diabetes, and now we're going to start to work back up towards the other end of the diabetes continuum.
These are data which were recently submitted to the FDA and which we'll be presenting at the American Diabetes Association in June of this year.  This is a study which was done in Canada in which we added troglitazone to people who had failed metformin/sulfonylurea combination up there.  The reason we did this study in Canada is sulfonylurea or metformin has been available for many years, and there were a  large number of patients that we could draw from for this trial.

This is the baseline characteristics of these patients.  They had been diagnosed with diabetes for around 11 years.  They had poor glucose control with an A1c of 9.7 percent in spite of being on two drugs.
They had reasonable beta cell function, and they were obese consistent with most of the other populations that we've studied, and certainly consistent with Type 2 diabetes.
This is the study design.  All patients underwent a four-week run-in in which they were maxed on doses of metformin and sulfonylurea.  At that point they were randomized to either placebo added to their metformin/sulfonylurea combination or troglitazone at 400 milligrams per day.  That's the only dose that was studied in this trial.
They were then followed for 24 weeks.  We have an open label extension of this trial, which we are analyzing the data for now.
This is the response.  This is in fasting glucose in millimoles.  What was seen in the people that were still just on metformin and sulfonylurea was the glucoses continuing to drift up over time compared with a fall when troglitazone was added.  Most of the effect was actually seen by about four weeks of therapy, and it was sustained across the six months of this trial.  So a very nice fall in glucose.

Just doing the math from this, there was a fall of 2.6 millimoles or 50 milligrams per deciliter or so of fasting plasma glucose compared to a slight increase in the placebo group as being statistically significant.
Again, there was a fall in A1c which mirrored this, a fall of 1.3 percent in combination with metformin, troglitazone, and sulfonylurea, compared to a slight increase of 0.1 percent, again being statistically significant.
Now, one of the important considerations, and I'm going to start to develop this in the next couple of data talks here, is the number of people who reach appropriate targets.  We've look at data both at A1c's less than eight or seven percent at the end of the trial.  These are the data.  There were six percent of the patients on the sulfonylurea-metformin combination, who had an A1c less than eight percent at the end of the study and an A1c less than seven percent was seen in actually one patient in the placebo group.
There were 43 percent of people, less than eight, and 14 percent, less than seven, at the end of the trial, remembering again that these people started out on average at 9.7 percent.

So there was significant glucose lowering in patients who failed sulfonylurea-metformin combination.
So moving back up the continuum now to people with slightly earlier diabetes perhaps, those are failing on glyburide by itself.  So this was a study in which we looked at troglitazone added onto maximal dose glyburide, 12 milligrams per day.  This was a 12-month study.  It was one of our studies which was used in support of the indication for combination with sulfonylurea.  These were people who had failed SU.  They had an average FSG that was over 140 milligrams per day, on maximal doses of glyburide. 
They were randomized to one of three doses of troglitazone either added to glyburide, switched abruptly to glyburide, or continued on glyburide by itself.
For sake of simplicity, I'm going to show you the time curves here.  One monotherapy, the glyburide group, and one of the combination groups.  The glyburide group, which is shown here in blue, over the course of the trial had a continued increase in glucose, which is what you'd expect.  Obviously these people were uncontrolled at the beginning, the natural course being continued failure.  So a rise of about 20 milligrams per deciliter of fasting glucose.

The abrupt switch to monotherapy showed a rise and then a fall at 600 milligrams.  This is consistent with what we would expect because troglitazone requires the presence of endogenous insulin.  The sudden removal of an insulin secretagogue basically left plasma insulin levels very low, and it takes a lot longer for the drug to work in that situation.
This also has led us to the recommendation that in patients who are either sulfonylurea failures or who are well controlled on sulfonylurea, that troglitazone should be added to, not switched as drug therapy.
Now, the story is very different when you look at the combination.  This is the combination of 600 milligrams added, and there's a fall of about 60 milligrams per deciliter in fasting serum glucose by four weeks of therapy, which is then sustained across the course of the trial.  I will show you some open label extension data on this particular study in just a minute.
The A1c's basically mirror this.  People had started out at about nine and a half, go down and stay down with a mean of 7.8 percent at the end of the trial, A1c's drifting up here for both groups.

Now, these are all of the data groups in terms of combination.  This is a comparison of the primary analysis for the study, was the mean difference versus control at 12 months.  This is the intention to treat population.  There was a fall of 54, 61, and almost 80 milligrams per deciliter of fasting glucose compared to glyburide during the course of the study.  This was mirrored by a fall in HBA1c of between 1.6 and 2.7 percent compared to glyburide at the end of the study.
Again looking at the number of patients able to achieve American Diabetes Association goals and targets, the glyburide dose -- remember, again, these were people who were failing the drug.  So this is not surprising -- only ten percent were less than eight and one percent less than seven at the end of the study, compared to 33, 33, and 60 percent of patients, less than eight percent at the end of one year; 22, 21, and 41 percent were less than seven percent at the end of the trial.

Weight gain was seen in this particular trial in combination with sulfonylurea.  This has been observed in other combination studies.  We believe it's a function of the improvement in glycemic control that happens in the study.  For example, in the metformin combination trial I just showed you a few minutes ago, there was a  gain of a couple of kilograms in the troglitazone combination group.
Now, what happens to this effect over time?  At the end of the 52 weeks of the trial, we allowed patients to enter an open label extension phase, and this is the group who elected to do that.
Remember there were 78 patients originally in this group.  All but about five or six patients actually completed the 52 week trial, and 58 of these elected to go into the open label extension.  So this is the intention to treat analysis on those 58 people who entered the open label study.
What you see is this fall in HBA1c, which we originally saw is sustained for an additional 72 weeks beyond the 52 weeks of the original study.  So 124 weeks of glucose control was evidenced in this trial, and we presented these data at the ADA last year.  So very nice, sustained glucose lowering as mirrored by this fall in A1c, which is sustained over time.

Now, in terms of the number of people who get to target levels, this is the A1c group.  Less than seven percent who went into the open label extension at 52 weeks; there was 47 percent of people with an A1c less than seven percent, and 52 percent at 124 weeks of treatment had an A1c less than seven percent.
I'm going to talk in a little bit about why we think that this sustained glucose lowering that we see with this particular drug is occurring or at least one hypothesis.
So in summary, in terms of significant clinical benefits, there is significant and sustained glucose lowering in combination with sulfonylureas, added onto the other findings that we've already seen.
Now, what about troglitazone as initial monotherapy?  This has not been as well studied as the prior combinations, but we do have a fair amount of experience with this.
This is a six-month, double blind, placebo controlled study that was one of the trials that was used in support of the application and the approval for monotherapy.  The data were published last year in the JCE&M.
There were 402 patients in this particular trial.  Eighty-six of these were naive to drug therapy.  So about 300 people had previously been treated with SU.

The mean A1c was 8.5 percent, and in this particular group we studied four different does of troglitazone.
Now, because really the question of interest is really using the product as initial monotherapy in patients, we focused the presentation today really trying to look at that question.  So the patient numbers that we'll be showing you are small because they deal with the diet only patients.
This is the fasting serum glucose over time.  These again are from the JCE&M publication.  This is the placebo group.  They basically stay about the same during the course of the study.
There was a fall in all of the treatment groups, and you see really most of the effect here by about a month or so of therapy.  There is some drifting down over this period of time.  These are the mean data, and there's a fall also at two and 400 milligrams.
Now, one of the aberrancies of this particular trial is this is the only study in which we have not seen a clear dose response at 400 milligrams.  As evidenced by the sulfonylurea combination study I've just showed you, that's much more typical.

There was not as much response in the 400 milligram group in this trial even as there was at 200 milligram, both in terms of glucose and in terms of A1c, but focusing on the 600 milligram group here for a second, there was a fall of 42 milligrams per deciliter compared to placebo, which led to a 1.4 percent fall compared to placebo.  An absolute fall of one percent was seen in this particular study.
This is the serum insulins from this trial.  I've not talked about this to this point.  This is the logical place to look at it.  These are monotherapy patients.  There is a very rapid fall in insulin, which is sustained across the course of all the studies that we've done with troglitazone.
This is about a 25 percent fall in plasma insulin in these patients at 600 milligrams per day, again, consistent with the mechanism of action of reducing insulin resistance.
Now, one of the questions that we've asked is we've seen that the glucose lowering effect of troglitazone in combination with SU is sustained.  What do we know about its effects as monotherapy?
This is some data actually that was shown as part of an analysis to the Committee two years ago.  These are data actually from a cardiac safety study.  So the main purpose of this trial was not to show a lowering of glucose.  

The patient numbers are small.  We had a lot of dropouts early in this trial.  There ended up being 22 patients in the troglitazone arm compared with about 35 in the glyburide arm.
We did instruct physicians during this trial to titrate glyburide for maximal glucose control.  The doses of troglitazone were 600 milligrams in the first year and 800 milligrams in the second year.
The point I want to make has nothing to do with absolute fall.  It has to do with the pattern.  When you look at the intention to treat analysis, which I did not show you here today, you see the same pattern.  The absolute magnitude between the two bars is only about a half a percent apart, but the pattern is sustained.
And what we've done is to take the monotherapy trial that I showed you before, the six month study, and we allowed the patients to go into an open label extension.  We allowed them to titrate up, and what I've show you here are the patients who were either on four or 600 milligrams at the end of the trial.  They were all naive patients.  So this is the diet only subset.

Thirty-six patients are indicated here.  This is a completer analysis.  There is a difference between the beginning and the end here of about seven patients across the period of time.
There is a sustained and continued fall in HBA1c across time to where the mean at the end is about 7.1 percent.  I didn't put a P value on this, but this is highly statistically significant compared to the baseline.  Obviously you can't do a placebo analysis on this because the placebo group at six months in this trial was allowed to titrate up, but the same pattern does appear to be emerging in terms of this.
Now, the other question that has been asked is what is the efficacy of troglitazone relative to other agents.  This has been a recurring question, and so we wanted to present these data.
This is a head-to-head study which was done in Europe by Glaxo.  This is Type 2 patients, again, a mixture of diet only and prior SU treated patients.  They were given either one, two or 600 milligrams of troglitazone at a fixed dose.  They were titrated up on that form into the maximal tolerated dose.  The average dose of metformin at the end of the trial was 1.6 grams as initial monotherapy in these patients.

Now, these are the HBA1c's and fasting serum glucose.  This trial was designed to use metformin as the comparator.  This is two and 600 milligrams, and basically what you can derive from the conclusion here is that there is not a statistically significant difference in glucose lowering as measured by A1c or glucose compared to the metformin arm of this particular trial.
The other thing that we've looked at is a responder analysis showing the number of people who had at least a one percent fall in HBA1c.  This was part of the predetermined analyses for these studies, and what you see is that there is around 39 percent in the troglitazone group and about 35 percent in the metformin group.  These were not statistically significantly different from each other.  Both of these were greater than 200 milligrams per day.
The insulin levels, there was a difference between these, as you would expect.  There was a difference in the lipids, as well.  The pattern that we've seen previously of increased LDL, HDL, and total cholesterol compared to metformin was observed in this trial.

There was a fall in free fatty acids, but interestingly enough, in this study there was not a statistically significant difference in triglycerides, but the patients really were not very hypertriglyceridemic, unlike our U.S. populations.
This is the change in body weight from this trial.  There was a fall of 1.6 kilograms, which is what we would expect to see in the metformin only arm.  There really wasn't much change at all in the troglitazone arm.  This may have been statistically significantly lower than these.  Clinical significance I leave up to your judgment.
So it appears that troglitazone is effective as monotherapy, both short and long term.
Now, the other interesting thing about looking at the metabolic staging of diabetes is that this red circle over here on the beta cell defect may have profound effects on the time course of what happens down through here.
One of the interesting hypotheses that has been raised is that the sustained glucose lowering which is observed with troglitazone may be due to the fact that it is either having primary or secondary effects on beta cell function.

So we've started to look at this in a number of model.  This is some data from the Zucker diabetic fatty rat in which these animals were pretreated with troglitazone.  This is the only animal slide I'm going to show in this presentation.
Basically what you see is in the lean controls after 18 weeks there's a very normal architecture to this islet, normal appearing beta cells.  However, after 18 weeks in the Zucker rat there's hyperplasia, hypertrophy.  This is the same magnification here, and disordered array within the beta cell itself.
This is absolutely prevented by troglitazone after 18 weeks of treatment.  You do not see this hyperplasia occur.  The natural time course for this is to go on and completely destroy the beta cells.  We do not have a -- or the islet -- we do not have troglitazone data at 36 weeks.
So the question is:  what does this mean in man?  Obviously we're unable to do these kind of pancreatic studies in people.  So we've started to look using some other techniques.

These are some data from Dr. Ken Polonsky at the University of Chicago.  Ken and his group have conducted a number of studies to determine whether the alterations in insulin secretion and beta cell glucose seen in subjects with impaired glucose tolerance are reversible by treatment with troglitazone.  They've used a couple of techniques.  I want to show one of them here just for orientation.
This is a glucose oscillatory curve in which what they're able to do is using intravenous infusions of glucose is to actually raise glucose levels and cause them to fall in a periodic rate.
They are then able to measure the normal entrainment of the pancreas to this, and this, in Ken's opinion and the opinion of many others, signals normal beta cell function that you can entrain normally.
Now, in people with impaired glucose tolerance, the prediabetic condition, you are unable to entrain them normally.  The glucose rhythmicity here that you saw before you're able to sustain, but you can't get the beta cell to respond normally.  So this is one technique that can be used to measure this response.

Another technique that has been used is using a graded glucose infusion in which you look at the insulin secretory response as a function of fatty or body mass index.  In the control population there is the appropriate steep response of the pancreas to this.  So very small changes in glucose concentration peripherally cause a very abrupt response in changes in insulin.
As people develop IGT, this curve flattens, and then as Type 2 diabetes progresses, it gets even worse.  So it takes more and more glucose to get the same type of insulin out of the pancreas.
So what does this look like in people with IGT before and after troglitazone?  The reason that they've studied IGT patients is these are people without fasting hyperglycemia.  We currently have a trial going on in patients with diabetes to see if this same phenomenon holds true.
This was 24 subjects who received either troglitazone or placebo, and these data were published in the JCI in 1997.  They looked at a frequently sampled IVGTT to measure insulin sensitivity and the glucose oscillations and the graded IV response I just showed you using those techniques.
This is the subject characteristics.  They were obese.  They had IGT as evidenced by a two hour glucose of 186.  They did not have fasting hyperglycemia.
Insulin sensitivity was doubled following treatment with troglitazone, very consistent with all other patient models that we've looked at.  No change in the placebo group.

The graded glucose infusion, remember that the normal has a much steeper curve.  This is troglitazone before and after, and notice the way that that curve moves back up to the left.  This is statistically significant.  There's no change at all in the placebo group.
So it appears looking at this technique that the insulin secretory response is moving much more towards normal.
Now, what about the insulin entrainment.  You see here the glucose oscillations going up and down and the complete lack of entrainment here in the IGT, patients treated with placebo before and after.  However, using troglitazone after 12 weeks you're able to entrain the pancreas normally to these glucose oscillations and actually lower the total amount of insulin that was required to meet that need.
So troglitazone does appear as well to have positive effects on beta cell function, as I said.  How this translates into Type 2 diabetes is something that is currently under investigation.

Now, we don't have time today to go through all of the lipid and atherosclerotic data which has emerged on this drug over the last few years.  I've summarized the lipid data on here.  I'd be glad to show any of this later in the discussion if it's of interest.
What's been documented in a lot of publications, including some of our own, is that the drug causes a decrease in free fatty acids, trigercerides, an increase in HDL, an increase in LDL particle size, a decrease in LDL oxidation, and a decrease or no change in ApoB levels.
One of the interesting emerging areas is the effect on vascular function.  This was alluded to earlier in the public session.  It's becoming clear that based upon data in man and in animals that there is a reduction in PAI-1 activity.  This has been demonstrated in man.  Platelet activation decreases.  This has been demonstrated in vitro.  The decrease intimal medial thickening has been shown in man and published last year in the JC&M.  Decreases in E-selectin level have been shown in man and decreases in vascular reactivity and flow mediated coronary dilation have also been shown in man.
One of these studies, and I'm just going to show you one piece of data from this, which is very interesting.  These are data presented at the American College of Cardiology last year.

They looked at diabetic patients with angiographically documented coronary vasospasm and residual angina pectoris who were treated for four months with troglitazone.  They looked at them at baseline and at four months of treatment, and they also looked at flow mediated vasodilation.
What they demonstrated was a statistically significant decrease in angina pectoris following treatment with the drug, as well as a statistically significant increase in flow mediated dilation, leaving us to think that, in fact, there may be something there that is worth pursuing, and there's a number of studies going on now in larger populations looking at these data.
So troglitazone appears to have positive effects on both beta cell function and atherosclerotic risk factor.
Now, I've shown you data which demonstrate that troglitazone as monotherapy or added onto other treatment failures provides significant and sustained glucose control.  An important question to ask is how might this translate into impacting on clinical endpoints.

We have not yet obviously had the time to conduct a long-term endpoint study.  Yet based on the results in the U.K. PDS and the DCCT, as well as the Kumomoto in Japan and the Wester study, which Professor Home made reference to, we would anticipate a positive effect particularly in microvascular disease.
We have used the published model by the group at NIDDK to model and estimate the effect on endpoints using our demonstrated controlled data at 124 weeks from the glyburide comparison.  We have assumed conservatively that beyond that 124 weeks where we have surety of data that control worsens at that point in time in a manner seen in the U.K. PDS.
We have no data to suggest that control would worsen at that point in time.  So this is a conservative estimate.
The impact on microvascular data falls between the risk reduction between the U.K. PDS and the DCCT.  Now, this translates into a reduction of over 7,000 cases of blindness, amputation and renal failure, assuming you followed 100,000 patients over ten years.  So the benefits are very substantial.
I'd like to turn this back over now to Dr. Zerbe for the summation.

DR. ZERBE:  In this final section of our presentation, it's my intention to summarize the major points and attempt to put the risk-benefit assessment for Rezulin into perspective.
FDA Commissioner Haney in a recent presentation to the National Health Council summarized our challenge very clearly, which he said, "We need to be very precise when we talk about the whole issue of safety because it is really a judgment made of risk and benefit," end quote.
Precision is key, and all of us must resist the temptation to be influenced by sensationalism and rumor when we assess drug safety.  It would be a mistake for this Committee to ignore a significant safety issue, but it would be no less a tragedy for the actions of the Committee to discourage patients with diabetes from seeking appropriate treatment or to seek treatments which provide less overall benefit.
In an attempt to put into perspective the many facts and interpretations that have been presented today, I will frame them as a response to six questions.  
First, does troglitazone play a causative role in cases of severe hepatotoxicity?
Two, assuming troglitazone plays some role in such cases, what is the risk of such events?

Three, how does the risk of Rezulin treatment compare to that of other available agents?
Four, what are the benefits of Rezulin?
Five, is the risk-benefit ratio for Rezulin favorable?
And last, what additional steps can be taken to further improve both the safety and efficacy of Rezulin?
In answer to the first question, does Rezulin play a causative role in cases of severe hepatotoxicity, both Parke-Davis and the FDA agree that the data indicate that Rezulin is associated with rare cases of idiosyncratic liver failure.
That then leads us to the second question.  What is the risk of such events?   There remains some disagreement between the FDA and Parke-Davis on the role of the drug in some individual cases, but since we are evaluating safety, we've taken a conservative approach, and we've used the larger number of 35 deaths or transplants as determined by the FDA to calculate the rate.
Using this number, the incidence is one in 45,000 patients exposed or approximately one in 34,000 if one considers patient-years of exposure.

Though it has been suggested that this rate may be an under statement of the true rate because of under reporting, two points are worth emphasizing.
First, published data on the risk of drug therapy is rarely corrected for under reporting since it cannot be accurately quantitated for any agent.  So in considering how the risk compares to that of other agents, such unadjusted rate is an appropriate figure to consider.
Second, the data presented by Dr. Pierce support a relatively high rate of reporting for Rezulin.  Thus, though no risk should be trivialized, we feel that the rate is low.
Furthermore, the rate estimate of one in 45,000 is based on data from the whole period of Rezulin being on the market.  Both Dr. Graham and Dr. Pierce clearly showed that the rate since the label change has decreased significantly.  These estimates, based on the second year of marketing were one in 104,000 patients exposed.
So even assuming that all of the cases identified by the FDA were truly related to Rezulin, the risk is low and has decreased since monitoring has been implemented.

These estimates may be low, but if there's a safer alternative with comparative benefits, the patient is assuming excess risk by using the drug, and that brings us to the third question.  How does the risk of Rezulin treatment compare to that of other therapies?
First, we need to agree that the treatment of diabetes is not optional.  In the case of impotence, incontinence, acne, or alopecia, for example, patients can elect no treatment and the overall survival is not adversely affected.
No one, however, would argue that pharmacologic treatment of Type 2 diabetes is optional after diet has failed.  So when considering the safety of Rezulin, the risk compared to alternative treatments is more relevant than the consideration of absolute risk.
In our presentation we have focused mostly on the risk associated with metformin, and this is not because metformin is an unsafe medication, but because it is used in a way very similar to troglitazone, yet like troglitazone is a relatively recent entry into the U.S. market, and it has clearly identifiable toxicity, that is, lactic acidosis.

Dr. Home showed in his presentation that based on publicly available data, the rate of fatal lactic acidosis associated with metformin was very similar to that of fatal hepatotoxicity associated with troglitazone.  Fortunately changes in labeling and better patient selection have decreased the rate of fatal complications for both drugs.
Likewise the risk of fatal hypoglycemia with insulin or sulfonylureas is reported to be similar to the fatalities with either metformin or troglitazone.
We would conclude from this that though the pathologies differ from drug to drug, all of the available treatments for Type 2 diabetes, including troglitazone, carry a similar, albeit small, risk of death.
A word about future therapies is also appropriate at this time.  Much has been speculated about the safety of the newer agents, some of which will be reviewed by this Committee next month.  It's worth noting that rare events like lactic acidosis and liver failure are usually not identified until wide exposure in clinical practice.

It would be inappropriate to compare and act upon safety profiles related to serious but rare adverse events between marketed drugs which have exposure in millions of patients and those still in an investigational stage which have exposures in thousands of patients.
Rare but serious adverse events cannot be reliably excluded by experience in relatively small databases.
Though we conclude that the safety of Rezulin is comparable to alternative pharmacologic treatments available in the Type 2 patient, the benefit must be as good or better if the overall risk-benefit ratio is to be comparable, and thus, we come to the fourth question.  What are the benefits of Rezulin?
The unique mechanism of action of Rezulin, that of increasing the sensitivity of cells to circulating insulin, makes it a particularly attractive choice for the treatment of Type 2 patients where a critical defect is insulin resistance.  Dr. Whitcomb has shown marked improvements in glucose control when Rezulin is added to the treatment regimen of patients who have failed insulin therapy or failed the combination of sulfonylureas and metformin, shown here.  For these patients Rezulin has been critical for the achievement of adequate glycemic control.  

Remarkable improvements in glycemic control have also been seen when Rezulin is added to patients who fail sulfonylureas, and this is achieved with lower circulating insulin levels and appears to provide better control for a longer period of time.
Because of its mechanism of action, Rezulin is also a logical choice for naive patients.  By improving insulin sensitivity, pancreatic responsiveness is maintained, pancreatic entrainment is preserved, and this translates into long-term benefit in monotherapy patients who respond.
This level of improved control provides substantial benefit.  Data from the DCCT and U.K. PDS studies would indicate that if we were able to provide this level of control and improvement in hemoglobin A1c to the six million patients in this country who are inadequately controlled by their current treatment and maintain that control for ten years, we would be able to prevent nearly half a million cases of renal failure, amputations, and blindness.
So what are the benefits of Rezulin?  Efficacy has been demonstrated in a spectrum of combinations, as well as monotherapy.  Its unique mechanism of action is complementary and appears to be preserving endogenous pancreatic function, which translates into better and longer lasting control.

That brings us to the penultimate question.  Is the risk-benefit ratio for Rezulin favorable?  The available data show that the risk is low and comparable to alternative therapies.  The benefit is complementary and unique, adding significantly to the therapeutic armamentarium in a life threatening disease.
Therefore, the risk-benefit is surely acceptable given the uniqueness of the benefit.  Twenty patients every hour die in the United States as a result of diabetes and its complications.  Approximately 100 patients with diabetes have died since the beginning of this meeting.  These patients desperately need medications that can help them control their disease.
Our final question then is:  what additional steps can be taken to further improve the safety and efficacy of Rezulin?  Just because we conclude that the risk-benefit ratio is favorable doesn't mean that it cannot be improved further.  So what would we propose to do?
In order to further improve safety, we will submit labeling changes to the U.S. that will warn against the use of troglitazone in any patient who has a history of liver disease of any etiology or any patient with a history of alcohol abuse.

We will propose refinement of the trial period for the assessment of efficacy in naive patients so that only those patients gaining benefit will be continued on the drug.
We will issue a patient package insert, which has already been reviewed by the FDA, so that patients can take a more active role in the management of their disease.
And we will expand patient and physician education programs, such as the Rezulin results program, which provide monthly reminders for liver monitoring.
And last, to enhance the global benefit of the use of Rezulin, we will continue studies to identify those patients most likely to benefit, and we look forward to the opportunity for direct comparative studies with the newer glitizones so that rumor can be replaced by fact.
Some have proposed drastic action, but this morning you heard very compelling anecdotes from physicians dealing with patients who have had dramatic benefits from Rezulin.  Denying this drug to those patients would be a serious step, and it must be based on compelling data.

As Dr. Haney said, the evaluation of drug safety must be precise.  This Committee would be doing the patients with Type 2 diabetes a tremendous disservice if it recommended actions which prevented or discouraged physicians or patients from using this drug in a beneficial way as supported by data.
Thank you.  We will be glad to entertain your questions.
CHAIRMAN BONE:  Thank you, Dr. Zerbe.
We'll take some time now for questions addressed by members of the Committee to the sponsor with respect to their specific presentations, and we will try to keep focused on questions of fact or information here and go into our general discussion and broader discussion of specific points a little later on in the program.
I think Dr. Braunstein had the first question.
DR. BRAUNSTEIN:  Actually it's both the sponsor and the FDA.  Do you want me to hold off then?

CHAIRMAN BONE:  I'm going to suggest that we focus on the questions for the sponsor at the moment so that we can kind of stay organized.  Otherwise I think we may lose track, and then I think if you wanted to ask your question of the sponsor now and clarification from the FDA later, that would be fine or we could do that during our general discussion period.
DR. BRAUNSTEIN:  There are a number of discrepancies between what the sponsor has stated and what the FDA has stated, and I'd really like to ask them both the same questions --
CHAIRMAN BONE:  All right.
DR. BRAUNSTEIN:  -- and have them respond to that.  So why don't I wait until the general discussion?
CHAIRMAN BONE:  I'm going to ask Dr. Braunstein to make a quick list of those.  We'll give a list to each of the people, and we can ask that question, and we'll expect crisp responses on both sides.
Thank you.
DR. BRAUNSTEIN:  Fine.
CHAIRMAN BONE:  We'll start over here and just work around.  Dr. Marcus.
DR. MARCUS:  I'm surprised not to have heard anything about tissue concentrations or plasma concentrations of the drug or its metabolite in whether there are people with various polymorphisms in the cytochrome P-450 system or whether there is any attempt to look prospectively at which individuals might be most likely to suffer an adverse consequence.

Surely you have access to tissues or plasma specimens on those people who have become ill, and the question is:  are they in any way distinguishable from those who have not?
DR. ZERBE:  It's really an excellent question.  At the time the first series of events occurred, we initiated as part of the REACH study, which was referred to in the program, a systematic collection of samples to be evaluated for a whole series of drug metabolizing enzymes and to try to identify those patients that were at risk or not.
As you probably recognize, that is a very difficult process, and it takes a very large population.  Even the REACH study, which is targeted to be about 5,000 patients, probably will not be large enough to clearly identify it, but we have systematically collected those samples to try to see if there are any genetic predispositions to this problem.
I don't know whether anyone wants to add anything.  Al, do you want to say anything or do you have a follow-up question?
DR. MARCUS:  Well, what our blood concentrations of troglitazone or its metabolites, do we know that?

DR. ZERBE:  Yes.  Well, go ahead, Al.  Do you want to?
DR. SALTIEL:  Maybe I can answer that question.  We've actually compared troglitazone and the quinone metabolite levels in patients with elevated ALTs and who do not have elevated ALTs, and they're actually absolutely the same.  So there's no prediction there of ALT elevation.
DR. MARCUS:  Okay.
DR. SALTIEL:  With regard to the other question, I have a list of some of the enzymes that we're looking at in these studies, in the samples which I can show you.  It's a list of the usual P-450 related enzymes, and nothing surprising there.  So far we haven't really seen anything.
CHAIRMAN BONE:  Also, anyone else on the left?  Dr. Cara and Dr. Molitch.
DR. CARA:  I have a few questions for you if you don't mind, and I'm a little bit confused because of some inconsistencies that I hope you can clarify.

One of them is on page 10 of Dr. Watkins' presentation compared to page 3 of Dr. Pierce's presentation.  I'm looking now at the U.S. reports of jaundice in Rezulin treated patients, and then looking at the worldwide clinical trial data of jaundice.
I mean, on the one hand, of the U.S. reports of jaundice in Rezulin treated patients, that total number is 290, whereas in the trials it's three.  What are the actual numbers of patients there?  What's the actual denominator there?
DR. ZERBE:  The denominator?  Well, perhaps I don't have the book in front of me.  So perhaps you --
DR. CARA:  Part of the problem I'm having is that there's little pieces of data sort of put in, but nothing bringing it all together.
DR. ZERBE:  Would it be worthwhile reviewing the set of numbers, this one?  And then maybe perhaps we can clarify it based on that series.
DR. CARA:  Well,  I have a couple of other questions --
DR. ZERBE:  Okay.
DR. CARA: -- related to specific numbers that maybe you can put together.
DR. ZERBE:  One at a time or --
DR. CARA:  However you want to do it.  Let me tell you what my questions are.

DR. ZERBE:  I'd suggest we do it one at a time because we probably will have to refer to different tables, if you'd like.
DR. CARA:  Okay.  So what's the actual number of patients on Rezulin here?
DR. ZERBE:  I think Dr. Pierce is behind you ready to address that question.
DR. PIERCE:  Well, the denominator in terms of the total number of patients, I suppose, is 1.58 million.  This is from the marketed drug experience.  Parts of the difference, as I indicated, all of the graphs that I showed with jaundice and bilirubinemia include all patients with jaundice and hyperbilirubinemia without attribution.  In other words, it's every case of jaundice and hyperbilirubinemia that we see.
Some of the slides that I showed differed slightly in numbers depending upon the purpose of the slide.  If we're looking at the duration of drug therapy, we need to know the onset date of therapy until the event date, and if we don't have both dates, we can't use that patient.
If we're looking at the effect of publicity, we need to know the time of the onset and the time of the report, and if we don't have both of those dates we can't use them.  So that's the reason for some of the small differences in numbers.

Does that answer your question?
DR. CARA:  Well, no, it doesn't answer my question.  It tells me why you can't answer my question.
(Laughter.)
DR. CARA:  The other question that I have is related to the data looking at the comparison of the metformin versus the troglitazone treatment, and then looking at patient years per 100,000 patient-years.
My concern is that that may not necessarily reflect true length of treatment per each individual patient., and what I'm concerned about specifically is the issue that was raised earlier this morning regarding patients needing to be on treatment at least six months before you can actually evaluate any sort of clinical data in regards to jaundice and potential liver damage.
Do you have any idea of what the actual incidence is for patients that were on treatment for greater than six months?
DR. ZERBE:  I believe that's shown on Dr. Pierce's slide talking about the duration of therapy and the number of cases that occur by duration of therapy.  I think you show both hyperbilirubinemia ‑-

DR. CARA:  Yeah, but he doesn't include number of patients on that.  It's just duration of treatment.
DR. ZERBE:  Yeah, you're right, but we can provide that.
DR. CARA:  But it could be one patient.
DR. ZERBE:  And particularly at the end it is one patient because the reason those numbers go up is because the denominator is falling so quickly, but we could actually calculate, I think the actual number of patients.
You want to know beyond six months?
DR. CARA:  Well, I want to know specifically when you're comparing metformin, the incidence of side effects for metformin and insulin and sulfonylureas and whatnot.  You made a pretty strong case that troglitazone was not any different, but obviously patients at treated with insulin, metformin, and sulfonylureas for significantly longer than what I've seen treated with troglitazone, which plays a very important role.  

I mean, it plays a very important role in potential development of side effects.  So if you have any data for patients that have been treated longer than six months in terms of the actual incidence of things like hyperbilirubinemia, jaundice, and actual acute hepatic failure, that would be very helpful.
DR. ZERBE:  Well, I think those data are actually, with the small derivation -- I think we could answer the question fairly quickly.
DR. CARA:  Great.
DR. ZERBE:  Of those patients, what the rate is, because we know both the denominator and the numerator  for all of the months beyond six months; so we could very, very quickly calculate that.
I think there might be some caution in sort of comparing that rate to, say, something with metformin.  I think we have to very carefully think through that because there could be other issues related to metformin where a population comparison to metformin may not actually match up or be valid to an after six month comparison with troglitazone, but we would be happy to provide the troglitazone half of that estimate, if that would help.
DR. CARA:  Your point is well taken, and I would look forward to seeing the troglitazone data in that regard.
DR. ZERBE:  So we can probably do that fairly quickly.
DR. CARA:  That would be great.

DR. ZERBE:  I'll volunteer my colleagues for that.
CHAIRMAN BONE:  Fine.  We'll expect to hear that within the questioning period.
DR. ZERBE:  Okay.
CHAIRMAN BONE:  Let's see.  Dr. Colley, I think, has a question.
DR. COLLEY:  Regardless of what estimates of numbers of patients might be at risk for toxicity you place confidence in, I think we're all in agreement there is some risk, and one way to reduce that risk is to limit the drug to patients that we know will get an adequate response.
What factors have you identified that predict that patients will respond to troglitazone therapy, either monotherapy or combination?
DR. ZERBE:  Well, first, I think it's important to reemphasize one point that Dr. Bilstad made very early on when we talked about the label change.  The restriction of duration of therapy, sort of a test of response, is already in place at two months for monotherapy.

We did that in the final label change.  So basically even assessing, you know, the safety risk-benefit in monotherapy to existing data or old data prior to that label change probably isn't valid because the patients after the label change, if physicians are following the guidelines, would not continue therapy beyond two months if, in fact, they weren't getting benefit.
So the overall risk-benefit has already been improved in that way.
Now, in terms of estimating patients that might benefit preferentially, I think one thing that we are, I guess, looking more carefully at, and Dr. Whitcomb might want to address, and that is patients with particularly high, you know, glucose levels at the time of presentation for monotherapy may not respond as well as patients at the lower levels.
And, frankly, it fits the diabetes model because one of the things that, you know, Rezulin is dependent upon, potentiating the effects of circulating insulin.  So if, in fact, it's far advanced and there's less circulating insulin, the benefit may not be as great.
It's difficult to get a clear answer to that question, but that's been one of the possible things that we've talked about as well.
Randy, do you want to add anything to that?

DR. WHITCOMB:  The question that you're asking is really a good one.  I think the response rates for people with combination therapy, no matter which model you look in, are extremely high, and I think the other point to be made is if you looked at the mean time curves for the response for the population, you see most of the effect by about four weeks or so if you're going to see it.
I think the issue with initial monotherapy is that it's not as clear that the responder time course is as precise.  It looks like it's around four weeks by the time you see the response, but again, it depends on where the patient is kind of starting out at, and it looks like people are, say, less than about 250 milligrams per deciliter or so with the fasting glucose initially respond better than those that are higher than that, for example.
We originally thought that maybe something closer to 200 was the right number, but based on analyses I don't think that's the case.  I think it's more like 250 or lower as initial monotherapy.

That's not true for combination where the response rate appears to be very high in all models kind of that we've looked at.  Again, it depends on how you define responder, which has been one of the great conundrums out of this.
CHAIRMAN BONE:  Thank you.
Drs. Molitch and then Genuth and then New.
DR. MOLITCH:  I just have a question of clarification for Dr. Pierce for his second to last slide, which looked at the reports of serious liver events by duration on drug.  Is there a way to put that up?
My only question is in looking at the data, it's sort of reassuring that it goes down with duration, but since its rate per 100,000 patient-years, how many patients do you have who are on the drug for more than a year that will allow you to come up with a number out past the year that will give you reasonable confidence that it's close to zero?
DR. PIERCE:  Yeah, it's similar to the question that was asked earlier, and I believe I have the answer to that now.
With regard to death and transplants beyond one year, we have none that are attributable.
DR. MOLITCH:  What's the denominator?
DR. PIERCE:  The denominator beyond one year would be about 400,000, as I've indicated for the persistency.  That's for death and transplant.

DR. MOLITCH:  But each time point as you go out further and further, that number gets smaller and smaller?
DR. PIERCE:  That's correct.
And the answer to the earlier question about the number of cases of death and transplant beyond six months are seven, and the denominator is 600,000.  So that's 1.1 per 100,000.
CHAIRMAN BONE:  All right.  Thank you very much.
Let's see.  Dr. Genuth.
DR. GENUTH:  I'd like to ask one question of Dr. Whitcomb and one of Dr. Zerbe.
There's been a lot of emphasis comparing troglitazone and metformin in terms of their safety.  So I'd like to understand better the head-to-head comparison between them with regard to efficacy.  I'm having a little trouble understanding page 30 and 31 which  were slides you showed of the only study I'm aware of anyway where there's direct comparison between the two drugs.
I'm just confused as to what the baseline glucoses and A1c's were and --
DR. WHITCOMB:  What page?
DR. GENUTH:  Page 30 and 31 in the red Parke-Davis handout.

DR. WHITCOMB:  Yeah, that's the slide.
DR. GENUTH:  Could you just take me through the numbers?
DR. WHITCOMB:  Sure.  I'm sorry.  I didn't clarify that very much.
Actually if you go to the next slide, I might be able to help you a little bit better.  These are the Ns of patients in each of the group.  You know, it's a little less than 100 percent treatment group, is the N of patients.
The A1c at baseline for the population was about 8.2 percent.  So they were fairly mild, if you will, Type 2 patients.
DR. GENUTH:  So looking at that slide, troglitazone at 600 milligrams lowered hemoglobin A1c from 8.2 to 7.3?
DR. WHITCOMB:  In this particular trial, yes.
DR. GENUTH:  As did metformin?
DR. WHITCOMB:  And this, importantly, a dose of metformin -- the instructions to the investigators were to titrate to maximally tolerated dose, which ended up being a mean of 1.6 grams in this particular trial.
DR. GENUTH:  Okay.  

DR. WHITCOMB:  Is that the question?
DR. GENUTH:  Yeah.  That's the farthest out you have data, is 26 weeks.
DR. WHITCOMB:  That is correct.  This trial was truncated at the end of six months.
DR. GENUTH:  Okay.  I'd like to ask Dr. Zerbe.  You, I think, suggested in your last summary slide, and I think it's in the new labeling that you're suggesting, that one way to increase the safety of using troglitazone would be to define what a trial period of treatment would be in naive patients previously treated with diet alone.
And I think what it says here is that they get one month at 400 milligrams and another month at 600 milligrams, and then if there's no adequate response, something else should be done for the patient.
Now, first of all, I wonder what the company means by not responding adequately.  What's the definition the doctor is supposed to use for an adequate response?

DR. ZERBE:  I think there are criteria, are there not, that we actually specify that were agreed to with the FDA?  I don't have a package insert in front of me.  So we can explain what that was, if you don't mind, Randy.
DR. WHITCOMB:  The definition -- and, again, this was done very arbitrarily -- was a fall of at least 30 milligrams per deciliter of fasting plasma glucose, was the responder definition that was used actually in the monotherapy trials as well as in several other studies.
The data that I showed you for the head to head with metformin was based upon an A1c responder definition, by the way, which is why the numbers are lower than what we've seen generally.
DR. GENUTH:  In fact, 30 milligram per deciliter indicator of response irrespective of the starting fasting glucose?
DR. WHITCOMB:  That's what we have indicated to this point in time.  One of the proposals is that if you have patients that fall at least 30 milligrams per deciliter, but haven't reached ADA goals, is that you add another drug onto it, you know, like a sulfonylurea where there's clearly an added benefit to the patients.
DR. GENUTH:  I'm probably not supposed to comment at this point, but I think there's a big difference between dropping from a fasting of 250 to 220 and dropping from a fasting of 150 to 120.

DR. WHITCOMB:  Right.  I think one of the important things, and you know this better than I do, is that the definition of, quote, response is not standardized, and when you look across drug products, it's very hard to kind of get these data for other drugs to make some comparisons, and you end up with some anecdotal experience.  So that's been part of the problem.
DR. GENUTH:  If there is no adequate response, is the advice to the physician to try another oral agent as monotherapy or is the advice to the physician to add another drug to troglitazone?
DR. WHITCOMB:  Yeah.  The current labeling is to seek alternative therapeutic options, I believe is what the labeling says.
DR. GENUTH:  Yeah.  I'm trying to define that.
DR. WHITCOMB:  Well, I'm trying to tell you what was in the labeling.  I mean what we think makes sense, quite frankly, is to add something onto it if you've not responded adequately, but I think the question is -- and this gets back into risk-benefit again -- if you respond to the drug as monotherapy but don't reach target, I think it makes sense to add something on.

The question is -- and actually the studies are going on now to define this -- if you don't respond as well and you add on other drugs, what is the response?  And those trials are going on right now.
DR. GENUTH:  Well, there's a big difference between substituting and adding in the sense that when you add, you continue the risk of liver failure from troglitazone.  When you substitute, you get rid of that risk and maybe you --
DR. WHITCOMB:  Maybe you pick up another one, right.
DR. GENUTH:  -- have a different, competing one.
DR. WHITCOMB:  Which is why the notion of adding something on where you've then ratcheted the benefit up another level was the logic in that.  Does that make sense, Dr. Genuth?
CHAIRMAN BONE:  Thank you.

Dr. New has a question.  Dr. Braunstein has kindly written out his two questions, which we'll get to in a few minutes after the FDA and company have had a chance to look at them and formulate the answers so that we can be concise, and from looking at these questions, I think if we can achieve closure on those questions, it will be very helpful.
Dr. New had the next question.
DR. NEW:  I need clarification on the following.  What is the evidence that monthly monitoring of liver chemistries is preventive of liver failure, and if there is evidence, I just don't understand entirely what it is, and if there isn't good evidence, why do it?
DR. ZERBE:  Well, it's another excellent question, and I think no one knows the true benefit of liver function monitoring.  I think we can only approach it sort of in a circumstantial way.
We do know that the label changes that were made called for both monitoring, but at the same time, there was substantial publicity.  There was information, professional education about monitoring that increased awareness of the problem.
I think probably you can't totally ascribe the decreased rate in the events to monitoring alone.  We believe the monitoring is taking place much more frequently than Dr. Graham suggested.  However, I think we would be, you know, insincere if we said that we believe that physicians are monitoring perfectly according to the label.

But I think just the awareness of it, recognizing the importance of taking the measurements even if they may be at, you know, five and a half weeks instead of exactly at four weeks, probably has contributed to the benefit and also the awareness.  That is, if people come in feeling badly, physicians in general are more aware of this as being a potential problem.
So I think it isn't strictly monitoring, but I think the overall awareness is substantial, as we demonstrated in the survey, and I'm sure that has an impact on behavior.
I think we would be reluctant to reach the conclusion that monitoring was playing no role and, therefore, eliminate it.
DR. NEW:  Okay.
CHAIRMAN BONE:  Dr. Lewis had a question.  Oh, Dr. New, did you have --
DR. NEW:  No.  Just so that you would say that you are convinced that monitoring plays some role in preventing complications of the liver?
DR. ZERBE:  I personally would say that, yes, it plays some role.  I think the more significant issue is probably that I don't think -- this is a serious enough problem that I don't think we would suggest that it not be done, if that's the question.

CHAIRMAN BONE:  Dr. Lewis and then Dr. Kreisberg.
DR. LEWIS:  This is sort of a comment on the same point.  I don't think there's any question that monitoring when done in a frequent basis like this for a drug that causes unpredictable or what we call idiosyncratic injury, where there's really no markers of who's going to develop that injury; it occurs after several months in moth patients.  The only way you can find who's likely to develop more severe injury, not who's going to develop the first instance of injury, but try to prevent them from going on to more severe injury, is with frequent monitoring.
And this is not a drug that's an allergic type reaction, with fever and rash and eosinophils and things like that, which announces itself as an allergic type reaction and you know something's wrong.  This doesn't do that until you actually develop the severe liver injury.
And by that time you have hepatitis-like symptoms, which if the patient recognizes them or the physician recognizes them, even if it's in between those monthly periods, additional monitoring should be done according to the new guidelines.

One of my question is I'm not sure if we've heard whether there have been any further deaths or transplants since the new monitoring guidelines have been in place, and if there have been, did any of those individuals have symptoms in between the monitoring that should have triggered further monitoring and get the drug stopped perhaps sooner.
This relates to Dr. Graham's definition of these rapid risers, which is simply another way of saying hyper acute or acute fulminant hepatic failure, which occurs out of the blue in somebody whose liver is normal to begin with.
But there's no question that I think monitoring of all the types we're talking about is the only way you can pick up these idiosyncratic events.
CHAIRMAN BONE:  Dr. Zerbe, did you have an answer for Dr. Lewis' question?
DR. ZERBE:  Well, I think the best way perhaps to answer it, if you don't mind, Paul, would be to refer to your slide on rapid risers.
CHAIRMAN BONE:  No.
DR. ZERBE:  Oh, I'm sorry.
CHAIRMAN BONE:  I meant the question about the -- he had a specific question about whether there have been -- about new cases since the most recent set of guidelines were introduced.

DR. ZERBE:  There have been cases since the most recent guideline.  The rate appears to have decreased, and there were two questions related.  I think the other one was related to whether these individual -- any of the people in that time frame represented this rapid riser or did they actually -- were they just not perhaps monitored or managed according to label.
Again, I think the reference to Paul's slide might be the best.  We did go through all of these cases with the FDA.  There is some disagreement on some of those cases.  I don't know that we want to get into a public debate about the individual cases.  That was not our intent.   We don't want in any way, shape or form to try to discount the cases, but I think they are complicated cases, and we don't necessarily agree in every situation.
If you would like to do that, we can show that slide, show Paul's slide again, which designated all of those.
CHAIRMAN BONE:  If that's going to answer Dr. Lewis' question.

DR. LEWIS:  Well, it's more to whether they had symptoms in between the monitoring times that should have alerted somebody under the new monitoring guidelines to do more monitoring, and they might have been picked up before they became fatal or needed liver transplant.
DR. ZERBE:  Paul.  I think he'd be the best person to answer that.
DR. WHITCOMB:  I think it's fair to say, based on the data we have, that symptoms haven't reliably indicated this problem, although there clearly are many cases where in between blood values we have the person that developed abdominal pain, nausea.  We heard about a couple of those cases, and I did not systematically review each case looking at it, but it's quite clear there are a sizable proportion of the cases where symptoms didn't appear that the patient would have gone to the physician for, I think it's fair to say.
DR. ZERBE:  It is fair to say, Paul, I believe there was one case in which symptoms actually preceded.
DR. WHITCOMB:  Oh, there have been several cases where, I guess --
DR. ZERBE:  That preceded actual initiation of the drug.  I think that was one of the cases of rapid riser, symptoms such as the one you described.

DR. WHITCOMB:  Yes.  Well, I guess it's whether the glass is half empty or half full.  There is no question there are many cases where there were symptoms present and were ignored and the drug continued.  However, I'm taking the most conservative position saying there are definitely cases where things had gotten out of control without at least reported at documented symptoms.
Is that -- Jim, am I close to the market here?
DR. LEWIS:  Yeah.  I mean we're only dealing with a very few number of patients here where full monitoring was going on, and if you're telling me that symptoms may have not been recognized or weren't present, I mean that's not inconsistent with what we see with other idiosyncratic drug reactions.  Not everybody gets symptoms, which is why monitoring is imperfect, but it's about the best we can do.
DR. WHITCOMB:  That's right.  The only other comment is once somebody becomes jaundice obviously there's no need for monitoring.  Everyone is aware they have a problem.  So I was referring to symptoms really prior to jaundice and the entire data set.
CHAIRMAN BONE:  Right.  Thank you.

We'll have a question from Dr. Molitch and then Dr. Braunstein's questions.  Dr. Kreisberg.  Excuse me.  I'm sorry, and then Dr. Molitch. 
Everybody will get their question asked.  I'm sorry if I got them out of order.
DR. MOLITCH:  Well, I'm allowed to go ahead apparently.
CHAIRMAN BONE:  Please, go ahead, Mark.
DR. MOLITCH:  Okay.  I want to come back to Dr. New's and Dr. Lewis' question again because I think this is the crux of the problem that many of us are having at the moment in trying to figure out where we're going here, and that is about the efficacy of monitoring in preventing disease.

And we obviously don't have any kind of prospective randomized study with or without monitoring, and that will never happen, but our understanding from what you've said, I think, is that based on experience with this drug and with other drugs that cause similar types of idiosyncratic hepatotoxicity, that, in fact, if we set up a monitoring program and are able to, in fact, have patients monitored, detect the earliest rise in ALT levels at a two to threefold, whatever level we set, say, two to threefold elevation, and then stop the drug when that is immediately done, is it my understanding or your understanding that we will largely prevent most cases from going on to jaundice and liver failure?
DR. LEWIS:  Yes, that's the understanding, that we'll prevent most cases, not everybody perhaps.  Probably the best example is with isoniazid, INH.  There was a recent modeling study published in the Annals of Internal Medicine which clearly demonstrated that biochemical monitoring, in addition to the clinical monitoring, prior to jaundice and other things, reduced the chance of developing a fatal INH hepatitis dramatically, and this is not dissimilar.  They're both drugs that cause, you know, idiosyncratic disease by some toxic metabolite presumably, and it worked in that instance.
It didn't eliminate it.  Nothing eliminates it, but it gets it down to a very low level.
DR. MOLITCH:  Can you just put a guesstimate number on that most figure?  Does it reduce it by 50 percent, 75 percent, 90 percent?  What's a guess?

DR. LEWIS:  My guess would be 75 percent or more.  You'd be able to pick up, stop the drug, and not have liver disease progress, and that's from experience with monitoring from other drugs.
DR. MOLITCH:  Thank you.
CHAIRMAN BONE:  All right.  We're going to stay with questions, please, for the Parke-Davis people for now, and then we'll come back.
I've got several people in a row, I think.  Dr. Kreisberg, and then we have Dr. Braunstein's list of questions, and we'll get to everybody.  Don't worry.  Okay.
DR. KREISBERG:  I don't mean to beat a dead horse, but I think the screening issue is a very important one for me.
First of all, it seems prudent, I mean, to do something like that.  It's also very expensive to have to do that.
On the one hand, the Parke-Davis people tell us that the risk virtually disappears over time, and in fact, with the new labeling and the letters to the doctors, the risk of developing this seems to have fallen considerably from about one in 36,000 to one in approximately 60,000.
On the other hand, the FDA, Dr. Graham says, it doesn't change over time.  I mean these people are continually at risk.

And I wonder if you would comment on the following question, is that there appears to be an association between the new labeling changes and the reduction in risk, but you're looking at a different population of patients who may have been on the drug for a much shorter period of time, and is this more apparent than real?
DR. ZERBE:  That's a very perceptive question, and that's, of course, one of the challenges that you have when you have new patients coming in at different time intervals in terms of you not only are taking calendar time and impacting it with external things like awareness, but you also have a population, a cohort that's moving out.
We have not done that analysis.  It would be very complex.  You'd have to look at the individual cases in a lot of detail with both bilirubin and jaundice, as well as death.  My guess is the death numbers are too small to actually get a reliable answer to that question.

I think the data, making the assumption that the risk, you know, is falling, we'll even take the assumption that the risk is maintained for the purpose of evaluating the calendar effects.  I think the data are very strong that the monitoring and awareness the "Dear Doctor" letters have had a substantial impact on the occurrence of the events.
I likewise feel though that the information on the risk over time -- granted as you get farther and farther out, whether it's David Graham's model or our model, gets more and more questionable -- it would appear that the numbers are going down, and really with a very small increase at the end, which is related to a very few patients in a very small denominator.  That appears to be a pretty clear message from our analysis of the data.
DR. KREISBERG:  Thank you.
CHAIRMAN BONE:  All right.  Now it's time for Dr. Braunstein's questions, which are related questions.
DR. BRAUNSTEIN:  Right.
DR. HIRSCH:  Excuse me.  I had one.
CHAIRMAN BONE:  Yes, you'll get yours, too.
DR. HIRSCH:  Oh, okay.
CHAIRMAN BONE:  This isn't the last question by any means.  I did not mean to imply that.

I see from the questions that this is going to be, I think, directly addressing several of the other questions in sequence.  So I would regard these as perhaps helpful in moving us closer to closure on some of these issues, if we can.
Dr. Braunstein, you have a list of five questions here, and I think we're asking both the sponsor and the agency to address these questions; is that right?
DR. ZERBE:  Are we prepared to address it, Mark?
CHAIRMAN BONE:  We can give you a few more minutes if you want to.  You're ready?
DR. PIERCE:  Yes.  
DR. BRAUNSTEIN:  First of all, there are differences in the number of total liver associated deaths that were reported in several other papers that we received.  Parke-Davis indicated that there were 70 liver associated deaths.  The FDA letter to Congressman Waxman in February of '99 indicated 100.  The L.A. Times through information they received through Freedom of Information Act reported on 91 liver associated deaths.  Yet we're talking about 35 that was agreed upon by the FDA and the company.
And so the first question I have is:  how were the others excluded?

DR. PIERCE:  Well, the specific answer to the definitions for attributability would need to be answered by Dr. Watkins, but I think that the general answer to the question really, the discrepancies between Parke-Davis and the L.A. Times, will have to do with the issues both of timing and the issue of attributability, the definition of attributability.
This shows the situation as of March 5th, 1999.  The total number of reported deaths or liver transplants is 131; the deaths with a liver mention or liver transplants, 87; and of course, deaths without liver mention are 44.  So this deals with just total numbers of deaths report.
With regard to the ones that mention the liver or liver transplant, there are 12 which turned out not to be liver related, and there are 75 which may be.  Twelve of those had insufficient information.  Twenty-eight were possible, probably related to Rezulin therapy, as Dr. Watkins indicated, and 35 were unrelated.
Between the 12 and the 28 and the 35, as I said, we've agreed with the FDA that there are 35 that are possible or probably related to Rezulin therapy.

DR. ZERBE:  And then just to clarify, the 43 number that the FDA has, if there's any confusion, also includes non-deaths with encephalopathy, which we have not included in our analysis.
CHAIRMAN BONE:  Dr. Graham, if I understand correctly, they're saying that the difference here has to do with whether the deaths are attributed as being possibly or probably drug related as opposed to all cases in which there were both mentioned; is that right?
DR. GRAHAM:  I think that that's essentially correct.  The FDA numbers, I think, represent what the counts were in our computerized system, and that would include any case that's reported.  If the patient had cancer and for some reason or another it was being reported as a liver death or gall stones and they died for some reason, as well as duplicate reports, and then you have to go through those reports and get out the ones that you think are related to the drug.
DR. BRAUNSTEIN:  So the screen is sensitive, but not specific.
DR. GRAHAM:  Exactly.
DR. BRAUNSTEIN:  The second question has to do with frequency in reporting of the data.  Dr. Graham indicated that there didn't appear to be a change, and Parke-Davis indicated that there was a change after the "Dear Doctor" letter.

In fact, Dr. Graham showed a slide.  I think it was page 13 of the handout showing actually a continuous line of reporting over the various dates without a blip at the time either the "Dear Doctor" letters came out or the insert changes were made.
DR. GRAHAM:  May I comment?
I believe the explanation for the differences between the company and ourselves is that the data the company presented, they changed the baseline of what it is we're talking about.  We were talking about cases of acute liver failure.  If you look at the slide that they presented, it was all patients reported with jaundice, and if you subtract out those reports of jaundice and then just presented the stuff on liver failure, you'd see that there was no stimulation of reporting of cases of liver failure.
Now, it may be true that there was stimulation of reporting of jaundice.  I'm not prepared to answer that.  We haven't analyzed our data to answer that, but we can say that based on our analysis we don't believe that there's any evidence of stimulation of reporting of acute liver failure, and that's what is included in our slide.

DR. BRAUNSTEIN:  Well, is it possible then that there's no stimulation because you're capturing almost all the patients with acute liver failure?
DR. GRAHAM:  No, I don't think that that's the case at all.  I think what it represents is that when you get stimulated reporting, the stimulated reporting is the result of increased reporting by consumers, but not by physicians, and if you look at the acute liver failure cases that have been reported, that physicians aren't stimulated to report for whatever reasons.
I don't know the answer to that.
CHAIRMAN BONE:  Thank you.
A response from the sponsor?
DR. PIERCE:  Yeah, I think that the data that I showed indicated the effect of publicity on reporting of jaundice and bilirubin.  We picked that because there are a lot more cases and so the data is more robust.  Obviously there are many fewer cases of death due to liver failure and transplant.

I also showed data that at least the self-reported likelihood of reporting, you know, increases for death and transplant, is somewhat lower for jaundice, but we really take jaundice as a good index at least over time.  It's very, as with death and transplant, they're both very recognized, and we show over time a decrease in the incidence of jaundice and hyperbilirubinemia as well as the incidence of death.
The data that we presented was presented, and the data I showed in the table, were the cases divided by the denominator of new patient starts in each of those periods.  I think that we really don't differ a great deal with regard to that with the FDA.
Last Thursday when Dr. Graham and we had a meeting, he did present a slide, examination of reporting rates by time period where he did really a similar calculation.  His overall denominators are different because of a different data source.  His time cuts are a little different than the ones that I showed.
But he showed the number of patients in the interval and then divided by the number of new -- well, the number of cases in the interval divided by the number of patients who had a start in that interval and showed a decrease in reporting rate per persons of between 4.78 rate per ten to the sixth persons between March and November 1997, falling to a rate of 2.76 in the August -- well, actually 2.36 between December '97 and July '98, and a rate of 2.76 between August '98 and January of '98.

So I think I may have misunderstood the slide as it was presented last week, but I think that the issue -- there's not a great discrepancy on that point.
CHAIRMAN BONE:  I suppose there's a confounding question here as well because if we have now -- if it's true that this is much less of a problem after a year, there would be a dilution effect by those large number of people who have been on the drug for an extended period of time, and that would be influencing the rates.
DR. GRAHAM:  Well, if I can make one comment on that, in the sponsor's presentation of their methods, if you notice in the early part of their slide, they mention why their line was sort of flat up there.  It's because they were crediting everybody in the plan with an additional month of time being counted in treatment after they had evidence in their system that they were active.
And so rather than the line going sort of down in a linear fashion -- I forget which slide it was of theirs -- it sort of has this two or three-month blip, and then it goes down, and the speaker did refer to what the reasons for that was, but I believe that that introduces an artifact because what you're doing is you're basically crediting time to people that isn't really credited.

Well --
CHAIRMAN BONE:  That doesn't respond to mine.
DR. GRAHAM:  Well, then I don't understand your question.
CHAIRMAN BONE:  Well, we heard that they have 400,000 people who have been on this drug for more than a year.
DR. GRAHAM:  Right.  We don't -- well, there's two things going on here.  One is we based our analysis using a cutoff date of December '98.  They've extended their data another quarter, so another quarter of a year, and based it on that.  That introduces some difference.
The second difference has to do with how one measures persistency.  We looked at an entire population that was under surveillance for the entire time and were able to follow everybody and account for them, and this is the pattern that we saw, and we didn't have to credit extra time to people or make any assumptions, which at least in the description of their methods it seemed like they were crediting people with more time than they actually had on drug.

And what that would do is that would shift your curve over and make it look like you had people on the drug longer than they were actually on it for.
CHAIRMAN BONE:  Well, that might mean that some of these people were on for 11 months instead of 12, but it wouldn't change the point I was trying to ask about.
DR. GRAHAM:  Okay.  Well --
CHAIRMAN BONE:  Let's go on.
Dr. Braunstein.
DR. CARA:  Sorry.  Could I ask a related question to this before we move on?
I'm curious as to what this chart that you put together on page 13 of your presentation would look like if you actually put death/transplants rather than acute liver failure.
DR. GRAHAM:  All you'd have to do is -- I don't know which one that is.
DR. CARA:  It's on page 13.
DR. GRAHAM:  Okay.  The scatter plot.  Subtract out five dots.  I mean, just sort of pick them.
DR. CARA:  There's no difference in --
DR. GRAHAM:  No, there's no difference.
DR. CARA:  -- death/transplant?
DR. GRAHAM:  Right.  No.

DR. BRAUNSTEIN:  The next really had to do with this issue of decrease in death or liver failure following the labeling change and the "Dear Doctor" letters.  My understanding from Dr. Graham's presentation was that there wasn't any evidence of a decrease.  Am I incorrect in that?
DR. GRAHAM:  What I was talking about was the hazard rates over time and the cumulative risk over time.  In terms of actual reporting rates, I didn't present any data on that.
The data on reporting rates are that if you look at sort of what would correspond to our cohort one, that first time period, that the reporting rates are about like 4.8 per million persons, and if you go into the second time period, which sort of corresponds to the place between the two "Dear Doctor" letters, it's about 2.4, and if you go into the third time period, which goes, say, from August -- you know, from the second "Dear Doctor" letter to the end of the year, that also is 2.4.

And what you seen then so is a decline in the reporting rate.  We have done studies on a number of different drugs and shown that the reporting rate of a product drops from the very first year.  It just comes down.  It's just a function of reporting.  So the first year the reporting rates are higher, and then subsequently the reporting rates become lower.
And we see that with virtually every drug that we've looked at to examine it.  So the fact that reporting rates go down doesn't mean that anything has changed in the background population.
And if you're going to say that cases have declined and you're going to say that it's because monitoring has occurred, then you really have to examine whether or not that statement is accurate, whether monitoring has, in fact, occurred.
And our data, we would suggest, says that it has not.  So that can't be brought in as a reason to explain it away.
CHAIRMAN BONE:  Comments from the sponsor on this question?  It seems to me like it's a fairly important question for the Committee.
DR. PIERCE:  Yeah.  Whether one looks at this issue of the reporting rate either by new therapy starts, and that's what I showed in my slide, or by person-years, which takes into account this variable exposure, the results are the same.

If one does the periods that I showed instead of by new therapy starts, just number of individuals, but by person-years, one gets a value before December 1997 of one in 22,000 patient-years for the incidence of death due to liver failure/transplant, and after the period you get a rate of one in 44,000.  So that's another way to look at it.
I think, you know, the issue of -- of course, nobody knows the absolute level of reporting rate, and for sure we don't know how the reporting rate changes over time.  I think you can support any hypothesis by talking about changes in reporting rate over time.
So what we've shown you is the reports over time without making assumptions about changes in reporting rates or the reporting rate.
DR. BRAUNSTEIN:  There also seemed to be a fairly large discrepancy between the estimated frequency of liver failure between Dr. Graham's estimate and Parke-Davis' estimate.  Dr. Graham's numbers, if I understand the modeling and everything else correctly, indicated that the rate would be one in 1,000 to 2,000 individuals exposed to the drug for six-plus months, whereas the sponsor indicates that it's maybe at the most one in 34,000 patient-years of exposure, and that's a pretty large discrepancy there.

DR. GRAHAM:  Right.  What the sponsor has done is given you basically their estimation of a reporting rate, and they don't account for person-time in that analysis.
What we've given basically, that one per 2,000 at six months translates to a person-time rate of 1,000 per million person-years.  Now, if you look at the company's data from Table 2 of the briefing document that they sent you where they presented all their population based data -- see, that's the other thing.  Our rate comes from -- we're using the population based data from the REACH study, the DPP study, the UHC study, and the modeling that we did was spontaneous case reports that led us back to a very similar rate, and that's where we come up with that estimate.
If you look at that Table 2 from the sponsor's study where they did the aggregate analysis that in my presentation I indicated I didn't think that it was appropriate because it hides certain things about the data, they come up with an estimate there of 290 per million person-years for acute liver failure.

So compare 300 to 1,000.  See, it then -- all of a sudden the gap between what they're presenting, which is a frequency count -- it's a reporting count.  You have under reporting, and they've counted all the individuals and somebody on the drug for one week contributes the same amount of weight to the denominator as somebody on the drug for ten years, and so then you get a very different -- you get a very exaggerated difference in where we're coming from.
CHAIRMAN BONE:  Obviously we want to hear from the sponsor on this point.
DR. FAICH:  Well, let me just take those three sources of estimates.  We've already talked about the clinical trials at length, about whether the numerator is two or not two and how certain that number is and what the denominator is, and you've heard my views on that earlier.
I think that the best point estimate from the clinical trials is on the order of one per 5,000 to one per 7,000.
The issue of using person-time as opposed to persons, which is the same one in clinical trials as it is postmarketing, has to do with whether you think that there's a continuing not only risk but a cumulative effect in patients as opposed to an idiosyncratic effect that happens only once per person, whether it happens in the first month or the second month or third month of therapy.

So you have to think about what is the biologic mechanism which would then drive the epidemiologic denominator calculation.
I would submit as you look at the distribution by month of cases, it looks to me like, in fact, they are not continually happening over time; that they do, indeed, tail off in patients who have had four, five and six months of therapy; that that peak is somewhere between three and five months, and that's more suggestive.
It's true that could be a phenomenon of the reporting system, but if you believe that reporting is high, which is actually key to all of this discussion, then the suggestion from the spontaneous reports is that an individual is only susceptible once.  So, therefore, you would then count new starts as opposed to person-time, and that is a major difference.
I don't see a biologic compelling reason why you would see this cumulative toxicity in individuals.  That's probably the single biggest difference.

Looking at the database issue, the UHC data, we hold, is not yet reliable or useful to look at at this point and is a preliminary probe.  So I would contend the best data to look at, in fact, are the numerator data from reporting and the denominator data from the total number of patients treated, and you can take total numbers of patients treated and then look at treated for X number of months, and we did that, and we displayed those data.
CHAIRMAN BONE:  Right.  Thank you.
I think we --
DR. BRAUNSTEIN:  Does that actually address the last question?  He wants to respond to it.
DR. GRAHAM:  Yeah, no the --
DR. BRAUNSTEIN:  When the injury occurs.
DR. GENUTH:  On peak and what happens after that.  Well, it's clear from our data that based on the reporting that we have, that the peak we found is at six months, and that we don't have reporting of cases of liver failure beyond eight months.  So our last case occurred during the eight months of treatment that we have reported to us.
However, several lines of arguments.  One, we know the denominator is shrinking, and so there could be cases out there that haven't developed yet or that it takes longer to develop because you have to accrue enough person time in that exposure period to produce the cases.

A second thing is that from the sponsor's own clinical trials described in their briefing document, they had patients as far out as 18.2 months that had liver enzyme abnormalities that were above the three times upper limit of normal.
What you run into, the problem is that you're talking about a very shrinking denominator and what happens out there.  So it's hard to say.
With INH, if you read the literature on INH, the number of cases that occur with INH of fatal hepatitis with extended use is small, but that's because the denominator of patients at risk who are using the drug out that long is also small.
In some of the articles that I've read, authors actually make the comment that the actual hazard rate to patients with extended use may actually be higher than it is earlier on.  It's just that most people stop the drugs with six months or three months of treatment.
CHAIRMAN BONE:  Anything further from the sponsor on that point?
DR. CARA:  That's a very --  I'm sorry.
CHAIRMAN BONE:  Please, Dr. Cara, go ahead.
DR. CARA:  It's a --

CHAIRMAN BONE:  Jose, I was going to let the sponsor finish, and then we have -- I know everybody has questions about these data.
DR. PIERCE:  Could we show the next to the last slide in my presentation?
Just to show this again, both for jaundice and hyperbilirubinemia, and this is risk as a function of duration on drug, jaundice and hyperbilirubinemia peak at about three to four months.  Death and transplants peak perhaps four to five months and then decline thereafter, and we show both of them to show basically the parallelism between them both.  Jaundice and hyperbilirubinemia, this includes all cases, and it's also heading down.
You know, the slide that Dr. Graham showed also showed a similar peak.  What this is really -- this is showing the interval specific hazard rate at each interval each month.  Dr. Graham showed the slide and explained that the peak interval specific hazard rate occurs at six months and then declines.  There are only two more points on that curve because there are no cases beyond that point.

CHAIRMAN BONE:  Just for clarification, did I understand correctly that the number of patients who have been on drug for 12 months or more here is 400,000?  Is that correct?
DR. PIERCE:  That's correct.
CHAIRMAN BONE:  Is that agreed, Dr. Graham?
DR. GRAHAM:  No, we would not agree with that, with that estimate.
DR. FAICH:  What's your estimate?
CHAIRMAN BONE:  This sounds like it's probably going to be critical.  So let's settle this if we can.
DR. GRAHAM:  I don't have my slides right in front of me, but if you look at the slide on the UHC slide, it's early on in the drug use section of my presentation, and it's the slide that shows the falling prescriptions.
Go out to 12 months, and I think it was something like 16 percent at 12 months.
CHAIRMAN BONE:  Page 4?
DR. GRAHAM:  Well, no.  They want to know how many people have gotten the drug for more than a year.  Is that the question?
CHAIRMAN BONE:  That's what I'm trying to get clear about.

DR. GRAHAM:  Right.  Well, if you look at that slide and then look at month 13, and that will show you that percentage is less than 16 percent.  So let's pick 15 percent.
Fifteen percent of 1.23 million people are the number of people that we would estimate have used troglitazone for more than a year.
CHAIRMAN BONE:  So your estimate is about 190,000.
DR. GRAHAM:  Whatever that math works out to.
CHAIRMAN BONE:  Is that what that comes out?  I think that's about that.  All right.  So let's say in round numbers 200,000.
And the company has a different set of estimates, I take it, and I believe you said that you based this on pharmacy reports; is that right?  Go ahead, please.
DR. WATKINS:  Our estimates come from national data sources which samples from all new starts at 11,000 pharmacies during three different monthly periods.  So we had three different curves that we showed you, amounting to several thousand patients, actually five or 6,000 patients at the beginning of each of those cohorts, and then followed those individual patients as long as they kept refilling their prescriptions.

That is, it was a sizable number repeated times three, nationally represented because then it was extrapolated from the 11,000 to the 35,000 retail pharmacies.  We hold that it's a very good and stable and accurate measure and doesn't derive from one managed health care system.
So that as opposed to 16 percent in one year, our data is 40 percent of patients were persisting.  We can argue about that one month bump at the beginning, and that has to do with how the first prescription was written and whether it crosses over.  So their methodology is always to carry all of the patients from the first to the second month, but it does not affect the subsequent refilling over time.
So we can argue about this, but those data are very solid data.
DR. MARCUS:  Your data were collected up through March of this year, and yours were through December?
DR. WATKINS:  Through December, yes.  We based our analysis --
DR. MARCUS:  That's another three months that the number of people could have been on to pull out that --

DR. WATKINS:  But the critical issue is how many people are persisting at one year as opposed to whether you follow people along to say, well, how many go --
DR. MARCUS:  I understand that, but I'm trying to reconcile these two numbers.  It's conceivable with three months' more experience there could have been another 100,000 or so people who've been on it a year.
CHAIRMAN BONE:  Let me see if I get -- one projection is 200,000.  The other projection is 400,000.  One projection is based on data from the HMO group.
DR. GRAHAM:  Well, if I could explain though, that data comes from -- it's an IPA model plan, which means it's basically practitioners who contract with the plan to agree to that payment schedule, and it's over nine different states.  I mean, it's not unrepresentative of the country.
CHAIRMAN BONE:  I'm just trying to understand.  One is based on this IPA group and the other is based on the pharmacy group, but whether it's 200,000 or 400,000, no body has seen a death attributed to the drug due to liver failure after patients has been on a year; is that right?
DR. GRAHAM:  A case has not been reported.

CHAIRMAN BONE:  Okay.  That's --
DR. GRAHAM:  That's different.  That's different than saying it hasn't occurred.
(Laughter.)
CHAIRMAN BONE:  Do I understand correctly though that no case reports are known to the company or the agency for patients who have been on the drug for more than a year?
PARTICIPANT:  At this time.
(Laughter.)
CHAIRMAN BONE:  Thank you, Doctor.  
That's what I mean by known.  That's what I'm trying to find out.
DR. GENUTH:  Are you suggesting that if the patients just skipped the first year of therapy everything would be okay?
(Laughter.)
CHAIRMAN BONE:  Thank you.
I knew having with this kind of experience would get us to a solution to the problem.  No, I'm just trying to get one thing everybody agreed on.  I enjoyed the moment.
(Laughter.)

CHAIRMAN BONE:  Okay.  Everybody here has got questions, and I'm sure several people, and we're going to go around to the people who haven't asked questions yet and then come back.
Please, Dr. Hammes.
MR. HAMMES:  Just a comment on that.  The pharmacy data that the Parke-Davis folks are responding to, as a pharmacy professor and a pharmacist, I can comment on that.
Pharmacy students have been gathering that data since I was a student 30 years ago, and they actually go to community pharmacies and go through prescription files and record who got what and which companies was dispensed.  It's quite accurate data.
CHAIRMAN BONE:  All right.  So we have two sets of accurate date.  The question is how well we --
(Laughter.)
DR. GRAHAM:  That is correct.
CHAIRMAN BONE:  I think it's a question of how we extrapolate.
All right.  Let's see.  Dr. Fleischer.

DR. FLEISCHER:  I would like to ask, again, just to the hepatologists who are here whether or not such an asyncratic reaction should be looked at in terms of person-time or person numbers.  I mean, that's the next big discrepancy in the two ways to analyze the data, whether it needs to be done as numbers of people versus the numbers of people over time.
And that really is the second large discrepancy between the FDA report from Dr. Graham and the company, and I wonder  does anybody have any opinions about that.
CHAIRMAN BONE:  Although we're trying to stick to the questions related to the Parke-Davis presentation --
DR. FLEISCHER:  Oh, I'm sorry.
CHAIRMAN BONE:  -- we'll permit this particular one because it --
DR. FLEISCHER:  I didn't realize that.
CHAIRMAN BONE:  Well, let's --
DR. FLEISCHER:  We can wait on that.
CHAIRMAN BONE:  We can finish it now and then come back.  We've had the company's opinion and the FDA's opinion, and we'll ask the hepatologist's opinion, and then we'll be ready to go on with that.

DR. SEEFF:  Well, since we're talking about an idiosyncratic reaction, we don't know precisely what causes it, and it could occur fairly early or could occur late.  I think in general, at least in my experience, most cases if they have occurred have occurred within the first year.  It's been very rare to see severe hepatotoxicity occurring a year after one has begun this.
Now, the point that Dr. Graham makes is that this may be simply a question of the fact that there are very few people who are treated that long, and we may not have seen it, but I think the general consensus view and certainly among hepatologists is that if you're going to get your toxicity, it's going to occur within the first year.  At least that's my sense of it.  I don't know how Jim feels.
CHAIRMAN BONE:  Anything thing to add, Dr. Lewis?
DR. LEWIS:  Not really, but in answer to your question, I think it's a little bit of both.  There are patients who are clearly on long-term drugs, different diseases.  INH may stop at a year.  Most of that injury is within the first two months to six months, but there are anti-convulsants and other things, and it's very unusual for us to see other idiosyncratic reactions occur beyond the first year of therapy.

I don't know how to interpret the fact that the number of events has actually gone down.  If it's something idiosyncratic, it ought to be a constant rate per person, whatever that rare rate is, unless the population has changed in some way.
There's going to be genetics involved here, and as Dr. Watkins pointed out, there's P-450 interactions and other things, and we don't know what predisposes individuals.  You know, an unlucky individual gets this toxicity.  We don't know what those factors are, but the monitoring should be able to reduce the number of severe reactions from early onset liver injury, and that's really what I would be focusing on.
Unless we're after a year when we don't expect to see any further injury, but up to that year, I guess if the numbers are falling off among newly prescribed individuals who are taking it out for more than six months, I'm not sure, you know, what's different about them that they're not getting the same injury.
I certainly understand it if somebody has been on it for nine months or a year.  They're probably beyond the point where if they were going to develop a toxic metabolite or something, they're beyond that, and they're not going to get the toxicity, but I don't think the number should actually completely fall of detecting liver abnormalities.

But the monitoring will prevent the fominant hepatitis.
CHAIRMAN BONE:  Right.  Okay.  Just to close this point, I just want to ask a specific question, and I just want basically to know, and not a long discussion here.  We either have data or we don't have data.
Do we know for a fact whether prescribing practices have changed with regard to initial prescribing in patients who might be judged at higher risk for hepatic problem by their doctor?  In other words, are people being more careful about patients with alcohol histories or other reasons to be concerned about liver disease?
Does either the sponsor or the agency have actual data on that question?
DR. ZERBE:  Well, we don't have data.  I mean one would anticipate by the awareness and so forth it might decrease, but there are no data.
DR. GRAHAM:  The only data we have are that the prescribing of troglitazone as monotherapy has increased in each of the three cohorts that we described.
CHAIRMAN BONE:  But it doesn't address my question.

DR. GRAHAM:  It doesn't?  Well, we don't have that data.
CHAIRMAN BONE:  Thank you.  That's what I'm trying to find out.
DR. GRAHAM:  Well, unless monotherapy somehow or another was related.
CHAIRMAN BONE:  Okay.  All right.  Let's see.  Others.  I don't think Dr. Illingworth has asked a question of the sponsor yet.  Please do.
DR. ILLINGWORTH:  I raised this this morning, but given the potential for drug interactions through the cytochrome P3A4 system, if you look at the patients who have had liver toxicity, has there been any link with co-administration of other drugs metabolized by that, or by a patient suddenly deciding, hey, I'm going to drink three glasses of grapefruit juice a day?  Does that influence it?
DR. ZERBE:  Paul, I think you're the best.
DR. WATKINS:  There have been a couple of patients who were admitted to the hospital and then clearly had a great acceleration in the rate of liver injury in very confusing settings with fevers, antibiotics, et cetera.

And actually that was the first time, and this is an area of my expertise, I thought of the possibility that induction of 3A4 perhaps with a certain antibiotic or something might explain that, and it was a very perceptive point.
But there is no data that I'm aware of, and I'll go back now and take a look to see if something like that may make some sense.
And your second question?  Oh, the grapefruit juice.  Yeah, grapefruit juice only affects 3A4 in the intestine, which should be irrelevant to the issues we're talking about here, I think, unless you have more insight than I do.
DR. ILLINGWORTH:  I don't know.  Is the drug metabolized in part by the CYP 3A4 in the intestine?  Is less going to go to the liver because it's metabolized at the intestinal level?
DR. WATKINS:  Yes, it's a very good point.  I don't know the answer to that.  It's a good thought.
CHAIRMAN BONE:  Thank you, Dr. Illingworth.
Are there any other members of the Committee who have not asked a question yet of the sponsor?
Dr. Hirsch, please.

DR. HIRSCH:  I don't know.  The sponsor might know this, and I'm just wondering about as of this moment the current prescribing practice.  That is, I'm assuming that there's two reasons for using the drug.  One is that it might be better than other drugs for monotherapy, let's say, or useful as an adjunct to other drugs when the others are failing.
So I guess the question is in both sides.  Let's take the failing side.  What fraction of people on sulfonylurea, insulin, et cetera, are failing and now are getting Rezulin as compared with the total group who are succeeding?
DR. ZERBE:  Well, I think, if I can make the question simple, perhaps a proportion of patients that are on monotherapy versus combination, we just followed up on the comment made by Dr. Graham.  We don't agree that there's been a change in the frequency of monotherapy prescribing.  That, in fact, has remained stable.  This is worldwide -- well, not worldwide data but, you know, nationwide data, not within the specific health care system that Dr. Graham looked at.
So it's actually been very stable over that period of time, and as I recall, the number is around 20 percent monotherapy; is that right?
DR. HIRSCH:  Twenty percent of monotherapy is Rezulin; is that --

DR. ZERBE:  No, no, no.  I'm sorry.  Was that the question?  I thought the question was --
DR. HIRSCH:  Well, that's one question.
DR. ZERBE:  -- whether there's a difference between monotherapy and combination.
DR. HIRSCH:  In monotherapy, how much Rezulin is used, and how much Rezulin is used not in initial monotherapy?
MR. WITCHER:  I'm Jay Wright Witcher.
In the entire market, Rezulin monotherapy accounts for not more than approximately two percent of prescriptions.  The breakdown of usage of Rezulin is approximately in the period October to December 1998, for example, 20 percent monotherapy and 80 percent combination with one or more other drugs.
That percentage as a percentage of total has actually declined from early 1998 when monotherapy accounted during the first quarter of 1998 for as much as 28 percent of use.
DR. HIRSCH:  No, I've got two percent as monotherapy.  Tell me now the percent of people who are on multiple drugs who are getting Rezulin
MR. WITCHER:  The percent of the total or the percent of Rezulin?

DR. HIRSCH:  All people who are getting sulfonylurea, insulin, metformin, whatever, who also are -- what fraction of those fail and now get Rezulin?
MR. WITCHER:  That's a somewhat different question.
DR. HIRSCH:  Yes, it is.
(Laughter.)
MR. WITCHER:  Toughly in the market right now, the total amount of -- you sort of want to know what's the total amount of monotherapy versus combination therapy.
DR. HIRSCH:  No, no.  You've told me that two percent of people on monotherapy are getting Rezulin; is that correct?
MR. WITCHER:  That's correct.
DR. HIRSCH:  Okay.  Period.
MR. WITCHER:  Yes.
DR. HIRSCH:  Now, people on other therapies --
MR. WITCHER:  Yes.
DR. HIRSCH:  -- all of these other drugs, what fraction of them fail and get Rezulin or something of that sort?  
Do you see what I mean?
PARTICIPANT:  How many people are getting combination therapy with --

DR. HIRSCH:  With Rezulin versus those who get combination therapy without Rezulin.
MR. WITCHER:  Combination therapy with Rezulin right now is approximately 80 percent of Rezulin usage.  I think I'm missing the point.
CHAIRMAN BONE:  Dr. Hirsch is asking the question of all patients getting combination therapy, in what percentage is Rezulin being used.
DR. HIRSCH:  Is Rezulin one of the combo.
MR. WITCHER:  Of all patients, that would be probably -- of all patients getting combination therapy, which is roughly 27 percent right now of everybody, something like perhaps 20 or 30 percent of those would be getting Rezulin right now.
DR. HIRSCH:  Okay.  So 20 or 30 percent of those.
MR. WITCHER:  Right.
DR. HIRSCH:  I've got it.  Thank you.
CHAIRMAN BONE:  And that would be about five percent of all diabetics then or something like that?
MR. WITCHER:  Yes.
CHAIRMAN BONE:  Thank you.
DR. HIRSCH:  Good.

CHAIRMAN BONE:  Okay.  We got one.  Okay.  Dr. Hammes.
MR. HAMMES:  One key question comes to my mind, and I'm not a diabetes expert by any means.  I'm a nuclear pharmacist.  Dr. Graham's data on the population based risk basically hinges on two cases; is that correct?  Two in your studies.
DR. GRAHAM:  I mean, I think if you're talking about the DPP trial --
MR. HAMMES:  The DPP and the REACH.
DR. GRAHAM:  -- and the REACH trial.
MR. HAMMES:  yes.
DR. GRAHAM:  I think -- I don't think it just hinges on that.  I think that -- but you're entitled to draw your own conclusions.
MR. HAMMES:  Your incidence rate I'm looking at.
DR. GRAHAM:  Well, right.
MR. HAMMES:  You have two deaths basically.
DR. GRAHAM:  We have those population based studies, and then we have our life table modeling.
MR. HAMMES:  Okay.

DR. GRAHAM:  And that gives us a very similar rate to that found in the DPP and in the REACH.
MR. HAMMES:  And now we heard data from the sponsor that suggested that both of these cases were confounding diseases or etiologies that could explain at least a significant component of the liver failure.  I really need that expounded on.
If the risk from this side hinges on two people, and both of those could be explained by a different cause, I think that needs to be looked at a little harder here.
CHAIRMAN BONE:  Well, I guess have the medical officer of the FDA and the physicians from the sponsor met on those specific patients?
DR. GRAHAM:  We have, and the company has classified both of those as probable cases of acute liver failure with troglitazone, and that was on their slide.
CHAIRMAN BONE:  Right.  Now --
DR. ZERBE:  Well, I think to say it's probable and to say it's absolute, of course, are two different things.  We, in fact, have conceded the points.  There are complicating factors.  We are not trying to explain away any cases.

I think the other important point or perhaps even more important point to discuss with regard to the population estimates or the methodology are really selecting trial and not looking at the whole database.
If you look at the confidence intervals that are created when you look at the whole database, those confidence intervals actually do encompass our estimates of baseline spontaneous reports.  I think that is the more issue than to try to discount the cases.
There are many complicating factors on it, but we're not trying to walk away from the responsibility in those cases.
CHAIRMAN BONE:  I think that leaves that question partially answered.
Dr. Temple wishes to make a remark.
DR. TEMPLE:  There's been some discussion about the difference in methodology used to address the population based material, and there's one crucial point.  Dr. Faich explained why he thinks you should count each patient once whether they're on it for a week or a month or a year, and David, of course, did it differently.  He did it per patient-year.

When you use the same method, I suspect you get numbers that are not terribly different because you only had 5,000 patients.  So if the number changes by 30 percent, it won't change that much, but I had a question for Dr. Faich.
There's a continuing risk for at least six months that looks very much the same.  It's not one of these things where all of the risk is in the first week.  So don't you feel at least -- or month -- don't you feel at least some obligation to discount patients who are only on treatment for a very short time?
Maybe you don't like David's approach to do it per patient-year, but you've got to do something for people who are treated only briefly.
DR. FAICH:  Well, on the one hand, if we do that, then we have to throw out the cases that occurred in the first month of therapy from the numerator to some extent if we're going to do this, but, on the other hand, this is where this persistence issue becomes very important.
It is true that some 20 percent of starters don't have a second prescription, depending which data you look at.
DR. TEMPLE:  I just need the population data.  You have the duration of therapy in all those cases.  I mean just the population cases.

DR. FAICH:  So what you're saying is if you get rid of, adjust the denominator, take out those patients who discontinue early because they're not at risk.  Is that right?
DR. TEMPLE:  No -- yes, that their risk may be --
DR. FAICH:  In which case, you're going to remove ten percent or 20 percent of the total number of new starters.  I'm suggesting it's not that large.  In some areas, in some drug classes, it becomes very important because 80 percent of patients never fill the second prescription, but that doesn't appear to be the case here.
DR. TEMPLE:  But you actually have data here.  So you can do it.  The point is there seems to be a continuing risk or more or less constant risk you could actually say at least for six or eight months.  You just counted patients as one whether they were in for a month or for eight or nine months.  That's not what epidemiologists usually do, but you can argue those points.
But you might have done it zero to three months, three to six months.  There's a lot of ways to do it, but you only just said one exposure is an exposure.

DR. FAICH:  The issue here is whether your monthly risk changes over time.  You're just saying it's constant over time, but if we're going to sum -- what I'm saying is something different.  I'm saying that you have that monthly risk in month two, month three, month four, month five.  It's constant, but that, in fact, if you're susceptible -- it's an issue of susceptible -- you're only susceptible once.  You're only going to get it once.
So that you don't have to actually sum person times.  You sum the number of people who stayed in for more than -- I'm willing to acquiesce to saying, you know, you have minimal risk in the first month.
CHAIRMAN BONE:  Thank you.
Okay.  I think the Committee are intelligent enough to figure out which they think is appropriate here.
I think we have several questions left.  These are all questions pertinent to the sponsor presentation; is that right, from the Committee?  Dr. Illingworth just asked a question.  Dr. Molitch, did you have a question for the sponsor?
DR. MOLITCH:  Yes.
CHAIRMAN BONE:  Go ahead.

DR. MOLITCH:  Do we have a breakdown on the kinds of physicians who are prescribing Rezulin because this may have something to do with the ascertainment of cases?
DR. ZERBE:  I'm sure that's something we do have, but I don't have it at my fingertips, but can we go on with the next question?
DR. MOLITCH:  Sure.
DR. ZERBE:  And we'll come back with the answer just to be --
CHAIRMAN BONE:  Dr. Cara had a question.
DR. CARA:  If you don't think that there is continued risk with continued exposure, then what is the value of continued monitoring?
DR. ZERBE:  Well, there are changes in the -- there are changes in the recommendations for the frequency of monitoring after eight months.  So there is some decrease.  I think we have just been reluctant to totally eliminate monitoring.  We don't know yet whether there will be cases at a later point.
I think that, you know, the idea that there will be none is probably unrealistic.  At some point there will be cases later on.  They may or may not be related to the drug, but they will be reported, and I think that's a realistic expectation.

DR. CARA:  If you look at that graph that we've talked about a couple of times now that's on page 19 of Dr. Pierce's presentation, what's a little bit disturbing to me is if you look towards the tail end of that, you know, 18 to 19 months, there's a blip up that's fairly substantial.
Now, granted those are few patients, but if we're indeed talking about a few patients and the jaundice/hyperbilirubinemia rate per 100,000 patients is actually going up at that point --
DR. ZERBE:  I think I can answer the question.  If not, I'll call up the colleagues, but we obviously have looked very carefully at that.
Dr. Pierce pointed out that that basically is essentially one patient at each of those months, and the reason it appears to be going up is the denominator, the numbers of patients exposed at that very extreme end of the curve, is going down so dramatically.
So the problem is, you know, it's unstable data at that point, frankly, and bilirubin and jaundice, of course, is even more difficult to assess in terms of specific etiology.
CHAIRMAN BONE:  Thank you.
Are there other questions?  Dr. Illingworth and then Dr. Genuth.

DR. ILLINGWORTH:  Recognizing the sort of ethical issues concerning rechallenge, have any patients you've had a rise in liver enzymes then gone back down after the drug has been stopped been re-given the drug to see whether they re-get a rise in liver enzymes?
DR. ZERBE:  Well, in terms of a rechallenge, you mean?  I believe there have been some, but perhaps the more important issue, and I think Dr. Whitcomb mentioned it or somebody mentioned it -- it may have been Paul -- in the clinical trials there were patients that had elevations, as you'll recall, and 50 percent of those patients -- this was, you know, up to the discretion of the physician whether they stopped the drug -- 50 percent of the patients continued therapy and returned to normal while on drug.
Now, we're not suggesting that be done obviously, but it does point out that, in fact, you know, it's not irreversible in all situations.  Unfortunately, we can't tell which ones they are.  So they all have to stop.
CHAIRMAN BONE:  I'd also raise the possibility that they might have had some other reason for enzyme elevation besides what's going on here.

DR. ZERBE:  Yeah, and I think that's a very important point, particularly at the level of enzyme elevations that many of them, you know, were describing.
CHAIRMAN BONE:  Yeah.  I mean, we always see some changes in liver enzymes during clinical trials which may or may not be related to the test drug.  So we may be talking about two different or more than two different reasons for enzyme changes.
Was that the point you were getting at here?
DR. GRAHAM:  No.  We have -- one of our cases of acute liver failure was a patient who developed hepatitis, had an ALT that rose up to, I believe, around 700, was stopped on the drug, and then a couple of weeks later was restarted.  We don't know what their ALT was when it was restarted, but then that patient over the next six weeks went into liver failure.
DR. ZERBE:  Just so that, you know, there's full disclosure of information, I have been told that we have rechallenged six patients.  Three did return, go up.  I don't know whether this case was amongst them or not.  This was in clinical trials, and three went up and three did not go up on rechallenge.

CHAIRMAN BONE:  I take it you're not planning to do that again.
DR. ZERBE:  No.
CHAIRMAN BONE:  Thank you.
Dr. Marcus.
DR. MARCUS:  I see from those of us with airplane schedules that the two-minute warning has sounded.  I have a suggestion to make that I think may be helpful to the sponsor, and I want to make sure that it gets here before we have to disband early.
It's clear from what I've heard that it seems that the source of the reporting for jaundice and liver problems is coming not from physicians so much as it's patient driven.
Furthermore, I've heard from our hepatologist colleagues that the rate at which ALT goes up can be very precipitous, indeed, and so the question is whether a month, even once a month screening is adequate is questionable.
Now, if the patient has to come into the doctor's office once a month, that's a little bit of a burden.  If you're asking them to come in once a week, that's even more of a burden and probably impractical.

But the one thing we do know about diabetics, is that they are willing to do daily home glucose monitoring, and there are methods for doing home monitoring of all sorts of things on just a drop of blood.
You could ask for the first year of therapy, could you not, that a patient monitor his ALT once a week or even on a daily basis and try to pick up these things when it is in a very early stage.  I could see that even with the same drop of blood, if you had some clever device company that Dr. Sobel could push through approval for --
(Laughter.)
DR. MARCUS:  -- you could get a simultaneous readout of a blood glucose and an ALT, and that could solve a lot of this problem of screening.
CHAIRMAN BONE:  All right.  I think that's an interesting way to look at this in the future.
I think if we've completed asking our questions -- oh, no, Dr. Genuth.  I'm sorry.
DR. GENUTH:  I think the gentleman who is going to cure liver disease with a device might be interested you idea.
(Laughter.)

DR. GENUTH:  Some member of the sponsor's team -- I can't remember which -- emphasized the word "persistence," I think in connection with the fact that at the end of one year of Rezulin, there was still 40 percent of the people still taking it.  Now, maybe this is the cup is half full, the cup is half empty problem, but I would look at that and say at the end of one year 60 percent of the people who started on Rezulin are no longer taking it, and I'm wondering why.
Now, it's not because of jaundice or hepatic failure.  I think no matter what the debate is on the incidence, it's not 60 percent.  It's not likely to be side effects because in the clinical trials all the usual kinds of complaints of patients are not any higher than in the placebo group.
It might be lack of efficacy, that is, the physician has tried it and has given up, and it could be price, and I know this isn't exactly the place to get into economics, but some of my patients tell me that is a problem.
Do you have any idea?  I mean how good is a drug that's going to have to be given for life if after one year 60 percent of the people aren't on it anymore?

MR. WITCHER:  Well, unfortunately, the first part of the response to that question is that this data, which is broadly applicable to any chronic care therapy and is used as an industry standard, is not dissimilar for chronic use of virtually most any drug you can think of, Dr. Genuth, whether non-steroidals or, you know, statins or other drugs like that.
It is commonly the rule that in chronic care 50 percent of patients are off drug after six months, and we have -- the second part of the answer to the question is we have looked retrospectively using market research techniques to go back and ask about reasons for discontinuation, and you touched on them, and they're all over the map.
Patient lost to follow up, switched to another agent, does show up.  Cost influences it.  It's all over the map, and there's no particular pattern that emerges.
CHAIRMAN BONE:  What happens on your database if somebody just changes pharmacies?
MR. WITCHER:  That is also similar for other diabetes therapies.  Excuse me.  Pardon me.
CHAIRMAN BONE:  What happens if they just change pharmacies?

MR. WITCHER:  That's a phenomenon that causes a dropout in the way the data is collected, and we've worked extensively with the people who collect this data, and they feel very confident that the data is nonetheless broadly applicable.
CHAIRMAN BONE:  Obviously that consideration would not apply except in people changing their health plans.  Then I guess you'd have the same loss.
DR. GRAHAM:  Right.  I wanted to make a comment about why the difference in their persistence curve and our persistence curve, and I think it has to do with what we've measured and how we've measured it.
We took a cross-sectional snapshot of everybody within a captured population who ever took troglitazone, and that includes people -- a person who just started troglitazone, say, in November of '98 in our cross-sectional snapshot would show up as somebody who's only on the drug for one month.
What the company has done is they've taken sort of like three different periods of time and followed a cohort of 100 people or 1,000 people out as far as they can to see what the actual pattern of use is in those people.

But if you were to take those three things and superimpose them now to say, well, what does the overall shape of the curve look like, it would end up looking like our curve.
CHAIRMAN BONE:  Are you telling me that when you're saying that 16 percent of the people are remaining on drug after a year --
DR. GRAHAM:  No.  What that 16 percent says is that for the time the troglitazone has been on the market, 16 percent of people who ever used troglitazone, and that includes the people who just started it in December; those people, that 16 percent of all those people are still on it a year.
Now, if we were to break it down by cohorts, cohort one, cohort two, cohort three, well, the people who are contributing to the long time at the end are people who started in cohort one, because they had the opportunity to be on the drug that long.
CHAIRMAN BONE:  I think the Committee understood you to be saying that people who started the drug a year ago, only 16 percent were remaining.
DR. GRAHAM:  No, no, no.  This was cross-sectional data, and the importance of it is when you want to model what is the distribution of total prescription use in the country, that you have to do it that way.  You can't look at the model the way they have because it will overestimate what the total burden in the population is.

DR. HIRSCH:  What percent do remain?  I can't figure this out.
CHAIRMAN BONE:  Do I understand then -- I think what you have to do or what you don't have to do might depend on what you're trying to analyze, but do I understand then that Dr. Graham would not dispute the sponsor's estimate that of people who started the drug a year ago, 40 percent may remain on therapy at the present time?  Does that sound like we're not disagreeing about that?
DR. GRAHAM:  We haven't addressed that question and analyzed it.  So we're not in a position to say whether we agree or disagree.  We looked at something very different because we wanted to model all prescription use in the country.  We wanted to model time, exposure time and risk.
CHAIRMAN BONE:  Okay.  So you're looking at a different point there altogether.  I think that's very important for everybody to understand.  It wasn't clear to me until just now.
Thank you.
Dr. Seeff.
DR. SEEFF:  You sigh as you say that.

I'm very intrigued with a comment that was made earlier about the frequency of monitoring.  I think that all of us will agree, and I think that Dr. Watkins will agree that the ALT is not the best way to monitor.  It's the best thing that we have.  We really don't know how to monitor for hepatotoxicity and much more research needs to be done, and I can tell you that  NIDDK is thinking very seriously about this issue and wants to proceed by looking for a better way of monitoring for hepatotoxicity not only in people who have normal enzymes, but in people who have abnormal enzymes and who's put onto a drug.
I do think that the figure of three times the upper limit of normal is a rather arbitrary number, and while I think that the sponsor has done a great job with the hepatologists of trying to work out when to test, that is, if it goes up to more than one and a half times the upper limit of normal, call the patient back a week later, test, and then when you get to three times the upper limit of normal withdraw; I'm not sure that that should be done.

I think it maybe should be more sensitive, and if it goes up a second time, I would already begin to be very concerned, but I think that this is an unusual opportunity if everything works out otherwise to, in fact, do a study to look at this in people who are, in fact, having blood drawn on a regular basis and learning more about what happens and looking for other means of determining hepatotoxicity.
CHAIRMAN BONE:  Thank you, Dr. Seeff.
Are there any further questions directed at the sponsor?
(No response.)
CHAIRMAN BONE:  All right.  Thank you. 
All right.  It's now 4:18.  I think that we will clearly dispense with the intermission that was originally planned for the afternoon and ask everyone's endurance here.
I'm sorry.
(Pause in proceedings.)
CHAIRMAN BONE:  Thank you.
The next item will be the summary and charge to the Committee and introduction to the questions by Dr. Bilstad, followed by some discussion within the Committee, and then we'll address the questions.
Dr. Bilstad.
DR. BILSTAD:  Henry, I wonder if we could have just a moment to answer some points that were made about the United Health Care Study, some comments that were made by Dr. Pierce?
I would like Dr. Graham just to --

CHAIRMAN BONE:  Very briefly, please.
DR. BILSTAD:  -- address just a couple of issues that I think are important for understanding.
CHAIRMAN BONE:  All right if you're sure that the Committee didn't understand it before.
Thank you.
DR. GRAHAM:  Right.  Regarding the UHC data that we used for our enzyme monitoring study, Dr. Spurgeon is not the Chief Medical Officer for the United Health Care as stated by the company.  He is the Medical Director of one of the UHC affiliated health plans of which there are 13.
Now, the question Dr. Spurgeon raised in his letter to Parke-Davis was shared by Parke-Davis with us, and we immediately investigated the questions that were raised in Dr. Spurgeon's letter.
After doing that, we communicated our findings to the company yesterday.  It turns out that Dr. Spurgeon was talking about a small and not well documented survey that he and others in his plan conducted in a group of people in a rural setting.  The problem he identified was not found in metropolitan areas, which accounts for most of the UHC database.

Also, Dr. Spurgeon's health plan relies on capitated data, which is known to be of low quality because of incompleteness.  
For this reason, the Research Center for United Health Care does not use data from Dr. Spurgeon's capitated plan in their research database, and the problems he raised are not applicable to our study.
I also spoke with the real Director of Research for United Health Care, and she is confident that the problems described do not impact on our data.
CHAIRMAN BONE:  Thank you.
As I said -- thank you very much, Dr. Graham -- as I said, we'll now ask Dr. Bilstad to give his summary and charge to the Committee and introduction to the questions.  We'll have a period of time for the Committee to discuss further amongst ourselves, and then we'll address the questions concerning which the FDA has asked our advice.
DR. BILSTAD:  I'm going to speak from here, Henry.
CHAIRMAN BONE:  Fine.
DR. BILSTAD:  And my comments will be very brief.
CHAIRMAN BONE:  Thank you.

DR. BILSTAD:  Lanh, could you show the first projection?
Obviously assessing the benefits and the risks in this situation posed a significant challenge for all of us, and we've heard data from Dr. Graham on the risk side that we feel is cause for concern.  The sponsor has presented information about the short-term and potential long-term benefits of troglitazone.
Could I have the next one?
Certainly lowering blood sugar is well accepted as an important goal in the treatment of diabetes, and support for the effect of better control for hyperglycemia comes particularly from the DCT and from the U.K. PDS, and the data mostly support the effect on microvascular complications.
The next slide.
The problem really is how directly we can extrapolate from these data to troglitazone, which of course has not been studied long term.
I did want to just briefly, if you could go -- yes, I wanted to mention some of the regulatory options that are available in this situation, and this is by no means meant to be comprehensive or exhaustive.

The first option:  continue to monitor closely the number of reported cases of liver failure.  Basically that would be the watchful, waiting approach.  That could be combined with increased educational efforts and other efforts.
The second option listed is to decrease the recommended time interval for monitoring liver function, and that is if you believe that decreasing that interval would help to pick up some additional cases.  It raises the question how many cases it would pick up.  Obviously there becomes a point of diminishing returns.  That comes at a great cost, too.
The third option I have listed is to make the distribution of the drug dependent on monitoring liver function, and this can be done under what we refer to as  Subpart H of the regulations, the so-called accelerated approval regulations, a part of which deals with restricted distribution if that is necessary from a safety standpoint to be able to use the drug safely.  So that is an option if it was felt that monitoring is very essential to preventing cases of severe liver failure, and if, in fact, we were convinced that monitoring really was not being done even in the face of labeling recommendations and educational efforts.
Next slide.

And finally, another regulatory option would be, of course, to eliminate one or more of the indications based on the assessment of benefits and risks, and one of the ones certainly that has been questioned, whether the benefits do outweigh the risk, is in the case of monotherapy.
So with that, I will close.  Obviously there's a number of areas here where we don't have all the information, but we're asking the Committee to try to answer the questions based on the information that we have available at this time.
Thank you.
CHAIRMAN BONE:  Thank you, Dr. Bilstad.
I think what I'd like to do now -- did you have any further comments on the questions at all?
DR. BILSTAD:  No, I was going to leave those to you.  I have them on the projector if anybody -- but I don't think it's necessary.  Everybody has them.
CHAIRMAN BONE:  Yeah, and I think the audience all have copies, as well, if I'm not mistaken.
All right.  Well, everyone is familiar with the question.  I'm just going to give a quick overview, go back to the Commission discussion, and we can come back to the questions.

The first question has to do with whether the benefits of this therapy outweigh the risk for each of its approved indications.
The second question has to do with if the answer to the first question is yes, how can that be improved.  
And the third question, if the answer to the first question about the favorable benefit-risk ratio is no, how could it be modified or improved by a change in the labeling.
And the fourth question has to do with comments about the use in combination with both sulfonylurea and metformin.
And the fifth question has to do with what additional information should be sought.
I'm just going to go around, I think, in as systematic a way as any, to just go around the table and invite comments from each of the members of the Committee.  This may generate some discussion.
We're hoping to be able to conclude at a reasonable hour, but the most important thing is to adequately discuss this very serious issue.  So we want to make sure that we have done that, that important points are all given adequate consideration.

Perhaps I'll just start with Dr. Hirsch and work around the table.
DR. HIRSCH:  Well, I'm going to base my answers to the questions on the way I understand what happened today.
CHAIRMAN BONE:  Okay.
DR. HIRSCH:  And my own understanding of this, and I'll be very brief.
CHAIRMAN BONE:  I'm not asking you to answer the questions now.
DR. HIRSCH:  I'm not going to answer the questions, sir.
CHAIRMAN BONE:  Okay.
DR. HIRSCH:  I'm just going to give you the facts on which I'm going to answer the questions.
CHAIRMAN BONE:  Okay.
DR. HIRSCH:  As I understand them.
CHAIRMAN BONE:  Very good.  That's just what --
DR. HIRSCH:  And I hope everyone will do something like that because that might help us.

I have now some estimate in my own mind of the confidence limits of this problem, and I think that in five years either there will be hundreds of people who will have died of liver disease or thousands of people, and it's not clear, and I don't think I know how to make that evaluation, but I think it's somewhere in that range.
I think that the business of trying to determine by ALT or other available techniques who's going to get that is a weak read at best, but it is prudent, I think, to keep following this sort of thing in my own kind of mind.
Now, I'm going to base my judgments on the following.  Given the fact that there is this risk, which I believe has some tangible element to it, I now want to apply this drug to where it does definitely most good, and that is in the case where other known drugs have been tried and are failing, and this may prop up the patient and make a better situation vis-a-vis the complications.
There was no time to attend the many other matters, like the inevitable weight gain that does seem to go on in most of the studies, and I note that that's not factored in.  That is, weight loss modifies Type 2 diabetes.  Weight gain makes it worse, et cetera.
But even so, I do believe that troglitazone improves the lot of people who are on other drugs and are failing, and I think it should be used for that and that only.

CHAIRMAN BONE:  Thank you.
Ms. Killion.
MS. KILLION:  Well, I think there are some serious -- well, I think we know that there are serious areas of concern here.  The four that I seem to respond to from my perspective was that there seemed to be fundamental disagreement about whether the treatment, the use of the drug, whether there's a window of risk that you pass through at a certain time and then you're safe or safer, or whether there is a cumulative risk, that the longer you're exposed, the greater your risk of developing something, that you don't pass through safely at some time.
Then there seemed to be an idea of patients, which of course I'm concerned about whether there is in the patient population a certain percentage of people who are susceptible to this liver problem and, therefore, their exposure to the drug, which unfortunately we can't identify these people yet, is a problem, is a serious problem, or whether there is, again, this idea of cumulative risk where even if you were not susceptible, even if you're just otherwise functioning, your continued exposure may create a susceptibility that was not genetic or some otherwise in place at the time.

So those are the areas that I thought, and when I'm considering this as a patient, as someone with diabetes, I have to respond to a comment that was made earlier at the meeting that seared me, which was that patients don't care whether they die of a troglitazone reaction or diabetes.
That is not the case.  You know, the advances that have been made in diabetes over the last ten years are phenomenal.  I'd like to be around for as many of those years as possible.  Maybe we'll find a cure for this problem, but the treatment certainly ‑- I don't want the treatment to be worse than the disease.
And so it is important.  We do want something that works that has an efficacy value to it, and we want our risks reduced.  So limiting it to certain people, if we can identify, that is the way we need to go.
CHAIRMAN BONE:  Thank you.
Next is Dr. Fleischer.

DR. FLEISCHER:  Well, I think that the drug has excellent effect in diabetes management, but I think the issue is which of the models for the liver abnormalities are going to be correct, and so prudent continued monitoring and following of this in some accurate way is critical to what should happen.
CHAIRMAN BONE:  Thank you.
Dr. Colley, do you have comments?
DR. COLLEY:  I would echo that.  I don't think the story is completely known yet based on the huge discrepancy in the numbers of patients believed to be at risk for liver failure.  For that reason, limiting exposure and increasing the adherence to the monitoring would be critical, in addition to educating patients.
A lot of the symptoms that may occur are very nonspecific and may not otherwise cause concern, and before a patient takes this drug, they need to be very aware of what type of symptom they should be bringing to their provider's attention.
CHAIRMAN BONE:  Thank you.
Dr. Cara, do you have comments you want to make about the general discussion here? 

DR. CARA:  I've tried to sort of summarize in my own mind what I've learned or at least make some conclusions, try to reach some conclusions about the information that's been presented today, and what I've sort of thought about for my own based on what I've heard is that I think the incidence of liver disease is significant, but the mortality is relatively low when you look at it in the context of everything that can essentially hurt or kill a person with diabetes.
And in my best estimate from what I've heard, I'm sort of guessing at an average mortality rate of about one to 5,000 with metformin from liver disease.
The other conclusion is that monitoring has a place in reducing mortality, but it may not be carried out as indicated necessarily by physicians.  So that I think that full disclosure and patient awareness is especially critical.
I think the benefits are very clear, especially when used in combination with insulin mimetic or insulin treatment, insulin medications, such as sulfonylureas, perhaps metformin, and with insulin because of the fact that a glycohemoglobin drop of one and a half to two units is very -- has very significant impact on overall mortality and morbidity related to diabetes.
There's still the issue of weight gain, and that really needs to be adequately addressed and effectively treated.

Those are the conclusions that I've reached, and I would propose that Question 1 be modified a little bit based on the questions that followed to sort of cross off the part that says "with the currently labeled indications, warning, and precautions," and then talk about those in two and three.
CHAIRMAN BONE:  Dr. Kreisberg, please.
DR. KREISBERG:  Well, it's very apparent that reasonable people can disagree, and we've heard from noted experts today about what they think the risk is, and I find it incredible that there's so much divergence in opinion.
I think this is an important new class of drug, and I'm going to rely very heavily on valued colleagues who practice and take care of patients with diabetes on a day in and day out basis and see lots of them.
And I've read through all of the letters of testimony, as well as hearing the testimony today, and to a large extent, I think this information is as valuable or more valuable than the theoretic issues that have been brought up here that are based on modeling and very few events.
CHAIRMAN BONE:  Thank you, Dr. Kreisberg.
Dr. Molitch.

DR. MOLITCH:  I don't think I really have much to add, though much has been said already.  I do think it's still a valuable drug.  I think the liver toxicities, indeed, are unfortunate.  I'm quite concerned with the discrepancy between the two sides and the actual figures showing how much liver toxicity there is, what's actually been reported versus what might be out there in the world, but I think that it's probably not quite as much as has been said to be what's out there in the world, and I think that's something that based on liver consultants, that we may be able to markedly reduce by appropriate monitoring in the patients.
CHAIRMAN BONE:  Thank you.
Dr. Seeff, please.
DR. SEEFF:  Well, not being a diabetologist I can't speak to the effectiveness of the drug, but from what I've heard from everybody, it sounds like a very good drug.  It's not a great drug because we wouldn't be here if it were a great drug.  We are faced with a problem with this hepatotoxicity.
I think that if the final decision, which is to retain the use of the drug, I think we need to spend a little bit more time -- and this is not the place to fine tune this -- but to spend a little more time trying to find out the best way to monitor for potential hepatotoxicity.

I'm not sure.  I think that the job that was done is a very good one, but I think it could be improved upon.
I also think that if I were a patient, I would like to know that a drug I'm getting could kill me.  I don't see anything that's directed to the patient.  Even if it's uncommon, I don't want to be given something that might kill me, rare as it may be.
So I think that we should be not only educating the patients as to what they should be doing to look for the possibility, but to give them the option of knowing that they may receive a drug, that they are being offered a drug that could potentially cause their death, and they should then be able to make a choice as to whether or not they are willing to take that.
So I think it's a combination of the patient and perhaps a little more fine tuning on trying to monitor for hepatotoxicity.
CHAIRMAN BONE:  Thank you.
Dr. Lewis.

DR. LEWIS:  Yeah, that was well said, and I think, you know, we're talking about lots of discrepancies in the numbers, and I guess the only thing I would add is maybe we should try to do more in terms of improving our reporting system, the structure of it and other things so that we don't have to rely on discordant numbers sometimes.
We say a lot about the fact it's a voluntary reporting system.  There are other places around the world where it's mandatory.  I'm not sure that's going to work here right away, but something in between maybe, and we would have the answers perhaps to very important questions about the incidence rates of very serious reactions that occur uncommonly.  We need to collect that kind of information.
But, you know, I echo the comments of Dr. Seeff as well.
CHAIRMAN BONE:  Thank you.
Dr. Illingworth.
DR. ILLINGWORTH:  Yes.  I would echo those comments also.
I think the drug does add to the therapeutic options of a patient with Type 2 diabetes, and we've seen data that clearly shows the drug does add to improved glycemic control when used in combination.

I think the informed patient is their own best advocate,  and therefore, I would strongly endorse the previous comments that the more informed the patient is about the potential side effects, the more informed they are about what symptoms are linked to hepatotoxicity, nausea, anything like that, and even give them potential flow sheets that can put down their blood values so that if they change doctors or they move, they've got baseline values with them; I think education regarding hepatotoxicity.
And then the other thing is education regarding potential drug-drug interaction.  If somebody started on drug that we would know is metabolized by the cytochrome 3A4 system, have the patient made aware of that so they may go back to more frequent monitoring if they've been on the drug for a year.
CHAIRMAN BONE:  Thank you.
Dr. Hammes.
MR. HAMMES:  I'm going to put on my hat as a consumer's representative here.  Basically my opinion is life is fatal.  We're all going to die.  People have different perceptions of risk.  The best we can do is give them our best opinion of what risks are.

Some people will take the opinion that quality of life is everybody and other patients won't want to take the risk.  So I second what was just said about educating the patient.  I think that's foremost in this.
I think the low levels of monitoring that we saw are an indictment of our medical system certainly, but I think they also reflect the lack of compliance on the part of the patient, and educating the patient will go a long way toward taking care of that end of the problem.
Along with educating the patient, clearly we need to do a better job with educating the physicians, and what I didn't hear much of today was educating pharmacists.  They're seeing the patients more than the physicians, and a great deal of this education needs to go to them so that they can screen for some of these things in the pharmacy when prescriptions are being refilled.
So I think education needs to be a big component of this.

I think monitoring is something we need to do.  There needs to be strong follow-up on this whole thing to narrow down these risk and benefit analyses.  I think you have to look at risk in this regard as kind of a death incremental risk because clearly we saw that the risk of death from diabetes is very significant, and a small decrement in that death rate will offset a rather large risk from hepatotoxicity.
But we need to quantitate those risks and continue looking at that very closely.  Along those lines then, I think I feel quite strongly that monotherapy probably isn't what this drug ought to be used for.  It's been clearly shown to me that it has a strong value in the patients for other therapies that failed.  I don't know if this risk is worth it for a first line treatment.
CHAIRMAN BONE:  Thank you.
Dr. Genuth.
DR. GENUTH:  You have to excuse me.  I had to check out.
I believe that everything we've heard that I know previously persuades me that troglitazone is effective enough therapy for Type 2 diabetes to accept some risk in its use if it's used wisely.  I'm not persuaded that despite the new mechanism of action, which is certainly very provocative, that troglitazone produces better clinical results in the long term than any other single drug currently that we know about.
Obviously we need more data for long-term efficacy.  So I'm a little bit divided mind about monotherapy.

There was a lot of emphasis comparing the risks of liver injury and death with troglitazone, which I believe are real, to lactic acidosis risks with metformin.  I didn't hear anybody comment on what I think is a very important difference between the two.  Most of the cases of lactic acidosis due to metformin are probably preventable.  They've occurred under circumstances that we know increases the risk.
And I think education can hopefully get that risk down to near zero, but I don't believe we can completely prevent liver toxicity from troglitazone because of the unpredictable nature of it, no clues who's going to get it, and I think logistically there's no monitoring scheme that can be dictated from above that will be carried out perfectly enough to prevent liver deaths either.
So with some reluctance I think we have to accept if we move forward with this drug; we have to accept the fact that some of us are going to write prescriptions for patients, and in a rare circumstance that's going to lead to the death or hepatic transplant of the patient.
That doesn't thrill me, but I think physicians, as has already been said, have that responsibility to make judgments and help the patient make proper decisions with good education.

So I'm all for continuing use of the drug as adjunctive to anything else in combination therapy, and I think that for monotherapy, the suggestions that the sponsor has already made about changing the labeling so as to define clearly how it should be used, for what length of time, and I would somehow try to add some definition of adequate response in terms of hemoglobin A1c or like glucose.
CHAIRMAN BONE:  Thank you very much.
Dr. Braunstein.
DR. BRAUNSTEIN:  Well, I, too, agree that this drug is efficacious, and this group of drugs is an important addition to the available treatments for diabetes.  Obviously the liver toxicity is the major concern.
I do hope that with increased liver function testing, as suggested by our hepatologist consultants, that the risk or the requirement for transplant will be decreased.  I hope that Dr. Graham's model is wrong.  I don't think we have the data to really say that his model is right or wrong or the company's predictions that at the end of the year most of the risk is gone.

So I think we're just going to have to see with the collection of data over time, and I would use whatever means the FDA has available to require that collection of data by the company.
My final thought is I know that there are a number of other drugs in the pipeline in the same group, in the same class, and I'm hopeful that one or more of those will prove not to be hepatotoxic, and then we'll let the marketplace tell us which is the best drug.
CHAIRMAN BONE:  Thank you, Dr. Braunstein.
I find this weighing of risk and benefit in this situation troubling.  We have impressive evidence for the efficacy of this drug, and it's clear that the reduction in indices of blood sugar control, that would be hemoglobin A1c, for example, are of a magnitude which based on all the other drugs that have been evaluated should be expected to produce very substantial reductions in morbidity and eventually mortality.
So we would expect that the use of this medication in patients whose diabetes couldn't be controlled without it should produce a very substantial incremental benefit.  I think the evidence that it is superior for initial therapy is somewhat less impressive.

I think that the biggest problem for us is trying to get our hands on this risk assessment, and what I think we've heard here is proof that it's very difficult to do that.  The hard number that we have is the number of cases that the agency and the company have of patients who have ever died or required liver transplant, where it seems clear that the drug was at least likely, if not certain, to be the causae of the liver failure.
Everything after that is a problem.  We have a little bit of a problem deciding what the denominator is, and we have a much greater problem if we decide how to adjust that denominator for all the factors that Dr. Graham expounded on so eloquently.
The risk estimate of something like one to two per 1,000 is a very high risk estimate for a fatal complication.  It's on the order of surgery or general anesthesia.  It's not -- most major operations carry a considerably higher mortality rate because there's also risk over and above what's associated with the anesthesia that has something to do with why people are being operated on in the first place, but it's in that range.

But there's a wide estimate or there's a wide confidence limit around that if we look at the extrapolations, for example, from the clinical trials where the risk could be seven times as high or one-thirtieth.
And as was pointed out by the sponsor, this range is so wide that it actually incorporates the sponsor's estimate of the risk as well, making no adjustment at all for under reporting.
So this 200-fold span between the low and high end of that risk estimate makes it very difficult to get our hands on this risk, and I think this has troubled everyone.
The argument about the rate of under reporting has a certain circularity to it.  What we don't have is a very hard population based comparison between reporting rates and actual occurrence rates.  We don't have that absolutely solid, sorted out.  It would be very helpful here if we had that.
We have information that gives us hints about this, but it isn't as solid as we would like.  So this is really a matter of drawing inferences and trying to decide whether we really think the risk is that high or do we think it's somewhere near the middle of the range of estimates or even as low as the reported rate.

And I think these are the kinds of considerations that I'll be certainly taking into account as I consider my vote and additional comments.
Is there any burning point that has to be made by the agency or the sponsor or the member of the Committee before we proceed to take the vote?
(No response.)
CHAIRMAN BONE:  All right.  Then let's go ahead with the vote.
DR. ILLINGWORTH:  I'd just like to point out one thing with regard to monotherapy.
CHAIRMAN BONE:  Only if it's a point of fact, please.  Is it?
DR. ILLINGWORTH:  It is a point of fact.
CHAIRMAN BONE:  All right.
DR. ILLINGWORTH:  And that is, of course, monotherapy needs to be kept in mind, is limited after two months to patients that do benefit.
CHAIRMAN BONE:  Thank you.
DR. ILLINGWORTH:  And that substantially changes then the risk-benefit ratio.
CHAIRMAN BONE:  Point taken.  Thank you very much.
All right.  Anything further?  Everybody's said their piece?  Good.  We're going to vote now.

Not everyone who is sitting at the table is a voting member of the Committee.  So I will ask the voting members of the Committee to vote, and we'll just, I think, start around the table from the right this time, starting with Dr. Illingworth.
And Question 1 has three parts, and then the editorializing or commenting has either already been done or mostly go into the answers to Questions 2 and 3.
So, Dr. Illingworth, Question 1.
DR. ILLINGWORTH:  Question 1, based on the information with the current label indications, warnings and precautions, do the benefits outweigh the risks for (a) concomitant use with insulin?  Yes.
Concomitant use with sulfonylurea?  Yes.
Monotherapy?  No.
CHAIRMAN BONE:  Thank you.
Dr. Hammes.
MR. HAMMES:  I would vote the same, yes, yes, no.
CHAIRMAN BONE:  Thank you.
Dr. Genuth?

DR. GENUTH:  Yeah, I think the benefits outweigh the risks for combining troglitazone with insulin, with sulfonylurea, with metformin, with a combination of metformin and sulfonylurea, and I think if the labeling is changed somewhat in the manner suggested by the sponsor, for monotherapy.
CHAIRMAN BONE:  Would that mean -- is that a no for this question for monotherapy?
DR. GENUTH:  No.  It's a yes with a --
CHAIRMAN BONE:  Okay.  It's based on the current labeling.
DR. GENUTH:  -- contingency.  No.  Then it's a no based on the current labeling.
CHAIRMAN BONE:  All right.  Thank you.
Dr. Braunstein has left his votes, and we'll read those after everyone else has voted, and I will vote last.
Dr. Molitch.
DR. MOLITCH:  I agree with Dr. Genuth, I guess.  Yes and no with current labeling for monotherapy, but yes, if it gets modified as indicated.
CHAIRMAN BONE:  Thank you.
Dr. New is in the same situation as Dr. Braunstein.
Dr. Kreisberg?
DR. BILSTAD:  Henry, can I ask a question here?  There's been a couple of statements about based on currently labeling.  Do people really know what the current label says?

CHAIRMAN BONE:  Well, it's been distributed.
DR. BILSTAD:  Okay.  Everybody is aware that it is already in there that it be discontinued after -- the way it's worded, let me read it.
CHAIRMAN BONE:  I really think everybody has probably -- is there anyone here who's voting on this who hasn't read the labeling?
(No response.)
CHAIRMAN BONE:  Okay.  I think everybody has read it.
DR. BILSTAD:  Okay.
CHAIRMAN BONE:  Okay, Jim.  Thanks.
Dr. Kreisberg has also voted in writing.
Dr. Cara.
DR. CARA:  Yes, yes, no.
CHAIRMAN BONE:  Good.
DR. COLLEY:  Yes, yes, no.
CHAIRMAN BONE:  This would be -- that was Dr. Cara, Dr. Colley.  
We have a written vote from Dr. Marcus, and there'll be a vote from Dr. Hirsch.

DR. HIRSCH:  Yes.  I wish it had said -- it doesn't obviously -- but I wish it had said concomitant use when these other drugs are not giving optimum effects.
So in that respect, I would say yes, yes, and definitely no.
CHAIRMAN BONE:  Thank you.
Can we have the votes from those who had to vote in writing, please, from Kathleen Reedy?
MS. REEDY:  Dr. Marcus:  yes, yes, no.
Dr. Kreisberg:  no, yes, yes.
Dr. New:  yes, yes, and yes.
Dr. Braunstein:  yes, yes, and a gentle yes.
(Laughter.)
DR. HIRSCH:  Are you sure that Dr. Kreisberg one was right?  No, yes, yes?
MS. REEDY:  Yes.
CHAIRMAN BONE:  All right, and my votes would be yes, yes, and no, I think, at the present time.
Question No. 2:  if the answer to the first question was yes, can the current labeling be enhanced to further improve the risk-benefit relationship, and if yes, how?

I would ask you to -- we'll go around, and we'll ask you to address the items on which you voted yes, and then we'll come back and have people comment on the items on which they voted no.
So Dr. Illingworth.
DR. ILLINGWORTH:  I think the labeling, as I read it, I think is fairly comprehensive.  I would just emphasize, as I emphasized earlier on, give the patient information as well so the patients are aware about what they need to do for monitoring.  So I think that's my major focus in terms of improving the labeling and make sure patients are aware what are the symptoms of liver toxicity.
CHAIRMAN BONE:  Thank you, Dr. Illingworth.
Dr. Hammes, comments on items on which you may have voted yes.
MR. HAMMES:  The first two I voted yes.  I would like to second that.  I'd like to see a patient package insert type of thing developed explaining the risks, benefits, side effects for the patient's use, along with more extensive education of all the health care fields.
CHAIRMAN BONE:  Dr. Genuth.
DR. GENUTH:  Just the same as my colleagues.
CHAIRMAN BONE:  Thank you.
Dr. Molitch.

DR. MOLITCH:  I agree with the patient insert.  I think that based on the information that we heard today that perhaps monthly monitoring perhaps ought to be extended out for a year and every two months for the next three times, say, for six months, and then quarterly thereafter since we are concerned about the duration of potential toxicity of this.
CHAIRMAN BONE:  Okay.
DR. MOLITCH:  So I'd like to see that monitoring extended.
CHAIRMAN BONE:  Dr. Cara.
DR. CARA:  Yes, I think current labeling can be enhanced, and what I would suggest is that there be very strong statements made that this treatment should not be considered for other conditions other than diabetes.  I think that's very important until we have data regarding its efficacy and things like polycystic ovary syndrome and its potential side effects.
We need to be very, very cautious about this drug being used for other conditions.
I would also add that the medication should be only considered with failure of the primary, i.e., insulin or sulfonylurea or metformin, therapy alone.

The other thing that I would add is the need for continued monitoring.  I don't think a patient insert is enough.  I think there ought to be greater efforts at patient education and perhaps even a central registry where patients can be informed as additional information comes out so that they can take the appropriate steps to protect themselves.
I'm concerned about the delay between the findings and the information getting back to patients.
CHAIRMAN BONE:  Thank you.
Dr. Colley.
DR. COLLEY:  I would echo those comments that for insulin and sulfonylureas it should be restricted to patients who have failed to achieve their goal on maximal doses of the sulfonylurea.
And if I could just ask Dr. Bilstad to just explain briefly the Subpart H that you alluded to in your slide.
DR. BILSTAD:  It would be a situation where the drug would be -- through a special distribution scheme, would not be distributed to patients unless they had actual evidence of having gotten the laboratory test.

DR. COLLEY:  I would encourage that to be considered until we have more data on what the actual risk is.  It appears that the rate of adherence to the recommended laboratory monitoring is pretty abysmal, and that just encouraging that to be done is clearly not enough through the efforts made so far.
And as Dr. Cara said up front, patients should be informed of the risks.  A patient insert I don't think is enough.  They need to know this before starting the drug.  They need to know what to expect in terms of symptoms that may arise.  They need to know that they should be monitored, what the expectations are in terms of monitoring so that they know that they need to go to the lab, they need to have this done, and they need to hear back from their providers about it.
CHAIRMAN BONE:  Dr. Hirsch.

DR. HIRSCH:  I guess I would be much stronger in the labeling.  I would like to see it stating that X deaths, whatever it is that we decided, or roughly X deaths have been reported and are believed to be attributable to this drug, reported during the year 1998, and the rough range that is covered by this is currently unknown.  It may be equivalent or more than this in the future, and there may be a cumulative effect.  It simply is not known, and for these reasons this is not to be used ever as a first line drug in the treatment of diabetes until more information is available.  It is only to be used after other drug failures occur, and then as an adjunct to those other drugs.
And when it is used, although not proven, it is currently prudent to obtain frequent sampling of blood for liver enzymes since this may assist in not having so many deaths or may be a helpful evaluation.
I would feel that that's extremely important to put all of those pieces of information into the labeling, which are not there now.
CHAIRMAN BONE:  Thank you.
For myself, I would comment.  I'm in agreement with several of the other comments, what is really a change in the indication.

I said that I found the balancing of risk and benefit here rather troubling because of the great difficulties we have in making those estimates with any confidence or precision in the precision.  So I think that with the currently labeled indications, that's a much more difficult balance to draw than it would be if the indication were changed along the lines suggested, which would be that this drug is essentially to be used in patients which have failed to achieve adequate control on primary therapy, and it's an adjunctive treatment, with the same kind of qualifications that others have mentioned.
And I think that's not just a passing comment.  That's a specific recommendation about the indication, and I think that's a central point, I think, here.  It goes beyond warnings and precautions, which of course I agree with the other comments on.
DR. HIRSCH:  Could I just make one last comment exactly on -- we've had some difficulty -- I had -- today in following some of the data because sometimes we sort of think of the comparison as many of the anecdotes that came out as though this is the drug and we're comparing this versus no treatment.  What we really should be comparing this against is optimal treatment with other drugs and looking for the additional incremental advantage of having this drug when those others fail.
CHAIRMAN BONE:  Well, some of the clinical trials were designed in that way, as you know.
Yes, Dr. Fleischer.

DR. FLEISCHER:  I'm not a voting member of the panel.  I just am obviously concerned, as everyone here is, about the drug, but I would also just caution that you may, as someone who takes care of patients with diabetes, you make the restrictions on this drug so onerous that for medical legal reasons no physician would dare give it to a patient.  You might as well just ban it.
I mean, in other words, I think it should be properly done, but the language should not be so, you know, overly restrictive.  That's all.
CHAIRMAN BONE:  All right.  So you would ‑- okay.
DR. FLEISCHER:  And I think some of the concern really is going to be resolved with data hopefully.
CHAIRMAN BONE:  Thank you.
All right.  Then the next question is for those questions that were answered no, could modification of the current labeling result in the favorable risk-benefit relationship, and if yes, how or what other steps should be taken?
Again, we'll start with Dr. Illingworth.  This would be -- I think you voted no on --
DR. ILLINGWORTH:  On monotherapy.
CHAIRMAN BONE:  -- on monotherapy, yeah.

DR. ILLINGWORTH:  Well, I think we just need more data on what are the factors that are causing the liver toxicity.  Are there some predisposing factors, drug interactions, genetic variance in the cytochrome system?  Are there other factors that can identify a patient who shouldn't be on this drug?
I think until we know that, if a person can be controlled on another medication, a sulfonylurea, metformin with a better safety record or less risk of hepatic toxicity, then that should be the recommendations.
CHAIRMAN BONE:  Dr. Hammes.
MR. HAMMES:  On the monotherapy, given our lack of precision on our risk estimates, I see no place for this as a first line treatment.  If we get enough data to narrow these risk estimates down so at we can put a good handle on it, you know, that could certainly be reevaluated, but right now I don't think so.
CHAIRMAN BONE:  Dr. Genuth?

DR. GENUTH:  Well, like everybody else I find this very difficult to come to a precise and satisfactory conclusion.  What I guess I would like to see is that in an ideal world other drugs with possibly better safety records be tried first, and if they don't work, the Rezulin given, but that's a Catch-22 because most of the studies have already shown that if a patient doesn't respond to one oral drug, he's not likely to another oral drug.
So you would almost then be forced into the position of saying that Rezulin could only be used in combination therapy, and I'm not ready to abandon monotherapy, but I think it can be made safer with the restrictions that I mentioned before.
CHAIRMAN BONE:  Right.  Thank you.
Let's see.  Next is Dr. Molitch.  Did you vote no on anything?
DR. MOLITCH:  I think I may have voted no incorrectly.  If Dr. Bilstad is correct, then I didn't fully understand the restriction.  In fact, I would vote yes based on what actually the labeling is.
CHAIRMAN BONE:  I'm sorry.  Clarify the point you're making here.
DR. MOLITCH:  I think I'm voting yes, and I have no noes.
CHAIRMAN BONE:  And the distinction you're drawing is?
DR. MOLITCH:  For monotherapy that, in fact, there's this two-month window to document efficacy.
CHAIRMAN BONE:  I see.  All right.
Dr. Cara.

DR. CARA:  No.  No, there's nothing that I would recommend to really make this a single use drug.
CHAIRMAN BONE:  Thank you.
Dr. Colley.
DR. COLLEY:  Nothing at this time until more data's available.
CHAIRMAN BONE:  Dr. Hirsch.
DR. HIRSCH:  No, and I have no verbal pyrotechnics to change it.  So no.
CHAIRMAN BONE:  The only thing that I could imagine that would change that would be something where you could actually predict who the sensitive people were or protect patients in some way here.	
The fourth question is, and this, it seems like to me is a short answer rather than a yes or no question, is:  does the Committee have any comments about the use of troglitazone in combination with a sulfonylurea and metformin together?
And we'll just go around the table, and short comments.  We're not being asked to have an up or down vote on this.
Dr. Hirsch.
DR. HIRSCH:  As before, us only when these are not doing the job adequately.

CHAIRMAN BONE:  Thank you.
Dr. Colley.
DR. COLLEY:  I would agree with Dr. Hirsch.
CHAIRMAN BONE:  Dr. Cara.
DR. CARA:  Agreed.
CHAIRMAN BONE:  Dr. Molitch or Dr. Genuth.  Well, no comment.  Dr. Hammes or Dr. Illingworth?
MR. HAMMES:  Yeah, I think there's real good data on using that as a combination again in the people that have failed the sulfonylurea/metformin therapy.
CHAIRMAN BONE:  Thank you.
And Dr. Illingworth.
DR. GENUTH:  I'd just like to add that's what I did say before.
CHAIRMAN BONE:  Yes.
DR. GENUTH:  That I would approve its use in combination.
CHAIRMAN BONE:  I remember, yeah.

DR. ILLINGWORTH:  I'd just endorse combination therapy in patients who are inadequately controlled on other drugs.  The drug has a synergistic mechanism of action with other drugs used to treat diabetes.  Use it synergistically with other medications.
CHAIRMAN BONE:  All right.  The fifth question is what, if any, additional information is needed -- people may have suggestions -- to further evaluation the risks and benefits of troglitazone.  Does the Committee have any recommendations for obtaining additional information about the hepatic effects of troglitazone?
So just sort of a two-part question, one more general about risks and benefits and one very specific about the hepatic effects.
We'll just start with Dr. Illingworth, I guess.
DR. ILLINGWORTH:  For the first part of the question, additional information needed to further evaluate the risks and benefits of troglitazone, I think obviously anybody with any preexistent liver disease should be -- is contraindicated.
I think more information about potential drug-drug interactions will be helpful.  Which drugs?  Drugs for hypertension, lipid lowering drugs, particularly ones that are metabolized by the C3A4 system.  Perhaps that may be a potential avenue for further exploration.

And the second portion of the question, I would encourage the sponsors to look into more causation risk factors, genetic variance in the C3A4 system, differences in drug metabolism that may be predictive of risk.
I'd also explore further drug-drug interactions.
CHAIRMAN BONE:  Thank you.
Dr. Hammes.
MR. HAMMES:  I think perhaps an appear from the FDA and the company through professional associations to encourage pharmacists/physicians to report this would be helpful.  I don't think requiring much more, and clearly we need to collect the data, you know, and we need just more longevity in the data.
CHAIRMAN BONE:  Dr. Genuth.
DR. GENUTH:  I have nothing to say about the liver.  However, I would encourage the sponsors and other scientists to try and develop a clinically applicable way of determining which patients have the sort of insulin resistance that is most likely to respond to this drug or this class of drugs.
I think that's really the most logical way to approach the problem we have.  We would reduce the risk if we narrowed the population to those most likely to benefit.

CHAIRMAN BONE:  Thank you.
Dr. Hirsch, how about that?
DR. HIRSCH:  In answer to the question, I think we're just sorely in need of new information.  I've almost never had a meeting here in which there's something that had so -- that so confounded me, and this is not because of any malice of anyone, but I just think the information base is very inadequate to help us make the best conclusions about this, and therefore, I urge everybody involved to aid that, and I think it's true in both areas.  
I think we need more information about the risk.  That is, we need basic information on the mode of action of troglitazone on liver cells or whatever, any kind of basic thing.
But also we very much need information on whether the current surrogate endpoints that we're using like hemoglobin A1c and glucose are really as meaningful here as they are with other anti-diabetic agents.  Very difficult to accumulate, but clearly if you're to do risk-benefit, this is what you have to have, and we don't have it.
CHAIRMAN BONE:  Fair enough.  Thank you.
Dr. Colley.
DR. COLLEY:  I don't have anything to add.

CHAIRMAN BONE:  Okay.  Dr. Molitch.
DR. MOLITCH:  I was encouraged by the liver function tests being a good indicator of patients going on to develop liver failure, but I'm still concerned about the fast risers, and I was intrigued by Dr. Marcus' idea of measuring ALT levels on a weekly basis using a filter paper method or capillary tube method.
I perhaps would urge the sponsor in one of their cohort studies to perhaps actually do that in a portion of patients to see if we could try to pick this up at an early point in time and see if it, in fact, is of benefit in identifying those patients at risk.
CHAIRMAN BONE:  Thank you.
I think that the most crucial thing I can think of is to try to get hard population based data, and also to really look hard at this question of what happens with exposure past the first several months.
I think the models we've had, you know, are sharply disparate on these points, and having real information from large managed care organizations, perhaps Saskatchewan and some of the other systems where we can look at this, is crucial.

And I think the weighing or weighting that everyone here on the Committee has done would be influenced heavily if we saw that kind of information either confirming or modifying any of the estimates that we've heard.  I think that's the kind of thing that we really need very, very badly.
I'm going to ask the nonvoting members who are here if they have any additional comments before I summarize.
Dr. Seeff?
DR. SEEFF:  I agree with you.  This is an opportunity to learn more about this.  We have to gather more facts about the frequency of hepatotoxicity.  As I say earlier, as I mentioned earlier, I think that there will be an opportunity to look perhaps at a subgroup very carefully.
This, after all, is a drug that we do know causes hepatotoxicity, not at a high, tremendously high frequency, but enough that this would be a wonderful opportunity to look into this and try to learn more about this in terms of monitoring.
Excuse me.  I've got laryngitis.
CHAIRMAN BONE:  Right.  Thank you.
Dr. Lewis, please.

DR. LEWIS:  I agree.  We need to learn now to monitor better, and this is one way to try and do that.
I would just add that, I mean, there are confounders to monitoring:  alcoholics who have elevated enzymes, patients with underlying liver disease.  There's very little information, however, that patients with underlying liver disease are more at risk for an idiosyncratic reaction than people without that, but obviously it confounds the issue. There are certain drugs you don't want to give in patients who are alcoholic, and whatnot.
Well, we can use this as an opportunity to try and learn how better to monitor, whether it's more frequently or however.
CHAIRMAN BONE:  Thank you.
Let's see.  Ms. Killion, please.
MS. KILLION:  I'm very encouraged by the emphasis on patient education because I think that's really the key to managing this disease from any aspect, and the idea of working in concert with your doctor with full information I think is really the only approach that a patient can take.
CHAIRMAN BONE:  Thank you, and Dr. Fleischer.

DR. FLEISCHER:  Well, I certainly hope that both the incidence and hopefully the way of preventing the adverse effects of this drug can be clarified because this drug and I'm sure others in its class are truly very effective.
CHAIRMAN BONE:  Thank you.
I will just try to summarize here just before we adjourn, and it's going to be challenging to summarize this meeting of the Endocrine and Metabolic Drugs Advisory Committee.
Basically we've been trying to weigh the risk and benefits of using troglitazone in diabetic patients under various circumstances, as outlined in Question 1.  There is enormous concern about the evidence of hepatic toxicity.  
There is no dispute about whether lightning has struck, as Dr. Graham has said.  I think the members of the Committee have in many cases expressed concern about how well we can estimate the likely frequency of these lightning strikes, however, and this is weighed against the expected benefits of therapy based on the assumption that the long-term benefits with endpoints will be similar to the improvements that have been experienced by patients achieving improved glycemic control with other drugs, also the sparing of insulin effect.

And after a spirited and thorough discussion, I think that the majority of the Committee -- and I don't have the counts here, do we? -- has voted 11 to one that the -- felt that with the current indications, warnings and precautions the benefits of troglitazone do outweigh the risk for concomitant use with insulin, and 12 to zero with sulfonylurea, but the Committee did not feel that the risks outweighed the benefits for monotherapy at this point, with the vote being four in favor and eight against.
Many of the Committee members have made suggestions about how the risk-benefit ratio could be enhanced further by changing in the labeling and prescribing practices and monitoring as they have outlined.
The majority of members of the Committee felt that their comments about combination therapy as in Question 1 would generally apply in Question 4, although this was not voted upon.
And the Committee very strongly indicated a need for additional epidemiologic and mechanistic information in order to better quantify the risk and better understand the mechanism of toxicity.

I want to thank the members of the Committee.  I want to thank the presenters from Parke-Davis.  I want to thank the agency.  I want to particularly thank Ms. Reedy and the group that manages the advisors and consultants process, and I want to thank the audience.
This session is closed.
(Whereupon, at 5:22 p.m., the Advisory Committee meeting was concluded.)